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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Pafolacianine


Pafolacianine skeletal.svg
ChemSpider 2D Image | OTL-38 | C61H67N9O17S4
2D chemical structure of 1628858-03-6
img

Pafolacianine

OTL-38

  • Molecular FormulaC61H67N9O17S4
  • Average mass1326.495 Da

FDA APPROVED NOV 2021

2-{(E)-2-[(3E)-2-(4-{2-[(4-{[(2-Amino-4-oxo-3,4-dihydro-6-pteridinyl)methyl]amino}benzoyl)amino]-2-carboxyethyl}phenoxy)-3-{(2E)-2-[3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-1,3-dihydro-2H-indol-2-ylidene ]ethylidene}-1-cyclohexen-1-yl]vinyl}-3,3-dimethyl-1-(4-sulfobutyl)-3H-indolium-5-sulfonate OTL-38Tyrosine, N-[4-[[(2-amino-3,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-O-[(6E)-6-[(2E)-2-[1,3-dihydro-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-2H-indol-2-ylidene]ethylidene]-2-[(E)-2-[3,3-dimethy l-5-sulfo-1-(4-sulfobutyl)-3H-indolium-2-yl]ethenyl]-1-cyclohexen-1-yl]-, inner salt

 2-(2-(2-(4-((2S)-2-(4-(((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl)amino)benzamido)-2-carboxyethyl)phenoxy)-3-(2-(3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-1,3-dihydro-2H-indol-2-ylidene)ethylidene)cyclohex-1-en-1-yl)ethenyl)-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-3H-indolium inner salt,sodium salt (1:4)

  • 3H-Indolium, 2-(2-(2-(4-((2S)-2-((4-(((2-amino-3,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)amino)-2-carboxyethyl)phenoxy)-3-(2-(1,3-dihydro-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-2H-indol-2-ylidene)ethylidene)-1-cyclohexen-1-yl)ethenyl)-3,3-dimethyl-5-sulfo-1 (4-sulfobutyl)-, inner salt,sodium salt (1:4)

1628423-76-6 [RN]

Pafolacianine sodium.png

Pafolacianine sodium [USAN]
RN: 1628858-03-6
UNII: 4HUF3V875C

C61H68N9Na4O17S4+5

  • Intraoperative Imaging and Detection of Folate Receptor Positive Malignant Lesions

Pafolacianine, sold under the brand name Cytalux, is an optical imaging agent.[1][2]

The most common side effects of pafolacianine include infusion-related reactions, including nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, itching and hypersensitivity.[2]

It was approved for medical use in the United States in November 2021.[2][3]

Pafolacianine is a fluorescent drug that targets folate receptor (FR).[1]

Medical uses

Pafolacianine is indicated as an adjunct for intraoperative identification of malignant lesions in people with ovarian cancer.[1][2]

History

The safety and effectiveness of pafolacianine was evaluated in a randomized, multi-center, open-label study of women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer who were scheduled to undergo surgery.[2] Of the 134 women (ages 33 to 81 years) who received a dose of pafolacianine and were evaluated under both normal and fluorescent light during surgery, 26.9% had at least one cancerous lesion detected that was not observed by standard visual or tactile inspection.[2]

The U.S. Food and Drug Administration (FDA) granted the application for pafolacianine orphan drugpriority review, and fast track designations.[2][4] The FDA granted the approval of Cytalux to On Target Laboratories, LLC.[2]

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SYN

WO 2014149073

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014149073

In another aspect of the invention, this disclosure provides a method of synthesizing a compound having the formula

[0029] In a fourth embodiment of the invention, this disclosure provides a method of synthesizing a compound having the formula

[0030] 

 [0032] wherein C is any carbon isotope. In this embodiment, the amino acid linker is selected from a group consisting of methyl 2-di-tert-butyl dicarbonate-amino-3-(4-phenyl)propanoate, 3-(4-hydroxyphenyl)-2-(di-tert-butyl-dicarbonate methylamino)propanoic acid, 2-amino-4-(4-hydroxyphenyl)butanoic acid, and Tert-butyl (2-di-tert-butyl dicarbonate- amino)-3-(4-hydroxyphenyl)propanoate . In a particular embodiment, the aqueous base is potassium hydroxide (KOH). The method of this embodiment may also further include purifying the compound by preparatory HPLC.

EXAMPLE 1 : General synthesis of Pte – L Tyrosine – S0456 (OTL-0038)

[0088] Scheme:

C33H37CIF3N

Reactants for Step I:

[0089] A 500 mL round bottom flask was charged with a stirring bar, pteroic acid

(12.0 g, 29.40 mmol, 1 equiv), (L)-Tyr(-OfBu)-OfBu- HCI (1 1 .63 g, 35.28 mmol, 1 .2

equiv) and HATU (13.45 g, 35.28 mmol, 1 .2 equiv) then DMF (147 mL) was added to give a brown suspension [suspension A]. DIPEA (20.48 mL, 1 17.62 mmol, 4.0 equiv) was added slowly to suspension A at 23 °C, over 5 minutes. The suspension turned in to a clear brown solution within 10 minutes of addition of DIPEA. The reaction was stirred at 23 °C for 2.5 h. Reaction was essentially complete in 30 minutes as judged by LC/MS but was stirred further for 2.5 h. The formation of Pte_N10(TFA)_L_Tyr(-OfBu)-OfBu HCI (Figure 12) was confirmed by LC/MS showing m/z 409→m/z 684. LC/MS method: 0-50% acetonitrile in 20 mM aqueous NH4OAc for 5 min using Aquity UPLC-BEH C18, 1 .7μιη 2.1 * 50 mm column . The reaction mixture was cannulated as a steady stream to a stirred solution of aq. HCI (2.0 L, 0.28 M) over the period of 30 minutes to give light yellow precipitate of Pte_N10(TFA)_L_Tyr(-OfBu)-OfBu HCI. The precipitated Pte_N 10(TFA)_L_Tyr(- OfBu)-OfBu HCI was filtered using sintered funnel under aspirator vacuum, washed with water (8 * 300 mL) until the pH of the filtrate is between 3 and 4. The wet solid was allowed to dry under high vacuum for 12 hours on the sintered funnel. In a separate batch, where this wet solid (3) was dried under vacuum for 48 hours and then this solid was stored at -20 0 C for 48 h. However, this brief storage led to partial decomposition of 3. The wet cake (58 g) was transferred to a 500 mL round bottom flask and was submitted to the next step without further drying or purification.

Reactants for Step II:

The wet solid (58 g) was assumed to contain 29.40 mmol of the desired compound (3) (i. e. quantitative yield for the step I ).

[0090] A 500 mL round bottom flask was charged with a stirring bar, Pte_N10(TFA)_L_Tyr(-OfBu)-OfBu HCI as a wet cake (58 g, 29.40 mmol, 1 equiv). A solution of TFA:TIPS:H20 (95:2.5:2.5, 200 mL) was added at once to give a light brown suspension. The reaction content was stirred at 23°C for 1 .5 hours and was monitored by LC/MS. The suspension became clear dull brown solution after stirring for 5 minutes. LC/MS method: 0-50% acetonitrile in 20 mM aqueous NH4OAc for 5 min using Aquity UPLC-BEH C18, 1 .7μιη 2.1 * 50 mm column. The formation of Pte_TFA_L_Tyr (Figure 12) was confirmed by showing m/z 684→m/z 572. Reaction time varies from 30 min to 1 .5 hours depending on the water content of Pte_N10(TFA)_L_Tyr(-OfBu)-OfBu HCI. The reaction mixture was cannulated as a steady stream to a stirred MTBE (1 .8 L) at 23 °C or 100 °C to give light yellow precipitate of Pte_TFA_L_Tyr. The precipitated Pte_TFA_L_Tyr was filtered using sintered funnel under aspirator vacuum, washed with MTBE (6 * 300 mL) and dried under high vacuum for 8 hours to obtain Pte_TFA_L_Tyr (14.98 g, 83.98% over two steps) as a pale yellow solid. The MTBE washing was tested for absence of residual TFA utilizing wet pH paper (pH between 3-4). The yield of the reaction was between 80-85% in different batches. The deacylated side product was detected in 3.6% as judged by LC/MS. For the different batches this impurity was never more than 5%.

Reactants for Step III:

[0091] A 200 mL round bottom flask was charged with a stirring bar and Pte_TFA_L_Tyr (13.85 g, 22.78 mmol, 1 equiv), then water (95 mL) was added to give a yellow suspension [suspension B]. A freshly prepared solution of aqueous 3.75 M NaOH (26.12 mL, 97.96 mmol, 4.30 equiv), or an equivalent base at a corresponding temperature using dimethylsulfoxide (DMSO) as a solvent (as shown in Table 1 ), was added dropwise to suspension B at 23 °C, giving a clear dull yellow solution over 15 minutes [solution B]. The equivalence of NaOH varied from 3.3 to 5.0 depending on the source of 4 (solid or liquid phase synthesis) and the residual TFA. Trianion 5 (Figure 12) formation was confirmed by LC/MS showing m/z 572→m/z 476 while the solution pH was 9-10 utilizing wet pH paper. The pH of the reaction mixture was in the range of 9-10. This pH is crucial for the overall reaction completion. Notably, pH more than 10 leads to hydrolysis of S0456. Excess base will efficiently drive reaction forward with potential hydrolysis of S0456. The presence of hydrolysis by product can be visibly detected by the persistent opaque purple/blue to red/brown color.

TABLE 1 : Separate TFA deprotection via trianion formation; S0456

[0092] The precipitated OTL-0038 product could also be crashed out by adding the reaction solution steady dropwise to acetone, acetonitrile, isopropanol or ethyl acetate/acetone mixture. Acetone yields optimal results. However, viscous reactions could be slower due to partial insolubility and/or crashing out of S0456. In this reaction, the equivalence of the aqueous base is significant. Excess base will efficiently drive reaction forward with potential hydrolysis of S0456. This solution phase synthesis provides Pte_N10(TFA)_Tyr-OH »HCI salt and desires approximately 4.1 to approximately 4.8 equiv base as a source to hydrolyze the product. Particularly, precipitation of Pte_Tyr_S0456 was best achieved when 1 mL of reaction mixture is added dropwise to the stirred acetone (20 mL). Filtration of the precipitate and washing with acetone (3 x10 mL) gave the highest purity as judged from LC/MS chromatogram.

[0093] During experimentation of this solution-phase synthesis of Pte – L Tyrosine -S0456 (OTL-0038) at different stages, some optimized conditions were observed:

Mode of addition: Separate TFA deprotection via trianion formation; S0456 @ 23 °C; reflux.

Stability data of Pte – L Tyrosine – S0456 (OTL-0038):

Liquid analysis: At 40 °C the liquid lost 8.6% at 270 nm and 1 % at 774 nm. At room temperature the liquid lost about 1 .4% at 270 nm and .5% at 774 nm. At 5 °C the

270 nm seems stable and the 774 nm reasonably stable with a small degradation purity.

Source Purity Linker S0456 Base Solvent Duration % Conversion

4.3-4.6

Solution 0.95

95% 1 equiv equiv H20 15 min 100% phase equiv

K2C03

PATENT

 US 20140271482

FDA approves pafolacianine for identifying malignant ovarian cancer lesions

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pafolacianine-identifying-malignant-ovarian-cancer-lesions

On November 29, 2021, the Food and Drug Administration approved pafolacianine (Cytalux, On Target Laboratories, LLC), an optical imaging agent, for adult patients with ovarian cancer as an adjunct for interoperative identification of malignant lesions. Pafolacianine is a fluorescent drug that targets folate receptor which may be overexpressed in ovarian cancer. It is used with a Near-Infrared (NIR) fluorescence imaging system cleared by the FDA for specific use with pafolacianine.

Efficacy was evaluated in a single arm, multicenter, open-label study (NCT03180307) of 178 women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer scheduled to undergo primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery. All patients received pafolacianine. One hundred and thirty-four patients received fluorescence imaging evaluation in addition to standard of care evaluation which includes pre-surgical imaging, intraoperative palpation and normal light evaluation of lesions. Among these patients, 36 (26.9%) had at least one evaluable ovarian cancer lesion detected with pafolacianine that was not observed by standard visual or tactile inspection. The patient-level false positive rate of pafolacianine with NIR fluorescent light with respect to the detection of ovarian cancer lesions confirmed by central pathology was 20.2% (95% CI 13.7%, 28.0%).

The most common adverse reactions (≥1%) occurring in patients were nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, pruritus, and hypersensitivity.

The recommended pafolacianine dose is 0.025 mg/kg administered intravenously over 60 minutes, 1 to 9 hours before surgery. The use of folate, folic acid, or folate-containing supplements should be avoided within 48 hours before administration of pafolacianine.

View full prescribing information for Cytalux.

This application was granted priority review, fast track designation, and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

USFDA approves new drug to help identify cancer lesions

This drug is indicated for use in adult patients with ovarian cancer to help identify cancerous lesions during surgery.By The Health Master -December 2, 2021

The U.S. Food and Drug Administration (USFDA) has approved Cytalux (pafolacianine), an imaging drug intended to assist surgeons in identifying ovarian cancer lesions. The drug is designed to improve the ability to locate additional ovarian cancerous tissue that is normally difficult to detect during surgery.

Cytalux is indicated for use in adult patients with ovarian cancer to help identify cancerous lesions during surgery. The drug is a diagnostic agent that is administered in the form of an intravenous injection prior to surgery.

Alex Gorovets, M.D., deputy director of the Office of Specialty Medicine in the FDA’s Center for Drug Evaluation and Research said, “The FDA’s approval of Cytalux can help enhance the ability of surgeons to identify deadly ovarian tumors that may otherwise go undetected.

By supplementing current methods of detecting ovarian cancer during surgery, Cytalux offers health care professionals an additional imaging approach for patients with ovarian cancer.”

The American Cancer Society estimates there will be more than 21,000 new cases of ovarian cancer and more than 13,000 deaths from this disease in 2021, making it the deadliest of all female reproductive system cancers.

Conventional treatment for ovarian cancer includes surgery to remove as many of the tumors as possible, chemotherapy to stop the growth of malignant cells or other targeted therapy to identify and attack specific cancer cells.

Ovarian cancer often causes the body to overproduce a specific protein in cell membranes called a folate receptor. Following administration via injection, Cytalux binds to these proteins and illuminates under fluorescent light, boosting surgeons’ ability to identify the cancerous tissue.

Currently, surgeons rely on preoperative imaging, visual inspection of tumors under normal light or examination by touch to identify cancer lesions. Cytalux is used with a Near-Infrared fluorescence imaging system cleared by the FDA for specific use with pafolacianine.

The safety and effectiveness of Cytalux was evaluated in a randomized, multi-center, open-label study of women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer who were scheduled to undergo surgery.

Of the 134 women (ages 33 to 81 years) who received a dose of Cytalux and were evaluated under both normal and fluorescent light during surgery, 26.9% had at least one cancerous lesion detected that was not observed by standard visual or tactile inspection.

The most common side effects of Cytalux were infusion-related reactions, including nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, itching and hypersensitivity. Cytalux may cause fetal harm when administered to a pregnant woman.

The use of folate, folic acid, or folate-containing supplements should be avoided within 48 hours before administration of Cytalux. There is a risk of image interpretation errors with the use of Cytalux to detect ovarian cancer during surgery, including false negatives and false positives.

References

  1. Jump up to:a b c d https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214907s000lbl.pdf
  2. Jump up to:a b c d e f g h i “FDA Approves New Imaging Drug to Help Identify Ovarian Cancer Lesions”U.S. Food and Drug Administration (FDA) (Press release). 29 November 2021. Retrieved 30 November 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ “On Target Laboratories Announces FDA Approval of Cytalux (pafolacianine) injection for Identification of Ovarian Cancer During Surgery”. On Target Laboratories. 29 November 2021. Retrieved 30 November 2021 – via PR Newswire.
  4. ^ “Pafolacianine Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 23 December 2014. Retrieved 30 November 2021.
Clinical data
Trade namesCytalux
Other namesOTL-0038
License dataUS DailyMedPafolacianine
Pregnancy
category
Not recommended
Routes of
administration
Intravenous
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
showIUPAC name
CAS Number1628423-76-6
PubChem CID135565623
DrugBankDB15413
ChemSpider64880249
UNIIF7BD3Z4X8L
ChEMBLChEMBL4297412
Chemical and physical data
FormulaC61H67N9O17S4
Molar mass1326.49 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////////Pafolacianine, FDA 2021, APPROVALS 2021,  Cytalux, OVARIAN CANCER, OTL 38, 

[Na+].[Na+].[Na+].[Na+].CC1(C)\C(=C/C=C/2\CCCC(=C2Oc3ccc(C[C@H](NC(=O)c4ccc(NCc5cnc6N=C(N)NC(=O)c6n5)cc4)C(=O)O)cc3)\C=C\C7=[N](CCCCS(=O)(=O)O)c8ccc(cc8C7(C)C)S(=O)(=O)O)\N(CCCCS(=O)(=O)O)c9ccc(cc19)S(=O)(=O)O

NEW DRUG APPROVALS

ONE TIME

$10.00

TNO 155


TNO155 Chemical Structure

TNO 155

2-Oxa-8-azaspiro[4.5]decan-4-amine, 8-[6-amino-5-[(2-amino-3-chloro-4-pyridinyl)thio]-2-pyrazinyl]-3-methyl-, (3S,4S)-

  • (3S,4S)-8-[6-Amino-5-[(2-amino-3-chloro-4-pyridinyl)thio]-2-pyrazinyl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine
  • (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine
Molecular Weight

421.95

Formula

C₁₈H₂₄ClN₇OS

CAS No.
  • PTPN11 inhibitor TNO155
  • SHP2 inhibitor TNO155
  • TNO-155
  • TNO155
  • UNII-FPJWORQEGI

TNO155 is a potent selective and orally active allosteric inhibitor of wild-type SHP2 (IC50=0.011 µM). TNO155 has the potential for the study of RTK-dependent malignancies, especially advanced solid tumors.

  • Originator Novartis
  • Developer Mirati Therapeutics; Novartis
  • Class Antineoplastics
  • Mechanism of ActionProtein tyrosine phosphatase non receptor antagonists
  • Phase I/IISolid tumours
  • Phase IColorectal cancer
  • 11 Jul 2021Phase I trial in Solid tumours is still ongoing in USA, Canada, Japan, South Korea, Netherlands, Singapore, Spain, Taiwan (NCT03114319)
  • 04 Jun 2021Efficacy, safety and pharmacokinetics data from phase I trial in Solid tumours presented at 57th Annual Meeting of the American Society of Clinical Oncology (ASCO-2021)
  • 08 Jan 2021Novartis plans a phase Ib/II trial for Solid tumours (Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater) in February 2021 (NCT04699188)

CLIP

Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling

Chen Liu,

Results: In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRASG12C cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASG12Ci and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient–derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti–PD-1 antibody.

Conclusions: Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.

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PATENT

WO 2015107495

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015107495

PATENT

WO 2020065453

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020065453

(3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, which has the formula I,

WO/2015/107495 A1 describes a method for the manufacture of the compound of the formula I which can be characterized by the following reaction scheme 1:

Scheme 1:

[0008] The last compound resulting from step g above was then reacted as in the following scheme 2:

Scheme 2:

[0009] Thus the compound of formula I is obtained (last compound in the scheme 2, above). The synthesis requires at least the 9 steps shown and is rather appropriate for synthesis in laboratory amounts.

Scheme 1A:

[0016] Therefore, the process, though readily feasible on a laboratory scale, is not ideal for manufacture at a large scale.

[0017] The compound added in reaction b in Scheme 2 is obtained in WO

2015/107495 A1 as “Intermediate 10” follows:

Scheme 3:

[0018] An issue here is the relatively low yield of the amine resulting from reaction a in

Scheme 3.

[0019] In addition, while WO 2015/107495 A1 generically mentions that pharmaceutically acceptable salts of the compound of the formula I may be obtainable, no concrete reason for obtaining such salts and no specific examples of salts are described.

[0020] In addition, given the many potentially salt forming groups in formula I, it is not clear whether any salts with a clear stoichiometry can be formed at all.

Example 1

Method of synthesis of the compound of the formula I ((3S,4S)-8-(6-amino-5-((2-amino-3- chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine):

The overall synthesis can be described by the following Reaction Scheme A:

Scheme A:

Step a


[00293] To a solution of A1 (10.4 kg, 100 mol, 1.0 Eq) in CH2Cl2 (50 L) was added imidazole (8.16 kg, 120 mol, 1.2eq) and TBSCl (18 kg, 120 mol, 1.2 Eq) at 0 °C. After addition, the mixture was stirred at 0°C for 4 h . GC showed the reaction was finished. (A1/ (A1 + A2) < 1%). The reaction mixture was quenched with saturated NaHCO3 (14L) at 0-5°C. Phases were separated. The organic phase was washed with brine (14L). The organic layer was dried over Na2SO4, concentrated under vacuum at 40-45°C to afford A2 (23.3 kg, assay 88%, yield 94%) which was used for the next step directly. 1H NMR (400 MHz, CDC13) δ = 4.35 (d, J= 8.8 Hz, 1H), 3.74 (s, 3H), 2.48 (s, J= 8.8

Hz, 3H), 0.93 (s, 9H), 0.09 (s, 6H).

Step b

[00294] To a solution of A2 (7.5 kg, 34.3 mol, 1.0 Eq) and N,O-dimethylhydroxylamine hydrochloride (6.69 kg, 68.6mol, 2.0 Eq) in THF (20 L) was added drop-wise a solution

of chloro(isopropyl)magnesium (2 M, 51.45 L, 3.5 Eq) at 0 °C under N2 over 5-6 h. After addition, the reaction mixture was stirred at 0 °C for 1h, GC showed the reaction was finished (A2/(A2+A3) < 2 %). The mixture was quenched with NH4Cl (25 L) slowly by keeping the temperature at 0-5°C. After addition, the reaction mixture was stirred for 30min. Phase was separated. The aqueous layer was extracted with EA(2 x 20 L). The combined organic phase was washed with brine (25L), dried over Na2SO4, concentrated to give A3(9.4 kg, assay 86%, yield 95%) which was used for the next step directly. 1HNMR (400 MHz, CDCl3) δ = 4.67 (m, J= 6.6 Hz, 1H), 3.70 (s, 3H), 3.21 (s, 3H), 3.17 (d, 3H)2.48 (s , J= 6.6 Hz, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H).

Step c

[00295] To a solution of A3 (7.1 kg, assay 86%, 24.65 mol, 1.0 Eq) in DCM (30 L) was added dropwise a solution of LiAlH4 (2.4 M, 11.3 L, 1.1 Eq) at -70 °C under N2. Then the reaction mixture was stirred at -70 °C for 3h, and TLC showed the reaction was finished (PSC-1). The mixture was warmed to 0 °C, and then quenched with sat. potassium sodium tartrate (35 L) at 0 °C. After addition, DCM (20L) was added and stirred for 2h at 20-25°C. Phases were separated. The aqueous layer was extracted with DCM (25 L). The combined organic phase was charged with sat. citric acid (45L) and stirred at 0°C for 8h. Phase was separated. The organic phase was washed with NaHCO3 (25L), brine (25 L), dried over Na2SO4, and the solvent was removed under vacuum at 25-30°C. n-Heptane (10 L) was added to the residue and concentrated under vacuum at 30-35°C. n-Heptane (10 L) was added to the residue again and concentrated under vacuum at 30-35°C to give A4 (4.2 kg, assay

60%, yield 54%) which was used for the next step directly.

Step d

[00296] To a solution of diisopropylamine (3.06 kg, 30.3 mol, 1.5 eq) in THF (20 L) cooled to approximately -10°C was added 2.5 M n-BuLi (12.12 L, 30.3 mol, 1.5 eq) under N2. The resulting mixture was stirred at approximately -10 °C for 30min, then a solution of A5 (5.2 kg, 20.20 mol, 1.0eq) in THF (10 L) was added slowly. After addition, the reaction mixture was stirred at -10°C for 30 min, and then cooled to -50°C. A4 (4.18 kg, 22.22 mol, 1.1eq) was added dropwise. After addition, the reaction mixture was stirred at -50°C for 30 min. The mixture was quenched with saturated aqueous NH4Cl (30L) and water (10L) at -50°C. The reaction mixture was warmed to 20-25°C. Phase was separated. The aqueous phase was extracted with EA (3 x 20 L). All organic phases were combined and washed with brine(20L), then concentrated to a yellow oil which was purified by column (silica gel, 100-200 mesh, eluted with n-heptane:EA from 50:1 to 10:1) to give A6 (5.5 kg, assay 90 %, yield 55%) as pale yellow oil. 1H NMR (400 MHz, CDCl3) δ = 4.35-4.15 (m, 2H), 3.95-3.74 (m, 3H), 3.52 (m, 2H), 2.67(m, 2H), 2.12-1.98 (m, 2H), 1.75-1.52 (m, 4H), 1.49 (s, 9H), 1.35-1.10 (m, 6H), 0.98 (s,

9H), 0.02 (s, 6H).

Step e

[00297] To a solution of A6 (11.4 kg, 25.58 mol, 1.0eq) in THF (60 L) was added LiBH4

(836 g, 38.37 mol, 1.5eq) in portions at 5-10 °C, and the reaction mixture was stirred at 20-25 °C for 18 h. HPLC showed the reaction was finished (A6/(A6+A7)<2%). The mixture was cooled to l0°C and slowly quenched with saturated NaHCO3 solution (15 L) and water (25L) with vigorously stirring. After gas formation stopped, vacuum filtration was applied to remove solids. The solid was washed with EA (2 x 15 L). Phase was separated; the aqueous phase was extracted with EA (3 x15L). All organic phases were combined and washed with brine (15L), and concentrated to obtain crude A7 (13.8 kg, assay 58%, yield 77%) which was used for the next step directly.

Step f

[00298] To a solution of A7 (8 kg, 19.82 mol, 1.0 eq) in THF (40 L) under nitrogen atmosphere was added TsCl (5.28 kg, 27.75 mol, 1.4 eq) at 10-15°C. After addition, the mixture was cooled to 0 °C, and 1M LiHMDS (29.7 L, 29.73 mol, 1.5 eq) was added dropwise during 2h. After addition, the mixture was stirred at 0°C for 3h. HPLC showed the reaction was finished (PSC-1 A7/ (A7+A8)<7%). TBAF (20.72 kg, 65.67 mol, 3.3 eq) was added into the mixture at 0 °C and the reaction mixture was stirred at 25-30 °C for 48h. HPLC showed the reaction was finished ( PSC-2, A9-intermedaite/(A9-intermediate+A9) < 2%). The mixture was quenched with saturated aqueous sodium bicarbonate solution (32L) and stirred for 30min at 0 °C. Phase was separated, and the aqueous phase was extracted with EA (3 x 20 L). The combined organic phase was washed with brine(20 L), dried over Na2SO4, and concentrated to a yellow oil which was purified by column (eluted with n-heptane:EA from 10:1 to 1:1) to give A9 (4.42 kg, assay 90%, yield 74 %) as pale yellow solid.

Step g

[00299] To a solution of A9 (4.0 kg, 14.74 mol, 1.0 eq) in DCM (40 L) cooled on an ice-bath was added DMP (9.36 kg, 23.58mol, 1.6eq) in portions, and it resulted in a suspension. After addition, the mixture stirred for 4 hours at 20-25°C. HPLC showed the reaction was finished (A9/(A9+A10)<2%). DCM (30L) was added at 0°C. After addition, the mixture was quenched with saturated aqueous Na2SO3 (20 L). The mixture was stirred for 30min at 0 °C, filtered and the white solid was washed with DCM (2 x15L). Phase was separated, and the organic phase was cooled to 0°C, to which was added saturated aqueous NaHCO3 (20L) and stirred for 1h. Phase was separated, and the organic phase was washed with brine(25L), dried over Na2SO4, and concentrated to a yellow oil which was purified by column (eluted with n-heptane:EA from 50:1 to 10:1) to give A10 (3.70 kg, assay 88%, ee value 95.3%, yield 82%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ = 4.20 (d, J = 8.0 Hz,

1H), 3.98-3.67 (m, 4H), 3.08-2.90 (m, 2H), 1.54-1.39(m, 13H), 1.18 (d, J = 8.0 Hz, 3H).

Step h

[00300] To a solution of A10 (4.60 kg, 17.08 mol, 1.0 eq) in THF (40 L) was added

Ti(OEt)4 (15.58 kg, 68.32 mol, 4.0 eq) and (R)-t-Butyl sulfmamide (4.14 kg, 34.16 mol, 2.0 eq) at 25 °C. After addition, the mixture was heated to 70°C and stirred for 20h. HPLC showed the reaction was finished (PSC-l, A10/(A10+A12)<4%). The mixture was cooled to -30— 40°C, and MeOH (4 L) was added dropwise within 30 min and stirred for 1 h. 2M L1BH4 (8.1 L) solution was added dropwise to the reaction mixture at -40- -50°C and stirred for 1h. HPLC indicated all of imine was consumed (PSC-2, A12/(A12+A13)<1%). The mixture was warmed to -30 °C and stirred for 1h, then warmed to 0 °C within 2 h and stirred for 1h, then warmed to 20-25 °C and stirred for 30min. IP AC ( 25L) was added to above mixture, NaHCO3(5L) was added dropwise in about 1h at 25 °C and stirred for 30 min. The mixture was filtered under vacuum and the cake was washed with IP AC (8 x15L). The combined organic phase was washed with brine (25L), then evaporated under vacuum to get a solution of A13

(about 28kg) which was used for next step.

Step i

[00301] To a mixture of A13 in IPAC (about 28 kg, 17.08 mol, 1.0 eq) was added dropwise

4M HCl/IPA (8.54 L, 34.16 mol, 2.0 eq) at -5 °C and stirred for 5h at -5 °C. HPLC showed that A13 was consumed completely (A13/(A14+A13)<1%). MTBE (25 L) was added to above mixture within

30 min and stirred for 30 min at -5 °C .The solid was collected by vacuum filtration. The cake was washed with MTBE (2 x 2.5 L). The wet cake was used for next step directly.

Step j

[00302] The wet solid A14 (from 9.2 kg A10) was stirred in MTBE(76 L) at 25°C, then the

16% NaOH (9.84 kg) solution was added dropwise to the MTBE suspension while maintaining IT<10ºC. After addition, the mixture was stirred for 15 min and all solids were dissolved at 0°C. The organic phase was separated, and the aqueous phase was extracted with MTBE (2 x 20L). The combined organic phase was washed with brine (10 L) and evaporated under vacuum to remove all MTBE. ACN (24 L) was added to above residue, and the mixture was evaporated under vacuum to remove the organic solvents and yielded a crude A15 (5.42 kg, qnmr 90%, 18.04 mol, 1.0 eq). ACN (34.68 kg) was added to above residue and stirred for 10 min at 65°C. A solution of (-)-O-acetyl-D-mandelic acid (3.15kg,16.2 mol, 0.9 eq) in ACN(11.6 kg) was added drop-wise to the mixture (firstly added 1/3, stirred for 0.5 h, then added the others) over 3h. The mixture was stirred for 1 h at 65°C, then cooled to 25°C over 4h and stirred for l2h at 25°C . The solid was collected by vacuum filtration, and the cake was washed with pre-cooled ACN (2 x15kg) (PSC-1) and dried under vacuum to give

A16 (7.36 kg, yield 46% from A10 to A16). 1H NMR (400 MHz, DMSO-d6) δ = 7.43-7.29 (m, 5H),

5.58 (s, 2H), 4.12-4.07 (m, 1H), 3.75-3.65 (m, 3H), 3.51-3.49 (m, 1H), 3.18-3.17 (m, 1H), 2.84 (bs,

2H), 2.05 (s, 3H), 1.60-1.40 (m, 13H), 1.14-1.12 (d, J= 8.0 Hz, 3H).

Step k

[00303] To a solution of A16 (15 g) in MeOH (90 mL) was added dropwise 5N HC1/IPA

(45 mL) at room temperature within 15 minutes. After the addition, the mixture was stirred for 6 hours.

IP AC (180 mL) was added dropwise to above mixture within 1h at room temperature. The resulting mixture was stirred for another 30 minutes before it was cooled to 0-5 °C. The mixture was stirred at 0- 5 °C for another 2h and the precipitants were collected by filtration. The cake was washed with (45*2 mL) IP AC, dried under vacuum at 60 °C overnight to afford the product as a white solid. 1H NMR (400

MHz, DMSO-d6) δ = 9.37 (br s, 1H), 9.25 (br s, 1H), 8.42 (br s, 3H), 4.26 – 4.17 (m, 1H), 3.72 (ABq, J

= 9.1 Hz, 2H), 3.50 – 3.41 (m, 1H), 3.28 – 3.18 (m, 1H), 3.18 – 3.09 (m, 1H), 2.99 – 2.74 (m, 2H), 2.07 – 1.63 (m, 4H), 1.22 (d, J= 6.5 Hz, 3H).

Step l

[00304] To a mixture of A17 (10 g) and Z17a (9.5 g) in DMAC (60 mL) was added K2CO3

(22.5 g) and H2O (40 mL) at room temperature. The mixture was degassed with nitrogen and stirred at

90 °C overnight. The mixture was cooled to room temperature, diluted with Me-THF (500 mL) and

H2O (280 mL). The organic phase was separated and the aqueous phase was extracted with Me-THF

(300 mL*2). The combined organic phases were washed with brine (200 mL*3), concentrated under

vacuum to remove most of the solvent. The residue was diluted with IPA (60 mL) and H2O (20 mL), stirred at 50 °C for 1h, cooled to 5 °C within 3h, stirred at this temperature for 1h. The solid was collected by vacuum filtration, dried under vacuum to afford the product as a yellow solid (l2g,

87.4%). 1H NMR (400 MHz, DMSO-d6)δ = 7.64 (d, J= 6.2 Hz, 1H), 7.62 (s, 1H), 6.26 (s, 2H), 6.13 (s, 2H), 5.74 (d, J= 5.3 Hz, 1H), 4.12 – 4.02 (m, 1H), 3.90 – 3.78 (m, 2H), 3.67 (d, J= 8.4 Hz, 1H), 3.49 (d, J= 8.4 Hz, 1H), 3.33 (s, 2H), 2.91 (d, J= 5.1 Hz, 1H), 1.78 – 1.68 (m, 1H), 1.67 – 1.57 (m, 1H), 1.56 – 1.41 (m, 2H), 1.08 (d, J= 6.5 Hz, 3H).

Example 2

Formation of the succinate salt of the compound of the formula I:

[00305] The reaction is summarized by the following Reaction Scheme:

[00306] To a mixture of A18 (10 g) in MeOH (76 g) and H2O (24 g) was added succinic acid (2.94 g) at room temperature. The mixture was heated to 50 °C and stirred for 30 minutes to dissolve all solid. The solution was added to IPA (190 mL) at 60-65 °C. The resulting mixture was stirred at 60 °C >5 hours, cooled to -15 °C within 5 hours and stirred at this temperature >4 hours. The solid was collected by vacuum filtration, dried under vacuum to afford the product as an off-white solid(l0.8 g, 82.8%). 1H NMR (400 MHz, DMSO-d6)δ = 7.64 (d, J= 6.2 Hz, 1H), 7.63 (s, 1H), 6.26 (s, 2H), 6.16 (s, 2H), 5.74 (d, J= 5.3 Hz, 1H), 4.12 – 4.02 (m, 1H), 3.90 – 3.78 (m, 2H), 3.67 (d, J= 8.4 Hz, 1H), 3.49 (d, J= 8.4 Hz, 1H), 3.33 (s, 2H), 2.91 (d, J= 5.1 Hz, 1H), 2.34 (s, 4H), 1.71 – 1.60 (m, 4H), 1.13 (d, J = 6.5 Hz, 3H).

[00307] In a special variant, the reaction follows the following Reaction Scheme, also including an optional milling to yield the final product:

Example 3

Formation of the intermediate Z17a (3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2- amine). Variant 1:

[00308] The compound Z17a was obtained by reaction according to the following Reaction

Scheme:

[00309] In detail, the synthesis of Compound Z17a was carried out as follows:

Step a


[00310] Under nitrogen atmosphere, n-BuLi (2.5M, 7.6 L) was added dropwise to a solution of 3-chloro-2-fluoropyridine (2 kg) in THF (15 L) at -78°C. Then the resultant mixture was stirred for 1h. Then a solution of I2 (4.82 kg) in THF (6 L) was added dropwise. After addition, the reaction mixture was stirred for 30 min, and then quenched with sat. Na2SO3 (10 L), and warmed to 20- 25°C. Phase was separated. The aqueous phase was extracted with EA (2 x 10 L). The combined organic phase was washed with sat.Na2SO3 (2 x 8 L), brine (8 L), and dried over Na2SO4. The organic phase was concentrated under vacuum. The residue was slurried in MeOH (4 L), filtered, and dried to offer 3-chloro-2-fluoro-4-iodopyridine 1c (2.2 kg, yield 68%).

Step b

[00311] Into a solution of Compound 1c (8 kg) in DMSO (48 L) was passed through NH3

(gas) at 80 °C overnight. TLC showed the reaction was finished. The reaction mixture was cooled to RT. The reaction mixture was added to water (140 L). The solid was collected and washed with water (25 L), dried to afford Z17b (6.91 kg, yield 87%). 1H NMR (400 MHz, CDC13) δ = 7.61 (d, J= 6.8 Hz,

1H), 7.14 (s , J= 6.8 Hz, 1H), 5.09 (bs, 2H).

Step c

[00312] A solution of 2-amino-6-chloro-pyrazine la (1 kg, 7.69 mol) in DCM (15 L) was heated to reflux, to which was charged NBS (4l7g) in portions during 1 h. The reaction was cooled to room temperature. The reaction mixture was washed with water (3 L) and brine (3 L). The organic phase was evaporated, and the residue was purified by column chromatography to give product Z17f

(3-bromo-6-chloropyrazin-2-amine) (180 g, 11% yield).

Step d

[00313] To a solution of 3-bromo-6-chloropyrazin-2-amine Z17f (6.0 kg, 28.78 mol) in 1,4- Dioxane (40 L) was added Pd(OAc)2 (64.56 g, 287.6 mmol), Xantphos (333 g, 575.6 mmol), and DIPEA (7.44 kg, 57.56 mol) at room temperature under nitrogen. After another 30 minutes purging with nitrogen, methyl 3-mercaptopropanoate (3.81 kg, 31.70 mol) was added, resulting in darkening of the orange mixture. The mixture was heated to 90°C. HPLC showed complete conversion of the starting material. The mixture was allowed to cool to about room temperature, then diluted with EtOAc (40L). After aging for 30 min with stirring, the entire mixture was filtered and solids were washed with EtOAc (3 x 15L). The combined orange filtrate was concentrated to dryness and the solid residue was suspended in DCM (45 L). The mixture was heated to 35-40 °C and stirred for 1h until all solids were dissolved. Then n-heptane (45L) was added dropwise. Upon complete addition, the mixture was cooled to 15-20 °C with stirring for 1h. The solids were collected by vacuum filtration and solids were washed with cold 1:1 DCM/heptane (25 L), then heptane (25 L) (PSC-2). The solids were dried over the weekend to give Z17d (5.32 kg, yield 75%). 1H NMR (400 MHz, CDCl3) δ = 7.83 (s, 1H), 4.88 (bs,

2H), 3.73 (s, 3H), 3.47 (t, J= 9.2 Hz, 2H), 2.79 (t, J= 9.2 Hz, 2H).

Step e

[00314] To a solution of Z17d (8.0 kg, assay 95%, 30.68 mol) in THF (70 L) was added

EtONa (prepared from 776 g Na and 13.6 L EtOH) at room temperature and the mixture was stirred at

ambient temperature for 1 hour. The mixture was then concentrated to a wet yellow solid by rotary evaporation and the residue was suspended in DCM (40L). The mixture stirred under N2 for l6h. The solids were collected by vacuum filtration and the cake was washed with DCM (about 15 L) until the filtrate was colorless (PSC-2). The solids were then dried under vacuum to give Z17c (6.93 kg, qNMR

72 %, yield 88%). 1H NMR (400 MHz, D2O) δ = 7.37 (s, 1H).

Step f

[00315] To a mixture of Z17c (6.95 kg, assay 72%, 27.23 mol) in l,4-dioxane (72 L) was added Xantphos (233 g, 411 mmol, 0.015 eq), Pd2(dba)3 (186 g, 206 mmol, 0.0075 eq), Z17b (7.13 kg, 28.02 mol) and DIPEA (7.02 kg, 54.46 mol). The system was vacuated and purged with nitrogen gas three times. The mixture was stirred at 65 °C for 16 h under N2. The mixture was cooled to RT and water (50 L) was added, filtered. The cake was washed with EA (25 L). The filtrate was extracted with EA (4 x 20 L). The organic phase was concentrated in vacuum to offer the crude product which was combined with the cake. Then DCM (60 L) was added to the crude product and stirred at 25-30°C for l8h and then filtered. The filter cake was slurried with CH2Cl2 (30 L) for 4 hrs and filtered. The filter cake was slurred in CH2Cl2 (30 L) for 16 hrs and filtered. Then the filter cake was dried in vacuum to give Z17a (3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-amine; 9.1 kg, 84 %) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.89 (s, 1H), 7.7 (d, J= 7.6 Hz, 1H), 7.18 (bs, 2H), 6.40 (bs, 2H), 5.97 (d, J= 7.6 Hz, 1H).

Example 4

Alternative formation of the intermediate Z17a (here also named Y7a)

[00316] By way of alternative and according to a preferred reaction method, the compound of the formula Z17a was obtained according to the following Reaction Scheme:

In detail, the synthesis of the compound of the formula Y7a = Z17a was carried out as follows:

Step a

[00317] 2, 3, 5-trichloropyrazine (70.50 g, 384.36 mmol, 1 equiv) and ammonia solution

(25% wt, 364.00 g, 400 mL, 2.68 mol, 6.14 equiv) were added to a 1-L sealed reactor. The mixture was heated to 80 °C and stirred for 24 h, and the reaction was completed. The reaction mixture was cooled to 30 °C and filtered to give a brown filter cake. The brown filter cake was dissolved in acetone

(50 mL), and filtered. To the filtrate was added petroleum ether (300 mL). The suspension was stirred for 4 h, and filtered to give the crude product. The crude product was slurried in combined solvents of petroleum ether and acetone (10/1, 200 mL) and filtered to give the product Y7d (51.00 g, 307.91 mmol, 80% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.63 (s, 1H).

Step b

[00318] To a 200 mL round bottom flask was added Na2S (10.816 g, 44wt% containing crystalline water, 60.978mmol) and toluene (100 mL). The mixture was heated to reflux, and water was removed with a Dean-Stark trap (about 5~6 mL water was distilled out). After cooling, the mixture was concentrated to dryness.

[00319] To above round bottom flask was added Y7d (5.000 g, 30.489mmol) and 2-methylbutan-2-ol (50 mL), the reaction was heated to reflux and stirred for 36 h. After cooling to 25 °C, the mixture was filtered. The solvent of the filtrate was exchanged with n-heptane (5 V, 3 times, based on Y7d), and finally concentrated to IV residue. THF (25 mL) was charged to the residue at 25 °C and stirred. The suspension was filtered and washed with THF/n-heptane (5 mL/5 mL) to give a brown solid (6.200 g).

[00320] To another 200 mL round bottom flask was added above brown solid (6.200 g),

10% brine (25 mL), Me-THF (30 mL) and n-Bu4NBr (9.829 g, 30.489 mmol). The mixture was stirred for 0.5 h at room temperature, and the phases were separated. The organic phase was washed with 20% brine (25 mL), and exchanged the solvent with iso-propanol (5 V *3 times, based on Y7d) to give the iso-propanol solution of Y7c (27.000g, 99.2% purity by HPLC area, 58.08% assay yield). 1H NMR (400 MHz, DMSO-d6) δ = 6.88 (s, 1H), 2.97 – 2.92 (m, 14H), 1.38 – 1.31 (m, 14H), 1.13 – 1.04 (m,

14H), 0.73 – 0.69 (t, 21H).

Step c

[00321] To a 25-mL round-bottom flask was added Y7c (4.7g, 23.27wt%, IPA solution from Step b, 2.723 mmol, 1.0 equiv), Y7b (1.052 g, 4.085 mmol, 1.5 equiv), l,lO-Phenanthroline (0.05 g, 0.272 mmol) and water (8 mL). The mixture was purged with nitrogen gas three times, and Cul (0.026 g, 0.136 mmol) was added under nitrogen atmosphere. The mixture was heated up to 65 °C and stirred for 3 h, and the reaction was completed. The reaction was cooled to room temperature and filtered, and the filter cake was washed with water (4 mL*3). The filter cake was slurried in MTBE (6 mL) for 30 min and filtered. The filter cake was washed with MTBE (6 mL) and dried to afford Y7a which is Z17a (565 mg, 72% yield).

[00322] Z17b is synthesized as described in Example 3 Step a and Step b.

Example 5

Alternative Synthesis of the intermediate Z17a:

[00323] According to another preferred method, the compound of the formula Z17a was obtained in accordance with the following Reaction Scheme:

[00324] The reactions were carried out as follows:

Step a

Y7d was synthesised as described in Example 4 step a.

Step b

[00325] To a three-necked round-bottle flask was added Y7d (200 mg, 1.22 mmol, 1 equiv), dioxane (4 mL). The solution was vacuated and purged with nitrogen gas three times. Xantphos (14mg, 0.024 mmol, 0.02 equiv), PdCl2(dppf) (8.9 mg, 0.012 mmol, 0.1 equiv), and DIPEA (0.32 g, 2.44 mmol, 2.0 equiv) were added under nitrogen atmosphere. The solution was heated to 85 °C for overnight. The reaction was cooled and evaporated. The residue was purified by column chromatography (eluent/ethyl acetate/heptane = 1/1) to give Z17d (259 mg, 0.99 mmol, 81%). 1H NMR (400 MHz, CDCl3) δ = 7.83 (s, 1H), 4.88 (bs, 2H), 3.73 (s, 3H), 3.47 (t, J= 9.2 Hz, 2H), 2.79 (t, J= 9.2 Hz, 2H).

[00326] The remaining steps were carried out as described in Example 4, Steps e and f, to yield Z17a. Z17b was synthesized as described in Example 3 Step a and Step b.

Example 6

(3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8- azaspiro[4.5]decan-4-amine. succinate (1:1) hemihydrate. modification (form) HA:Variant a)

[00327] 50 ml ethanol and 2.5 ml water were added to a 100ml flask containing 3.0 g of free base of 3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (obtained as A18 for example as described in Example 1) and 848.0 mg of succinic acid. The mixture was heated to 50°C to generate a clear solution. The temperature was lowered to 15°C during a period of 3 hours. The solution was kept stirring at 15°C overnight.

Precipitated solid was separated via suction filtration and 50 ml of acetone was added to produce a suspension. The suspension was stirred at 50°C for 3 hours. The solid was separated with suction filtration and dried at room temperature under vacuum for 3 hours. Yield was about 60%.

[00328] The succinate appeared as a highly crystalline solid, with a melting point onset of

94.4°C and an accompanying enthalpy of 96 J/g. The succinate salt crystals showed aggregates of broken drusy tabular particles.

[00329] Variant b)

[00330] 14.34 g of 3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)- 3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine free form (obtained as A18 for example as described in Example 1) and 4.053 g of succinic acid were equilibrated in 100 mL 95% EtOH at 50°C. Add 5 mL of water into the system and heat to 70-75 °C. Add 95 mL of pure EtOH and heat for 30 min more. Stir over night at 25 oC. Filter the mixture wash with EtOH and dry under vacuum in an oven at room temperature. Yield is 87.5%.

PATENT

WO 2020065452

PATENT

WO/2021/224867

PHARMACEUTICAL COMBINATION COMPRISING TNO155 AND NAZARTINIB

PAPER

Journal of Medicinal Chemistry (2020), 63(22), 13578-13594.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01170

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein–ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.

Abstract Image

file:///C:/Users/Inspiron/Downloads/jm0c01170_si_001.pdf

(3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8- azaspiro[4.5]decan-4-amine (1):

Step a: A mixture of (3S,4S)-tert-butyl 4-((R)-1,1-dimethylethylsulfinamido)-3-methyl-2-oxa-8- azaspiro[4.5]decane-8-carboxylate (51 mg, 0.136 mmol) and HCl (4 M in dioxane, 340 L, 1.362 mmol) in MeOH (5 mL) was stirred for 1 h at 40 °C. After cooling to RT, the volatiles were removed under reduced pressure to give (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine which was used in next step without further purification. MS m/z 171.1 (M+H)+. Step b: A mixture of (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine crude, 3-((2-amino3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-amine (35.5 mg, 0.123 mmol), and DIPEA (193 L, 1.11 mmol) in DMSO (600 L) was stirred for 16 h at 100 °C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was purified by HPLC (gradient elution 15-40% acetonitrile in water, 5 mM NH4OH modifier) to give (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (11 mg, 0.026 mmol). 1 H NMR (400 MHz, METHANOL-d4) δ ppm 7.67-7.47 (m, 2 H), 5.91 (d, J=5.5 Hz, 1 H), 4.22 (qd, J=6.4, 4.8 Hz, 1 H), 4.03 (ddt, J=13.5, 8.9, 4.7 Hz, 2 H), 3.86 (d, J=8.7 Hz, 1 H), 3.71 (d, J=8.7 Hz, 1 H), 3.37 (td, J=9.9, 4.9 Hz, 1 H), 3.29-3.23 (m, 1 H), 3.00 (d, J=5.0 Hz, 1H) 1.91-1.56 (m, 4 H), 1.21 (d, J=6.4 Hz, 3 H). HRMS calcd for C18H25ClN7OS (M+H)+ 422.1530, found 422.1514.

//////////TNO 155, CANCER

 

RP 12146


RP 12146

RP-12146 is an oral poly (ADP-ribose) polymerase (PARP) inhibitor in phase I clinical development at Rhizen Pharmaceuticals for the treatment of adult patients with locally advanced or metastatic solid tumors.

Solid TumorExtensive-stage Small-cell Lung CancerLocally Advanced Breast CancerMetastatic Breast CancerPlatinum-sensitive Ovarian CancerPlatinum-Sensitive Fallopian Tube CarcinomaPlatinum-Sensitive Peritoneal Cancer

Poly(ADP-ribose) polymerase (PARP) defines a family of 17 enzymes that cleaves NAD+ to nicotinamide and ADP-ribose to form long and branched (ADP-ribose) polymers on glutamic acid residues of a number of target proteins, including PARP itself. The addition of negatively charged polymers profoundly alters the properties and functions of the acceptor proteins. Poly(ADP-ribosyl)ation is involved in the regulation of many cellular processes, such as DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions and genomic stability. These functions have been mainly attributed to PARP-1 that is regarded as the best characterized member of the PARP family. However, the identification of novel genes encoding PARPs, together with the characterization of their structure and subcellular localization, have disclosed different roles for poly(ADP-ribosyl)ation in cells, including telomere replication and cellular transport.

Recently, poly(ADP-ribose) binding sites have been identified in many DNA damage checkpoint proteins, such as tumor suppressor p53, cyclin-dependent kinase inhibitor p21Cip1/waf1, DNA damage recognition factors (i.e., the nucleotide excision repair xeroderma pigmentosum group A complementing protein and the mismatch repair protein MSH6), base excision repair (BER) proteins (i.e. DNA ligase III, X-ray repair cross-complementing 1, and XRCC1), DNA-dependent protein kinase (DNA-PK), cell death and survival regulators (i.e.,

NF-kB, inducible nitric oxide synthase, and telomerase). These findings suggest that the different components of the PARP family might be involved in the DNA damage signal network, thus regulating protein-protein and protein-DNA interactions and, consequently, different types of cellular responses to genotoxic stress. In addition to its involvement in BER and single strand breaks (SSB) repair, PARP-1 appears to aid in the non-homologous end-joining (NHEJ) and homologous recombination (HR) pathways of double strand breaks (DSB) repair. See Lucio Tentori et al., Pharmacological Research, Vol. 45, No. 2, 2002, page 73-85.

PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutations but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway. Further, the existing clinical data (e.g., Csaba Szabo et al., British Journal of Pharmacology (2018) 175: 192-222) also indicate that stroke, traumatic brain injury, circulatory shock and acute myocardial infarction are some of the indications where PARP activation has been demonstrated to contribute to tissue necrosis and inflammatory responses.

As of now, four PARP inhibitors, namely olaparib, talazoparib, niraparib, and rucaparib have been approved for human use by regulatory authorities around the world.

Patent literature related to PARP inhibitors includes International Publication Nos. WO 2000/42040, WO 2001/016136, WO 2002/036576, WO 2002/090334, WO2003/093261, WO 2003/106430, WO 2004/080976, WO 2004/087713, WO 2005/012305, WO 2005/012524, WO 2005/012305, WO 2005/012524, WO 2005/053662, W02006/033003, W02006/033007, WO 2006/033006, WO 2006/021801, WO 2006/067472, WO 2007/144637, WO 2007/144639, WO 2007/144652, WO 2008/047082, WO 2008/114114, WO 2009/050469, WO 2011/098971, WO 2015/108986, WO 2016/028689, WO 2016/165650, WO 2017/153958, WO 2017/191562, WO 2017/123156, WO 2017/140283, WO 2018/197463, WO 2018/038680 and WO 2018/108152, each of which is incorporated herein by reference in its entirety for all purposes.

There still remains an unmet need for new PARP inhibitors for the treatment of various diseases and disorders associated with cell proliferation, such as cancer.

PATENT

Illustration 1

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https://cancerres.aacrjournals.org/content/81/13_Supplement/1233

Abstract 1233: Preclinical profile of RP12146, a novel, selective, and potent small molecule inhibitor of PARP1/2

Srikant Viswanadha, Satyanarayana Eleswarapu, Kondababu Rasamsetti, Debnath Bhuniya, Gayatriswaroop Merikapudi, Sridhar Veeraraghavan and Swaroop VakkalankaProceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA 

Abstract

Background: Poly (ADP-ribose) polymerase (PARP) activity involves synthesis of Poly-ADP ribose (PAR) polymers that recruit host DNA repair proteins leading to correction of DNA damage and maintenance of cell viability. Upon combining with DNA damaging cytotoxic agents, PARP inhibitors have been reported to demonstrate chemo- and radio-potentiation albeit with incidences of myelosuppression. A need therefore exists for the development selective PARP1/2 inhibitors with a high therapeutic window to fully exploit their potential as a single agent or in combination with established therapy across various tumor types. Additionally, with the emerging concept of ‘synthetic lethality’, the applicability PARP inhibitors can be expanded to cancers beyond the well-defined BRCA defects. Herein, we describe the preclinical profile of RP12146, a novel and selective small molecule inhibitor of PARP1 and PARP2.

Methods: Enzymatic potency was evaluated using a PARP Chemiluminescent Activity Assay Kit (BPS biosciences). Cell growth was determined following incubation with RP12146 in BRCA1 mutant and wild-type cell lines across indications. Apoptosis was evaluated following incubation of cell lines with compound for 120 h, subsequent staining with Annexin-V-PE and 7-AAD, and analysis by flow cytometry. For cell cycle, cells were incubated with compound for 72 h, and stained with Propidium Iodide prior to analysis by flow cytometry. Expression of downstream PAR, PARP-trapping, phospho-γH2AX and cleaved PARP expression were determined in UWB1.289 (BRCA1 null) cells by Western blotting. Anti-tumor potential of RP12146 was tested in OVCAR-3 Xenograft model. Pharmacokinetic properties of the molecule were also evaluated. Results: RP12146 demonstrated equipotent inhibition of PARP1 (0.6 nM) and PARP2 (0.5 nM) with several fold selectivity over the other members of the PARP family. Compound caused a dose-dependent growth inhibition of both BRCA mutant and non-mutant cancer cell lines with GI50 in the range of 0.04 µM to 9.6 µM. Incubation of UWB1.289 cells with RP12146 caused a G2/M arrest with a corresponding dose-dependent increase in the percent of apoptotic cells. Expression of PAR was inhibited by 86% at 10 nM with a 2.3-fold increase in PARP-trapping observed at 100 nM in presence of RP12146. A four-fold increase in phospho-γH2AX and > 2-fold increase in cleaved PARP expression was observed at 3 µM of the compound. RP12146 exhibited anti-tumor potential with TGI of 28% as a single agent in OVCAR-3 xenograft model. Efficay was superior compared to Olaparib tested at an equivalent dose. Pharmacokinetic studies in rodents indicated high bioavailability with favorable plasma concentrations relevant for efficacy

Conclusions: Data demonstrate the therapeutic potential of RP12146 in BRCA mutant tumors. Testing in patients is planned in H1 2021.

Citation Format: Srikant Viswanadha, Satyanarayana Eleswarapu, Kondababu Rasamsetti, Debnath Bhuniya, Gayatriswaroop Merikapudi, Sridhar Veeraraghavan, Swaroop Vakkalanka. Preclinical profile of RP12146, a novel, selective, and potent small molecule inhibitor of PARP1/2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1233.

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https://www.businesswire.com/news/home/20211101005515/en/Rhizen-Pharmaceuticals-AG-Announces-First-Patient-Dosing-in-a-Phase-IIb-Study-of-Its-Novel-PARP-Inhibitor-RP12146-in-Patients-With-Advanced-Solid-Tumors

Rhizen Pharmaceuticals AG Announces First Patient Dosing in a Phase I/Ib Study of Its Novel PARP Inhibitor (RP12146) in Patients With Advanced Solid Tumors

RHIZEN’S PARP INHIBITOR EFFORTS ARE PART OF A LARGER DDR PLATFORM THAT ALSO INCLUDES AN EARLY STAGE POLθ-DIRECTED PROGRAM; PLATFORM ENABLES PROPRIETARY IN-HOUSE COMBINATIONS

  • Rhizen Pharma commences dosing in a phase I/Ib trial to evaluate its novel PARP inhibitor (RP12146) in patients with advanced cancers.
  • Rhizen indicated that RP12146 has comparable preclinical activity vis-à-vis approved PARP inhibitors and shows improved preclinical safety that it expects will translate in the clinic.
  • The two-part multi-center phase I/Ib study is being conducted in Europe and is designed to initially determine safety, tolerability and MTD/RP2D of RP12146 and to subsequently assess its anti-tumor activity in expansion cohorts with HRR mutation-enriched ES-SCLC, ovarian and breast cancer patients.
  • RP12146 is part of a larger DDR platform at Rhizen that includes a preclinical-stage Polθ inhibitor program; the DDR platform enables novel, proprietary, in-house combinations

November 01, 2021 07:24 AM Eastern Daylight Time

BASEL, Switzerland–(BUSINESS WIRE)–Rhizen Pharmaceuticals AG (Rhizen), a Switzerland-based privately held, clinical-stage oncology & inflammation-focused biopharmaceutical company, announced today that it has commenced dosing in a multi-center, phase I/Ib trial to evaluate its novel poly (ADP-ribose) polymerase (PARP) inhibitor (RP12146) in patients with advanced solid tumors. This two-part multi-center phase I/Ib study is being conducted in Europe and has been designed to initially determine safety, tolerability, maximum tolerated dose (MTD), and/or recommended phase II dose (RP2D) of RP12146 and to subsequently assess its anti-tumor activity in expansion cohorts with HRR mutation-enriched ES-SCLC, ovarian and breast cancer patients.

“Our PARP program is foundational for our DDR platform efforts and will be the backbone for several novel proprietary combinations that we hope to bring into development going forward.”

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Rhizen indicated that RP12146 has shown preclinical activity and efficacy comparable to the approved PARP inhibitor Olaparib, and shows improved safety as seen in the preclinical IND-enabling toxicology studies; an advantage that Rhizen hopes will translate in the clinical studies. Rhizen also announced that its PARP program is part of a larger DNA Damage Response (DDR) platform effort, which includes a preclinical-stage polymerase theta (Polθ) inhibitor program. Rhizen expects the platform to enable novel proprietary combinations of its PARP and Polθ assets given the mechanistic synergy and opportunity across PARP resistant/refractory settings.

PARP inhibitors are a great success story in the DNA damage response area, but they are not without safety concerns that have limited realization of their full potential. Although our novel PARP inhibitor is competing in a crowded space, we expect its superior preclinical safety to translate into the clinic which will differentiate our program and allow us to extend its application beyond the current landscape of approved indications and combinations”, said Swaroop Vakkalanka, Founder & CEO of Rhizen Pharma. Swaroop also added that “Our PARP program is foundational for our DDR platform efforts and will be the backbone for several novel proprietary combinations that we hope to bring into development going forward.

About Rhizen Pharmaceuticals AG.:

Rhizen Pharmaceuticals is an innovative, clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology & inflammation therapeutics. Since its establishment in 2008, Rhizen has created a diverse pipeline of proprietary drug candidates targeting several cancers and immune associated cellular pathways.

Rhizen has proven expertise in the PI3K modulator space with the discovery of our first PI3Kδ & CK1ε asset Umbralisib, that has been successfully developed & commercialized in MZL & FL by our licensing partner TG Therapeutics (TGTX) in USA. Beyond this, Rhizen has a deep oncology & inflammation pipeline spanning discovery to phase II clinical development stages.

Rhizen is headquartered in Basel, Switzerland.

REF

Safety, Pharmacokinetics and Anti-tumor Activity of RP12146, a PARP Inhibitor, in Patients With Locally Advanced or Metastatic Solid Tumors….https://clinicaltrials.gov/ct2/show/NCT05002868

//////////RP 12146,  oral poly (ADP-ribose) polymerase (PARP) inhibitor, phase I,  clinical development, INCOZEN,  Rhizen Pharmaceuticals, adult patients,  locally advanced, metastatic solid tumors, PARP, CANCER

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AUPM 170, CA 170, PD-1-IN-1


str1
 https://www.nature.com/articles/s42003-021-02191-1
str1
str1

(2S,3R)-2-(3-((S)-3-amino-1-(3-((R)-1-amino-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-3-oxopropyl)ureido)-3-hydroxybutanoic acid

CA-170
GLXC-15291
str1
PD-1-IN-1 Chemical Structure
Molecular Weight (MW) 360.33
Formula C12H20N6O7
CAS No. 1673534-76-3

N-[[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-L-threonine

L-Threonine, N-[[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-

 AUPM 170, CA 170, AUPM-170, CA-170, PD-1-IN-1

Novel inhibitor of programmed cell dealth-1 (PD-1)

CA-170 (also known as AUPM170 or PD-1-IN-1) is a first-in-class, potent and orally available small molecule inhibitor of the immune checkpoint regulatory proteins PD-L1 (programmed cell death ligand-1), PD-L2 and VISTA (V-domain immunoglobulin (Ig) suppressor of T-cell activation (programmed death 1 homolog; PD-1H). CA-170 was discovered by Curis Inc. and has potential antineoplastic activities. CA-170 selectively targets PD-L1 and VISTA, both of which function as negative checkpoint regulators of immune activation. Curis is currently investigating CA-170 for the treatment of advanced solid tumours and lymphomas in patients in a Phase 1 trial (ClinicalTrials.gov Identifier: NCT02812875).

References: www.clinicaltrials.gov (NCT02812875); WO 2015033299 A1 20150312.

Aurigene Discovery Technologies Limited INNOVATOR

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CURIS AND AURIGENE ANNOUNCE AMENDMENT OF COLLABORATION FOR THE DEVELOPMENT AND COMMERCIALIZATION OF CA-170

PRESS RELEASE

https://www.aurigene.com/curis-and-aurigene-announce-amendment-of-collaboration-for-the-development-and-commercialization-of-ca-170/

Curis and Aurigene Announce Amendment of Collaboration for the Development and Commercialization of CA-170

– Aurigene to fund and conduct a Phase 2b/3 randomized study of CA-170 in patients with non-squamous non-small cell lung cancer (nsNSCLC) –

– Aurigene to receive Asia rights for CA-170; Curis entitled to royalty payments in Asia –

LEXINGTON, Mass., February 5, 2020 /PRNewswire/ — Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, today announced that it has entered into an amendment of its collaboration, license and option agreement with Aurigene Discovery Technologies, Ltd. (Aurigene). Under the terms of the amended agreement, Aurigene will fund and conduct a Phase 2b/3 randomized study evaluating CA-170, an orally available, dual
inhibitor of VISTA and PDL1, in combination with chemoradiation, in approximately 240 patients with nonsquamous
non-small cell lung cancer (nsNSCLC). In turn, Aurigene receives rights to develop and commercialize CA-170 in Asia, in addition to its existing rights in India and Russia, based on the terms of the original agreement. Curis retains U.S., E.U., and rest of world rights to CA-170, and is entitled to receive royalty payments on potential future sales of CA-170 in Asia.

In 2019, Aurigene presented clinical data from a Phase 2a basket study of CA-170 in patients with multiple tumor types, including those with nsNSCLC. In the study, CA-170 demonstrated promising signs of safety and efficacy in nsNSCLC patients compared to various anti-PD-1/PD-L1 antibodies.

“We are pleased to announce this amendment which leverages our partner Aurigene’s expertise and resources to support the clinical advancement of CA-170, as well as maintain our rights to CA-170 outside of Asia,” said James Dentzer, President and Chief Executive Officer of Curis. “Phase 2a data presented at the European Society for Medical Oncology (ESMO) conference last fall supported the potential for CA-170 to serve as a therapeutic option for patients with nsNSCLC. We look forward to working with our partner Aurigene to further explore this opportunity.”

“Despite recent advancements, patients with localized unresectable NSCLC struggle with high rates of recurrence and need for expensive intravenous biologics. The CA-170 data presented at ESMO 2019 from Aurigene’s Phase 2 ASIAD trial showed encouraging results in Clinical Benefit Rate and Prolonged PFS and support its potential to provide clinically meaningful benefit to Stage III and IVa nsNSCLC patients, in combination with chemoradiation and as oral maintenance” said Kumar Prabhash, MD, Professor of Medical Oncology at Tata Memorial Hospital, Mumbai, India.

Murali Ramachandra, PhD, Chief Executive Officer of Aurigene, commented, “Development of CA-170, with its unique dual inhibition of PD-L1 and VISTA, is the result of years of hard-work and commitment by many people, including the patients who participated in the trials, caregivers and physicians, along with the talented teams at Aurigene and Curis. We look forward to further developing CA-170 in nsNSCLC.”

About Curis, Inc.

Curis is a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, including fimepinostat, which is being investigated in combination with venetoclax in a Phase 1 clinical study in patients with DLBCL. In 2015, Curis entered into a collaboration with Aurigene in the areas of immuno-oncology and precision oncology. As part of this collaboration, Curis has exclusive licenses to oral small molecule antagonists of immune checkpoints including, the VISTA/PDL1 antagonist CA-170, and the TIM3/PDL1 antagonist CA-327, as well as the IRAK4 kinase inhibitor, CA- 4948. CA-4948 is currently undergoing testing in a Phase 1 trial in patients with non-Hodgkin lymphoma.
In addition, Curis is engaged in a collaboration with ImmuNext for development of CI-8993, a monoclonal anti-VISTA antibody. Curis is also party to a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are commercializing Erivedge® for the treatment of advanced basal cell carcinoma. For more information, visit Curis’ website at http://www.curis.com.

About Aurigene

Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY). Aurigene is focused on precision- oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene currently has several programs from its pipeline in clinical development. Aurigene’s ROR-gamma inverse agonist AUR-101 is currently in phase 2 clinical development under a US FDA IND. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has partnered with many large and mid-pharma companies in the United States and Europe and has 15 programs  currently in clinical development. For more information, please visit Aurigene’s website at https://www.aurigene.com/

Curis with the option to exclusively license Aurigene’s orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field

Addressing immune checkpoint pathways is a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients.

Through its collaboration with Aurigene, Curis is now engaged in the discovery and development of the first ever orally bioavailable, small molecule antagonists that target immune checkpoint receptor-ligand interactions, including PD-1/PD-L1 interactions.  In the first half of 2016, Curis expects to file an IND application with the U.S. FDA to initiate clinical testing of CA-170, the first small molecule immune checkpoint antagonist targeting PD-L1 and VISTA.  The multi-year collaboration with Aurigene is focused on generation of small molecule antagonists targeting additional checkpoint receptor-ligand interactions and Curis expects to advance additional drug candidates for clinical testing in the coming years. The next immuno-oncology program in the collaboration is currently targeting the immune checkpoints PD-L1 and TIM3.

In November 2015, preclinical data were reported. Data demonstrated tha the drug rescued and sustained activation of T cells functions in culture. CA-170 resulted in anti-tumor activity in multiple syngeneic tumor models including melanoma and colon cancer. Similar data were presented at the 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference in Boston, MA

By August 2015, preclinical data had been reported. Preliminary data demonstrated that in in vitro studies, small molecule PD-L1 antagonists induced effective T cell proliferation and IFN-gamma production by T cells that were specifically suppressed by PD-L1 in culture. The compounds were found to have effects similar to anti-PD1 antibodies in in vivo tumor models

 (Oral Small Molecule PD-L1/VISTAAntagonist)

Certain human cancers express a ligand on their cell surface referred to as Programmed-death Ligand 1, or PD-L1, which binds to its cognate receptor, Programmed-death 1, or PD-1, present on the surface of the immune system’s T cells.  Cell surface interactions between tumor cells and T cells through PD-L1/PD-1 molecules result in T cell inactivation and hence the inability of the body to mount an effective immune response against the tumor.  It has been previously shown that modulation of the PD-1 mediated inhibition of T cells by either anti-PD1 antibodies or anti-PD-L1 antibodies can lead to activation of T cells that result in the observed anti-tumor effects in the tumor tissues.  Therapeutic monoclonal antibodies targeting the PD-1/PD-L1 interactions have now been approved by the U.S. FDA for the treatment of certain cancers, and multiple therapeutic monoclonal antibodies targeting PD-1 or PD-L1 are currently in development.

In addition to PD-1/PD-L1 immune regulators, there are several other checkpoint molecules that are involved in the modulation of immune responses to tumor cells1.  One such regulator is V-domain Ig suppressor of T-cell activation or VISTA that shares structural homology with PD-L1 and is also a potent suppressor of T cell functions.  However, the expression of VISTA is different from that of PD-L1, and appears to be limited to the hematopoietic compartment in tissues such as spleen, lymph nodes and blood as well as in myeloid hematopoietic cells within the tumor microenvironment.  Recent animal studies have demonstrated that combined targeting/ blockade of PD-1/PD-L1 interactions and VISTA result in improved anti-tumor responses in certain tumor models, highlighting their distinct and non-redundant functions in regulating the immune response to tumors2.

As part of the collaboration with Aurigene, in October 2015 Curis licensed a first-in-class oral, small molecule antagonist designated as CA-170 that selectively targets PD-L1 and VISTA, both of which function as negative checkpoint regulators of immune activation.  CA-170 was selected from the broad PD-1 pathway antagonist program that the companies have been engaged in since the collaboration was established in January 2015.  Preclinical data demonstrate that CA-170 can induce effective proliferation and IFN-γ (Interferon-gamma) production (a cytokine that is produced by activated T cells and is a marker of T cell activation) by T cells that are specifically suppressed by PD-L1 or VISTA in culture.  In addition, CA-170 also appears to have anti-tumor effects similar to anti-PD-1 or anti-VISTA antibodies in multiple in vivo tumor models and appears to have a good in vivo safety profile.  Curis expects to file an IND and initiate clinical testing of CA-170 in patients with advanced tumors during the first half of 2016.

Jan 21, 2015

Curis and Aurigene Announce Collaboration, License and Option Agreement to Discover, Develop and Commercialize Small Molecule Antagonists for Immuno-Oncology and Precision Oncology Targets

— Agreement Provides Curis with Option to Exclusively License Aurigene’s Antagonists for Immuno-Oncology, Including an Antagonist of PD-L1 and Selected Precision Oncology Targets, Including an IRAK4 Kinase Inhibitor —

— Investigational New Drug (IND) Application Filings for Both Initial Collaboration Programs Expected this Year —

— Curis to issue 17.1M shares of its Common Stock as Up-front Consideration —

— Management to Host Conference Call Today at 8:00 a.m. EST —

LEXINGTON, Mass. and BANGALORE, India, Jan. 21, 2015 (GLOBE NEWSWIRE) — Curis, Inc. (Nasdaq:CRIS), a biotechnology company focused on the development and commercialization of innovative drug candidates for the treatment of human cancers, and Aurigene Discovery Technologies Limited, a specialized, discovery stage biotechnology company developing novel therapies to treat cancer and inflammatory diseases, today announced that they have entered into an exclusive collaboration agreement focused on immuno-oncology and selected precision oncology targets. The collaboration provides for inclusion of multiple programs, with Curis having the option to exclusively license compounds once a development candidate is nominated within each respective program. The partnership draws from each company’s respective areas of expertise, with Aurigene having the responsibility for conducting all discovery and preclinical activities, including IND-enabling studies and providing Phase 1 clinical trial supply, and Curis having responsibility for all clinical development, regulatory and commercialization efforts worldwide, excluding India and Russia, for each program for which it exercises an option to obtain a license.

The first two programs under the collaboration are an orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field and an orally-available small molecule inhibitor of Interleukin-1 receptor-associated kinase 4 (IRAK4) in the precision oncology field. Curis expects to exercise its option to obtain exclusive licenses to both programs and file IND applications for a development candidate from each in 2015.

“We are thrilled to partner with Aurigene in seeking to discover, develop and commercialize small molecule drug candidates generated from Aurigene’s novel technology and we believe that this collaboration represents a true transformation for Curis that positions the company for continued growth in the development and eventual commercialization of cancer drugs,” said Ali Fattaey, Ph.D., President and Chief Executive Officer of Curis. “The multi-year nature of our collaboration means that the parties have the potential to generate a steady pipeline of novel drug candidates in the coming years. Addressing immune checkpoint pathways is now a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients. Recent studies have also shown that alterations of the MYD88 gene lead to dysregulation of its downstream target IRAK4 in a number of hematologic malignancies, including Waldenström’s Macroglobulinemia and a subset of diffuse large B-cell lymphomas, making IRAK4 an attractive target for the treatment of these cancers. We look forward to advancing these programs into clinical development later this year.”

Dr. Fattaey continued, “Aurigene has a long and well-established track record of generating targeted small molecule drug candidates with bio-pharmaceutical collaborators and we have significantly expanded our drug development capabilities as we advance our proprietary drug candidates in currently ongoing clinical studies. We believe that we are well-positioned to advance compounds from this collaboration into clinical development.”

CSN Murthy, Chief Executive Officer of Aurigene, said, “We are excited to enter into this exclusive collaboration with Curis under which we intend to discover and develop a number of drug candidates from our chemistry innovations in the most exciting fields of cancer therapy. This unique collaboration is an opportunity for Aurigene to participate in advancing our discoveries into clinical development and beyond, and mutually align interests as provided for in our agreement.  Our scientists at Aurigene have established a novel strategy to address immune checkpoint targets using small molecule chemical approaches, and have discovered a number of candidates that modulate these checkpoint pathways, including PD-1/PD-L1. We have established a large panel of preclinical tumor models in immunocompetent mice and can show significant in vivo anti-tumor activity using our small molecule PD-L1 antagonists.  We are also in the late stages of selecting a candidate that is a potent and selective inhibitor of the IRAK4 kinase, demonstrating excellent in vivo activity in preclinical tumor models.”

In connection with the transaction, Curis has issued to Aurigene approximately 17.1 million shares of its common stock, or 19.9% of its outstanding common stock immediately prior to the transaction, in partial consideration for the rights granted to Curis under the collaboration agreement. The shares issued to Aurigene are subject to a lock-up agreement until January 18, 2017, with a portion of the shares being released from the lock-up in four equal bi-annual installments between now and that date.

The agreement provides that the parties will collaborate exclusively in immuno-oncology for an initial period of approximately two years, with the option for Curis to extend the broad immuno-oncology exclusivity.

In addition Curis has agreed to make payments to Aurigene as follows:

  • for the first two programs: up to $52.5 million per program, including $42.5 million per program for approval and commercial milestones, plus specified approval milestone payments for additional indications, if any;
  • for the third and fourth programs: up to $50 million per program, including $42.5 million per program for  approval and commercial milestones, plus specified approval milestone payments for additional indications, if any; and
  • for any program thereafter: up to $140.5 million per program, including $87.5 million per program in approval and commercial milestones, plus specified approval milestone payments for additional indications, if any.

Curis has agreed to pay Aurigene royalties on any net sales ranging from high single digits to 10% in territories where it successfully commercializes products and will also share in amounts that it receives from sublicensees depending upon the stage of development of the respective molecule.
About Immune Checkpoint  Modulation and Programmed Death 1 Pathway

Modulation of immune checkpoint pathways has emerged as a highly promising therapeutic approach in a wide range of human cancers. Immune checkpoints are critical for the maintenance of self-tolerance as well as for the protection of tissues from excessive immune response generated during infections. However, cancer cells have the ability to modulate certain immune checkpoint pathways as a mechanism to evade the immune system. Certain immune checkpoint receptors or ligands are expressed by various cancer cells, targeting of which may be an effective strategy for generating anti-tumor activity. Some immune-checkpoint modulators, such as programmed death 1 (PD-1) protein, specifically regulate immune cell effector functions within tissues. One of the mechanisms by which tumor cells block anti-tumor immune responses in the tumor microenvironment is by upregulating ligands for PD-1, such as PD-L1. Hence, targeting of PD-1 and/or PD-L1 has been shown to lead to the generation of effective anti-tumor responses.
About Curis, Inc.

Curis is a biotechnology company focused on the development and commercialization of novel drug candidates for the treatment of human cancers. Curis’ pipeline of drug candidates includes CUDC-907, a dual HDAC and PI3K inhibitor, CUDC-427, a small molecule antagonist of IAP proteins, and Debio 0932, an oral HSP90 inhibitor. Curis is also engaged in a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are developing and commercializing Erivedge®, the first and only FDA-approved medicine for the treatment of advanced basal cell carcinoma. For more information, visit Curis’ website at www.curis.com.

About Aurigene

Aurigene is a specialized, discovery stage biotechnology company, developing novel and best-in-class therapies to treat cancer and inflammatory diseases. Aurigene’s Programmed Death pathway program is the first of several immune checkpoint programs that are at different stages of discovery and preclinical development. Aurigene has partnered with several large- and mid-pharma companies in the United States and Europe and has delivered multiple clinical compounds through these partnerships. With over 500 scientists, Aurigene has collaborated with 6 of the top 10 pharma companies. Aurigene is an independent, wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (NYSE:RDY). For more information, please visit Aurigene’s website at http://aurigene.com/.

POSTER

STR3
STR3
STR3

WO2011161699, WO2012/168944, WO2013144704 and WO2013132317 report peptides or peptidomimetic compounds which are capable of suppressing and/or inhibiting the programmed cell death 1 (PD1) signaling pathway.

PATENT

WO 2015033299

Inventors

  • SASIKUMAR, Pottayil Govindan Nair
  • RAMACHANDRA, Muralidhara
  • NAREMADDEPALLI, Seetharamaiah Setty Sudarshan

Priority Data

4011/CHE/2013 06.09.2013 IN

Example 4: Synthesis of Co

str1

The compound was synthesised using similar procedure as depicted in Example 2 for synthesising compound 2 using 
instead of H-Ser(‘Bu)-0’Bu (in synthesis of compound 2b) to yield 0.35 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.2 (M+H)+, HPLC: tR = 12.19 min.

Pottayil Sasikumar

Pottayil Sasikumar

Murali Ramachandra

Murali Ramachandra

REFERENCES

US20150073024

WO2011161699A227 Jun 201129 Dec 2011Aurigene Discovery Technologies LimitedImmunosuppression modulating compounds
WO2012168944A121 Dec 201113 Dec 2012Aurigene Discovery Technologies LimitedTherapeutic compounds for immunomodulation
WO2013132317A14 Mar 201312 Sep 2013Aurigene Discovery Technologies LimitedPeptidomimetic compounds as immunomodulators
WO2013144704A128 Mar 20133 Oct 2013Aurigene Discovery Technologies LimitedImmunomodulating cyclic compounds from the bc loop of human pd1

http://www.curis.com/pipeline/immuno-oncology/pd-l1-antagonist

http://www.curis.com/images/stories/pdfs/posters/Aurigene_PD-L1_VISTA_AACR-NCI-EORTC_2015.pdf

References:

1) https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-021-00446-4

2) https://www.nature.com/articles/s42003-021-02191-1

3) https://www.esmoopen.com/article/S2059-7029(20)30108-3/fulltext

4) https://www.mdpi.com/1420-3049/24/15/2804

////////Curis, Aurigene,  AUPM 170, CA 170, AUPM-170, CA-170, PD-L1, VISTA antagonist, PD-1-IN-1, phase 2, CANCER

N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)[C@@H](C)O)CC(N)=O

NEW DRUG APPROVALS

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$9.00

Mobocertinib


Mobocertinib - Wikipedia
Mobocertinib.png

Mobocertinib

1847461-43-1

MF C32H39N7O4
MW 585.70

propan-2-yl 2-[4-[2-(dimethylamino)ethyl-methylamino]-2-methoxy-5-(prop-2-enoylamino)anilino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate

TAK-788AP32788TAK788UNII-39HBQ4A67LAP-3278839HBQ4A67L

US10227342, Example 10MFCD32669806NSC825519s6813TAK-788;AP32788WHO 11183

NSC-825519example 94 [WO2015195228A1]GTPL10468BDBM368374BCP31045EX-A3392

US FDA APPROVED 9/15/2021, Exkivity, To treat locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutation

Mobocertinib succinate Chemical Structure

Mobocertinib succinate Chemical Structure

CAS No. : 2389149-74-8

Molecular Weight703.78
FormulaC₃₆H₄₅N₇O₈
img

Mobocertinib mesylateCAS# 2389149-85-1 (mesylate)C33H43N7O7S
Molecular Weight: 681.809

CAS #: 2389149-85-1 (mesylate)   1847461-43-1 (free base)   2389149-74-8 (succinate)   2389149-76-0 (HBr)   2389149-79-3 (HCl)   2389149-81-7 (sulfate)   2389149-83-9 (tosylate)   2389149-87-3 (oxalate)   2389149-89-5 (fumarate)

JAPANESE ACCEPTED NAME

Mobocertinib Succinate

Propan-2-yl 2-[4-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxy-5-(prop-2-enamido)anilino]-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate monosuccinate

C32H39N7O4▪C4H6O4 : 703.78
[2389149-74-8]

FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations……. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mobocertinib-metastatic-non-small-cell-lung-cancer-egfr-exon-20

On September 15, 2021, the Food and Drug Administration granted accelerated approval to mobocertinib (Exkivity, Takeda Pharmaceuticals, Inc.) for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

Today, the FDA also approved the Oncomine Dx Target Test (Life Technologies Corporation) as a companion diagnostic device to select patients with the above mutations for mobocertinib treatment.

Approval was based on Study 101, an international, non-randomized, open-label, multicohort clinical trial (NCT02716116) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Efficacy was evaluated in 114 patients whose disease had progressed on or after platinum-based chemotherapy. Patients received mobocertinib 160 mg orally daily until disease progression or intolerable toxicity.

The main efficacy outcome measures were overall response rate (ORR) according to RECIST 1.1 as evaluated by blinded independent central review (BICR) and response duration. The ORR was 28% (95% CI: 20%, 37%) with a median response duration of 17.5 months (95% CI: 7.4, 20.3).

The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Product labeling includes a boxed warning for QTc prolongation and Torsades de Pointes, and warnings for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.

The recommended mobocertinib dose is 160 mg orally once daily until disease progression or unacceptable toxicity.

View full prescribing information for mobocertinib.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), and United Kingdom’s Medicines & Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 6 weeks ahead of the FDA goal date.

This application was granted priority review, breakthrough therapy designation and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.Takeda’s EXKIVITY™ (mobocertinib) Approved by U.S. FDA as the First Oral Therapy Specifically Designed for Patients with EGFR Exon20 Insertion+ NSCLC…….. https://www.takeda.com/newsroom/newsreleases/2021/takeda-exkivity-mobocertinib-approved-by-us-fda/September 15, 2021

  • Approval based on Phase 1/2 trial results, which demonstrated clinically meaningful responses with a median duration of response (DoR) of approximately 1.5 years
  • Next-generation sequencing (NGS) companion diagnostic test approved simultaneously to support identification of patients with EGFR Exon20 insertion mutations

OSAKA, Japan, and CAMBRIDGE, Mass. September 15, 2021 – Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced that the U.S. Food and Drug Administration (FDA) has approved EXKIVITY (mobocertinib) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. EXKIVITY, which was granted priority review and received Breakthrough Therapy Designation, Fast Track Designation and Orphan Drug Designation from the FDA, is the first and only approved oral therapy specifically designed to target EGFR Exon20 insertion mutations. This indication is approved under Accelerated Approval based on overall response rate (ORR) and DoR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

“The approval of EXKIVITY introduces a new and effective treatment option for patients with EGFR Exon20 insertion+ NSCLC, fulfilling an urgent need for this difficult-to-treat cancer,” said Teresa Bitetti, president, Global Oncology Business Unit, Takeda. “EXKIVITY is the first and only oral therapy specifically designed to target EGFR Exon20 insertions, and we are particularly encouraged by the duration of the responses observed with a median of approximately 1.5 years. This approval milestone reinforces our commitment to meeting the needs of underserved patient populations within the oncology community.”

The FDA simultaneously approved Thermo Fisher Scientific’s Oncomine Dx Target Test as an NGS companion diagnostic for EXKIVITY to identify NSCLC patients with EGFR Exon20 insertions. NGS testing is critical for these patients, as it can enable more accurate diagnoses compared to polymerase chain reaction (PCR) testing, which detects less than 50% of EGFR Exon20 insertions.

“EGFR Exon20 insertion+ NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” said Pasi A. Jänne, MD, PhD, Dana Farber Cancer Institute. “The approval of EXKIVITY (mobocertinib) marks another important step forward that provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population that has shown clinically meaningful and sustained responses.”

“Patients with EGFR Exon20 insertion+ NSCLC have historically faced a unique set of challenges living with a very rare lung cancer that is not only underdiagnosed, but also lacking targeted treatment options that can improve response rates,” said Marcia Horn, executive director, Exon 20 Group at ICAN, International Cancer Advocacy Network. “As a patient advocate working with EGFR Exon20 insertion+ NSCLC patients and their families every day for nearly five years, I am thrilled to witness continued progress in the fight against this devastating disease and am grateful for the patients, families, healthcare professionals and scientists across the globe who contributed to the approval of this promising targeted therapy.”

The FDA approval is based on results from the platinum-pretreated population in the Phase 1/2 trial of EXKIVITY, which consisted of 114 patients with EGFR Exon20 insertion+ NSCLC who received prior platinum-based therapy and were treated at the 160 mg dose. Results were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting from the Phase 1/2 trial and demonstrated a confirmed ORR of 28% per independent review committee (IRC) (35% per investigator) as well as a median DoR of 17.5 months per IRC, a median overall survival (OS) of 24 months and a median progression-free survival (PFS) of 7.3 months per IRC.

The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. The EXKIVITY Prescribing Information includes a boxed warning for QTc prolongation and Torsades de Pointes, and warnings and precautions for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.

The FDA review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE), which provides a framework for concurrent submission and review of oncology products among international partners. We look forward to continuing our work with regulatory agencies across the globe to bring mobocertinib to patients.

About EXKIVITY (mobocertinib)

EXKIVITY is a first-in-class, oral tyrosine kinase inhibitor (TKI) specifically designed to selectively target epidermal growth factor receptor (EGFR) Exon20 insertion mutations.

EXKIVITY is approved in the U.S. for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

Results from the Phase 1/2 trial of mobocertinib have also been accepted for review by the Center for Drug Evaluation (CDE) in China for locally advanced or metastatic NSCLC patients with EGFR Exon20 insertion mutations who have been previously treated with at least one prior systemic chemotherapy.

For more information about EXKIVITY, visit http://www.EXKIVITY.com. For the Prescribing Information, including the Boxed Warning, please visit https://takeda.info/Exkivity-Prescribing-Information.

About EGFR Exon20 Insertion+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of the estimated 2.2 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization.1,2 Patients with epidermal growth factor receptor (EGFR) Exon20 insertion+ NSCLC make up approximately 1-2% of patients with NSCLC, and the disease is more common in Asian populations compared to Western populations.3-7 This disease carries a worse prognosis than other EGFR mutations, as EGFR TKIs – which do not specifically target EGFR Exon20 insertions – and chemotherapy provide limited benefit for these patients.

Takeda is committed to continuing research and development to meet the needs of the lung cancer community through the discovery and delivery of transformative medicines.

EXKIVITY IMPORTANT SAFETY INFORMATION

QTc Interval Prolongation and Torsades de PointesEXKIVITY can cause life-threatening heart rate-corrected QT (QTc) prolongation, including Torsades de Pointes, which can be fatal, and requires monitoring of QTc and electrolytes at baseline and periodically during treatment. Increase monitoring frequency in patients with risk factors for QTc prolongation.  Avoid use of concomitant drugs which are known to prolong the QTc interval and use of strong or moderate CYP3A inhibitors with EXKIVITY, which may further prolong the QTc.  Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of QTc prolongation.

Interstitial Lung Disease (ILD)/Pneumonitis: Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold EXKIVITY in patients with suspected ILD/pneumonitis and permanently discontinue EXKIVITY if ILD/pneumonitis is confirmed.

Cardiac Toxicity: Monitor cardiac function, including left ventricular ejection fraction, at baseline and during treatment. Withhold, resume at reduced dose or permanently discontinue based on severity.

Diarrhea: Diarrhea may lead to dehydration or electrolyte imbalance, with or without renal impairment. Monitor electrolytes and advise patients to start an antidiarrheal agent at first episode of diarrhea and to increase fluid and electrolyte intake. Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity.

Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective non-hormonal contraception.

Mobocertinib, sold under the brand name Exkivity, is used for the treatment of non-small cell lung cancer.[2][3]

The most common side effects include diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychiafatigue, dry skin, and musculoskeletal pain.[2]

Mobocertinib is a small molecule tyrosine kinase inhibitor. Its molecular target is epidermal growth factor receptor (EGFR) bearing mutations in the exon 20 region.[4][5]

Mobocertinib was approved for medical use in the United States in September 2021.[2][3] It is a first-in-class oral treatment to target EGFR Exon20 insertion mutations.[3]

Medical uses

Mobocertinib is indicated for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.[2]

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PATENT

WO 2019222093

https://patents.google.com/patent/WO2019222093A1

Figure imgf000004_0002

Scheme I

Figure imgf000018_0001
Figure imgf000020_0001
Figure imgf000024_0001

Example 1 Procedure for the preparation of isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indol-3- yl)pyrimidine-5-carboxylate (Compound (A)).

Figure imgf000049_0001

[00351] Step 1 : Preparation of isopropyl 2-chloro-4-(l -methyl- lH-indo 1-3 -yl)pyrimidine-5- carboxylate.

Figure imgf000049_0002

[00352] To a 2 L Radley reactor equipped with a mechanical stirrer, a thermometer, and a refluxing condenser was charged isopropyl 2,4-dichloropyrimidine-5-carboxylate (100 g, 42.5 mmol, 1.00 eq.) andl,2-dimethoxyethane (DME, 1.2 L, 12 vol) at RT. The mixture was cooled to 3 °C, and granular AlCb (65.5 g, 49.1 mmol, 1.15 eq.) was added in 2 portions (IT 3-12 °C, jacket set 0 °C). The white slurry was stirred 15-25 °C for 60 minutes. 1 -Methylindole (59 g, 44.9 mmol, 1.06 eq.) was added in one portion (IT 20-21°C). DME (100 mL) was used to aid 1- Methylindole transfer. The reaction mixture was aged for at 35 °C for 24 h. Samples (1 mL) were removed at 5 h and 24 h for HPLC analysis (TM1195).[00353] At 5 h the reaction had 70 % conversion, while after 24 h the desired conversion was attained (< 98%).[00354] The reaction mixture was cooled to 0 °C to 5 °C and stirred for 1 h. The solids were collected via filtration and washed with DME (100 mL). The solids (AlCb complex) were charged back to reactor followed by 2-MeTHF (1 L, 10 vol), and water (400 mL, 4 vol). The mixture was stirred for 10 minutes. The stirring was stopped to allow the layers to separate.The organic phase was washed with water (200 mL, 2 vol). The combined aqueous phase was re-extracted with 2-MeTHF (100 mL, 1 vol).[00355] During workup a small amount of product title compound started to crystallize.Temperature during workup should be at about 25-40 °C.[00356] The combined organic phase was concentrated under mild vacuum to 300-350 mL (IT 40-61 °C). Heptane (550 mL) was charged while maintaining the internal temperature between 50 °C and 60 °C. The resulting slurry was cooled at 25 °C over 15 minutes, aged for 1 h (19-25 °C) and the resulting solids isolated by filtration.[00357] The product was dried at 50 °C under vacuum for 3 days to yield 108.1 g (77 % yield) of the title compound, in 100% purity (AUC) as a yellow solid.‘H NMR (400 MHz, DMSO-i/e) d ppm 1.24 (d, J= 6.53 Hz, 6 H) 3.92 (s, 3 H) 5.19 (spt, J=6.27 Hz, 1 H) 7.25 – 7.35 (m, 2 H) 7.59 (d, J=8.03 Hz, 1 H) 8.07 (s, 1 H) 8.16 (d, J= 7.53 Hz, 1 H) 8.82 (s, 1 H).[00358] Step 2: Preparation of isopropyl 2-((4-fhioro-2-methoxy-5-nitrophenyl)amino)-4-(l- methyl-lH-indol-3-yl)pyrimidine-5-carboxylate.

Figure imgf000050_0001

[00359] A mixture of the product of step 1 (85.0 g, 258 mmol, 1.0 eq.), 4-fluoro-2-methoxy- 5nitroaniline (57.0 g, 306 mmol, 1.2 eq.) and PTSA monohydrate (13.3 g, 70.0 mmol, 0.27 eq.) in acetonitrile (1.4 L, 16.5 v) was heated to 76-81 °C under nitrogen in a 2 L Radley reactor. IPC at 19 h indicated that the reaction was complete.[00360] The reaction mixture was cooled to 25 °C and water (80 mL) was charged in one portion (IT during charge dropped from 25 °C to 19 °C). The reaction mixture was aged for 1 h at 21 °C and then the resulting solids were isolated by filtration. The product was washed with EtOAc (2 x 150 mL) and dried in high vacuum at 50 °C to 60 °C for 44 h to give 121.5 g of the title compound (98% yield), HPLC purity 100 % a/a; NMR indicated that PTSA was purged.¾ NMR (400 MHz, DMSO-7,) d ppm 1.21 (d, 7=6.02 Hz, 6 H) 3.91 (s, 3 H) 4.02 (s, 3 H) 5.09 (spt, 7=6.27 Hz, 1 H) 7.10 (t, 7=7.53 Hz, 1 H) 7.26 (t, 7=7.58 Hz, 1 H) 7.42 (d, 7=13.05 Hz, 1 H) 7.55 (d, 7=8.53 Hz, 1 H) 7.90 (br d, 7=7.53 Hz, 1 H) 7.98 (s, 1 H) 8.75 (s, 1 H) 8.88 (d, 7=8.03 Hz, 1 H) 9.03 (s, 1 H).[00361] Step 3: Preparation of isopropyl 2-((4-((2-(dimethylamino)ethyl(methyl)amino)-2- methoxy-5-nitrophenyl)amino)-4-(l-methyl-lH-indol-3-yl)pyrimidine-5-carboxylate.

Figure imgf000051_0001

[00362] A 50 L flask was charged 1.500 kg of the product of step 2 (3.1 moles, l.O equiv.), 639.0 g A,A,A-trimethylethylenediamine (6.3 mol, 2 equiv.), and 21 L MeCN. The resulting slurry was mixed for 7 hours at reflux. The reaction was cooled overnight. Water (16.5 L) was added before the solids were isolated. After isolation of the solids, a wash of 2.25 L MeCN in 2.25 L water was conducted to provide the title compound. The solids were dried, under vacuum, at 75 °C. HPLC purity a/a % of the dry solid was 99.3%.¾ NMR (400 MHz, DMSO-7,) d ppm 1.22 (d, 7=6.02 Hz, 6 H) 2.09 – 2.13 (m, 1 H) 2.19 (s, 6 H) 2.49 – 2.52 (m, 1 H) 2.89 (s, 3 H) 3.29 – 3.35 (m, 2 H) 3.89 (s, 3 H) 3.94 (s, 3 H) 5.10 (spt, 7=6.19 Hz, 1 H) 6.86 (s, 1 H) 7.07 (br t, 7=7.53 Hz, 1 H) 7.24 (t, 7=7.28 Hz, 1 H) 7.53 (d, 7=8.53Hz, 1 H) 7.86 – 8.02 (m, 2 H) 8.36 (s, 1 H) 8.69 (s, 1 H) 8.85 (s, 1 H).[00363] Step 4: Preparation of isopropyl 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)- amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indo 1-3 -yl)pyrimidine-5-carboxy late.

Figure imgf000051_0002

[00364] To a mixture of the product of step 3 (1.501 kg, 2.67 mol, 1.00 eq.) and 10% Pd/C (64 % wet, 125.0 g, 0.01 1 eq.) was added 2-MeTHF (17.7 L) in a 20 L pressure reactor. The mixture was hydrogenated at 6- 10 psi ¾ and at 40 °C until IPC indicated complete conversion (1 1 h, the reaction product 99.0%). The reaction mixture was filtered (Celite), and the pad rinsed with MeTHF (2.5 L total). The filtrate was stored under N2 in a refrigerator until crystallization.[00365] Approximately 74% of 2-MeTHF was evaporated under reduced pressure while maintaining IT 23-34 °C (residual volume in the reactor was approximately 4.8 L). To the mixture was added n-heptane (6 L) over 15 min via dropping funnel. The resulting slurry was aged at room temperature overnight. The next day the solids on the walls were scraped to incorporate them into the slurry and the solids were isolated by filtration. The isolated solids were washed with n-heptane containing 5% MeTFlF (2 x 750 mL), and dried (75 °C, 30 inch Flg) to yield 1287 g (91 % yield) of the title compound as a yellow solid. F1PLC purity: 99.7% pure.[00366] ¾ NMR (400 MHz, DMSO- ) d ppm 1.20 (d, .7=6.02 Hz, 6 H) 2.21 (s, 6 H) 2.37 -2.44 (m, 2 H) 2.68 (s, 3 H) 2.93 (t, .7=6.78 Hz, 2 H) 3.74 (s, 3 H) 3.90 (s, 3 H) 4.60 (s, 2 H) 5.08 (spt, 7=6.19 Hz, 1 H) 6.80 (s, 1 H) 7.08 – 7.15 (m, 1 H) 7.19 – 7.26 (m, 2 H) 7.52 (d, .7=8.03 Hz, 1 H) 7.94 – 8.01 (m, 2 H) 8.56 (s, 1 H) 8.66 (s, 1 H).[00367] Step 5: Preparation of isopropyl 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxy-5 -(3 -(phenylsulfonyl)propanamido)phenyl)amino)-4-(l -methyl- lH-indol-3- yl)pyrimidine-5-carboxylate.

Figure imgf000052_0001

lnt-5[00368] A mixture of the product of step 4 (1.284 kg, 2.415 mol, 1.0 eq.) and 3- (phenylsulfonyl)propionic acid (0.5528 kg, 2.580 mol, 1.07 eq.) in anhydrous DCM (8.5 L) was cooled to 2 °C, and treated with DIEA (0.310 kg, 2.399 mol, 1.0 eq.). To the reaction mixture was charged over 40 min, 50 % w/w T3P in MeTHF (1.756 kg, 2.759 mol, 1.14 eq.) while maintaining the internal temperature between 0 °C and 8 °C. The mixture was stirred at 0 °C to 5 °C for 15 minutes and then warmed over 30 min to 15 °C then held at 15 °C to 30 °C for 60 min.[00369] The reaction was quenched with water (179 mL). The reaction mixture was stirred at ambient temperature for 30 min then DIEA (439 g) was charged in one portion. The resulting mixture was aged for 15 min, and then treated with 5% aqueous K2CO3 (7.3 L) at 22-25 °C. The organic layer was separated and the aqueous layer back extracted with DCM (6.142 L). The combined organic extract was washed with brine (2 x 5.5 L).[00370] The organic extract was concentrated to 6.5 L, diluted with EtOFl, 200 Proof (14.3 kg), and the mixture concentrated under vacuum (23-25 inch Flg/IT40-60 °C) to a residual volume of 12.8 L.[00371] The residual slurry was treated with EtOFl, 200 Proof (28.8 Kg), and heated to 69 °C to obtain a thin slurry. The reaction mixture was cooled to 15 °C over 2 h, and stored overnight at 15 °C under nitrogen.[00372] The next day, the mixture was cooled to 5 °C, and aged for 30 minutes. The resulting solid was isolated by filtration, washed with EtOFl (2 x 2.16 kg) and dried to give 1.769 kg (100% yield) of the title compound. F1PLC purity 99.85%.‘H NMR (400 MHz, DMSO-i¾ d ppm 1.08 – 1.19 (m, 8 H) 2.15 (s, 6 H) 2.32 (t, J= 5.77 Hz, 2 H) 2.66 – 2.76 (m, 5 H) 2.88 (br t, J= 5.52 Hz, 2 H) 3.48 (qd, J= 7.03, 5.02 Hz, 1 H) 3.60 – 3.69 (m, 2 H) 3.83 (s, 3 H) 3.89 (s, 3 H) 4.40 (t, J=5.02 Hz, 1 H) 5.04 (quin, J=6.27 Hz, 1 H) 7.01 – 7.09 (m, 2 H) 7.22 (t, J= 7.53 Hz, 1 H) 7.52 (d, J= 8.53 Hz, 1 H) 7.67 – 7.82 (m, 4 H) 7.97 (s, 1 H) 7.98 – 8.00 (m, 1 H) 8.14 (s, 1 H) 8.61 – 8.70 (m, 3 H) 10.09 (s, 1 H).[00373] Step 6: Preparation of isopropyl 2-((5-acrylamido-4-((2-(dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indol-3-yl)pyrimidine-5-carboxylate (Compound (A)).

Figure imgf000053_0001

compound (A)[00374] The product of step 5 (1.600 kg, 2.198 mol, 1.0 equiv.) was dissolved in anhydrous THF (19.5 kg) and was treated at -1 °C to 1 °C with 2M KOSi(CH3)3 in THF (2.72 L, 5.44 mol, 2.47 equiv.). KOSi(CFb)3 was added over 5 minutes, reactor jacket set at -5 °C to 10 °C. 2 M KOSi(CFh)3 solution was prepared by dissolving 871 g of KOSi(CFh)3 technical grade (90%) in 3.056 L of anhydrous TF1F.[00375] The reaction mixture was aged for 60 minutes. Potable water (22 L) was charged to the reaction mixture over 1 10 minutes, while maintaining temperature at 2-7 °C. The resulting suspension was aged at 3-7 °C for 60 minutes; the product was isolated by filtration (the filtration rate during crude product isolation was (1.25 L/min), washed with potable water (2 x 1.6 L) and air dried overnight and then in high vacuum for 12 h at 45 °C to give 1.186 kg of crude title compound (92% yield).‘H NMR (500 MHz, DMSO-i¾ d ppm 1.05 (t, J= 7.09 Hz, 2 H) 1.1 1 (d, J= 6.36 Hz, 6 H) 2.1 1 (s, 6 H) 2.28 (br t, .7=5.38 Hz, 3 H) 2.55 – 2.67 (m, 3 H) 2.69 (s, 3 H) 2.83 (br t, .7=5.38 Hz, 3 H) 3.31 (s, 3 H) 3.36 – 3.51 (m, 2 H) 3.54 – 3.70 (m, 3 H) 3.75 – 3.82 (m, 3 H) 4.33 (t, .7=5.14 Hz, 1 H) 4.99 (dt, 7=12.35, 6.30 Hz, 2 H) 5.75 (s, 1 H) 6.95 – 7.07 (m, 2 H) 7.17 (br t, .7=7.58 Hz, 2 H) 7.48 (d, 7=8.31 Hz, 2 H) 7.62 – 7.71 (m, 3 H) 7.71 – 7.83 (m, 2 H) 7.93 (d, .7=7.83 Hz, 3 H) 8.09 (s, 2 H) 8.53 – 8.67 (m, 3 H) 10.03 (s, 2 H).[00376] Step 7: Preparation of polymorphic Form-I of isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indol-3- yl)pyrimidine-5-carboxylate (Free base Compound (A)).[00377] Method 1 : The crude product of step 6 (1.130 kg) was recrystallized by dissolving it in EtOAc (30.1 kg) at 75 °C, polish filtered (1.2 pm in-line filter), followed by concentration of the filtrate to 14 L of residue (IT during concentration is 58-70 °C). The residual slurry was cooled to 0 °C over 70 minutes and then aged at 0-2 °C for 30 minutes. Upon isolation the product was dried to a constant weight to give 1.007 kg (89% recovery) of the title compound as polymorphic Form-I. Purity (HPLC, a/a %, 99.80%).

PATENT

WO 2015195228

https://patents.google.com/patent/WO2015195228A1/en

PATENT

US10227342, Example 10

https://patents.google.com/patent/US10227342

 
 isopropyl 2-((5-acrylamido-4-((2-R13
 (dimethylamino)ethyl)(methyl)amino)-2- 
 methoxyphenyl)amino)-4-(1-methyl-1H- 
 indol-3-yl)pyrimidine-5-carboxylate 
 1H NMR (CDCl3) δ 10.15 (s, 1 H), 9.80 
 (s, 1 H), 8.91 (s, 1 H), 8.70 (br. s., 1 H), 
 7.91 (s, 1 H), 7.48-7.71 (m, 1 H), 7.15- 
 7.37 (m, 3 H), 6.81 (s, 1 H), 6.49 (dd, 
 J = 17.07, 1.88 Hz, 1 H), 6.36 (dd, 
 J = 16.94, 10.04 Hz, 1 H), 5.73 (dd, 
 J = 10.04, 1.88 Hz, 1 H), 5.02 (dt, 
 J = 12.45, 6.26 Hz, 1 H), 4.00 (s, 3 H), 
 3.90 (s, 3 H), 2.86-2.93 (m, 2 H), 2.76 
 (s, 3 H), 2.26-2.31 (m, 8 H), 1.05 (d, 
 J = 6.15 Hz, 6 H) 
 ESI-MS m/z: 586.3 [M + H]+

 

 

 

 

 

 

 

 

 

 

 

 

 

References

  1. Jump up to:a b https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215310s000lbl.pdf
  2. Jump up to:a b c d e “FDA grants accelerated approval to mobocertinib for metastatic non-sma”U.S. Food and Drug Administration (FDA). 16 September 2021. Retrieved 16 September 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b c “Takeda’s Exkivity (mobocertinib) Approved by U.S. FDA as the First Oral Therapy Specifically Designed for Patients with EGFR Exon20 Insertion+ NSCLC” (Press release). Takeda Pharmaceutical Company. 15 September 2021. Retrieved 16 September 2021 – via Business Wire.
  4. ^ “TAK-788 as First-line Treatment Versus Platinum-Based Chemotherapy for Non-Small Cell Lung Cancer (NSCLC) With EGFR Exon 20 Insertion Mutations”Clinicaltrials.gov. Retrieved 17 February 2021.
  5. ^ Zhang SS, Zhu VW (2021). “Spotlight on Mobocertinib (TAK-788) in NSCLC with EGFR Exon 20 Insertion Mutations”Lung Cancer. Auckland, N.Z. 12: 61–65. doi:10.2147/LCTT.S307321PMC 8286072PMID 34285620.

External links

Clinical data
Trade namesExkivity
Other namesTAK-788
License dataUS DailyMedMobocertinib
Pregnancy
category
Contraindicated[1]
Routes of
administration
By mouth
Drug classAntineoplastic
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
showIUPAC name
CAS Number1847461-43-12389149-74-8
PubChem CID118607832
DrugBankDB16390DBSALT003192
ChemSpider84455481
UNII39HBQ4A67L
KEGGD12001D11969
ChEMBLChEMBL4650319
Chemical and physical data
FormulaC32H39N7O4
Molar mass585.709 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////////mobocertinib, Exkivity, TAK 788, AP32788, fda 2021, approvals 2021, cancer

CC(C)OC(=O)C1=CN=C(N=C1C2=CN(C3=CC=CC=C32)C)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC

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Piflufolastat F 18 injection, Dcfpyl F-18


Dcfpyl F-18.png
ChemSpider 2D Image | N-{[(1S)-1-Carboxy-5-({[6-(~18~F)fluoro-3-pyridinyl]carbonyl}amino)pentyl]carbamoyl}-L-glutamic acid | C18H2318FN4O8
img

Piflufolastat F 18 injection

Dcfpyl F-18

CAS 207181-29-0

PLAIN F 1423758-00-2  WITHOUT RADIO LABELC18 H23 F N4 O8, 441.4L-Glutamic acid, N-[[[(1S)-1-carboxy-5-[[[6-(fluoro-18F)-3-pyridinyl]carbonyl]amino]pentyl]amino]carbonyl]-2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)­ amino]-pentyl}ureido)-pentanedioic acid

Other Names

  • N-[[[(1S)-1-Carboxy-5-[[[6-(fluoro-18F)-3-pyridinyl]carbonyl]amino]pentyl]amino]carbonyl]-L-glutamic acid
  • [18F]DCFPyl

Dcfpyl F-18

(18F)Dcfpyl

UNII-3934EF02T7

18F-DCFPyL

3934EF02T7

Progenics Pharmaceuticals, Inc.

APPROVED 5/26/2021 fda, Pylarify

For positron emission tomography imaging of prostate-specific membrane antigen-positive lesions in men with prostate cancer

For positron emission tomography (PET) of prostatespecific membrane antigen (PSMA) positive lesions in men with prostate cancer: • with suspected metastasis who are candidates for initial definitive therapy. • with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level.

  • Originator Johns Hopkins University School of Medicine
  • Developer Curium Pharma; Progenics Pharmaceuticals
  • Class Amides; Carboxylic acids; Fluorinated hydrocarbons; Imaging agents; Pyridines; Radiopharmaceutical diagnostics; Radiopharmaceuticals; Small molecules; Urea compounds
  • Mechanism of ActionPositron-emission tomography enhancers
  • Orphan Drug StatusNo
  • MarketedProstate cancer
  • 28 May 2021Registered for Prostate cancer (Diagnosis) in USA (IV) – First global approval
  • 28 May 2021Adverse events data from phase III CONDOR and phase II/III OSPREY trials in prostate cancer released by Lantheus Holdings
  • 27 May 2021Lantheus Holdings intends to launch Fluorine-18 DCFPyL in USA at end of 2021

PYLARIFY contains fluorine 18 (F 18), radiolabeled prostate-specific membrane antigen inhibitor imaging agent. Chemically piflufolastat F 18 is 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)­ amino]-pentyl}ureido)-pentanedioic acid. The molecular weight is 441.4 and the structural formula is:

str1

The chiral purity of the unlabeled piflufolastat F 18 precursor is greater than 99% (S,S). PYLARIFY is a sterile, non-pyrogenic, clear, colorless solution for intravenous injection. Each milliliter contains 37 to 2,960 MBq (1 to 80 mCi) piflufolastat F 18 with ≤0.01 µg/mCi of piflufolastat at calibration time and date, and ≤ 78.9 mg ethanol in 0.9% sodium chloride injection USP. The pH of the solution is 4.5 to 7.0. PYLARIFY has a radiochemical purity of at least 95% up to 10 hours following end of synthesis, and specific activity of at least 1000 mCi/µmol at the time of administration.

PYLARIFY contains fluorine 18 (F 18), radiolabeled prostate-specific membrane antigen inhibitor imaging agent. Chemically piflufolastat F 18 is 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)amino]-pentyl}ureido)-pentanedioic acid. The molecular weight is 441.4 and the structural formula is:

PYLARIFY® (piflufolastat F 18) Structural Formula - Illustration

The chiral purity of the unlabeled piflufolastat F 18 precursor is greater than 99% (S,S).

PYLARIFY is a sterile, non-pyrogenic, clear, colorless solution for intravenous injection. Each milliliter contains 37 to 2,960 MBq (1 to 80 mCi) piflufolastat F 18 with ≤0.01 μg/mCi of piflufolastat at calibration time and date, and ≤ 78.9 mg ethanol in 0.9% sodium chloride injection USP. The pH of the solution is 4.5 to 7.0.

PYLARIFY has a radiochemical purity of at least 95% up to 10 hours following end of synthesis, and specific activity of at least 1000 mCi/μmol at the time of administration.

Physical Characteristics

PYLARIFY is radiolabeled with fluorine 18 (F 18), a cyclotron produced radionuclide that decays by positron emission to stable oxygen 18 with a half-life of 109.8 minutes. The principal photons useful for diagnostic imaging are the coincident pair of 511 keV gamma photons, resulting from the interaction of the emitted positron with an electron (Table 3).

Table 3: Principal Radiation Produced from Decay of Fluorine 18

 Radiation Energy (keV)Abundance (%)
Positron249.896.9
Gamma511193.5

FDA

Label (PDF)

PATENT

WO 2016030329

WO 2017072200

PAPER

Journal of Labelled Compounds and Radiopharmaceuticals (2016), 59(11), 439-450

CLIP

https://ejnmmires.springeropen.com/articles/10.1186/s13550-016-0195-6

Automated synthesis of [18F]DCFPyL via direct radiofluorination and validation in preclinical prostate cancer models

Radiosynthesis of [ 18 F]DCFPyL  

Radiosynthesis of [ 18 F]DCFPyL

figure2
figure3
figure4
figure1

Structure of 18F-labeled small-molecule PSMA inhibitors

/////////piflufolastat F 18,  injection, Orphan Drug , Prostate cancer, [18F]DCFPyL, 18F-DCFPYL, DCFPYL F-18, fda 2021, approvals 2021

C1=CC(=NC=C1C(=O)NCCCCC(C(=O)O)NC(=O)NC(CCC(=O)O)C(=O)O)F

wdt-9

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Sotorasib


AMG 510.svg
4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one.png

Sotorasib

6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]pyrido[2,3-d]pyrimidin-2-one

AMG 510
AMG-510
AMG510

FormulaC30H30F2N6O3
CAS2296729-00-3
Mol weight560.5944

FDA APPROVED, 2021/5/28 Lumakras

Antineoplastic, Non-small cell lung cancer (KRAS G12C-mutated)

ソトラシブ (JAN);

2296729-00-3 (racemate)

4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]pyrido[2,3-d]pyrimidin-2-one

Sotorasib [INN]

6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-((2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl)pyrido(2,3-d)pyrimidin-2-one

Sotorasib

(1M)-6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one

C30H30F2N6O3 : 560.59
[2296729-00-3]

Sotorasib is an inhibitor of the RAS GTPase family. The molecular formula is C30H30F2N6O3, and the molecular weight is 560.6 g/mol. The chemical name of sotorasib is 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2enoyl) piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one. The chemical structure of sotorasib is shown below:

LUMAKRAS™ (sotorasib) Structural Formula Illustration

Sotorasib has pKa values of 8.06 and 4.56. The solubility of sotorasib in the aqueous media decreases over the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL.

LUMAKRAS is supplied as film-coated tablets for oral use containing 120 mg of sotorasib. Inactive ingredients in the tablet core are microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The film coating material consists of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow.

FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc

On May 28, 2021, the Food and Drug Administration granted accelerated approval to sotorasib (Lumakras™, Amgen, Inc.), a RAS GTPase family inhibitor, for adult patients with KRAS G12C ‑mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA ‑approved test, who have received at least one prior systemic therapy.

FDA also approved the QIAGEN therascreen® KRAS RGQ PCR kit (tissue) and the Guardant360® CDx (plasma) as companion diagnostics for Lumakras. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

Approval was based on CodeBreaK 100, a multicenter, single-arm, open label clinical trial (NCT03600883) which included patients with locally advanced or metastatic NSCLC with KRAS G12C mutations. Efficacy was evaluated in 124 patients whose disease had progressed on or after at least one prior systemic therapy. Patients received sotorasib 960 mg orally daily until disease progression or unacceptable toxicity.

The main efficacy outcome measures were objective response rate (ORR) according to RECIST 1.1, as evaluated by blinded independent central review and response duration. The ORR was 36% (95% CI: 28%, 45%) with a median response duration of 10 months (range 1.3+, 11.1).

The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.

The recommended sotorasib dose is 960 mg orally once daily with or without food.

The approved 960 mg dose is based on available clinical data, as well as pharmacokinetic and pharmacodynamic modeling that support the approved dose. As part of the evaluation for this accelerated approval, FDA is requiring a postmarketing trial to investigate whether a lower dose will have a similar clinical effect.

View full prescribing information for Lumakras.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada, and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, the Assessment Aid, and the Product Quality Assessment Aid (PQAA), voluntary submissions from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 10 weeks ahead of the FDA goal date.

This application was granted priority review, fast-track, breakthrough therapy and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Sotorasib, sold under the brand name Lumakras is an anti-cancer medication used to treat non-small-cell lung cancer (NSCLC).[1][2] It targets a specific mutation, G12C, in the protein KRAS which is responsible for various forms of cancer.[3][4]

The most common side effects include diarrhea, musculoskeletal pain, nausea, fatigue, liver damage and cough.[1][2]

Sotorasib is an inhibitor of the RAS GTPase family.[1]

Sotorasib is the first approved targeted therapy for tumors with any KRAS mutation, which accounts for approximately 25% of mutations in non-small cell lung cancers.[2] KRAS G12C mutations represent about 13% of mutations in non-small cell lung cancers.[2] Sotorasib was approved for medical use in the United States in May 2021.[2][5]

Sotorasib is an experimental KRAS inhibitor being investigated for the treatment of KRAS G12C mutant non small cell lung cancer, colorectal cancer, and appendix cancer.

Sotorasib, also known as AMG-510, is an acrylamide derived KRAS inhibitor developed by Amgen.1,3 It is indicated in the treatment of adult patients with KRAS G12C mutant non small cell lung cancer.6 This mutation makes up >50% of all KRAS mutations.2 Mutant KRAS discovered in 1982 but was not considered a druggable target until the mid-2010s.5 It is the first experimental KRAS inhibitor.1

The drug MRTX849 is also currently being developed and has the same target.1

Sotorasib was granted FDA approval on 28 May 2021.6

Medical uses

Sotorasib is indicated for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.[1][2]

Clinical development

Sotorasib is being developed by Amgen. Phase I clinical trials were completed in 2020.[6][7][8] In December 2019, it was approved to begin Phase II clinical trials.[9]

Because the G12C KRAS mutation is relatively common in some cancer types, 14% of non-small-cell lung cancer adenocarcinoma patients and 5% of colorectal cancer patients,[10] and sotorasib is the first drug candidate to target this mutation, there have been high expectations for the drug.[10][11][12] The Food and Drug Administration has granted a fast track designation to sotorasib for the treatment of metastatic non-small-cell lung carcinoma with the G12C KRAS mutation.[13]

Chemistry and pharmacology

Sotorasib can exist in either of two atropisomeric forms and one is more active than the other.[10] It selectively forms an irreversible covalent bond to the sulfur atom in the cysteine residue that is present in the mutated form of KRAS, but not in the normal form.[10]

History

Researchers evaluated the efficacy of sotorasib in a study of 124 participants with locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy.[2] The major outcomes measured were objective response rate (proportion of participants whose tumor is destroyed or reduced) and duration of response.[2] The objective response rate was 36% and 58% of those participants had a duration of response of six months or longer.[2]

The U.S. Food and Drug Administration (FDA) granted the application for sotorasib orphan drugfast trackpriority review, and breakthrough therapy designations.[2] The FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA).[2] The application reviews are ongoing at the other regulatory agencies.[2]

The FDA granted approval of Lumakras to Amgen Inc.[2]

Society and culture

Economics

Sotorasib costs US$17,900 per month.[5]

Names

Sotorasib is the recommended international nonproprietary name (INN).[14]

PAPER

Nature (London, United Kingdom) (2019), 575(7781), 217-223

https://www.nature.com/articles/s41586-019-1694-1

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3,4,5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.

Paper

Scientific Reports (2020), 10(1), 11992

PAPER

European journal of medicinal chemistry (2021), 213, 113082.

https://www.sciencedirect.com/science/article/abs/pii/S0223523420310540

Image 1

KRAS is the most commonly altered oncogene of the RAS family, especially the G12C mutant (KRASG12C), which has been a promising drug target for many cancers. On the basis of the bicyclic pyridopyrimidinone framework of the first-in-class clinical KRASG12C inhibitor AMG510, a scaffold hopping strategy was conducted including a F–OH cyclization approach and a pyridinyl N-atom working approach leading to new tetracyclic and bicyclic analogues. Compound 26a was identified possessing binding potency of 1.87 μM against KRASG12C and cell growth inhibition of 0.79 μM in MIA PaCa-2 pancreatic cancer cells. Treatment of 26a with NCI–H358 cells resulted in down-regulation of KRAS-GTP levels and reduction of phosphorylation of downstream ERK and AKT dose-dependently. Molecular docking suggested that the fluorophenol moiety of 26a occupies a hydrophobic pocket region thus forming hydrogen bonding to Arg68. These results will be useful to guide further structural modification.

PAPER

Journal of Medicinal Chemistry (2020), 63(1), 52-65.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01180

KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-“undruggable” target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12C inhibitor currently in phase I clinical trials (NCT03600883).

AMG 510 [(R)-38]. (1R)-6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1-piperazinyl]-pyrido[2,3-d]pyrimidin-2(1H)-one

………… concentrated in vacuo. Chromatographic purification of the residue (silica gel; 0–100% 3:1 EtOAc–EtOH/heptane) followed by chiral supercritical fluid chromatography (Chiralpak IC, 30 mm × 250 mm, 5 μm, 55% MeOH/CO2, 120 mL/min, 102 bar) provided (1R)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1-piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one (AMG 510; (R)-38; 2.25 g, 43% yield) as the first-eluting peak. 1H NMR (600 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 8.39 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.9 Hz, 0.5H), 8.27 (d, J = 8.7 Hz, 0.5H), 7.27 (q, J = 8.4 Hz, 1H), 7.18 (d, J = 4.9 Hz, 1H), 6.87 (dd, J = 16.2, 10.8 Hz, 0.5H), 6.84 (dd, J = 16.2, 10.7 Hz, 0.5H), 6.74 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 8.4 Hz, 1H), 6.21 (d, J = 16.2 Hz, 0.5H), 6.20 (d, J = 16.2 Hz, 0.5H), 5.76 (d, J = 10.8 Hz, 0.5H), 5.76 (d, J = 10.7 Hz, 0.5H), 4.91 (m, 1H), 4.41 (d, J = 12.2 Hz, 0.5H), 4.33 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 12.2 Hz, 0.5H), 4.14 (d, J = 12.2 Hz, 0.5H), 4.02 (d, J = 13.6 Hz, 0.5H), 3.69 (m, 1H), 3.65 (d, J = 13.6 Hz, 0.5H), 3.52 (t, J = 12.2 Hz, 0.5H), 3.27 (d, J = 12.2 Hz, 0.5H), 3.15 (t, J = 12.2 Hz, 0.5H), 2.72 (m, 1H), 1.90 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H). 
19F NMR (376 MHz, DMSO-d6) δ −115.6 (d, J = 5.2 Hz, 1 F), −128.6 (br s, 1 F). 
13C NMR (151 MHz, DMSO-d6) δ ppm 165.0 (1C), 163.4 (1C), 162.5 (1C), 160.1 (1C), 156.8 (1C), 153.7 (1C), 151.9 (1C), 149.5 (1C), 148.3 (1C), 145.2 (1C), 144.3 (1C), 131.6 (1C), 130.8 (1C), 127.9 (0.5C), 127.9 (0.5C), 127.8 (0.5C), 127.7 (0.5C), 123.2 (1C), 122.8 (1C), 111.7 (1C), 109.7 (1C), 105.7 (1C), 105.3 (1C), 51.4 (0.5C), 51.0 (0.5C), 48.9 (0.5C), 45.4 (0.5C), 44.6 (0.5C), 43.7 (0.5C), 43.5 (0.5C), 41.6 (0.5C), 29.8 (1C), 21.9 (1C), 21.7 (1C), 17.0 (1C), 15.5 (0.5C), 14.8 (0.5C). 
FTMS (ESI) m/z: [M + H]+ calcd for C30H30F2N6O3 561.24202. Found 561.24150. 

d (1R)-6-Fluoro7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1- piperazinyl]-pyrido[2,3-d]pyrimidin-2(1H)-one ((R)-38; AMG 510; 2.25 g, 43% yield) as the first-eluting peak.1 H NMR (600 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 8.39 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.9 Hz, 0.5H), 8.27 (d, J = 8.7 Hz, 0.5H), 7.27 (q, J = 8.4 Hz, 1H), 7.18 (d, J = 4.9 Hz, 1H), 6.87 (dd, J = 16.2, 10.8 Hz, 0.5H), 6.84 (dd, J = 16.2, 10.7 Hz, 0.5H), 6.74 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 8.4 Hz, 1H), 6.21 (d, J = 16.2 Hz, 0.5H), 6.20 (d, J = 16.2 Hz, 0.5H), 5.76 (d, J = 10.8 Hz, 0.5H), 5.76 (d, J = 10.7 Hz, 0.5H), 4.91 (m, 1H), 4.41 (d, J = 12.2 Hz, 0.5H), 4.33 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 12.2 Hz, 0.5H), 4.14 (d, J = 12.2 Hz, 0.5H), 4.02 (d, J = 13.6 Hz, 0.5H), 3.69 (m, 1H), 3.65 (d, J = 13.6 Hz, 0.5H), 3.52 (t, J = 12.2 Hz, 0.5H), 3.27 (d, J = 12.2 Hz, 0.5H), 3.15 (t, J = 12.2 Hz, 0.5H), 2.72 (m, 1H), 1.90 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H). 
19F NMR (376 MHz, DMSO-d6) δ –115.6 (d, J = 5.2 Hz, 1 F), –128.6 (br. s., 1 F). 
13C NMR (151 MHz, DMSO-d6) δ ppm 165.0 (1C), 163.4 (1C), 162.5 (1C), 160.1 (1C), 156.8 (1C), 153.7 (1C), 151.9 (1C), 149.5 (1C), 148.3 (1C), 145.2 (1C), 144.3 (1C), 131.6 (1C), 130.8 (1C), 127.9 (0.5C), 127.9 (0.5C), 127.8 (0.5C), 127.7 (0.5C), 123.2 (1C), 122.8 (1C), 111.7 (1C), 109.7 (1C), 105.7 (1C), 105.3 (1C), 51.4 (0.5C), 51.0 (0.5C), 48.9 (0.5C), 45.4 (0.5C), 44.6 (0.5C), 43.7 (0.5C), 43.5 (0.5C), 41.6 (0.5C), 29.8 (1C), 21.9 (1C), 21.7 (1C), 17.0 (1C), 15.5 (0.5C), 14.8 (0.5C). 
FTMS (ESI) m/z: [M+H]+ Calcd for C30H30F2N6O3 561.24202; Found 561.24150. Atropisomer configuration (R vs. S) assigned crystallographically.The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01180.

PATENT

WO 2021097212

The present disclosure relates to an improved, efficient, scalable process to prepare intermediate compounds, such as compound of Formula 6A, having the structure,


useful for the synthesis of compounds for the treatment of KRAS G12C mutated cancers.

BACKGROUND

[0003] KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gall bladder cancer, thyroid cancer, and bile duct cancer. KRAS mutations are also observed in about 25% of patients with NSCLC, and some studies have indicated that KRAS mutations are a negative prognostic factor in patients with NSCLC. Recently, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been found to confer resistance to epidermal growth factor receptor (EGFR) targeted therapies in colorectal cancer; accordingly, the mutational status of KRAS can provide important information prior to the prescription of TKI therapy. Taken together, there is a need for new medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, especially those who have been diagnosed to have such cancers characterized by a KRAS mutation, and including those who have progressed after chemotherapy.

Related Synthetic Processes

[0126] The following intermediate compounds of 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one are representative examples of the disclosure and are not intended to be construed as limiting the scope of the present invention.

[0127] A synthesis of Compound 9 and the relevant intermediates is described in U.S. Serial No.15/984,855, filed May 21, 2018 (U.S. Publication No.2018/0334454, November 22, 2018) which claims priority to and the benefit claims the benefit of U.S. Provisional Application No.62/509,629, filed on May 22, 2017, both of which are incorporated herein by reference in their entireties for all purposes. 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using the following process, in which the isomers of the final product were isolated via chiral chromatography.

[0128] Step 1: 2,6-Dichloro-5-fluoronicotinamide (Intermediate S). To a mixture of 2,6-dichloro-5-fluoro-nicotinic acid (4.0 g, 19.1 mmol, AstaTech Inc., Bristol, PA) in dichloromethane (48 mL) was added oxalyl chloride (2M solution in DCM, 11.9 mL, 23.8 mmol), followed by a catalytic amount of DMF (0.05 mL). The reaction was stirred at room temperature overnight and then was concentrated. The residue was dissolved in 1,4-dioxane (48 mL) and cooled to 0 °C. Ammonium hydroxide solution (28.0-30% NH3 basis, 3.6 mL, 28.6 mmol) was added slowly via syringe. The resulting mixture was stirred at 0 °C for 30 min and then was concentrated. The residue was diluted with a 1:1 mixture of EtOAc/Heptane and agitated for 5 min, then was filtered. The filtered solids were discarded, and the remaining mother liquor was partially concentrated to half volume and filtered. The filtered solids were washed with heptane and dried in a reduced-pressure oven (45 °C) overnight to provide 2,6-dichloro-5-fluoronicotinamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J = 7.9 Hz, 1 H) 8.09 (br s, 1 H) 7.93 (br s, 1 H). m/z (ESI, +ve ion): 210.9 (M+H)+.

[0129] Step 2: 2,6-Dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide. To an ice-cooled slurry of 2,6-dichloro-5-fluoronicotinamide (Intermediate S, 5.0 g, 23.9 mmol) in THF (20 mL) was added oxalyl chloride (2 M solution in DCM, 14.4 mL, 28.8 mmol) slowly via syringe. The resulting mixture was heated at 75 °C for 1 h, then heating was stopped, and the reaction was concentrated to half volume. After cooling to 0 °C, THF (20 mL) was added, followed by a solution of 2-isopropyl-4-methylpyridin-3-amine (Intermediate R, 3.59 g, 23.92 mmol) in THF (10 mL), dropwise via cannula. The resulting mixture was stirred at 0 °C for 1 h and then was quenched with a 1:1 mixture of brine and saturated aqueous ammonium chloride. The mixture was extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to provide 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide. This material was used without further purification in the following step. m/z (ESI, +ve ion): 385.1(M+H)+.

[0130] Step 3: 7-Chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. To an ice-cooled solution of 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (9.2 g, 24.0 mmol) in THF (40 mL) was added KHMDS (1 M solution in THF, 50.2 mL, 50.2 mmol) slowly via syringe. The ice bath was removed and the resulting mixture was stirred for 40 min at room temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-50% 3:1 EtOAc-EtOH/heptane) to provide 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (br s, 1H), 8.48-8.55 (m, 2 H), 7.29 (d, J = 4.8 Hz, 1 H), 2.87 (quin, J = 6.6 Hz, 1 H), 1.99-2.06 (m, 3 H), 1.09 (d, J = 6.6 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H).19F NMR (376 MHz, DMSO-d6) δ: -126.90 (s, 1 F). m/z (ESI, +ve ion): 349.1 (M+H)+.

[0131] Step 4: 4,7-Dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one. To a solution of 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4.7 g, 13.5 mmol) and DIPEA (3.5 mL, 20.2 mmol) in acetonitrile (20 mL) was added phosphorus oxychloride (1.63 mL, 17.5 mmol), dropwise via syringe. The resulting mixture was heated at 80 °C for 1 h, and then was cooled to room temperature and concentrated to provide 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one. This material was used without further purification in the following step. m/z (ESI, +ve ion): 367.1 (M+H)+.

[0132] Step 5: (S)-tert-Butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. To an ice-cooled solution of 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (13.5 mmol) in acetonitrile (20 mL) was added DIPEA (7.1 mL, 40.3 mmol), followed by (S)-4-N-Boc-2-methyl piperazine (3.23 g, 16.1 mmol, Combi-Blocks, Inc., San Diego, CA, USA). The resulting mixture was warmed to room temperature and stirred for 1 h, then was diluted with cold saturated aqueous sodium bicarbonate solution (200 mL) and EtOAc (300 mL). The mixture was stirred for an additional 5 min, the layers were separated, and the aqueous layer was extracted with more EtOAc (1x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-50% EtOAc/heptane) to provide (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. m/z (ESI, +ve ion): 531.2 (M+H)+.

[0133] Step 6: (3S)-tert-Butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. A mixture of (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (4.3 g, 8.1 mmol), potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate (Intermediate Q, 2.9 g, 10.5 mmol), potassium acetate (3.2 g, 32.4 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (661 mg, 0.81 mmol) in 1,4-dioxane (80 mL) was degassed with nitrogen for 1 min. De-oxygenated water (14 mL) was added, and the resulting mixture was heated at 90 °C for 1 h. The reaction was allowed to cool to room temperature, quenched with half-saturated aqueous sodium bicarbonate, and extracted with EtOAc (2x) and DCM (1x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-60% 3:1 EtOAc-EtOH/heptane) to provide (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate.1H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (br s, 1 H), 8.38 (d, J = 5.0 Hz, 1 H), 8.26 (dd, J = 12.5, 9.2 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.18 (d, J = 5.0 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.68 (t, J = 8.9 Hz, 1 H), 4.77-4.98 (m, 1 H), 4.24 (br t, J = 14.2 Hz, 1 H), 3.93-4.08 (m, 1 H), 3.84 (br d, J=12.9 Hz, 1 H), 3.52-3.75 (m, 1 H), 3.07-3.28 (m, 1 H), 2.62-2.74 (m, 1 H), 1.86-1.93 (m, 3 H), 1.43-1.48 (m, 9 H), 1.35 (dd, J = 10.8, 6.8 Hz, 3 H), 1.26-1.32 (m, 1 H), 1.07 (dd, J = 6.6, 1.7 Hz, 3 H), 0.93 (dd, J = 6.6, 2.1 Hz, 3 H).19F NMR (376 MHz, DMSO-d6) δ: -115.65 (s, 1 F), -128.62 (s, 1 F). m/z (ESI, +ve ion): 607.3 (M+H)+.

[0134] Step 7: 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one. Trifluoroacetic acid (25 mL, 324 mmol) was added to a solution of (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (6.3 g, 10.4 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 1 h and then was concentrated. The residue was dissolved in DCM (30 mL), cooled to 0 °C, and sequentially treated with DIPEA (7.3 mL, 41.7 mmol) and a solution of acryloyl chloride (0.849 mL, 10.4 mmol) in DCM (3 mL; added dropwise via syringe). The reaction was stirred at 0 °C for 10 min, then was quenched with half-saturated aqueous sodium bicarbonate and extracted with DCM (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-100% 3:1 EtOAc-EtOH/heptane) to provide 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.1H NMR (400 MHz, DMSO-d6) δ ppm 10.20 (s, 1 H), 8.39 (d, J = 4.8 Hz, 1 H), 8.24-8.34 (m, 1 H), 7.23-7.32 (m, 1 H), 7.19 (d, J = 5.0 Hz, 1 H), 6.87 (td, J = 16.3, 11.0 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 6.69 (t, J = 8.6 Hz, 1 H), 6.21 (br d, J = 16.2 Hz, 1 H), 5.74-5.80 (m, 1 H), 4.91 (br s, 1 H), 4.23-4.45 (m, 2 H), 3.97-4.21 (m, 1 H), 3.44-3.79 (m, 2 H), 3.11-3.31 (m, 1 H), 2.67-2.77 (m, 1 H), 1.91 (s, 3 H), 1.35 (d, J = 6.8 Hz, 3 H), 1.08 (d, J = 6.6 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H).19F NMR (376 MHz, DMSO-d6) δ ppm -115.64 (s, 1 F), -128.63 (s, 1 F). m/z (ESI, +ve ion): 561.2 (M+H)+.

[0135] Another synthesis of Compound 9 and the relevant intermediates was described in a U.S. provisional patent application filed November 16, 2018, which is incorporated herein by reference in its entirety for all purposes.

Representative Synthetic Processes

[0136] The present disclosure comprises the following steps wherein the synthesis and utilization of the boroxine intermediate is a novel and inventive step in the manufacture of AMG 510 (Compound 9):

Raw Materials

Step la

[0137] To a solution of 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (25kg; 119. lmol) in dichloromethane (167kg) and DMF (592g) was added Oxalyl chloride (18.9kg; 148.9mol) while maintaining an internal temp between 15-20 °C. Additional dichloromethane (33kg) was added as a rinse and the reaction mixture stirred for 2h. The reaction mixture is cooled then quenched with ammonium hydroxide (40.2L; 595.5mol) while maintaining internal temperature 0 ± 10°C. The resulting slurry was stirred for 90min then the product collected by filtration. The filtered solids were washed with DI water (3X 87L) and dried to provide 2,6-dichloro-5-fluoronicotinamide (Compound 1).

Step 1b

[0138] In reactor A, a solution of 2,6-dichloro-5-fluoronicotinamide (Compound 1) (16.27kg; 77.8mol) in dichloromethane (359.5kg) was added oxalyl chloride (11.9kg;

93.8mol) while maintaining temp ≤ 25°C for 75min. The resulting solution was then headed to 40°C ± 3°C and aged for 3h. Using vacuum, the solution was distilled to remove dichloromethane until the solution was below the agitator. Dichloromethane (300 kg) was then added and the mixture cooled to 0 ± 5°C. To a clean, dry reactor (reactor B) was added,2-isopropyl-4-methylpyridin-3-amine (ANILINE Compound 2A) (12.9kg; 85.9mol) followed by dichloromethane (102.6 kg). The ANILINE solution was azeodried via vacuum distillation while maintaining an internal temperature between 20-25 °), replacing with additional dichloromethane until the solution was dry by KF analysis (limit ≤ 0.05%). The solution volume was adjusted to approx. 23L volume with dichloromethane. The dried ANILINE solution was then added to reactor A while maintaining an internal temperature of 0 ± 5°C throughout the addition. The mixture was then heated to 23 °C and aged for 1h. the solution was polish filtered into a clean reactor to afford 2,6-dichloro-5-fluoro-N-((2- isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (Compound 3) as a solution in DCM and used directly in the next step.

Step 2

[0139] A dichloromethane solution of 2,6-dichloro-5-fluoro-N-{[4-methyl-2-(propan-2- yl)pyridin-3-yl]carbamoyl}pyridine-3-carboxamide (UREA (Compound 3)) (15kg contained; 38.9mol) was solvent exchanged into 2-MeTHF using vacuum distillation while maintaining internal temperature of 20-25 °C. The reactor volume was adjusted to 40L and then

additional 2-MeTHF was charged (105.4 kg). Sodium t-butoxide was added (9.4 kg;

97.8mol) while maintaining 5-10 °C. The contents where warmed to 23 °C and stirred for 3h. The contents where then cooled to 0-5C and ammonium chloride added (23.0kg; 430mol) as a solution in 60L of DI water. The mixture was warmed to 20 C and DI water added (15L) and further aged for 30min. Agitation was stopped and the layers separated. The aqueous layer was removed and to the organic layer was added DI water(81.7L). A mixture of conc HCl (1.5kg) and water (9L) was prepared then added to the reactor slowly until pH measured between 4-5. The layers were separated, and the aqueous layer back extracted using 2-MeTHF (42.2kg). The two organic layers combined and washed with a 10% citric acid solution (75kg) followed by a mixture of water (81.7L) and saturated NaCl (19.8 kg). The organic layer was then washed with saturated sodium bicarbonate (75kg) repeating if necessary to achieve a target pH of ≥ 7.0 of the aqueous. The organic layer was washed again with brine (54.7kg) and then dried over magnesium sulfate (5kg). The mixture was filtered to remove magnesium sulfate rinsing the filtered bed with 2-MeTHF (49.2 kg). The combined filtrate and washes where distilled using vacuum to 40L volume. The concentrated solution was heated to 55 °C and heptane (10-12kg) slowly added until cloud point. The solution was cooled to 23 °C over 2h then heptane (27.3 kg) was added over 2h. The product slurry was aged for 3h at 20-25 °C then filtered and washed with a mixture of 2-MeTHF (2.8kg) and heptane (9kg). The product was dried using nitrogen and vacuum to afford solid 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (rac-DIONE (Compound 4)).

Step 3

[0140] To a vessel, an agitated suspension of Compound 4, (1.0 eq.) in 2- methylterahydrofuran (7.0 L/kg) was added (+)-2,3-dibenzoyl-D-tartaric acid (2.0 eq.) under an atmosphere of nitrogen. 2-MeTHF is chiral, but it is used as a racemic mixture. The different enantiomers of 2-MeTHF are incorporated randomly into the co-crystal. The resulting suspension was warmed to 75°C and aged at 75°C until full dissolution was observed (< 30 mins.). The resulting solution was polish filtered at 75°C into a secondary vessel. To the polish filtered solution was charged n-Heptane (2.0 L/kg) at a rate that maintained the internal temperature above 65°C. The solution was then cooled to 60°C, seeded with crystals (0.01 kg/kg) and allowed to age for 30 minutes. The resulting suspension was cooled to 20°C over 4 hours and then sampled for chiral purity analysis by HPLC. To the suspension, n-Heptane (3.0 L/kg) was charged and then aged for 4 hours at 20°C under an atmosphere of nitrogen. The suspension was filtered, and the isolated solids were washed two times with (2:1) n-Heptane:2-methyltetrahydrofuran (3.0 L/kg). The material was dried with nitrogen and vacuum to afford M-Dione:DBTA: Me-THF complex (Compound 4a).

Step 4

[0141] To vessel A, a suspension of disodium hydrogen phosphate (21.1 kg, 2.0 equiv) in DI water (296.8 L, 6.3 L/kg) was agitated until dissolution was observed (≥ 30 min.). To vessel B, a suspension of the M-Dione:DBTA: Me-THF complex (Composition 4a)[46.9 kg (25.9 kg corrected for M-dione, 1.0 equiv.)] in methyl tert-butyl ether (517.8 L, 11.0 L/kg) was agitated for 15 to 30 minutes. The resulting solution from vessel A was added to vessel B, and then the mixture was agitated for more than 3 hours. The agitation was stopped, and the biphasic mixture was left to separate for more than 30 minutes. The lower aqueous phase was removed and then back extracted with methyl tert-butyl ether (77.7 L, 1.7 L/kg). The organic phases were combined in vessel B and dried with magnesium sulfate (24.8 kg, 0.529 kg/kg). The resulting suspension from vessel B was agitated for more than three hours and then filtered into vessel C. To vessel B, a methyl tert-butyl ether (46.9 L, 1.0 L/kg) rinse was charged and then filtered into vessel C. The contents of vessel C were cooled to 10 °C and then distilled under vacuum while slowly being warmed to 35°C. Distillation was continued until 320-350 kg (6.8-7.5 kg/kg) of methyl tert-butyl ether was collected. After cooling the contents of vessel C to 20°C, n-Heptane (278.7 L, 5.9 L/kg) was charged over one hour and then distilled under vacuum while slowly being warmed to 35°C. Distillation was continued until a 190-200 kg (4.1-4.3 kg/kg) mixture of methyl tert-butyl ether and n-Heptane was collected. After cooling the contents of vessel C to 20°C, n-Heptane (278.7 L, 5.9 L/kg) was charged a second time over one hour and then distilled under vacuum while slowly being warmed to 35°C. Distillation was continued until a 190-200 kg (4.1-4.3 kg/kg) mixture of methyl tert-butyl ether and n-Heptane was collected. After cooling the contents of vessel C to 20°C, n-Heptane (195.9 L, 4.2 L/kg) was charged a third time over one hour and then sampled for solvent composition by GC analysis. The vessel C suspension continued to agitate for more than one hour. The suspension was filtered, and then washed with a n-Heptane (68.6 L, 1.5 L/kg) rinse from vessel C. The isolated solids were dried at 50°C, and a sample was submitted for stock suitability. Afforded 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (M-DIONE) Compound 5M.

[0142] The first-generation process highlighted above has been successfully scaled on 200+ kg of rac-dione starting material (Compound 4). In this process, seeding the crystallization with the thermodynamically-stable rac-dione crystal form (which exhibits low solubility) would cause a batch failure. Based on our subsequent studies, we found that increasing the DBTA equivalents and lowering the seed temperature by adjusting heptane

charge schedule improves robustness of the process. The improved process is resistant to the presence of the thermodynamically-stable rac-dione crystal form and promotes successful separation of atropisomers. Subsequent batches will incorporate the improved process for large scale manufacture.

Step 5

Note: All L/kg amounts are relative to M-Dione input; All equiv. amounts are relative to M-Dione input after adjusted by potency.

[0143] M-Dione (Compound 5M, 1.0 equiv.) and Toluene-1 (10.0 L/kg) was charged to Vessel A. The resulting solution was dried by azeotropic distillation under vacuum at 45 °C until 5.0 L/kg of solvents has been removed. The contents of Vessel A were then cooled to 20 °C.

[0144] Vessel C was charged with Toluene-3 (4.5 L/kg), Phosphoryl chloride (1.5 equiv.) and N,N-Diisopropylethylamine-1 (2.0 equiv.) while maintaining the internal temperature below 20 ± 5 °C.

Upon finishing charging, Vessel C was warmed to 30 ± 5 °C. The contents of Vessel A were then transferred to Vessel C over 4 hours while maintaining the internal temperature at 30 ± 5°C. Vessel A was rinsed with Toluene-2 (0.5 L/kg) and transferred to Vessel C. The contents of Vessel C were agitated at 30°C for an additional 3 hours. The contents of Vessel C were cooled to 20 ± 5 °C. A solution of (s)-1-boc-3-methylpiperazine (1.2 equiv.), N,N-Diisopropylethylamine-2 (1.2 equiv.) in isopropyl acetate-1 (1.0 L/kg) was prepared in Vessel D. The solution of Vessel D was charged to vessel C while maintaining a batch temperature of 20 ± 5 °C (Note: Exotherm is observed). Upon the end of transfer, Vessel D was rinsed with additional dichloromethane (1.0 L/kg) and transferred to Vessel C. The contents of Vessel C were agitated for an additional 60 minutes at 20 °C. A solution of sodium bicarbonate [water-1 (15.0 L/kg + Sodium bicarbonate (4.5 equiv.)] was then charged into Vessel C over an hour while maintaining an internal temperature at 20 ± 5 °C throughout the addition. The contents of Vessel C were agitated for at least 12 hours at which point the Pipazoline (Compound 6) product was isolated by filtration in an agitated filter dryer. The cake was washed with water-2 and -3 (5.0 L/kg x 2 times, agitating each wash for 15 minutes) and isopropyl acetate-2 and 3 (5.0 L/kg x 2 times, agitating each wash for 15 min). The cake as dried under nitrogen for 12 hours.

Acetone Re-slurry (Optional):

[0145] Pipazoline (Compound 6) and acetone (10.0 L/kg) were charged to Vessel E. The suspension was heated to 50 °C for 2 hours. Water-4 (10.0 L/kg) was charged into Vessel E over 1 hour. Upon completion of water addition, the mixture was cooled to 20 °C over 1 hour. The contents of Vessel E were filtered to isolate the product, washing the cake with 1:1 acetone/water mixture (5.0 L/kg). The cake was dried under nitrogen for 12 hours.

Step 6

General Note: All equivalents and volumes are reported in reference to Pipazoline input

Note: All L/kg and kg/kg amounts are relative to Pipazoline input

[0146] Reactor A is charged with Pipazoline (Compound 6, 1.0 equiv), degassed 2- MeTHF (9.0 L/kg) and a solution of potassium acetate (2.0 equiv) in degassed water (6.5 L/kg). The resulting mixture is warmed to 75 ± 5 °C and then, charge a slurry of

Pd(dpePhos)Cl2 (0.003 equiv) in 2-MeTHF (0.5 L/kg). Within 2 h of catalyst charge, a solution of freshly prepared Boroxine (Compound 6A, 0.5 equiv) in wet degassed 2-MeTHF (4.0 L/kg, KF > 4.0%) is charged over the course of >1 hour, but < 2 hours, rinsing with an additional portion of wet 2-MeTHF (0.5 L/kg) after addition is complete. After reaction completion ( <0.15 area % Pipazoline remaining, typically <1 h after boroxine addition is complete), 0.2 wt% (0.002 kg/kg) of Biaryl seed is added as a slurry in 0.02 L/kg wet 2- MeTHF, and the resulting seed bed is aged for > 60 min. Heptane (5.0 L/kg) is added over 2 hours at 75 ± 5 °C. The batch is then cooled to 20 ± 5 °C over 2 hours and aged for an additional 2 h. The slurry is then filtered and cake washed with 1 x 5.0L/kg water, 1 x 5.0L/kg 1:1 iPrOH:water followed by 1 x 5.0 L/kg 1:1 iPrOH:heptane (resuspension wash: the cake is resuspended by agitator and allow to set before filtering) . The cake (Biaryl, Compound 7) is then dried under vacuum with a nitrogen sweep.

Note: If the reaction stalls, an additional charge of catalyst and boroxine is required

Step 7 Charcoal Filtration for Pd removal


General Note: All equivalents and volumes are reported in reference to crude Biaryl input

Note: All L/kg and kg/kg amounts are relative to crude Biaryl input

[0147] In a clean Vessel A, charge crude Biaryl (1 equiv) and charge DCM (10 L/kg). Agitate content for > 60 minutes at 22 ± 5 °C, observing dissolution. Pass crude Biaryl from Vessel A, through a bag filter and carbon filters at a flux ≤ 3 L2/min/m and collect filtrate in clean Vessel B. Charge DCM rinse (1 L/kg) to Vessel A, and through carbon filters to collect in vessel B.

[0148] From filtrate in Vessel B, pull a solution sample for IPC Pd content. Sample is concentrated to solid and analyzed by ICP-MS. IPC: Pd ≤ 25 ppm with respect to Biaryl. a. If Pd content is greater than 25 ppm with respect to Biaryl on first or second IPC sample, pass solution through carbon filter a second time at ≤ 3 L2/min/m2, rinsing with 1 L/kg DCM; sample filtrate for IPC.

b. If Pd content remains greater than 25 ppm after third IPC, install and condition fresh carbon discs. Pass Biaryl filtrate through refreshed carbon filter, washing with 1 L/kg DCM. Sample for IPC.

[0149] Distill and refill to appropriate concentration. Prepare for distillation of recovered filtrate by concentrating to ≤ 4 L/kg DCM, and recharge to reach 5.25 ± 0.25 L/kg DCM prior to moving into Step 7 Boc-deprotection reaction.

Step 7

 General Note: All equivalents and volumes are reported in reference to crude Biaryl input

Note: All L/kg and kg/kg amounts are relative to Biaryl input

[0150] To Reactor A was added: tert-butyl (3S)-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate (Biaryl) (1.0 equiv), dichloromethane (5.0 L/kg), and the TFA (15.0 equiv, 1.9 L/kg) is charged slowly to maintain the internal temperature at 20 ± 5 °C. The reaction was stirred for 4 h at 20 ± 5 °C.

[0151] To Reactor B was added: potassium carbonate (18.0 equiv), water (20.0 L/kg), and NMP (1.0) to form a homogenous solution. While agitating at the maximum acceptable rate for the equipment, the reaction mixture in A was transferred into the potassium carbonate solution in B over 30 minutes (~ 0.24 L/kg/min rate). The mixture was stirred at 20 ± 5 °C for an additional 12 h.

[0152] The resulting slurry was filtered and rinsed with water (2 x 10 L/kg). The wet cake was dried for 24 h to give 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2S)-2-methylpiperazin- 1-yl]-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidin-2(1H)-one (Des- Boc, Compound 8).

Step 8

Note: All L/kg and kg/kg amounts are relative to Des-Boc input

[0153] Des-Boc (Compound 8, 1.0 equiv) and NMP (4.2 L/kg) are charged to Vessel A under nitrogen, charge the TFA (1.0 equiv.) slowly to maintain the Tr <25 °C. The mixture is aged at 25 °C until full dissolution is observed (about 0.5 hour). The solution is then polish filtered through a 0.45 micron filter into Vessel B, washing with a NMP (0.8 L/kg). The filtrate and wash are combined, and then cooled to 0 °C. To the resulting solution, Acryloyl Chloride (1.3 equiv.) is added while maintaining temperature < 10 C. The reaction mixture is then aged at 5 ±5°C until completed by IPC (ca.1.5 hrs).

Preparation of Aqueous Disodium Phosphate Quench:

[0154] Disodium Phosphate (3.0 equiv) and Water (15.0 L/kg) are charged to Vessel C. The mixture is aged at 25 °C until full dissolution is observed. The solution is warmed to 45 ±5°C. A seed slurry of AMG 510 (0.005 equiv.) in Water (0.4 L/kg) is prepared and added to Vessel C while maintaining temperature at 45 ±5°C.

[0155] The reaction mixture in Vessel B is transferred to Vessel C (quench solution) while maintaining temperature at 45 ±5°C (ca.1 hrs). Vessel B is washed with a portion of NMP (0.5 L/kg). The product slurry is aged for 2 hrs at 45 ±5°C, cooled to 20 °C over 3 hrs, aged at 20 °C for a minimum of 12 hrs, filtered and washed with Water (2 x 10.0 L/kg). The product is dried using nitrogen and vacuum to afford Crude AMG 510 (Compound 9A).

Step 9

 General Note: All equivalents and volumes are reported in reference to crude AMG 510 input

Note: All L/kg and kg/kg amounts are relative to Crude AMG 510 input

[0156] Reactor A was charged with 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4- methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1- yl]pyrido[2,3-d]pyrimidin-2(1H)-one (Crude AMG 510) (1.0 equiv), ethanol (7.5 L/kg), and water (1.9 L/kg). The mixture heated to 75 °C and polish filtered into a clean Reactor B. The solution was cool to 45 °C and seeded with authentic milled AMG 510 seed (0.015 േ 0.005

1 Seed performs best when reduced in particle size via milling or with other type of mechanical grinding if mill is not available (mortar/ pestle). Actual seed utilized will be based on seed availability. 1.0- 2.0% is seed is target amount.

kg/kg); the resulting slurry was aged for 30 min. Water (15.0 L/kg) was added over 5h while maintaining an internal temperature > 40 °C; the mixture was aged for an additional 2h.

[0157] The mixture was cooled to 20 °C over 3 hours and aged for 8h, after which the solid was collected by filtration and washed using a mixture of ethanol (2.5 L/kg) and water (5.0 L/kg). The solid was dried using vacuum and nitrogen to obtain 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one (AMG 510, Compound 9).

Compound 6A Boroxine Synthesis:

Lithiation/borylation

[0158] Reactor A was charged with THF (6 vol), a secondary amine base, Diisopropylamine (1.4 equiv), and a catalyst, such as triethylamine hydrochloride (0.01 equiv.). The resulting solution was cooled to -70 °C and a first base, n-BuLi (2.5 M in hexane, 1.5 equiv) was slowly added. After addition is complete, a solution of 3-fluoroanisole (1.0 equiv) in THF (6 vol) was added slowly and kept at -70 °C for 5 min. Concurrently or subsequently, a reagent, B(EtO)3 (2.0 equiv), was added slowly and kept at -70 °C for 10 min. The reaction mixture was quenched with an acid, 2N HCl. The quenched reaction mixture was extracted with MTBE (3 x 4 vol). The combined organic phases were concentrated to 1.5-3 total volumes. Heptane (7-9 vol) was added drop-wise and the mixture was cooled to 0-10 °C and stirred for 3 h. The mixture was filtrated and rinsed with heptane (1.5 vol). The solid was dried under nitrogen at < 30 °C to afford (2-fluoro-6-methoxyphenyl)boronic acid.

Demethylation:

Note: All L/kg and kg/kg amounts are relative to (2-fluoro-6-methoxyphenyl)boronic acid input

[0159] To a reactor, charge dichloromethane (solvent, 4.0 L/kg) and an acid, BBr3 (1.2 equiv), and cool to -20 °C. To this solution, a suspension of (2-fluoro-6-methoxyphenyl)boronic acid (1.0 equiv) in dichloromethane (4.0 L/kg) was added into the BBr3/DCM mixture while keeping temperature -15 to -25 °C. The reaction was allowed to proceed for approximately 2 hours while monitored by HPLC [≤1% (2-fluoro-6-methoxyphenyl)boronic acid] before reverse quenching into water (3.0 L/kg). The precipitated solid was then isolated by filtration and slurried with water (3.0 L/kg) on the filter prior to deliquoring. The filtrates were adjusted to pH 4-6 by the addition of sodium bicarbonate. The bottom organic phase was separated and the resulting aqueous layer was washed with dichloromethane (solvent, 5.0 Vol) and adjusted to pH = 1 by addition of concentrated hydrochloric acid. The resulting solids were isolated by filtration, washing the cake with water (2 x 5.0 L/kg)

Purification via Reslurry (required)

[0160] The combined crude solids were charged into a reactor and slurried with 5% EtOH/water (5.0 L/kg) at 20 °C for >1 h. The purified product was then isolated by filtration and rinsed with water (2 x 3 L/kg) before drying on the filter at < 30 °C to with nitrogen/vacuum to afford 2,2′,2”-(1,3,5,2,4,6-trioxatriborinane-2,4,6-triyl)tris(3-fluorophenol) (Boroxine, Compound 6A).

PATENT

WO 2020102730

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020102730

PATENT

US 20180334454

References

  1. Jump up to:a b c d e “Lumakras- sotorasib tablet, coated”DailyMed. Retrieved 6 June 2021.
  2. Jump up to:a b c d e f g h i j k l m n “FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy”U.S. Food and Drug Administration (FDA). 28 May 2021. Retrieved 28 May 2021.  This article incorporates text from this source, which is in the public domain.
  3. ^ “KRAS mutant-targeting AMG 510”NCI Drug Dictionary. National Cancer Institute. 2 February 2011. Retrieved 16 November2019.
  4. ^ Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. (November 2019). “The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity”. Nature575 (7781): 217–23. Bibcode:2019Natur.575..217Cdoi:10.1038/s41586-019-1694-1PMID 31666701.
  5. Jump up to:a b “FDA approves Amgen drug for lung cancer with specific mutation”CNBC. 28 May 2021. Retrieved 28 May 2021.
  6. ^ Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. (2020). “KRASG12C inhibition with sotorasib in advanced solid tumors”N Engl J Meddoi:10.1056/NEJMoa1917239PMC 7571518.
  7. ^ Clinical trial number NCT03600883 for “A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation ” at ClinicalTrials.gov
  8. ^ “The Discovery Of Amgen’s Novel Investigational KRAS(G12C) Inhibitor AMG 510 Published In Nature” (Press release). Amgen. 30 October 2019. Retrieved 16 November 2019.
  9. ^ Irving M (24 December 2019). “Drug targeting common cancer cause enters phase 2 clinical trials”New Atlas. Retrieved 24 December 2019.
  10. Jump up to:a b c d Halford B (3 April 2019). “Amgen unveils its KRas inhibitor in human clinical trials: AMG 510 shuts down a mutant version of the cancer target via covalent interaction”Chemical & Engineering News97 (4). Retrieved 16 November 2019.
  11. ^ Al Idrus A (9 September 2019). “Amgen’s KRAS drug continues to deliver but faces ‘curse’ of high expectations”. fiercebiotech.com. Retrieved 16 November 2019.
  12. ^ Kaiser J (30 October 2019). “Two new drugs finally hit ‘undruggable’ cancer target, providing hope for treatments”Science Magazine. AAAS. Retrieved 16 November 2019.
  13. ^ Astor L (9 September 2019). “FDA Grants AMG 510 Fast Track Designation for KRAS G12C+ NSCLC”. targetedonc.com. Retrieved 16 November 2019.
  14. ^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85” (PDF). WHO Drug Information35 (1).

Further reading

External links

  • “Sotorasib”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03600883 for “A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100)” at ClinicalTrials.gov
Clinical data
Trade namesLumakras
Other namesAMG 510
License dataUS DailyMedSotorasib
Routes of
administration
By mouth
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
showIUPAC name
CAS Number2252403-56-6
PubChem CID137278711
DrugBankDB15569
ChemSpider72380148
UNII2B2VM6UC8G
KEGGD12055
Chemical and physical data
FormulaC30H30F2N6O3
Molar mass560.606 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////Sotorasib, ソトラシブ , FDA 2021,  APPROVALS 2021,  Lumakras, CANCER, ANTINEOPLASTIC, AMG 510, AMG-510, AMG510, AMGEN, priority review, fast-track, breakthrough therapy, orphan drug

CC1CN(CCN1C2=NC(=O)N(C3=NC(=C(C=C32)F)C4=C(C=CC=C4F)O)C5=C(C=CN=C5C(C)C)C)C(=O)C=C

AMG 510.svg
4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one.png

Sotorasib

6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]pyrido[2,3-d]pyrimidin-2-one

AMG 510
AMG-510
AMG510

FormulaC30H30F2N6O3
CAS2296729-00-3
Mol weight560.5944

FDA APPROVED, 2021/5/28 Lumakras

Antineoplastic, Non-small cell lung cancer (KRAS G12C-mutated)

ソトラシブ (JAN);

2296729-00-3 (racemate)

4-((S)-4-Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]pyrido[2,3-d]pyrimidin-2-one

Sotorasib [INN]

6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-((2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl)pyrido(2,3-d)pyrimidin-2-one

Sotorasib

(1M)-6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one

C30H30F2N6O3 : 560.59
[2296729-00-3]

Sotorasib is an inhibitor of the RAS GTPase family. The molecular formula is C30H30F2N6O3, and the molecular weight is 560.6 g/mol. The chemical name of sotorasib is 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2enoyl) piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one. The chemical structure of sotorasib is shown below:

LUMAKRAS™ (sotorasib) Structural Formula Illustration

Sotorasib has pKa values of 8.06 and 4.56. The solubility of sotorasib in the aqueous media decreases over the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL.

LUMAKRAS is supplied as film-coated tablets for oral use containing 120 mg of sotorasib. Inactive ingredients in the tablet core are microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The film coating material consists of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow.

FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc

On May 28, 2021, the Food and Drug Administration granted accelerated approval to sotorasib (Lumakras™, Amgen, Inc.), a RAS GTPase family inhibitor, for adult patients with KRAS G12C ‑mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA ‑approved test, who have received at least one prior systemic therapy.

FDA also approved the QIAGEN therascreen® KRAS RGQ PCR kit (tissue) and the Guardant360® CDx (plasma) as companion diagnostics for Lumakras. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

Approval was based on CodeBreaK 100, a multicenter, single-arm, open label clinical trial (NCT03600883) which included patients with locally advanced or metastatic NSCLC with KRAS G12C mutations. Efficacy was evaluated in 124 patients whose disease had progressed on or after at least one prior systemic therapy. Patients received sotorasib 960 mg orally daily until disease progression or unacceptable toxicity.

The main efficacy outcome measures were objective response rate (ORR) according to RECIST 1.1, as evaluated by blinded independent central review and response duration. The ORR was 36% (95% CI: 28%, 45%) with a median response duration of 10 months (range 1.3+, 11.1).

The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.

The recommended sotorasib dose is 960 mg orally once daily with or without food.

The approved 960 mg dose is based on available clinical data, as well as pharmacokinetic and pharmacodynamic modeling that support the approved dose. As part of the evaluation for this accelerated approval, FDA is requiring a postmarketing trial to investigate whether a lower dose will have a similar clinical effect.

View full prescribing information for Lumakras.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada, and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, the Assessment Aid, and the Product Quality Assessment Aid (PQAA), voluntary submissions from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 10 weeks ahead of the FDA goal date.

This application was granted priority review, fast-track, breakthrough therapy and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Sotorasib, sold under the brand name Lumakras is an anti-cancer medication used to treat non-small-cell lung cancer (NSCLC).[1][2] It targets a specific mutation, G12C, in the protein KRAS which is responsible for various forms of cancer.[3][4]

The most common side effects include diarrhea, musculoskeletal pain, nausea, fatigue, liver damage and cough.[1][2]

Sotorasib is an inhibitor of the RAS GTPase family.[1]

Sotorasib is the first approved targeted therapy for tumors with any KRAS mutation, which accounts for approximately 25% of mutations in non-small cell lung cancers.[2] KRAS G12C mutations represent about 13% of mutations in non-small cell lung cancers.[2] Sotorasib was approved for medical use in the United States in May 2021.[2][5]

Sotorasib is an experimental KRAS inhibitor being investigated for the treatment of KRAS G12C mutant non small cell lung cancer, colorectal cancer, and appendix cancer.

Sotorasib, also known as AMG-510, is an acrylamide derived KRAS inhibitor developed by Amgen.1,3 It is indicated in the treatment of adult patients with KRAS G12C mutant non small cell lung cancer.6 This mutation makes up >50% of all KRAS mutations.2 Mutant KRAS discovered in 1982 but was not considered a druggable target until the mid-2010s.5 It is the first experimental KRAS inhibitor.1

The drug MRTX849 is also currently being developed and has the same target.1

Sotorasib was granted FDA approval on 28 May 2021.6

Medical uses

Sotorasib is indicated for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.[1][2]

Clinical development

Sotorasib is being developed by Amgen. Phase I clinical trials were completed in 2020.[6][7][8] In December 2019, it was approved to begin Phase II clinical trials.[9]

Because the G12C KRAS mutation is relatively common in some cancer types, 14% of non-small-cell lung cancer adenocarcinoma patients and 5% of colorectal cancer patients,[10] and sotorasib is the first drug candidate to target this mutation, there have been high expectations for the drug.[10][11][12] The Food and Drug Administration has granted a fast track designation to sotorasib for the treatment of metastatic non-small-cell lung carcinoma with the G12C KRAS mutation.[13]

Chemistry and pharmacology

Sotorasib can exist in either of two atropisomeric forms and one is more active than the other.[10] It selectively forms an irreversible covalent bond to the sulfur atom in the cysteine residue that is present in the mutated form of KRAS, but not in the normal form.[10]

History

Researchers evaluated the efficacy of sotorasib in a study of 124 participants with locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy.[2] The major outcomes measured were objective response rate (proportion of participants whose tumor is destroyed or reduced) and duration of response.[2] The objective response rate was 36% and 58% of those participants had a duration of response of six months or longer.[2]

The U.S. Food and Drug Administration (FDA) granted the application for sotorasib orphan drugfast trackpriority review, and breakthrough therapy designations.[2] The FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA).[2] The application reviews are ongoing at the other regulatory agencies.[2]

The FDA granted approval of Lumakras to Amgen Inc.[2]

Society and culture

Economics

Sotorasib costs US$17,900 per month.[5]

Names

Sotorasib is the recommended international nonproprietary name (INN).[14]

PAPER

Nature (London, United Kingdom) (2019), 575(7781), 217-223

https://www.nature.com/articles/s41586-019-1694-1

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3,4,5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.

Paper

Scientific Reports (2020), 10(1), 11992

PAPER

European journal of medicinal chemistry (2021), 213, 113082.

https://www.sciencedirect.com/science/article/abs/pii/S0223523420310540

Image 1

KRAS is the most commonly altered oncogene of the RAS family, especially the G12C mutant (KRASG12C), which has been a promising drug target for many cancers. On the basis of the bicyclic pyridopyrimidinone framework of the first-in-class clinical KRASG12C inhibitor AMG510, a scaffold hopping strategy was conducted including a F–OH cyclization approach and a pyridinyl N-atom working approach leading to new tetracyclic and bicyclic analogues. Compound 26a was identified possessing binding potency of 1.87 μM against KRASG12C and cell growth inhibition of 0.79 μM in MIA PaCa-2 pancreatic cancer cells. Treatment of 26a with NCI–H358 cells resulted in down-regulation of KRAS-GTP levels and reduction of phosphorylation of downstream ERK and AKT dose-dependently. Molecular docking suggested that the fluorophenol moiety of 26a occupies a hydrophobic pocket region thus forming hydrogen bonding to Arg68. These results will be useful to guide further structural modification.

PAPER

Journal of Medicinal Chemistry (2020), 63(1), 52-65.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01180

KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-“undruggable” target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12C inhibitor currently in phase I clinical trials (NCT03600883).

AMG 510 [(R)-38]. (1R)-6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1-piperazinyl]-pyrido[2,3-d]pyrimidin-2(1H)-one

………… concentrated in vacuo. Chromatographic purification of the residue (silica gel; 0–100% 3:1 EtOAc–EtOH/heptane) followed by chiral supercritical fluid chromatography (Chiralpak IC, 30 mm × 250 mm, 5 μm, 55% MeOH/CO2, 120 mL/min, 102 bar) provided (1R)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1-piperazinyl]pyrido[2,3-d]pyrimidin-2(1H)-one (AMG 510; (R)-38; 2.25 g, 43% yield) as the first-eluting peak. 1H NMR (600 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 8.39 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.9 Hz, 0.5H), 8.27 (d, J = 8.7 Hz, 0.5H), 7.27 (q, J = 8.4 Hz, 1H), 7.18 (d, J = 4.9 Hz, 1H), 6.87 (dd, J = 16.2, 10.8 Hz, 0.5H), 6.84 (dd, J = 16.2, 10.7 Hz, 0.5H), 6.74 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 8.4 Hz, 1H), 6.21 (d, J = 16.2 Hz, 0.5H), 6.20 (d, J = 16.2 Hz, 0.5H), 5.76 (d, J = 10.8 Hz, 0.5H), 5.76 (d, J = 10.7 Hz, 0.5H), 4.91 (m, 1H), 4.41 (d, J = 12.2 Hz, 0.5H), 4.33 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 12.2 Hz, 0.5H), 4.14 (d, J = 12.2 Hz, 0.5H), 4.02 (d, J = 13.6 Hz, 0.5H), 3.69 (m, 1H), 3.65 (d, J = 13.6 Hz, 0.5H), 3.52 (t, J = 12.2 Hz, 0.5H), 3.27 (d, J = 12.2 Hz, 0.5H), 3.15 (t, J = 12.2 Hz, 0.5H), 2.72 (m, 1H), 1.90 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H). 
19F NMR (376 MHz, DMSO-d6) δ −115.6 (d, J = 5.2 Hz, 1 F), −128.6 (br s, 1 F). 
13C NMR (151 MHz, DMSO-d6) δ ppm 165.0 (1C), 163.4 (1C), 162.5 (1C), 160.1 (1C), 156.8 (1C), 153.7 (1C), 151.9 (1C), 149.5 (1C), 148.3 (1C), 145.2 (1C), 144.3 (1C), 131.6 (1C), 130.8 (1C), 127.9 (0.5C), 127.9 (0.5C), 127.8 (0.5C), 127.7 (0.5C), 123.2 (1C), 122.8 (1C), 111.7 (1C), 109.7 (1C), 105.7 (1C), 105.3 (1C), 51.4 (0.5C), 51.0 (0.5C), 48.9 (0.5C), 45.4 (0.5C), 44.6 (0.5C), 43.7 (0.5C), 43.5 (0.5C), 41.6 (0.5C), 29.8 (1C), 21.9 (1C), 21.7 (1C), 17.0 (1C), 15.5 (0.5C), 14.8 (0.5C). 
FTMS (ESI) m/z: [M + H]+ calcd for C30H30F2N6O3 561.24202. Found 561.24150. 

d (1R)-6-Fluoro7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-4-[(2S)-2-methyl-4-(1-oxo-2-propen-1-yl)-1- piperazinyl]-pyrido[2,3-d]pyrimidin-2(1H)-one ((R)-38; AMG 510; 2.25 g, 43% yield) as the first-eluting peak.1 H NMR (600 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 8.39 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.9 Hz, 0.5H), 8.27 (d, J = 8.7 Hz, 0.5H), 7.27 (q, J = 8.4 Hz, 1H), 7.18 (d, J = 4.9 Hz, 1H), 6.87 (dd, J = 16.2, 10.8 Hz, 0.5H), 6.84 (dd, J = 16.2, 10.7 Hz, 0.5H), 6.74 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 8.4 Hz, 1H), 6.21 (d, J = 16.2 Hz, 0.5H), 6.20 (d, J = 16.2 Hz, 0.5H), 5.76 (d, J = 10.8 Hz, 0.5H), 5.76 (d, J = 10.7 Hz, 0.5H), 4.91 (m, 1H), 4.41 (d, J = 12.2 Hz, 0.5H), 4.33 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 12.2 Hz, 0.5H), 4.14 (d, J = 12.2 Hz, 0.5H), 4.02 (d, J = 13.6 Hz, 0.5H), 3.69 (m, 1H), 3.65 (d, J = 13.6 Hz, 0.5H), 3.52 (t, J = 12.2 Hz, 0.5H), 3.27 (d, J = 12.2 Hz, 0.5H), 3.15 (t, J = 12.2 Hz, 0.5H), 2.72 (m, 1H), 1.90 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H). 
19F NMR (376 MHz, DMSO-d6) δ –115.6 (d, J = 5.2 Hz, 1 F), –128.6 (br. s., 1 F). 
13C NMR (151 MHz, DMSO-d6) δ ppm 165.0 (1C), 163.4 (1C), 162.5 (1C), 160.1 (1C), 156.8 (1C), 153.7 (1C), 151.9 (1C), 149.5 (1C), 148.3 (1C), 145.2 (1C), 144.3 (1C), 131.6 (1C), 130.8 (1C), 127.9 (0.5C), 127.9 (0.5C), 127.8 (0.5C), 127.7 (0.5C), 123.2 (1C), 122.8 (1C), 111.7 (1C), 109.7 (1C), 105.7 (1C), 105.3 (1C), 51.4 (0.5C), 51.0 (0.5C), 48.9 (0.5C), 45.4 (0.5C), 44.6 (0.5C), 43.7 (0.5C), 43.5 (0.5C), 41.6 (0.5C), 29.8 (1C), 21.9 (1C), 21.7 (1C), 17.0 (1C), 15.5 (0.5C), 14.8 (0.5C). 
FTMS (ESI) m/z: [M+H]+ Calcd for C30H30F2N6O3 561.24202; Found 561.24150. Atropisomer configuration (R vs. S) assigned crystallographically.The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01180.

PATENT

WO 2021097212

The present disclosure relates to an improved, efficient, scalable process to prepare intermediate compounds, such as compound of Formula 6A, having the structure,


useful for the synthesis of compounds for the treatment of KRAS G12C mutated cancers.

BACKGROUND

[0003] KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gall bladder cancer, thyroid cancer, and bile duct cancer. KRAS mutations are also observed in about 25% of patients with NSCLC, and some studies have indicated that KRAS mutations are a negative prognostic factor in patients with NSCLC. Recently, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been found to confer resistance to epidermal growth factor receptor (EGFR) targeted therapies in colorectal cancer; accordingly, the mutational status of KRAS can provide important information prior to the prescription of TKI therapy. Taken together, there is a need for new medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, especially those who have been diagnosed to have such cancers characterized by a KRAS mutation, and including those who have progressed after chemotherapy.

Related Synthetic Processes

[0126] The following intermediate compounds of 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one are representative examples of the disclosure and are not intended to be construed as limiting the scope of the present invention.

[0127] A synthesis of Compound 9 and the relevant intermediates is described in U.S. Serial No.15/984,855, filed May 21, 2018 (U.S. Publication No.2018/0334454, November 22, 2018) which claims priority to and the benefit claims the benefit of U.S. Provisional Application No.62/509,629, filed on May 22, 2017, both of which are incorporated herein by reference in their entireties for all purposes. 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using the following process, in which the isomers of the final product were isolated via chiral chromatography.

[0128] Step 1: 2,6-Dichloro-5-fluoronicotinamide (Intermediate S). To a mixture of 2,6-dichloro-5-fluoro-nicotinic acid (4.0 g, 19.1 mmol, AstaTech Inc., Bristol, PA) in dichloromethane (48 mL) was added oxalyl chloride (2M solution in DCM, 11.9 mL, 23.8 mmol), followed by a catalytic amount of DMF (0.05 mL). The reaction was stirred at room temperature overnight and then was concentrated. The residue was dissolved in 1,4-dioxane (48 mL) and cooled to 0 °C. Ammonium hydroxide solution (28.0-30% NH3 basis, 3.6 mL, 28.6 mmol) was added slowly via syringe. The resulting mixture was stirred at 0 °C for 30 min and then was concentrated. The residue was diluted with a 1:1 mixture of EtOAc/Heptane and agitated for 5 min, then was filtered. The filtered solids were discarded, and the remaining mother liquor was partially concentrated to half volume and filtered. The filtered solids were washed with heptane and dried in a reduced-pressure oven (45 °C) overnight to provide 2,6-dichloro-5-fluoronicotinamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J = 7.9 Hz, 1 H) 8.09 (br s, 1 H) 7.93 (br s, 1 H). m/z (ESI, +ve ion): 210.9 (M+H)+.

[0129] Step 2: 2,6-Dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide. To an ice-cooled slurry of 2,6-dichloro-5-fluoronicotinamide (Intermediate S, 5.0 g, 23.9 mmol) in THF (20 mL) was added oxalyl chloride (2 M solution in DCM, 14.4 mL, 28.8 mmol) slowly via syringe. The resulting mixture was heated at 75 °C for 1 h, then heating was stopped, and the reaction was concentrated to half volume. After cooling to 0 °C, THF (20 mL) was added, followed by a solution of 2-isopropyl-4-methylpyridin-3-amine (Intermediate R, 3.59 g, 23.92 mmol) in THF (10 mL), dropwise via cannula. The resulting mixture was stirred at 0 °C for 1 h and then was quenched with a 1:1 mixture of brine and saturated aqueous ammonium chloride. The mixture was extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to provide 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide. This material was used without further purification in the following step. m/z (ESI, +ve ion): 385.1(M+H)+.

[0130] Step 3: 7-Chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. To an ice-cooled solution of 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (9.2 g, 24.0 mmol) in THF (40 mL) was added KHMDS (1 M solution in THF, 50.2 mL, 50.2 mmol) slowly via syringe. The ice bath was removed and the resulting mixture was stirred for 40 min at room temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-50% 3:1 EtOAc-EtOH/heptane) to provide 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (br s, 1H), 8.48-8.55 (m, 2 H), 7.29 (d, J = 4.8 Hz, 1 H), 2.87 (quin, J = 6.6 Hz, 1 H), 1.99-2.06 (m, 3 H), 1.09 (d, J = 6.6 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H).19F NMR (376 MHz, DMSO-d6) δ: -126.90 (s, 1 F). m/z (ESI, +ve ion): 349.1 (M+H)+.

[0131] Step 4: 4,7-Dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one. To a solution of 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4.7 g, 13.5 mmol) and DIPEA (3.5 mL, 20.2 mmol) in acetonitrile (20 mL) was added phosphorus oxychloride (1.63 mL, 17.5 mmol), dropwise via syringe. The resulting mixture was heated at 80 °C for 1 h, and then was cooled to room temperature and concentrated to provide 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one. This material was used without further purification in the following step. m/z (ESI, +ve ion): 367.1 (M+H)+.

[0132] Step 5: (S)-tert-Butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. To an ice-cooled solution of 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (13.5 mmol) in acetonitrile (20 mL) was added DIPEA (7.1 mL, 40.3 mmol), followed by (S)-4-N-Boc-2-methyl piperazine (3.23 g, 16.1 mmol, Combi-Blocks, Inc., San Diego, CA, USA). The resulting mixture was warmed to room temperature and stirred for 1 h, then was diluted with cold saturated aqueous sodium bicarbonate solution (200 mL) and EtOAc (300 mL). The mixture was stirred for an additional 5 min, the layers were separated, and the aqueous layer was extracted with more EtOAc (1x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-50% EtOAc/heptane) to provide (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. m/z (ESI, +ve ion): 531.2 (M+H)+.

[0133] Step 6: (3S)-tert-Butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. A mixture of (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (4.3 g, 8.1 mmol), potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate (Intermediate Q, 2.9 g, 10.5 mmol), potassium acetate (3.2 g, 32.4 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (661 mg, 0.81 mmol) in 1,4-dioxane (80 mL) was degassed with nitrogen for 1 min. De-oxygenated water (14 mL) was added, and the resulting mixture was heated at 90 °C for 1 h. The reaction was allowed to cool to room temperature, quenched with half-saturated aqueous sodium bicarbonate, and extracted with EtOAc (2x) and DCM (1x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-60% 3:1 EtOAc-EtOH/heptane) to provide (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate.1H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (br s, 1 H), 8.38 (d, J = 5.0 Hz, 1 H), 8.26 (dd, J = 12.5, 9.2 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.18 (d, J = 5.0 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.68 (t, J = 8.9 Hz, 1 H), 4.77-4.98 (m, 1 H), 4.24 (br t, J = 14.2 Hz, 1 H), 3.93-4.08 (m, 1 H), 3.84 (br d, J=12.9 Hz, 1 H), 3.52-3.75 (m, 1 H), 3.07-3.28 (m, 1 H), 2.62-2.74 (m, 1 H), 1.86-1.93 (m, 3 H), 1.43-1.48 (m, 9 H), 1.35 (dd, J = 10.8, 6.8 Hz, 3 H), 1.26-1.32 (m, 1 H), 1.07 (dd, J = 6.6, 1.7 Hz, 3 H), 0.93 (dd, J = 6.6, 2.1 Hz, 3 H).19F NMR (376 MHz, DMSO-d6) δ: -115.65 (s, 1 F), -128.62 (s, 1 F). m/z (ESI, +ve ion): 607.3 (M+H)+.

[0134] Step 7: 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one. Trifluoroacetic acid (25 mL, 324 mmol) was added to a solution of (3S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (6.3 g, 10.4 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 1 h and then was concentrated. The residue was dissolved in DCM (30 mL), cooled to 0 °C, and sequentially treated with DIPEA (7.3 mL, 41.7 mmol) and a solution of acryloyl chloride (0.849 mL, 10.4 mmol) in DCM (3 mL; added dropwise via syringe). The reaction was stirred at 0 °C for 10 min, then was quenched with half-saturated aqueous sodium bicarbonate and extracted with DCM (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-100% 3:1 EtOAc-EtOH/heptane) to provide 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.1H NMR (400 MHz, DMSO-d6) δ ppm 10.20 (s, 1 H), 8.39 (d, J = 4.8 Hz, 1 H), 8.24-8.34 (m, 1 H), 7.23-7.32 (m, 1 H), 7.19 (d, J = 5.0 Hz, 1 H), 6.87 (td, J = 16.3, 11.0 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 6.69 (t, J = 8.6 Hz, 1 H), 6.21 (br d, J = 16.2 Hz, 1 H), 5.74-5.80 (m, 1 H), 4.91 (br s, 1 H), 4.23-4.45 (m, 2 H), 3.97-4.21 (m, 1 H), 3.44-3.79 (m, 2 H), 3.11-3.31 (m, 1 H), 2.67-2.77 (m, 1 H), 1.91 (s, 3 H), 1.35 (d, J = 6.8 Hz, 3 H), 1.08 (d, J = 6.6 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H).19F NMR (376 MHz, DMSO-d6) δ ppm -115.64 (s, 1 F), -128.63 (s, 1 F). m/z (ESI, +ve ion): 561.2 (M+H)+.

[0135] Another synthesis of Compound 9 and the relevant intermediates was described in a U.S. provisional patent application filed November 16, 2018, which is incorporated herein by reference in its entirety for all purposes.

Representative Synthetic Processes

[0136] The present disclosure comprises the following steps wherein the synthesis and utilization of the boroxine intermediate is a novel and inventive step in the manufacture of AMG 510 (Compound 9):

Raw Materials

Step la

[0137] To a solution of 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (25kg; 119. lmol) in dichloromethane (167kg) and DMF (592g) was added Oxalyl chloride (18.9kg; 148.9mol) while maintaining an internal temp between 15-20 °C. Additional dichloromethane (33kg) was added as a rinse and the reaction mixture stirred for 2h. The reaction mixture is cooled then quenched with ammonium hydroxide (40.2L; 595.5mol) while maintaining internal temperature 0 ± 10°C. The resulting slurry was stirred for 90min then the product collected by filtration. The filtered solids were washed with DI water (3X 87L) and dried to provide 2,6-dichloro-5-fluoronicotinamide (Compound 1).

Step 1b

[0138] In reactor A, a solution of 2,6-dichloro-5-fluoronicotinamide (Compound 1) (16.27kg; 77.8mol) in dichloromethane (359.5kg) was added oxalyl chloride (11.9kg;

93.8mol) while maintaining temp ≤ 25°C for 75min. The resulting solution was then headed to 40°C ± 3°C and aged for 3h. Using vacuum, the solution was distilled to remove dichloromethane until the solution was below the agitator. Dichloromethane (300 kg) was then added and the mixture cooled to 0 ± 5°C. To a clean, dry reactor (reactor B) was added,2-isopropyl-4-methylpyridin-3-amine (ANILINE Compound 2A) (12.9kg; 85.9mol) followed by dichloromethane (102.6 kg). The ANILINE solution was azeodried via vacuum distillation while maintaining an internal temperature between 20-25 °), replacing with additional dichloromethane until the solution was dry by KF analysis (limit ≤ 0.05%). The solution volume was adjusted to approx. 23L volume with dichloromethane. The dried ANILINE solution was then added to reactor A while maintaining an internal temperature of 0 ± 5°C throughout the addition. The mixture was then heated to 23 °C and aged for 1h. the solution was polish filtered into a clean reactor to afford 2,6-dichloro-5-fluoro-N-((2- isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (Compound 3) as a solution in DCM and used directly in the next step.

Step 2

[0139] A dichloromethane solution of 2,6-dichloro-5-fluoro-N-{[4-methyl-2-(propan-2- yl)pyridin-3-yl]carbamoyl}pyridine-3-carboxamide (UREA (Compound 3)) (15kg contained; 38.9mol) was solvent exchanged into 2-MeTHF using vacuum distillation while maintaining internal temperature of 20-25 °C. The reactor volume was adjusted to 40L and then

additional 2-MeTHF was charged (105.4 kg). Sodium t-butoxide was added (9.4 kg;

97.8mol) while maintaining 5-10 °C. The contents where warmed to 23 °C and stirred for 3h. The contents where then cooled to 0-5C and ammonium chloride added (23.0kg; 430mol) as a solution in 60L of DI water. The mixture was warmed to 20 C and DI water added (15L) and further aged for 30min. Agitation was stopped and the layers separated. The aqueous layer was removed and to the organic layer was added DI water(81.7L). A mixture of conc HCl (1.5kg) and water (9L) was prepared then added to the reactor slowly until pH measured between 4-5. The layers were separated, and the aqueous layer back extracted using 2-MeTHF (42.2kg). The two organic layers combined and washed with a 10% citric acid solution (75kg) followed by a mixture of water (81.7L) and saturated NaCl (19.8 kg). The organic layer was then washed with saturated sodium bicarbonate (75kg) repeating if necessary to achieve a target pH of ≥ 7.0 of the aqueous. The organic layer was washed again with brine (54.7kg) and then dried over magnesium sulfate (5kg). The mixture was filtered to remove magnesium sulfate rinsing the filtered bed with 2-MeTHF (49.2 kg). The combined filtrate and washes where distilled using vacuum to 40L volume. The concentrated solution was heated to 55 °C and heptane (10-12kg) slowly added until cloud point. The solution was cooled to 23 °C over 2h then heptane (27.3 kg) was added over 2h. The product slurry was aged for 3h at 20-25 °C then filtered and washed with a mixture of 2-MeTHF (2.8kg) and heptane (9kg). The product was dried using nitrogen and vacuum to afford solid 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (rac-DIONE (Compound 4)).

Step 3

[0140] To a vessel, an agitated suspension of Compound 4, (1.0 eq.) in 2- methylterahydrofuran (7.0 L/kg) was added (+)-2,3-dibenzoyl-D-tartaric acid (2.0 eq.) under an atmosphere of nitrogen. 2-MeTHF is chiral, but it is used as a racemic mixture. The different enantiomers of 2-MeTHF are incorporated randomly into the co-crystal. The resulting suspension was warmed to 75°C and aged at 75°C until full dissolution was observed (< 30 mins.). The resulting solution was polish filtered at 75°C into a secondary vessel. To the polish filtered solution was charged n-Heptane (2.0 L/kg) at a rate that maintained the internal temperature above 65°C. The solution was then cooled to 60°C, seeded with crystals (0.01 kg/kg) and allowed to age for 30 minutes. The resulting suspension was cooled to 20°C over 4 hours and then sampled for chiral purity analysis by HPLC. To the suspension, n-Heptane (3.0 L/kg) was charged and then aged for 4 hours at 20°C under an atmosphere of nitrogen. The suspension was filtered, and the isolated solids were washed two times with (2:1) n-Heptane:2-methyltetrahydrofuran (3.0 L/kg). The material was dried with nitrogen and vacuum to afford M-Dione:DBTA: Me-THF complex (Compound 4a).

Step 4

[0141] To vessel A, a suspension of disodium hydrogen phosphate (21.1 kg, 2.0 equiv) in DI water (296.8 L, 6.3 L/kg) was agitated until dissolution was observed (≥ 30 min.). To vessel B, a suspension of the M-Dione:DBTA: Me-THF complex (Composition 4a)[46.9 kg (25.9 kg corrected for M-dione, 1.0 equiv.)] in methyl tert-butyl ether (517.8 L, 11.0 L/kg) was agitated for 15 to 30 minutes. The resulting solution from vessel A was added to vessel B, and then the mixture was agitated for more than 3 hours. The agitation was stopped, and the biphasic mixture was left to separate for more than 30 minutes. The lower aqueous phase was removed and then back extracted with methyl tert-butyl ether (77.7 L, 1.7 L/kg). The organic phases were combined in vessel B and dried with magnesium sulfate (24.8 kg, 0.529 kg/kg). The resulting suspension from vessel B was agitated for more than three hours and then filtered into vessel C. To vessel B, a methyl tert-butyl ether (46.9 L, 1.0 L/kg) rinse was charged and then filtered into vessel C. The contents of vessel C were cooled to 10 °C and then distilled under vacuum while slowly being warmed to 35°C. Distillation was continued until 320-350 kg (6.8-7.5 kg/kg) of methyl tert-butyl ether was collected. After cooling the contents of vessel C to 20°C, n-Heptane (278.7 L, 5.9 L/kg) was charged over one hour and then distilled under vacuum while slowly being warmed to 35°C. Distillation was continued until a 190-200 kg (4.1-4.3 kg/kg) mixture of methyl tert-butyl ether and n-Heptane was collected. After cooling the contents of vessel C to 20°C, n-Heptane (278.7 L, 5.9 L/kg) was charged a second time over one hour and then distilled under vacuum while slowly being warmed to 35°C. Distillation was continued until a 190-200 kg (4.1-4.3 kg/kg) mixture of methyl tert-butyl ether and n-Heptane was collected. After cooling the contents of vessel C to 20°C, n-Heptane (195.9 L, 4.2 L/kg) was charged a third time over one hour and then sampled for solvent composition by GC analysis. The vessel C suspension continued to agitate for more than one hour. The suspension was filtered, and then washed with a n-Heptane (68.6 L, 1.5 L/kg) rinse from vessel C. The isolated solids were dried at 50°C, and a sample was submitted for stock suitability. Afforded 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (M-DIONE) Compound 5M.

[0142] The first-generation process highlighted above has been successfully scaled on 200+ kg of rac-dione starting material (Compound 4). In this process, seeding the crystallization with the thermodynamically-stable rac-dione crystal form (which exhibits low solubility) would cause a batch failure. Based on our subsequent studies, we found that increasing the DBTA equivalents and lowering the seed temperature by adjusting heptane

charge schedule improves robustness of the process. The improved process is resistant to the presence of the thermodynamically-stable rac-dione crystal form and promotes successful separation of atropisomers. Subsequent batches will incorporate the improved process for large scale manufacture.

Step 5

Note: All L/kg amounts are relative to M-Dione input; All equiv. amounts are relative to M-Dione input after adjusted by potency.

[0143] M-Dione (Compound 5M, 1.0 equiv.) and Toluene-1 (10.0 L/kg) was charged to Vessel A. The resulting solution was dried by azeotropic distillation under vacuum at 45 °C until 5.0 L/kg of solvents has been removed. The contents of Vessel A were then cooled to 20 °C.

[0144] Vessel C was charged with Toluene-3 (4.5 L/kg), Phosphoryl chloride (1.5 equiv.) and N,N-Diisopropylethylamine-1 (2.0 equiv.) while maintaining the internal temperature below 20 ± 5 °C.

Upon finishing charging, Vessel C was warmed to 30 ± 5 °C. The contents of Vessel A were then transferred to Vessel C over 4 hours while maintaining the internal temperature at 30 ± 5°C. Vessel A was rinsed with Toluene-2 (0.5 L/kg) and transferred to Vessel C. The contents of Vessel C were agitated at 30°C for an additional 3 hours. The contents of Vessel C were cooled to 20 ± 5 °C. A solution of (s)-1-boc-3-methylpiperazine (1.2 equiv.), N,N-Diisopropylethylamine-2 (1.2 equiv.) in isopropyl acetate-1 (1.0 L/kg) was prepared in Vessel D. The solution of Vessel D was charged to vessel C while maintaining a batch temperature of 20 ± 5 °C (Note: Exotherm is observed). Upon the end of transfer, Vessel D was rinsed with additional dichloromethane (1.0 L/kg) and transferred to Vessel C. The contents of Vessel C were agitated for an additional 60 minutes at 20 °C. A solution of sodium bicarbonate [water-1 (15.0 L/kg + Sodium bicarbonate (4.5 equiv.)] was then charged into Vessel C over an hour while maintaining an internal temperature at 20 ± 5 °C throughout the addition. The contents of Vessel C were agitated for at least 12 hours at which point the Pipazoline (Compound 6) product was isolated by filtration in an agitated filter dryer. The cake was washed with water-2 and -3 (5.0 L/kg x 2 times, agitating each wash for 15 minutes) and isopropyl acetate-2 and 3 (5.0 L/kg x 2 times, agitating each wash for 15 min). The cake as dried under nitrogen for 12 hours.

Acetone Re-slurry (Optional):

[0145] Pipazoline (Compound 6) and acetone (10.0 L/kg) were charged to Vessel E. The suspension was heated to 50 °C for 2 hours. Water-4 (10.0 L/kg) was charged into Vessel E over 1 hour. Upon completion of water addition, the mixture was cooled to 20 °C over 1 hour. The contents of Vessel E were filtered to isolate the product, washing the cake with 1:1 acetone/water mixture (5.0 L/kg). The cake was dried under nitrogen for 12 hours.

Step 6

General Note: All equivalents and volumes are reported in reference to Pipazoline input

Note: All L/kg and kg/kg amounts are relative to Pipazoline input

[0146] Reactor A is charged with Pipazoline (Compound 6, 1.0 equiv), degassed 2- MeTHF (9.0 L/kg) and a solution of potassium acetate (2.0 equiv) in degassed water (6.5 L/kg). The resulting mixture is warmed to 75 ± 5 °C and then, charge a slurry of

Pd(dpePhos)Cl2 (0.003 equiv) in 2-MeTHF (0.5 L/kg). Within 2 h of catalyst charge, a solution of freshly prepared Boroxine (Compound 6A, 0.5 equiv) in wet degassed 2-MeTHF (4.0 L/kg, KF > 4.0%) is charged over the course of >1 hour, but < 2 hours, rinsing with an additional portion of wet 2-MeTHF (0.5 L/kg) after addition is complete. After reaction completion ( <0.15 area % Pipazoline remaining, typically <1 h after boroxine addition is complete), 0.2 wt% (0.002 kg/kg) of Biaryl seed is added as a slurry in 0.02 L/kg wet 2- MeTHF, and the resulting seed bed is aged for > 60 min. Heptane (5.0 L/kg) is added over 2 hours at 75 ± 5 °C. The batch is then cooled to 20 ± 5 °C over 2 hours and aged for an additional 2 h. The slurry is then filtered and cake washed with 1 x 5.0L/kg water, 1 x 5.0L/kg 1:1 iPrOH:water followed by 1 x 5.0 L/kg 1:1 iPrOH:heptane (resuspension wash: the cake is resuspended by agitator and allow to set before filtering) . The cake (Biaryl, Compound 7) is then dried under vacuum with a nitrogen sweep.

Note: If the reaction stalls, an additional charge of catalyst and boroxine is required

Step 7 Charcoal Filtration for Pd removal


General Note: All equivalents and volumes are reported in reference to crude Biaryl input

Note: All L/kg and kg/kg amounts are relative to crude Biaryl input

[0147] In a clean Vessel A, charge crude Biaryl (1 equiv) and charge DCM (10 L/kg). Agitate content for > 60 minutes at 22 ± 5 °C, observing dissolution. Pass crude Biaryl from Vessel A, through a bag filter and carbon filters at a flux ≤ 3 L2/min/m and collect filtrate in clean Vessel B. Charge DCM rinse (1 L/kg) to Vessel A, and through carbon filters to collect in vessel B.

[0148] From filtrate in Vessel B, pull a solution sample for IPC Pd content. Sample is concentrated to solid and analyzed by ICP-MS. IPC: Pd ≤ 25 ppm with respect to Biaryl. a. If Pd content is greater than 25 ppm with respect to Biaryl on first or second IPC sample, pass solution through carbon filter a second time at ≤ 3 L2/min/m2, rinsing with 1 L/kg DCM; sample filtrate for IPC.

b. If Pd content remains greater than 25 ppm after third IPC, install and condition fresh carbon discs. Pass Biaryl filtrate through refreshed carbon filter, washing with 1 L/kg DCM. Sample for IPC.

[0149] Distill and refill to appropriate concentration. Prepare for distillation of recovered filtrate by concentrating to ≤ 4 L/kg DCM, and recharge to reach 5.25 ± 0.25 L/kg DCM prior to moving into Step 7 Boc-deprotection reaction.

Step 7

 General Note: All equivalents and volumes are reported in reference to crude Biaryl input

Note: All L/kg and kg/kg amounts are relative to Biaryl input

[0150] To Reactor A was added: tert-butyl (3S)-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate (Biaryl) (1.0 equiv), dichloromethane (5.0 L/kg), and the TFA (15.0 equiv, 1.9 L/kg) is charged slowly to maintain the internal temperature at 20 ± 5 °C. The reaction was stirred for 4 h at 20 ± 5 °C.

[0151] To Reactor B was added: potassium carbonate (18.0 equiv), water (20.0 L/kg), and NMP (1.0) to form a homogenous solution. While agitating at the maximum acceptable rate for the equipment, the reaction mixture in A was transferred into the potassium carbonate solution in B over 30 minutes (~ 0.24 L/kg/min rate). The mixture was stirred at 20 ± 5 °C for an additional 12 h.

[0152] The resulting slurry was filtered and rinsed with water (2 x 10 L/kg). The wet cake was dried for 24 h to give 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2S)-2-methylpiperazin- 1-yl]-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidin-2(1H)-one (Des- Boc, Compound 8).

Step 8

Note: All L/kg and kg/kg amounts are relative to Des-Boc input

[0153] Des-Boc (Compound 8, 1.0 equiv) and NMP (4.2 L/kg) are charged to Vessel A under nitrogen, charge the TFA (1.0 equiv.) slowly to maintain the Tr <25 °C. The mixture is aged at 25 °C until full dissolution is observed (about 0.5 hour). The solution is then polish filtered through a 0.45 micron filter into Vessel B, washing with a NMP (0.8 L/kg). The filtrate and wash are combined, and then cooled to 0 °C. To the resulting solution, Acryloyl Chloride (1.3 equiv.) is added while maintaining temperature < 10 C. The reaction mixture is then aged at 5 ±5°C until completed by IPC (ca.1.5 hrs).

Preparation of Aqueous Disodium Phosphate Quench:

[0154] Disodium Phosphate (3.0 equiv) and Water (15.0 L/kg) are charged to Vessel C. The mixture is aged at 25 °C until full dissolution is observed. The solution is warmed to 45 ±5°C. A seed slurry of AMG 510 (0.005 equiv.) in Water (0.4 L/kg) is prepared and added to Vessel C while maintaining temperature at 45 ±5°C.

[0155] The reaction mixture in Vessel B is transferred to Vessel C (quench solution) while maintaining temperature at 45 ±5°C (ca.1 hrs). Vessel B is washed with a portion of NMP (0.5 L/kg). The product slurry is aged for 2 hrs at 45 ±5°C, cooled to 20 °C over 3 hrs, aged at 20 °C for a minimum of 12 hrs, filtered and washed with Water (2 x 10.0 L/kg). The product is dried using nitrogen and vacuum to afford Crude AMG 510 (Compound 9A).

Step 9

 General Note: All equivalents and volumes are reported in reference to crude AMG 510 input

Note: All L/kg and kg/kg amounts are relative to Crude AMG 510 input

[0156] Reactor A was charged with 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4- methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1- yl]pyrido[2,3-d]pyrimidin-2(1H)-one (Crude AMG 510) (1.0 equiv), ethanol (7.5 L/kg), and water (1.9 L/kg). The mixture heated to 75 °C and polish filtered into a clean Reactor B. The solution was cool to 45 °C and seeded with authentic milled AMG 510 seed (0.015 േ 0.005

1 Seed performs best when reduced in particle size via milling or with other type of mechanical grinding if mill is not available (mortar/ pestle). Actual seed utilized will be based on seed availability. 1.0- 2.0% is seed is target amount.

kg/kg); the resulting slurry was aged for 30 min. Water (15.0 L/kg) was added over 5h while maintaining an internal temperature > 40 °C; the mixture was aged for an additional 2h.

[0157] The mixture was cooled to 20 °C over 3 hours and aged for 8h, after which the solid was collected by filtration and washed using a mixture of ethanol (2.5 L/kg) and water (5.0 L/kg). The solid was dried using vacuum and nitrogen to obtain 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one (AMG 510, Compound 9).

Compound 6A Boroxine Synthesis:

Lithiation/borylation

[0158] Reactor A was charged with THF (6 vol), a secondary amine base, Diisopropylamine (1.4 equiv), and a catalyst, such as triethylamine hydrochloride (0.01 equiv.). The resulting solution was cooled to -70 °C and a first base, n-BuLi (2.5 M in hexane, 1.5 equiv) was slowly added. After addition is complete, a solution of 3-fluoroanisole (1.0 equiv) in THF (6 vol) was added slowly and kept at -70 °C for 5 min. Concurrently or subsequently, a reagent, B(EtO)3 (2.0 equiv), was added slowly and kept at -70 °C for 10 min. The reaction mixture was quenched with an acid, 2N HCl. The quenched reaction mixture was extracted with MTBE (3 x 4 vol). The combined organic phases were concentrated to 1.5-3 total volumes. Heptane (7-9 vol) was added drop-wise and the mixture was cooled to 0-10 °C and stirred for 3 h. The mixture was filtrated and rinsed with heptane (1.5 vol). The solid was dried under nitrogen at < 30 °C to afford (2-fluoro-6-methoxyphenyl)boronic acid.

Demethylation:

Note: All L/kg and kg/kg amounts are relative to (2-fluoro-6-methoxyphenyl)boronic acid input

[0159] To a reactor, charge dichloromethane (solvent, 4.0 L/kg) and an acid, BBr3 (1.2 equiv), and cool to -20 °C. To this solution, a suspension of (2-fluoro-6-methoxyphenyl)boronic acid (1.0 equiv) in dichloromethane (4.0 L/kg) was added into the BBr3/DCM mixture while keeping temperature -15 to -25 °C. The reaction was allowed to proceed for approximately 2 hours while monitored by HPLC [≤1% (2-fluoro-6-methoxyphenyl)boronic acid] before reverse quenching into water (3.0 L/kg). The precipitated solid was then isolated by filtration and slurried with water (3.0 L/kg) on the filter prior to deliquoring. The filtrates were adjusted to pH 4-6 by the addition of sodium bicarbonate. The bottom organic phase was separated and the resulting aqueous layer was washed with dichloromethane (solvent, 5.0 Vol) and adjusted to pH = 1 by addition of concentrated hydrochloric acid. The resulting solids were isolated by filtration, washing the cake with water (2 x 5.0 L/kg)

Purification via Reslurry (required)

[0160] The combined crude solids were charged into a reactor and slurried with 5% EtOH/water (5.0 L/kg) at 20 °C for >1 h. The purified product was then isolated by filtration and rinsed with water (2 x 3 L/kg) before drying on the filter at < 30 °C to with nitrogen/vacuum to afford 2,2′,2”-(1,3,5,2,4,6-trioxatriborinane-2,4,6-triyl)tris(3-fluorophenol) (Boroxine, Compound 6A).

PATENT

WO 2020102730

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020102730

PATENT

US 20180334454

References

  1. Jump up to:a b c d e “Lumakras- sotorasib tablet, coated”DailyMed. Retrieved 6 June 2021.
  2. Jump up to:a b c d e f g h i j k l m n “FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy”U.S. Food and Drug Administration (FDA). 28 May 2021. Retrieved 28 May 2021.  This article incorporates text from this source, which is in the public domain.
  3. ^ “KRAS mutant-targeting AMG 510”NCI Drug Dictionary. National Cancer Institute. 2 February 2011. Retrieved 16 November2019.
  4. ^ Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. (November 2019). “The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity”. Nature575 (7781): 217–23. Bibcode:2019Natur.575..217Cdoi:10.1038/s41586-019-1694-1PMID 31666701.
  5. Jump up to:a b “FDA approves Amgen drug for lung cancer with specific mutation”CNBC. 28 May 2021. Retrieved 28 May 2021.
  6. ^ Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. (2020). “KRASG12C inhibition with sotorasib in advanced solid tumors”N Engl J Meddoi:10.1056/NEJMoa1917239PMC 7571518.
  7. ^ Clinical trial number NCT03600883 for “A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation ” at ClinicalTrials.gov
  8. ^ “The Discovery Of Amgen’s Novel Investigational KRAS(G12C) Inhibitor AMG 510 Published In Nature” (Press release). Amgen. 30 October 2019. Retrieved 16 November 2019.
  9. ^ Irving M (24 December 2019). “Drug targeting common cancer cause enters phase 2 clinical trials”New Atlas. Retrieved 24 December 2019.
  10. Jump up to:a b c d Halford B (3 April 2019). “Amgen unveils its KRas inhibitor in human clinical trials: AMG 510 shuts down a mutant version of the cancer target via covalent interaction”Chemical & Engineering News97 (4). Retrieved 16 November 2019.
  11. ^ Al Idrus A (9 September 2019). “Amgen’s KRAS drug continues to deliver but faces ‘curse’ of high expectations”. fiercebiotech.com. Retrieved 16 November 2019.
  12. ^ Kaiser J (30 October 2019). “Two new drugs finally hit ‘undruggable’ cancer target, providing hope for treatments”Science Magazine. AAAS. Retrieved 16 November 2019.
  13. ^ Astor L (9 September 2019). “FDA Grants AMG 510 Fast Track Designation for KRAS G12C+ NSCLC”. targetedonc.com. Retrieved 16 November 2019.
  14. ^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85” (PDF). WHO Drug Information35 (1).

Further reading

External links

  • “Sotorasib”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03600883 for “A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100)” at ClinicalTrials.gov
Clinical data
Trade namesLumakras
Other namesAMG 510
License dataUS DailyMedSotorasib
Routes of
administration
By mouth
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
showIUPAC name
CAS Number2252403-56-6
PubChem CID137278711
DrugBankDB15569
ChemSpider72380148
UNII2B2VM6UC8G
KEGGD12055
Chemical and physical data
FormulaC30H30F2N6O3
Molar mass560.606 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////Sotorasib, ソトラシブ , FDA 2021,  APPROVALS 2021,  Lumakras, CANCER, ANTINEOPLASTIC, AMG 510, AMG-510, AMG510, AMGEN, priority review, fast-track, breakthrough therapy, orphan drug

CC1CN(CCN1C2=NC(=O)N(C3=NC(=C(C=C32)F)C4=C(C=CC=C4F)O)C5=C(C=CN=C5C(C)C)C)C(=O)C=C

wdt-6

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Loncastuximab tesirine


ZYNLONTA™ (loncastuximab tesirine-lpyl) Structural Formula - Illustration
Pharmaceuticals 14 00442 g047 550

Loncastuximab tesirine

ZYNLONTA FDA APPROVED 2021/4/23

FormulaC6544H10048N1718O2064S52
Exact mass147387.9585
CAS1879918-31-6
EfficacyAntineoplasitc, Anti-CD19 antibody
  DiseaseDiffuse large B-cell lymphoma not otherwise specified [DS:H02434]
CommentAntibody-drug conjugate
Treatment of hematological cancers

ロンカスツキシマブテシリン; ADCT-402, ADCX 19

Immunoglobulin G1, anti-​(human CD19 antigen) (human-​Mus musculus monoclonal RB4v1.2 γ1-​chain)​, disulfide with human-​Mus musculus monoclonal RB4v1.2 κ-​chain, dimer, bis(thioether) with N-​[31-​(3-​mercapt-​2,​5-​dioxo-​1-​pyrrolidinyl)​-​1,​29-​dioxo-​4,​7,​10,​13,​16,​19,​22,​25-​octaoxa-​28-​azahentriacont-​1-​yl]​-​L-​valyl-​N-​[4-​[[[[(11S,​11aS)​-​8-​[[5-​[[(11aS)​-​5,​11a-​dihydro-​7-​methoxy-​2-​methyl-​5-​oxo-​1H-​pyrrolo[2,​1-​c]​[1,​4]​benzodiazepin-​8-​yl]​oxy]​pentyl]​oxy]​-​11,​11a-​dihydro-​11-​hydroxy-​7-​methoxy-​2-​methyl-​5-​oxo-​1H-​pyrrolo[2,​1-​c]​[1,​4]​benzodiazepin-​10(5H)​-​yl]​carbonyl]​oxy]​methyl]​phenyl]​-​L-​alaninamide

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ONETIME

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Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetCD19
Clinical data
Trade namesZynlonta
Other namesADCT-402, loncastuximab tesirine-lpyl
License dataUS DailyMedLoncastuximab_tesirine
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
CAS Number1879918-31-6
DrugBankDB16222
ChemSpidernone
UNII7K5O7P6QIU
KEGGD11338
Chemical and physical data
FormulaC6544H10048N1718O2064S52
Molar mass147481.45 g·mol−1
NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
ZynlontaInjection, powder, lyophilized, for solution5 mg/1mLIntravenousADC Therapeutics America, Inc.2021-04-30Not applicableUS flag 

Loncastuximab tesirine-lpyl is a CD19-directed antibody and alkylating agent conjugate, consisting of a humanized IgG1 kappa monoclonal antibody conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxic alkylating agent, through a protease-cleavable valinealanine linker. SG3199 attached to the linker is designated as SG3249, also known as tesirine.

ZYNLONTA™ (loncastuximab tesirine-lpyl) Structural Formula - Illustration

Loncastuximab tesirine-lpyl has an approximate molecular weight of 151 kDa. An average of 2.3 molecules of SG3249 are attached to each antibody molecule. Loncastuximab tesirine-lpyl is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis.

ZYNLONTA (loncastuximab tesirine-lpyl) for injection is supplied as a sterile, white to off-white, preservative-free, lyophilized powder, which has a cake-like appearance, for intravenous infusion after reconstitution and dilution. Each single-dose vial delivers 10 mg of loncastuximab tesirine-lpyl, L-histidine (2.8 mg), L-histidine monohydrochloride (4.6 mg), polysorbate 20 (0.4 mg), and sucrose (119.8 mg). After reconstitution with 2.2 mL Sterile Water for Injection, USP, the final concentration is 5 mg/mL with a pH of approximately 6.0.

Loncastuximab tesirine , sold under the brand name Zynlonta, is used for the treatment of large B-cell lymphoma. It is an antibody-drug conjugate (ADC) composed of a humanized antibody targeting the protein CD19, which is expressed in a wide range of B cell hematological tumors.[2] The experimental drug, developed by ADC Therapeutics is being tested in clinical trials for the treatment of B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL).

On April 23, 2021, the Food and Drug Administration granted accelerated approval to loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics SA), a CD19-directed antibody and alkylating agent conjugate, for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

Approval was based on LOTIS-2 (NCT03589469), an open-label, single-arm trial in 145 adult patients with relapsed or refractory DLBCL or high-grade B-cell lymphoma after at least two prior systemic regimens. Patients received loncastuximab tesirine-lpyl 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles. Patients received treatment until progressive disease or unacceptable toxicity.

The main efficacy outcome measure was overall response rate (ORR), as assessed by an independent review committee using Lugano 2014 criteria. The ORR was 48.3% (95% CI: 39.9, 56.7) with a complete response rate of 24.1% (95% CI: 17.4, 31.9). After a median follow-up of 7.3 months, median response duration  was 10.3 months (95% CI: 6.9, NE). Of the 70 patients who achieved objective responses, 36% were censored for response duration prior to 3 months.

Most common (≥20%) adverse reactions in patients receiving loncastuximab tesirine-lpyl, including laboratory abnormalities, are thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

The prescribing information provides warnings and precautions for adverse reactions including edema and effusions, myelosuppression, infections, and cutaneous reactions.

The recommended loncastuximab tesirine-lpyl dosage is 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles, by intravenous infusion over 30 minutes on day 1 of each cycle (every 3 weeks). Patients should be premedicated with dexamethasone 4 mg orally or intravenously twice daily for 3 days beginning the day before loncastuximab tesirine-lpyl.

Technology

The humanized monoclonal antibody is stochastically conjugated via a valine-alanine cleavable, maleimide linker to a cytotoxic (anticancer) pyrrolobenzodiazepine (PBD) dimer. The antibody binds to CD19, a protein which is highly expressed on the surface of B-cell hematological tumors[3] including certain forms of lymphomas and leukemias. After binding to the tumor cells the antibody is internalized, the cytotoxic drug PBD is released and the cancer cells are killed. PBD dimers are generated out of PBD monomers, a class of natural products produced by various actinomycetes. PBD dimers work by crosslinking specific sites of the DNA, blocking the cancer cells’ division that cause the cells to die. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs.[4]

Clinical trials

Two phase I trials are evaluating the drug in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma and relapsed or refractory B-cell acute lymphoblastic leukemia.[5] At the 14th International Conference on Malignant Lymphoma interim results from a Phase I, open-label, dose-escalating study designed to evaluate the treatment of loncastuximab tesirine in relapsed or refractory non-Hodgkin’s lymphoma were presented.[6] Among the patients enrolled at the time of the data cutoff the overall response rate was 61% in the total patient population (42% complete response and 19% partial response) and in patients with relapsing or refractory diffuse large B-cell lymphoma (DLBCL) the overall response rate was 57% (43% complete response and 14% partial response).[7][8]

Orphan drug designation

Loncastuximab tesirine was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma and mantle cell lymphoma.[9]

References

  1. ^ https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761196s000lbl.pdf
  2. ^ WHO Drug Information: International Nonproprietary Names for Pharmaceutical Substances
  3. ^ Wang K, Wei G, Liu D (November 2012). “CD19: a biomarker for B cell development, lymphoma diagnosis and therapy”Experimental Hematology & Oncology1 (1): 36. doi:10.1186/2162-3619-1-36PMC 3520838PMID 23210908.
  4. ^ “Pyrrolobenzodiazepine”ADC Review.
  5. ^ Clinical trial number NCT02669017 for “ADCT-402 in B-NHL” at ClinicalTrials.gov
  6. ^ Kahl B, Hamadani M, Caimi PF, Reid EG, Havenith K, He S, Feingold JM, O’Connor O (June 2017). “First clinical results of ADCT‐402, a novel pyrrolobenzodiazepine-based antibody drug conjugate (ADC), in relapsed/refractory B‐cell linage NHL” (PDF). Hematol Oncol35 (S2): 49–51. doi:10.1002/hon.2437_33.
  7. ^ “First clinical results of ADCT-402”ADC Review.
  8. ^ Bainbridge K. “Grandfather fighting deadly cancer reveals scans of tumors after testing new drug”Mirror.
  9. ^ “ADCT-402 Orphan Drug Designation” (PDF). ADC Therapeutics press release.

External links

https://www.fda.gov/drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma

/////////Loncastuximab tesirine, FDA 2021, APPROVALS 2021, ZYNLONTA, ロンカスツキシマブテシリン, ORPHAN DRUG, ADCT-402, priority review, ADCX 19

Dostarlimab


(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYDMSWVRQA PGKGLEWVST ISGGGSYTYY
QDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCASPY YAMDYWGQGT TVTVSSASTK
GPSVFPLAPC SRSTSESTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS
LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP
PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE QFNSTYRVVS
VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS QEEMTKNQVS
LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS
CSVMHEALHN HYTQKSLSLS LGK
(Light chain)
DIQLTQSPSF LSAYVGDRVT ITCKASQDVG TAVAWYQQKP GKAPKLLIYW ASTLHTGVPS
RFSGSGSGTE FTLTISSLQP EDFATYYCQH YSSYPWTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H130-L214, H143-H199, H222-H’222, H225-H’225, H257-H317, H363-H421, H’22-H’96, H’130-L’214, H’143-H’199, H’257-H’317, H’363-H’421, L23-L88, L134-L194, L’23-L’88, L’194-L’134)

>Heavy Chain
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYY
QDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTK
GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS
CSVMHEALHNHYTQKSLSLSLGK
>Light Chain
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPS
RFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]

Dostarlimab

Immunoglobulin G4, anti-​(programmed cell death protein 1 (PDCD1)​) (humanized clone ABT1 γ4-​chain)​, disulfide with humanized clone ABT1 κ-​chain, dimer

Protein Sequence

Sequence Length: 1314, 443, 443, 214, 214multichain; modified (modifications unspecified)

  • GSK-4057190
  • GSK4057190
  • TSR 042
  • TSR-042
  • WBP-285
  • ANB 011
FormulaC6420H9832N1680O2014S44
CAS2022215-59-2
Mol weight144183.6677

Jemperli FDA 2021/4/22 AND EMA 2021/4/21

wdt-2

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Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.[1][2][3][4]

The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation.[1][2] The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased.[1][2]

Dostarlimab is a programmed death receptor-1 (PD-1)–blocking antibody.[1][2]

Dostarlimab was approved for medical use in the United States in April 2021.[1][2][5]

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
JemperliInjection50 mg/1mLIntravenousGlaxoSmithKline LLC2021-04-22Not applicableUS flag 

Medical uses

Dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen.[1][2]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior  platinum-containing regimen.

Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors. The efficacy population consisted of 71 patients with dMMR recurrent or advanced endometrial cancer who progressed on or after  a platinum-containing regimen. Patients received dostarlimab-gxly, 500 mg intravenously, every 3 weeks for 4 doses followed by 1,000 mg intravenously every 6 weeks.

The main efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review (BICR) according to RECIST 1.1. Confirmed ORR was 42.3% (95% CI: 30.6%, 54.6%). The complete response rate was 12.7% and partial response rate was 29.6%. Median DOR was not reached, with 93.3% of patients having  durations  ≥6 months (range: 2.6 to 22.4 months, ongoing at last assessment).

Serious adverse reactions occurred in 34% of patients receiving dostarlimab-gxly. Serious adverse reactions in >2% of patients included sepsis , acute kidney injury , urinary tract infection , abdominal pain , and pyrexia . The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dostarlimab-gxly dose and schedule (doses 1 through 4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.

View full prescribing information for Jemperli.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

FDA also approved the VENTANA MMR RxDx Panel as a companion diagnostic device for selecting endometrial cancer patients for treatment with dostarlimab-gxly.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Side effects

Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia.[1][2]

Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.[1][2]

History

Like several other available and experimental monoclonal antibodies, it is a PD-1 inhibitor. As of 2020, it is undergoing Phase I/II and Phase III clinical trials.[6][7][8] The manufacturer, Tesaro, announced prelimary successful results from the Phase I/II GARNET study.[6][9][10]

In 2020, the GARNET study announced that Dostarlimab was demonstrating potential to treat a subset of women with recurrent or advanced endometrial cancer.[11]

April 2021, Dostarlimab is approved for the treatment of recurrent or advanced endometrial cancer with deficient mismatch repair (dMMR), which are genetic anomalies abnormalities that disrupt DNA repair.[12]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC).[1] Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors.[1]

Society and culture

Legal status

On 25 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.[13] The applicant for this medicinal product is GlaxoSmithKline (Ireland) Limited.[13]

References[

  1. Jump up to:a b c d e f g h i j k “FDA grants accelerated approval to dostarlimab-gxly for dMMR endometri”U.S. Food and Drug Administration(FDA) (Press release). 22 April 2021. Retrieved 22 April 2021. This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d e f g h i “Jemperli- dostarlimab injection”DailyMed. Retrieved 28 April 2021.
  3. ^ Statement On A Nonproprietary Name Adopted By The USAN Council – DostarlimabAmerican Medical Association.
  4. ^ World Health Organization (2018). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 119” (PDF). WHO Drug Information32 (2).
  5. ^ “FDA grants accelerated approval for GSK’s Jemperli (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer” (Press release). GlaxoSmithKline. 22 April 2021. Retrieved 22 April 2021 – via PR Newswire.
  6. Jump up to:a b Clinical trial number NCT02715284 for “A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
  7. ^ Clinical trial number NCT03981796 for “A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)” at ClinicalTrials.gov
  8. ^ Clinical trial number NCT03602859 for “A Phase 3 Comparison of Platinum-Based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-Based Therapy as First-Line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST)” at ClinicalTrials.gov
  9. ^ “Data from GARNET study indicates robust activity of dostarlimab in patients with advanced or recurrent endometrial cancer”Tesaro (Press release). Retrieved 1 January 2020.
  10. ^ Scalea B (28 May 2019). “Dostarlimab Effective in Endometrial Cancer Regardless of MSI Status”Targeted Oncology. Retrieved 1 January 2020.
  11. ^ “GSK Presents New Data from the GARNET Study Demonstrating Potential of Dostarlimab to Treat a Subset of Women with Recurrent or Advanced Endometrial Cancer – Drugs.com MedNews”Drugs.com. Retrieved 29 April 2020.
  12. ^ “FDA Approves New Immunotherapy for Endometrial Cancer”Medscape. Retrieved 23 April 2021.
  13. Jump up to:a b “Jemperli: Pending EC decision”European Medicines Agency (EMA) (Press release). 25 February 2021. Retrieved 22 April 2021.

External links

  • “Dostarlimab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02715284 for “Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
  1. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
  2. Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
  3. Green AK, Feinberg J, Makker V: A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503. [Article]
  4. Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J: Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel). 2020 Nov 10;12(11). pii: cancers12113319. doi: 10.3390/cancers12113319. [Article]
  5. FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]
  6. FDA News Release: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Link]
  7. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]
Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetPCDP1
Clinical data
Trade namesJemperli
Other namesTSR-042, WBP-285, dostarlimab-gxly
License dataUS DailyMedDostarlimab
Routes of
administration
Intravenous
Drug classAntineoplastic
ATC codeL01XC40 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number2022215-59-2
PubChem SID384585344
DrugBankDB15627
UNIIP0GVQ9A4S5
KEGGD11366
Chemical and physical data
FormulaC6420H9832N1690O2014S44
Molar mass144325.73 g·mol−1

/////////Dostarlimab,  PEPTIDE, ANTINEOPLASTIC, CANCER, ドスタルリマブ , GSK 4057190, GSK4057190, TSR 042, TSR-042, WBP-285, FDA 2021, EU 2021

Sacituzumab govitecan-hziy


TRODELVY structure
Sacituzumab govitecan.png
Sacituzumab govitecan.png
Sacituzumab Govitecan for Metastatic Triple-Negative Breast Cancer -  National Cancer Institute

Sacituzumab govitecan-hziy

1601.8 g/mol

C76H104N12O24S

(2R)-2-amino-3-[1-[[4-[[1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-[2-[[(2S)-6-amino-1-[4-[[(19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-19-yl]oxycarbonyloxymethyl]anilino]-1-oxohexan-2-yl]amino]-2-oxoethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylcarbamoyl]cyclohexyl]methyl]-2,5-dioxopyrrolidin-3-yl]sulfanylpropanoic acid

Trodelvy 

  • hRS 7SN38
  • hRS7-SN38
  • IMMU 132
  • IMMU-132

CAS: 1491917-83-9

M9BYU8XDQ6

EX-A4354

UNII-DA64T2C2IO component ULRUOUDIQPERIJ-PQURJYPBSA-N

UNII-SZB83O1W42 component ULRUOUDIQPERIJ-PQURJYPBSA-N

EfficacyAntineoplastic, Topoisomerase I inhibitor
  DiseaseBreast cancer (triple negative)
sacituzumab govitecan-hziy Archives | Access Market Intelligence

Sacituzumab Govitecan is an antibody drug conjugate containing the humanized monoclonal antibody, hRS7, against tumor-associated calcium signal transducer 2 (TACSTD2 or TROP2) and linked to the active metabolite of irinotecan7-ethyl-10-hydroxycamptothecin (SN-38), with potential antineoplastic activity. The antibody moiety of sacituzumab govitecan selectively binds to TROP2. After internalization and proteolytic cleavage, SN-38 selectively stabilizes topoisomerase I-DNA covalent complexes, resulting in DNA breaks that inhibit DNA replication and trigger apoptosis. TROP2, also known as epithelial glycoprotein-1 (EGP-1), is a transmembrane calcium signal transducer that is overexpressed by a variety of human epithelial carcinomas; this antigen is involved in the regulation of cell-cell adhesion and its expression is associated with increased cancer growth, aggressiveness and metastasis.

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FDA Approves Trodelvy®, the First Treatment for Metastatic Triple-Negative Breast Cancer Shown to Improve Progression-Free Survival and Overall Survival

– Trodelvy Significantly Reduced the Risk of Death by 49% Compared with Single-Agent Chemotherapy in the Phase 3 ASCENT Study –

– Trodelvy is Under Regulatory Review in the EU and in the United Kingdom, Canada, Switzerland and Australia as Part of Project Orbis April 07, 2021 07:53 PM Eastern Daylight Time

FOSTER CITY, Calif.–(BUSINESS WIRE)–Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has granted full approval to Trodelvy® (sacituzumab govitecan-hziy) for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. The approval is supported by data from the Phase 3 ASCENT study, in which Trodelvy demonstrated a statistically significant and clinically meaningful 57% reduction in the risk of disease worsening or death (progression-free survival (PFS)), extending median PFS to 4.8 months from 1.7 months with chemotherapy (HR: 0.43; 95% CI: 0.35-0.54; p<0.0001). Trodelvy also extended median overall survival (OS) to 11.8 months vs. 6.9 months (HR: 0.51; 95% CI: 0.41-0.62; p<0.0001), representing a 49% reduction in the risk of death.

Trodelvy is directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including TNBC, where high expression is associated with poor survival and relapse. Prior to the FDA approval of Trodelvy, patients with previously treated metastatic TNBC had few treatment options in this high unmet-need setting. The FDA granted accelerated approval to Trodelvy in April 2020 based on objective response rate and duration of response results in a Phase 1/2 study. Today’s approval expands the previous Trodelvy indication to include treatment in adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.

“Women with triple-negative breast cancer have historically had very few effective treatment options and faced a poor prognosis,” said Aditya Bardia, MD, MPH, Director of Breast Cancer Research Program, Mass General Cancer Center and Assistant Professor of Medicine at Harvard Medical School, and global principal investigator of the ASCENT study. “Today’s FDA approval reflects the statistically significant survival benefit seen in the landmark ASCENT study and positions sacituzumab govitecan-hziy as a potential standard of care for pre-treated TNBC.”

“A metastatic TNBC diagnosis is frightening. As an aggressive and difficult-to-treat disease, it’s a significant advance to have an FDA-approved treatment option with a proven survival benefit for patients with metastatic disease that continues to progress,” said Ricki Fairley, Founder and CEO of Touch, the Black Breast Cancer Alliance. “For far too long, people with metastatic TNBC had very few treatment options. Today’s news continues the progress of bringing more options to treat this devastating disease.”

Among all patients evaluable for safety in the ASCENT study (n=482), Trodelvy had a safety profile consistent with the previously approved FDA label. The most frequent Grade ≥3 adverse reactions for Trodelvy compared to single-agent chemotherapy were neutropenia (52% vs. 34%), diarrhea (11% vs. 1%), leukopenia (11% vs. 6%) and anemia (9% vs. 6%). Adverse reactions leading to treatment discontinuation occurred in 5% of patients receiving Trodelvy.

“Today’s approval is the culmination of a multi-year development program and validates the clinical benefit of this important treatment in metastatic TNBC,” said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences. “Building upon this milestone, we are committed to advancing Trodelvy with worldwide regulatory authorities so that, pending their decision, Trodelvy may become available to many more people around the world who are facing this difficult-to-treat cancer.”

Regulatory submissions for Trodelvy in metastatic TNBC have been filed in the United Kingdom, Canada, Switzerland and Australia as part of Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE) that provides a framework for concurrent submission and review of oncology products among international partners, as well as in Singapore through our partner Everest Medicines.The European Medicines Agency has also validated a Marketing Authorization Application for Trodelvy in the European Union. All filings are based on data from the Phase 3 ASCENT study.

Trodelvy Boxed Warning

The Trodelvy U.S. Prescribing Information has a BOXED WARNING for severe or life-threatening neutropenia and severe diarrhea; see below for Important Safety Information.

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class antibody and topoisomerase inhibitor conjugate directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including metastatic triple-negative breast cancer (TNBC), where high expression is associated with poor survival and relapse.

Trodelvy is also being developed as an investigational treatment for metastatic urothelial cancer, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER 2-) metastatic breast cancer and metastatic non-small cell lung cancer. Additional evaluation across multiple solid tumors is also underway.

About Triple-Negative Breast Cancer (TNBC)

TNBC is an aggressive type of breast cancer, accounting for approximately 15% of all breast cancers. The disease is diagnosed more frequently in younger and premenopausal women and is more prevalent in African American and Hispanic women. TNBC cells do not have estrogen and progesterone receptors and have limited HER 2. Medicines targeting these receptors therefore are not typically effective in treating TNBC.

About the ASCENT Study

The Phase 3 ASCENT study, an open-label, active-controlled, randomized confirmatory trial, enrolled more than 500 patients with relapsed/refractory metastatic triple-negative breast cancer (TNBC) who had received two or more prior systemic therapies (including a taxane), at least one of them for metastatic disease. Patients were randomized to receive either Trodelvy or a chemotherapy chosen by the patients’ treating physicians. The primary efficacy outcome was progression-free survival (PFS) in patients without brain metastases at baseline, as measured by a blinded, independent, centralized review using RECIST v1.1 criteria. Additional efficacy measures included PFS for the full population (all patients with and without brain metastases) and overall survival (OS). More information about ASCENT is available at http://clinicaltrials.gov/show/NCT02574455.

Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

  • Severe, life-threatening, or fatal neutropenia may occur. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patient with febrile neutropenia without delay.
  • Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. Administer atropine, if not contraindicated, for early diarrhea of any severity. At the onset of late diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold TRODELVY until resolved to ≤ Grade 1 and reduce subsequent doses.

CONTRAINDICATIONS

  • Severe hypersensitivity to TRODELVY

WARNINGS AND PRECAUTIONS

Neutropenia: Dose modifications may be required due to neutropenia. Neutropenia occurred in 62% of patients treated with TRODELVY, leading to permanent discontinuation in 0.5% of patients. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 6%.

Diarrhea: Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3 diarrhea occurred in 12% of patients. Neutropenic colitis occurred in 0.5% of patients. Withhold TRODELVY for Grade 3-4 diarrhea and resume when resolved to ≤ Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: TRODELVY can cause severe and life-threatening hypersensitivity and infusion-related reactions, including anaphylactic reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients. Grade 3-4 hypersensitivity occurred in 1% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.4%. Pre-infusion medication is recommendedObserve patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use.

Nausea and Vomiting: Nausea occurred in 67% of all patients treated with TRODELVY. Grade 3-4 nausea occurred in 5% of patients. Vomiting occurred in 40% of patients and Grade 3-4 vomiting occurred in 3% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK-1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤ 1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Individuals who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with TRODELVY. The incidence of Grade 3-4 neutropenia in genotyped patients was 69% in patients homozygous for the UGT1A1*28, 48% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia in genotyped patients was 24% in patients homozygous for the UGT1A1*28 allele, 8% in patients heterozygous for the UGT1A1*28 allele, and 10% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose.

ADVERSE REACTIONS

In the ASCENT study (IMMU-132-05), the most common adverse reactions (incidence ≥25%) were nausea, neutropenia, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, rash, decreased appetite, and abdominal pain. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced hemoglobin, lymphocytes, leukocytes, and neutrophils.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with TRODELVY.

UGT1A1 Inducers: Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with TRODELVY

Please see full Prescribing Information, including BOXED WARNING.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Sacituzumab govitecan, sold under the brand name Trodelvy, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate indicated for the treatment of metastatic triple-negative breast cancer (mTNBC) in adult patients that have received at least two prior therapies.[1][2]

The most common side effects are nauseaneutropeniadiarrheafatigueanemiavomitingalopecia (hair loss), constipationdecreased appetiterash and abdominal pain.[1][2] Sacituzumab govitecan has a boxed warning about the risk of severe neutropenia (abnormally low levels of white blood cells) and severe diarrhea.[1][2] Sacituzumab govitecan may cause harm to a developing fetus or newborn baby.[1] Women are advised not to breastfeed while on sacituzumab govitecan and 1 month after the last dose is administered.[3]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[4]

Mechanism

Sacituzumab govitecan is a conjugate of the humanized anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan.[5] Each antibody having on average 7.6 molecules of SN-38 attached.[6] SN-38 is too toxic to administer directly to patients, but linkage to an antibody allows the drug to specifically target cells containing Trop-2.

Sacituzumab govitecan is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate, meaning that the drug targets the Trop-2 receptor that helps the cancer grow, divide and spread, and is linked to topoisomerase inhibitor, which is a chemical compound that is toxic to cancer cells.[1] Approximately two of every ten breast cancer diagnoses worldwide are triple-negative.[1] Triple-negative breast cancer is a type of breast cancer that tests negative for estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2) protein.[1] Therefore, triple-negative breast cancer does not respond to hormonal therapy medicines or medicines that target HER2.[1]

Development

Immunomedics announced in 2013, that it had received fast track designation from the US Food and Drug Administration (FDA) for the compound as a potential treatment for non-small cell lung cancer, small cell lung cancer, and metastatic triple-negative breast cancer. Orphan drug status was granted for small cell lung cancer and pancreatic cancer.[7][8] In February 2016, Immunomedics announced that sacituzumab govitecan had received an FDA breakthrough therapy designation (a classification designed to expedite the development and review of drugs that are intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition) for the treatment of patients with triple-negative breast cancer who have failed at least two other prior therapies for metastatic disease.[9][10]

History

Sacituzumab govitecan was added to the proposed INN list in 2015,[11] and to the recommended list in 2016.[12]

Sacituzumab govitecan-hziy was approved for use in the United States in April 2020.[1][13][14][2]

Sacituzumab govitecan-hziy was approved based on the results of IMMU-132-01, a multicenter, single-arm clinical trial (NCT01631552) of 108 subjects with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease.[1][14][2] Of the 108 patients involved within the study, 107 were female and 1 was male.[15] Subjects received sacituzumab govitecan-hziy at a dose of 10 milligrams per kilogram of body weight intravenously on days one and eight every 21 days.[14][15] Treatment with sacituzumab govitecan-hziy was continued until disease progression or unacceptable toxicity.[15] Tumor imaging was obtained every eight weeks.[14][2] The efficacy of sacituzumab govitecan-hziy was based on the overall response rate (ORR) – which reflects the percentage of subjects that had a certain amount of tumor shrinkage.[1][14] The ORR was 33.3% (95% confidence interval [CI], 24.6 to 43.1). [1][14][15] Additionally, with the 33.3% of study participants who achieved a response, 2.8% of patients experienced complete responses.[15] The median time to response in patients was 2.0 months (range, 1.6 to 13.5), the median duration of response was 7.7 months (95% confidence interval [CI], 4.9 to 10.8), the median progression free survival was 5.5 months, and the median overall survival was 13.0 months.[15] Of the subjects that achieved an objective response to sacituzumab govitecan-hziy, 55.6% maintained their response for six or more months and 16.7% maintained their response for twelve or more months.[1][14]

Sacituzumab govitecan-hziy was granted accelerated approval along with priority reviewbreakthrough therapy, and fast track designations.[1][14] The U.S. Food and Drug Administration (FDA) granted approval of Trodelvy to Immunomedics, Inc.[1]

References

  1. Jump up to:a b c d e f g h i j k l m n o “FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 22 April 2020.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d e f “Drug Trial Snapshot: Trodelvy”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 29 April 2020. This article incorporates text from this source, which is in the public domain.
  3. ^ (PDF)https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761115s000lbl.pdf. Missing or empty |title= (help)
  4. ^ “New Drug Therapy Approvals 2020”U.S. Food and Drug Administration (FDA). 31 December 2020. Retrieved 17 January2021.  This article incorporates text from this source, which is in the public domain.
  5. ^ Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. 2015
  6. ^ “Novel Agents are Targeting Drivers of TNBC”http://www.medpagetoday.com. 28 June 2016.
  7. ^ “Sacituzumab govitecan Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 22 April 2020.
  8. ^ “Sacituzumab govitecan Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 22 April 2020.
  9. ^ “New Therapy Shows Early Promise, Continues to Progress in Triple-Negative Breast Cancer”Cure Today.
  10. ^ “U.S. Food and Drug Administration (FDA) Grants Breakthrough Therapy Designation to Immunomedics for Sacituzumab Govitecan for the Treatment of Patients With Triple-Negative Breast Cancer”(Press release). Immunomedics. 5 February 2016. Retrieved 25 April 2020 – via GlobeNewswire.
  11. ^ World Health Organization (2015). “International nonproprietary names for pharmaceutical substances (INN): proposed INN: list 113”. WHO Drug Information29 (2): 260–1. hdl:10665/331080.
  12. ^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information30 (1): 151–3. hdl:10665/331046.
  13. ^ “Trodelvy: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 22 April 2020.
  14. Jump up to:a b c d e f g h “FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 23 April 2020.  This article incorporates text from this source, which is in the public domain.
  15. Jump up to:a b c d e f “Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer”The New England Journal of Medicine.

Further reading

External links

 
Monoclonal antibody
Type?
SourceHumanized (from mouse)
TargetTrop-2
Clinical data
Trade namesTrodelvy
Other namesIMMU-132, hRS7-SN-38, sacituzumab govitecan-hziy
AHFS/Drugs.comMonograph
MedlinePlusa620034
License dataUS DailyMedSacituzumab_govitecan
Pregnancy
category
Contraindicated
ATC codeNone
Legal status
Legal statusUS: ℞-only
Identifiers
CAS Number1491917-83-9
PubChem CID91668186
DrugBankDB12893
ChemSpidernone
UNIIM9BYU8XDQ6
KEGGD10985
Chemical and physical data
FormulaC76H104N12O24S
Molar mass1601.79 g·mol−1
3D model (JSmol)Interactive image
showSMILES
show 

//////////sacituzumab govitecan-hziy, fda 2021, approvals 2021, Trodelvy , hRS 7SN38, hRS7-SN38, IMMU 132, IMMU-132, MONOCLONAL ANTIBODY, Sacituzumab govitecan, sacituzumab govitecan-hziy, CANCER, MONOCLONAL ANTIBODIES

#sacituzumab govitecan-hziy, #fda 2021, #approvals 2021, #Trodelvy , #hRS 7SN38, #hRS7-SN38, #IMMU 132, #IMMU-132, #MONOCLONAL ANTIBODY, #Sacituzumab govitecan, #sacituzumab govitecan-hziy, #CANCER, #MONOCLONAL ANTIBODIES

CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)C4(CC)OC(=O)OCC5=CC=C(C=C5)NC(=O)C(CCCCN)NC(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN6C=C(N=N6)CNC(=O)C7CCC(CC7)CN8C(=O)CC(C8=O)SCC(C(=O)O)N)C2=NC9=C1C=C(C=C9)O

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