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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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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 PHARMACEUTICALS 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 year tenure till date Dec 2017, 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, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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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Teprotumumab-trbw


Image result for teprotumumab-trbw

Tepezza (teprotumumab-trbw)

Company: Horizon Therapeutics plc
Date of Approval: January 21, 2020
Treatment for: Thyroid Eye Disease

UNIIY64GQ0KC0A

CAS number1036734-93-6

R-1507 / R1507 / RG-1507 / RG1507 / RO-4858696 / RO-4858696-000 / RO-4858696000 / RO4858696 / RO4858696-000 / RV-001 / RV001

Tepezza (teprotumumab-trbw) is a fully human monoclonal antibody (mAb) and a targeted inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) for the treatment of active thyroid eye disease (TED).

FDA Approves Tepezza (teprotumumab-trbw) for the Treatment of Thyroid Eye Disease (TED) – January 21, 2020

Today, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis). Today’s approval represents the first drug approved for the treatment of thyroid eye disease.

“Today’s approval marks an important milestone for the treatment of thyroid eye disease. Currently, there are very limited treatment options for this potentially debilitating disease. This treatment has the potential to alter the course of the disease, potentially sparing patients from needing multiple invasive surgeries by providing an alternative, non surgical treatment option,” said Wiley Chambers, M.D., deputy director of the Division of Transplant and Ophthalmology Products in the FDA’s Center for Drug Evaluation and Research. “Additionally, thyroid eye disease is a rare disease that impacts a small percentage of the population, and for a variety of reasons, treatments for rare diseases are often unavailable. This approval represents important progress in the approval of effective treatments for rare diseases, such as thyroid eye disease.”

Thyroid eye disease is associated with the outward bulging of the eye that can cause a variety of symptoms such as eye pain, double vision, light sensitivity or difficulty closing the eye. This disease impacts a relatively small number of Americans, with more women than men affected. Although this condition impacts relatively few individuals, thyroid eye disease can be incapacitating. For example, the troubling ocular symptoms can lead to the progressive inability of people with thyroid eye disease to perform important daily activities, such as driving or working.

Tepezza was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive Tepezza or a placebo. Of the patients who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than 2 millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.

The most common adverse reactions observed in patients treated with Tepezza are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Tepezza should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for 6 months following the last dose of Tepezza.

The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Additionally, Tepezza received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases or conditions. Development of this product was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and efficacy of products for use in rare diseases or conditions.

The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.

Teprotumumab (RG-1507), sold under the brand name Tepezza, is a medication used for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis).[1]

The most common adverse reactions observed in people treated with teprotumumab-trbw are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache.[1] Teprotumumab-trbw should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for six months following the last dose of teprotumumab-trbw.[1]

It is a human monoclonal antibody developed by Genmab and Roche. It binds to IGF-1R.

Teprotumumab was first investigated for the treatment of solid and hematologic tumors, including breast cancer, Hodgkin’s and non-Hodgkin’s lymphomanon-small cell lung cancer and sarcoma.[2][3] Although results of phase I and early phase II trials showed promise, research for these indications were discontinued in 2009 by Roche. Phase II trials still in progress were allowed to complete, as the development was halted due to business prioritization rather than safety concerns.

Teprotumumab was subsequently licensed to River Vision Development Corporation in 2012 for research in the treatment of ophthalmic conditions. Horizon Pharma (now Horizon Therapeutics, from hereon Horizon) acquired RVDC in 2017, and will continue clinical trials.[4] It is in phase III trials for Graves’ ophthalmopathy (also known as thyroid eye disease (TED)) and phase I for diabetic macular edema.[5] It was granted Breakthrough TherapyOrphan Drug Status and Fast Track designations by the FDA for Graves’ ophthalmopathy.[6]

In a multicenter randomized trial in patients with active Graves’ ophthalmopathy Teprotumumab was more effective than placebo in reducing the clinical activity score and proptosis.[7] In February 2019 Horizon announced results from a phase 3 confirmatory trial evaluating teprotumumab for the treatment of active thyroid eye disease (TED). The study met its primary endpoint, showing more patients treated with teprotumumab compared with placebo had a meaningful improvement in proptosis, or bulging of the eye: 82.9 percent of teprotumumab patients compared to 9.5 percent of placebo patients achieved the primary endpoint of a 2 mm or more reduction in proptosis (p<0.001). Proptosis is the main cause of morbidity in TED. All secondary endpoints were also met and the safety profile was consistent with the phase 2 study of teprotumumab in TED.[8] On 10th of July 2019 Horizon submitted a Biologics License Application (BLA) to the FDA for teprotumumab for the Treatment of Active Thyroid Eye Disease (TED). Horizon requested priority review for the application – if so granted (FDA has a 60-day review period to decide) it would result in a max. 6 month review process.[9]

History[edit]

Teprotumumab-trbw was approved for use in the United States in January 2020, for the treatment of adults with thyroid eye disease.[1]

Teprotumumab-trbw was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive teprotumumab-trbw or a placebo.[1] Of the subjects who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than two millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.[1]

The U.S. Food and Drug Administration (FDA) granted the application for teprotumumab-trbw fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation.[1] The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.[1]

References

  1. Jump up to:a b c d e f g h “FDA approves first treatment for thyroid eye disease”U.S. Food and Drug Administration (FDA) (Press release). 21 January 2020. Retrieved 21 January 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ https://clinicaltrials.gov/ct2/show/NCT01868997
  3. ^ http://adisinsight.springer.com/drugs/800015801
  4. ^ http://www.genmab.com/product-pipeline/products-in-development/teprotumumab
  5. ^ http://adisinsight.springer.com/drugs/800015801
  6. ^ http://www.genmab.com/product-pipeline/products-in-development/teprotumumab
  7. ^ Smith, TJ; Kahaly, GJ; Ezra, DG; Fleming, JC; Dailey, RA; Tang, RA; Harris, GJ; Antonelli, A; Salvi, M; Goldberg, RA; Gigantelli, JW; Couch, SM; Shriver, EM; Hayek, BR; Hink, EM; Woodward, RM; Gabriel, K; Magni, G; Douglas, RS (4 May 2017). “Teprotumumab for Thyroid-Associated Ophthalmopathy”The New England Journal of Medicine376 (18): 1748–1761. doi:10.1056/NEJMoa1614949PMC 5718164PMID 28467880.
  8. ^ “Horizon Pharma plc Announces Phase 3 Confirmatory Trial Evaluating Teprotumumab (OPTIC) for the Treatment of Active Thyroid Eye Disease (TED) Met Primary and All Secondary Endpoints”Horizon Pharma plc. Retrieved 22 March 2019.
  9. ^ “Horizon Therapeutics plc Submits Teprotumumab Biologics License Application (BLA) for the Treatment of Active Thyroid Eye Disease (TED)”Horizon Therapeutics plc. Retrieved 27 August 2019.

External links

Teprotumumab
Monoclonal antibody
Type Whole antibody
Source Human
Target IGF-1R
Clinical data
Other names teprotumumab-trbw, RG-1507
ATC code
  • none
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
ECHA InfoCard 100.081.384 Edit this at Wikidata
Chemical and physical data
Formula C6476H10012N1748O2000S40
Molar mass 145.6 kg/mol g·mol−1

/////////Teprotumumab-trbw, APPROVALS 2020, FDA 2020, ORPHAN, BLA, fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation, Tepezza,  Horizon Therapeutics, MONOCLONAL ANTIBODY, 2020 APPROVALS,  active thyroid eye disease, Teprotumumab

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-thyroid-eye-disease

ENCORAFENIB, エンコラフェニブ


LGX818 structure.svg

2D chemical structure of 1269440-17-6

Encorafenib.png

ENCORAFENIB, エンコラフェニブ

UNII:8L7891MRB6

Formula:C22H27ClFN7O4S, Average: 540.01

1269440-17-6

  • BRAFTOVI
  • NVP-LGX818
  • NVP-LGX-818-NXA
  • NVP-LGX818-NXA
  • ENCORAFENIB [USAN]
  • ENCORAFENIB [WHO-DD]
  • ENCORAFENIB
  • ENCORAFENIB [INN]
  • METHYL N-((2S)-1-((4-(3-(5-CHLORO-2-FLUORO-3-(METHANESULFONAMIDO)PHENYL)(-1-(PROPAN-2-YL)-1H-PYRAZOL-4-YL(PYRIMIDIN-2-YL)AMINO)PROPAN-2-YL)CARBAMATE
  • CARBAMIC ACID, N-((1S)-2-((4-(3-(5-CHLORO-2-FLUORO-3-((METHYLSULFONYL)AMINO)PHENYL)-1-(1-METHYLETHYL)-1H-PYRAZOL-4-YL)-2-PYRIMIDINYL)AMINO)-1-METHYLETHYL)-, METHYL ESTER
  • LGX818
  • LGX-818

Encorafenib, also known as BRAFTOVI, is a kinase inhibitor. Encorafenib inhibits BRAF gene, which encodes for B-raf protein, which is a proto-oncogene involved in various genetic mutations Label. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which impacts cell division, differentiation, and secretion. Mutations in this gene, most frequently the V600E mutation, are the most commonly identified cancer-causing mutations in melanoma, and have been isolated in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of the lung 6.

On June 27, 2018, the Food and Drug Administration approved encorafenib and Binimetinib(BRAFTOVI and MEKTOVI, Array BioPharma Inc.) in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test Label.

Array Biopharma  (a wholly owned subsidiary of  Pfizer ), under license from  Novartis , and licensees  Pierre Fabre  and  Ono Pharmaceutical  have developed and launched the B-Raf kinase inhibitor encorafenib . In January 2020, the US FDA’s Orange Book was seen to list encorafenib patents such as US8946250 , US8501758 , US9314464 and US9763941 , expiring in the range of 2029-2032. At that time Orange Book also reported that encorafenib as having NCE exclusivity expiring on July 27, 2023.

Encorafenib (trade name Braftovi) is a drug for the treatment of certain melanomas. It is a small molecule BRAF inhibitor [1] that targets key enzymes in the MAPK signaling pathway. This pathway occurs in many different cancers including melanoma and colorectal cancers.[2] The substance was being developed by Novartis and then by Array BioPharma. In June 2018, it was approved by the FDA in combination with binimetinib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.[3][4]

The most common (≥25%) adverse reactions in patients receiving the drug combination were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.[3]

Indication

Used in combination with Binimetinib in metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test 5.

Associated Conditions

Pharmacodynamics

Encorafenib has shown improved efficacy in the treatment of metastatic melanoma 3.

Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis 7.

Once-daily dosing of single-agent encorafenib has a distinct tolerability profile and shows varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic stage melanoma 7.

Mechanism of action

Encorafenib is a kinase inhibitor that specifically targets BRAF V600E, as well as wild-type BRAF and CRAF while tested with in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, including BRAF V600E, result in activated BRAF kinases that mahy stimulate tumor cell growth. Encorafenib is able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and significantly reduce ligand binding to these kinases at clinically achievable concentrations (≤ 0.9 μM) Label.

In efficacy studies, encorafenib inhibited the in vitro cell growth of tumor cell lines that express BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing the BRAF V600E mutation, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression Label.

Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, co-administration of encorafenib and binimetinib result in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. In addition to the above, the combination of encorafenib and binimetinib acted to delay the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared with the administration of either drug alone Label.

Image result for ENCORAFENIB

Pharmacology

Encorafenib acts as an ATP-competitive RAF kinase inhibitor, decreasing ERK phosphorylation and down-regulation of CyclinD1.[5]This arrests the cell cycle in G1 phase, inducing senescence without apoptosis.[5] Therefore it is only effective in melanomas with a BRAF mutation, which make up 50% of all melanomas.[6] The plasma elimination half-life of encorafenib is approximately 6 hours, occurring mainly through metabolism via cytochrome P450 enzymes.[7]

Clinical trials

Several clinical trials of LGX818, either alone or in combinations with the MEK inhibitor MEK162,[8] are being run. As a result of a successful Phase Ib/II trials, Phase III trials are currently being initiated.[9]

History

Approval of encorafenib in the United States was based on a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453) in 577 patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.[3] Patients were randomized (1:1:1) to receive binimetinib 45 mg twice daily plus encorafenib 450 mg once daily, encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily.[3] Treatment continued until disease progression or unacceptable toxicity.[3]

The major efficacy measure was progression-free survival (PFS) using RECIST 1.1 response criteria and assessed by blinded independent central review.[3] The median PFS was 14.9 months for patients receiving binimetinib plus encorafenib, and 7.3 months for the vemurafenib monotherapy arm (hazard ratio 0.54, 95% CI: 0.41, 0.71, p<0.0001).[3] The trial was conducted at 162 sites in Europe, North America and various countries around the world.[4]

SYN

PATENT

WO2010010154 , expiry , EU states,  2029,  US in 2030 with US154 extension.

WO 2011025927

WO 2016089208

Patent

WO-2020011141

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020011141&tab=FULLTEXT&_cid=P20-K5QFFQ-43376-1

Novel deuterated analogs of diarylpyrazole compounds, particularly encorafenib are B-RAF and C-RAF kinase inhibitors, useful for treating proliferative diseases such as melanoma and colorectal cancer. Family members of the product case, WO2010010154 , expire in most of the EU states until 2029 and will expire in the US in 2030 with US154 extension. In January 2020, the US FDA’s Orange Book was seen to list encorafenib patents such as US8946250 , US8501758 , US9314464 and US9763941 , expiring in the range of 2029-2032. At that time Orange Book also reported that encorafenib as having NCE exclusivity expiring on July 27, 2023.

The mitogen-activated protein kinase (MAPK) pathway mediates the activity of many effector molecules that coordinately control cell proliferation, survival, differentiation, and migration. Cells are bound by plasma factors such as growth factors, cytokines, or hormones to plasma membrane-associated Ras and GTP and thereby activated to recruit Raf. This interaction induces Raf’s kinase activity, resulting in direct phosphorylation of MAPK / ERK (MEK), which in turn phosphorylates extracellular signal-related kinase (ERK). Activated ERK phosphorylates a range of effector molecules, such as kinases, phosphatases, transcription factors, and cytoskeleton proteins. Therefore, the Ras-Raf-MEK-ERK signaling pathway transmits signals from cell surface receptors to the nucleus and is essential for cell proliferation and survival.

[0003]
According to Raf’s ability to interact with upstream regulator Ras, Raf has three different isoforms, namely A-Raf, B-Raf, and C-Raf. An activating mutation of one of the Ras genes can be observed in about 20% of all tumors, and the Ras-Raf-MEK-ERK pathway is activated in about 30% of all tumors. Activation mutations in the B-Raf kinase domain occur in approximately 70% of melanoma, 40% of papillary cancer, 30% of low-grade ovarian cancer, and 10% of colorectal cancer. Most B-Raf mutations are found in the kinase domain, with a single substitution (V600E) accounting for 80%. The mutated B-Raf protein activates the Raf-MEK-ERK pathway by increasing kinase activity against MEK or by activating C-Raf. B-Raf inhibitors inhibit cells involved in B-Raf kinase by blocking the signal cascade in these cancer cells and eventually inducing cell arrest and / or death.

[0004]
Encorafenib (aka LGX-818, chemical name is (S)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1-iso Propyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) prop-2-yl) methyl carbamate, which has the following structural formula) is a new oral BRAF jointly developed by Novartis and Array Pharmaceuticals Inhibitors can inhibit the activation of the MAPK pathway caused by B-Raf kinase mutations (such as V600 mutations, that is, glutamate mutations at amino acid 600). Encorafenib alone or in combination with MEK inhibitor Binimetinib is used to treat patients with advanced BRAF v600 mutant melanoma. On June 27, 2018, the FDA approved Encorafenib (commercial name BRAFTOVI) capsules in combination with Binimetinib (commercial name: MEKTOVI) tablets for treating melanoma patients with BRAF V600E or BRAFV 600K mutations.
It is known that poor absorption, distribution, metabolism, and / or excretion (ADME) properties are the main cause of the failure of many candidate drug clinical trials. Many drugs currently on the market also limit their scope of application due to poor ADME properties. The rapid metabolism of drugs will cause many drugs that could be highly effective in treating diseases to be difficult to make because they are metabolized from the body too quickly. Although frequent or high-dose medication may solve the problem of rapid drug removal, this method will bring problems such as poor patient compliance, side effects caused by high-dose medication, and rising treatment costs. In addition, rapidly metabolizing drugs may also expose patients to adverse toxic or reactive metabolites.

[0007]
Although Encoratenib as a BRAF inhibitor can effectively treat BRAF V600 mutant melanoma, there are still serious clinical unmet needs in this field, and the Encoratenib compound is a class II BCS with poor water solubility at weakly acidic and neutral pH Compounds have poor oral availability, so finding new compounds that have a therapeutic effect on BRAF kinase mutations, have good oral bioavailability, and have pharmaceutical properties is still a challenging task. Therefore, there remains a need in the art to develop compounds that have selective inhibitory activity and / or better pharmacodynamics / pharmacokinetics for use as BRAF inhibitors, and the present invention provides such compounds.

PAPER

European journal of cancer (Oxford, England : 1990) (2018), 88, 67-76.

References

  1. ^ Koelblinger P, Thuerigen O, Dummer R (March 2018). “Development of encorafenib for BRAF-mutated advanced melanoma”Current Opinion in Oncology30 (2): 125–133. doi:10.1097/CCO.0000000000000426PMC 5815646PMID 29356698.
  2. ^ Burotto M, Chiou VL, Lee JM, Kohn EC (November 2014). “The MAPK pathway across different malignancies: a new perspective”Cancer120 (22): 3446–56. doi:10.1002/cncr.28864PMC 4221543PMID 24948110.
  3. Jump up to:a b c d e f g “FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations”U.S. Food and Drug Administration (FDA)(Press release). 27 June 2018. Archived from the original on 18 December 2019. Retrieved 28 June 2018.  This article incorporates text from this source, which is in the public domain.
  4. Jump up to:a b “Drug Trial Snapshot: Braftovi”U.S. Food and Drug Administration (FDA). 16 July 2018. Archived from the original on 19 December 2019. Retrieved 18 December 2019. This article incorporates text from this source, which is in the public domain.
  5. Jump up to:a b Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S (January 2016). “Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells”. Cancer Letters370 (2): 332–44. doi:10.1016/j.canlet.2015.11.015PMID 26586345.
  6. ^ Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. (July 2012). “A landscape of driver mutations in melanoma”Cell150 (2): 251–63. doi:10.1016/j.cell.2012.06.024PMC 3600117PMID 22817889.
  7. ^ Koelblinger P, Thuerigen O, Dummer R (March 2018). “Development of encorafenib for BRAF-mutated advanced melanoma”Current Opinion in Oncology30 (2): 125–133. doi:10.1097/CCO.0000000000000426PMC 5815646PMID 29356698.
  8. ^ “18 Studies found for: LGX818”Clinicaltrials.gove.
  9. ^ Clinical trial number NCT01909453 for “Study Comparing Combination of LGX818 Plus MEK162 and LGX818 Monotherapy Versus Vemurafenib in BRAF Mutant Melanoma (COLUMBUS)” at ClinicalTrials.gov

External links

  1. Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S: Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016 Jan 28;370(2):332-44. doi: 10.1016/j.canlet.2015.11.015. Epub 2015 Nov 14. [PubMed:26586345]
  2. Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018 Mar;30(2):125-133. doi: 10.1097/CCO.0000000000000426. [PubMed:29356698]
  3. Moschos SJ, Pinnamaneni R: Targeted therapies in melanoma. Surg Oncol Clin N Am. 2015 Apr;24(2):347-58. doi: 10.1016/j.soc.2014.12.011. Epub 2015 Jan 24. [PubMed:25769717]
  4. Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615. doi: 10.1016/S1470-2045(18)30142-6. Epub 2018 Mar 21. [PubMed:29573941]
  5. FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Link]
  6. BRAF B-Raf proto-oncogene, serine/threonine kinase [ Homo sapiens (human) ] [Link]
  7. Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma [Link]
  8. Encorafenib FDA label [File]
  9. Encorafenib review [File]
Encorafenib
LGX818 structure.svg
Clinical data
Trade names Braftovi
Other names LGX818
AHFS/Drugs.com Monograph
MedlinePlus a618040
License data
Routes of
administration
Oral
Drug class Antineoplastic Agents
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C22H27ClFN7O4S
Molar mass 540.011 g/mol g·mol−1
3D model (JSmol)

///////////ENCORAFENIB, 1269440-17-6, BRAFTOVI, NVP-LGX818, LGX818, LGX 818, エンコラフェニブ  ,

COC(=O)N[C@@H](C)CNc1nccc(n1)c2cn(nc2c3cc(Cl)cc(NS(=O)(=O)C)c3F)C(C)C

patent

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020011141&tab=FULLTEXT&_cid=P20-K5QFFQ-43376-1

Method for preparing compounds of the invention

[0165]
The compounds of the invention, including their salts, can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic routes, such as those in the schemes below. The reaction for preparing the compound of the present invention can be performed in a suitable solvent, and a person skilled in the art of organic synthesis can easily select a solvent. Suitable solvents may be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is performed (e.g., a temperature ranging from the solvent freezing temperature to the solvent boiling point temperature). A given reaction may be performed in one solvent or a mixture of more than one solvent. The skilled person can select a solvent for a specific reaction step depending on the specific reaction step.

[0166]
The preparation of the compounds of the invention may involve the protection and removal of different chemical groups. Those skilled in the art can easily determine whether protection and removal of protection are needed and the choice of an appropriate protecting group. The chemical nature of the protecting group can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.

[0167]
The compound of the present invention can be prepared into a single stereo by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomer isomer. Enantiomeric resolution can be performed using diastereomeric derivatives of the compounds of the present invention, with preferentially dissociable complexes (e.g., crystalline diastereomeric salts). Diastereomers have significantly different physical properties (eg, melting points, boiling points, solubility, reactivity, etc.) and can be easily separated by the advantages of these dissimilarities. Diastereomers can be separated by chromatography, preferably by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, along with the resolving reagent, by any practical means that does not allow racemization. A more detailed description of techniques suitable for resolution of stereoisomers of compounds starting from racemic mixtures can be found in Jean Jacques, Andre Collet, Samue1H. Wilen, “Enantiomers, Racemates and Resolution” (“Enantiomers, Racemates and Resolutions “), John Wiley And Sons, Inc., 1981.

[0168]
The reaction can be monitored according to any suitable method known in the art. For example, it may be by spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g. 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g. UV-visible light), mass spectrometry (MS)) or by chromatography Methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) to monitor product formation.

[0169]
The compound of formula (I) of the present invention can be prepared by the following reaction scheme 1:

[0170]
Reaction Flowchart 1

[0171]
WO2020011141 / pic / XxJADXdTFKEoDNpTEyy19bUgmH96fty917ouhkO5VZ8DxAcnBrNNXgNmrPfLZTkbnfDDV8tm_ImJg2inA4pPj9gRdLA4C4Y4C4Y4C4Y4C4R4A4

[0172]
Wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 and X 5 are as defined in the present invention. The compound of formula (I) can be obtained by using a compound of formula (I-1) and a sulfonating agent X 5 SO 2 Cl at a suitable base (for example, pyridine, triethylamine, 4- (N, N-dimethylamino) pyridine, etc.) Reaction with a suitable solvent (e.g., dichloromethane, THF, etc.). The reaction is performed at a temperature ranging from about 0 ° C to about 1000 ° C, and may take up to about 20 hours to complete. The reaction mixture is optionally further reacted to remove any protecting groups.

[0173]
The compound of formula (I-1) can be prepared by the following reaction scheme 2:

[0174]
Reaction Flowchart 2

[0175]
WO2020011141 / pic / 0j7t4gaakD7jifc_-mXUo7X65c8la3xpUvQQUfnz6tLaRlcSBbtBx_ehky4qNV0PICK_GRydD0JIoErMNKGqXAa-Pdt7Mtw-IlvJllyprtNJlkwQFY2QFKYFQFY2F2F2F-A

[0176]
Wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 and X 5 are as defined in the present invention, M is a leaving group (for example, iodine, bromine, chlorine, trifluoromethanesulfonyloxy, etc.), each Z may be, for example, hydrogen, methyl, etc., or two Z groups may be connected to form a boric acid ester. Both P groups can be H, or two P groups taken together represent a suitable nitrogen protecting group (eg, one P can be hydrogen and the other can be Boc). The compound of formula (I-2) can be obtained by using a compound of formula (I-4) and a compound of formula (I-3) in a suitable transition metal catalyst (for example, Pd (PPh 3 ) 4 or PdCl 2(dppf)), a suitable solvent (for example, DME, dioxane, toluene, ethanol, etc.) and a suitable base (for example, anhydrous potassium carbonate or sodium carbonate, etc.) are reacted. The reaction is carried out at a temperature ranging from about 20 ° C to 120 ° C, and may take about 2 hours to complete. Compounds of formula (I) can be synthesized by leaving the protecting group P from compounds of formula (I-2) (eg, by treatment with a strong acid such as hydrogen chloride in the presence of DME and dioxane).

[0177]
Compounds of formula (I-4) can be prepared by the following reaction scheme 3:

[0178]
Reaction Flowchart 3

[0179]
WO2020011141 / pic / H1aXUHL0cjl3M_4rpEpbJjUXM5MVl8eWmRAYSGnBPikn5V42NDHXIWwphroHiMSaKEOQI2xHvuG9rOZ0TmtIGAgEd55PYww1WwLNWYpYGOjx5MePjrwW1

[0180]
Wherein Y 1 , Y 2 , R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 and X 4 are as defined in the present invention, and M is a leaving group (for example, iodine, Bromine, chlorine, trifluoromethanesulfonyloxy, etc.), and V is a leaving group (eg, iodine, bromine, chlorine, trifluoromethanesulfonyloxy, etc.). Compounds of formula (I-4) can be prepared by reacting an amine compound of formula (I-5) and a compound of formula (I-6). The reaction is performed in a suitable solvent (for example, DMSO, NMP, dioxane, or isopropanol) in the presence of a suitable base (for example, sodium carbonate or potassium carbonate, etc.) at a temperature ranging from about 25 ° C to about 120 ° C.

[0181]
Examples

[0182]
The present invention will be further described below with reference to specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples are generally based on conventional conditions or conditions recommended by the manufacturer. Unless stated otherwise, parts and percentages are parts by weight and percent by weight.

[0183]
The abbreviations used in this article have the following meanings:

[0184]

[TABLE 0001]

APCI Atmospheric pressure chemical dissociation
HPLC High performance liquid chromatography
TLC TLC
h hour
DMF N, N-dimethylformamide
2 CO 3 Potassium carbonate
DCM Dichloromethane
THF Tetrahydrofuran
CH 3 MgBr Methyl magnesium bromide
PTSA p-Toluenesulfonic acid
TFA Trifluoroacetate
NMP N-methylpyrrolidone
Diguanidinium carbonate Guanidine carbonate
MTBE Methyl tert-butyl ether
POCl 3 Phosphorus oxychloride
DMSO Dimethyl sulfoxide
Pd (dppf) Cl 2 [1,1′-Bis (diphenylphosphino) ferrocene] Palladium dichloride
Dioxane Dioxane
TsCl 4-toluenesulfonyl chloride
Boc Tert-butoxy carbon
DIPEA N, N-diisopropylethylamine
CDCl 3 Deuterated chloroform
TEA Triethylamine
DMAP 4-dimethylaminopyridine
Na 2 CO 3 Sodium carbonate
HCl hydrochloric acid

[0185]

[表 0002]

MsCl Methanesulfonyl chloride
Tol Toluene

[0186]
Preparation of intermediate A 2-chloro-4- (3-iodo-1- (prop-2-yl-d 7) -1H-pyrazol-4-yl) pyrimidine.

[0188]
Use the following route for synthesis:

[0189]

[0187]
WO2020011141 / pic / FNMs_XnbU3RObeg6K-VT91xnEa9pD4CszLQIShhoBrnGwf4vFDH7dAkcn-3inZ_bWfKR2ST5u0v_zJNop7mFw4GGCQQ-n-KUOLKt_hScUwRV00GBR1

[0188]
Use the following route for synthesis:

[0189]
WO2020011141 / pic / X5sd0-Eb1TIYnP9Ih5i8tod2iaKSm99ccdy8emg0txiLBrTHdVUkygjUPWlzRjkQFaUW8mpEfWyY68vXxmmbEdx1Q3ZQZFZ1ZYZFZ5ZFJ2

[0190]
Step 1 Synthesis of Compound A-2

[0191]
Compound 1 (5.0 g, 73.4 mmol) was added to a 47% solution of hydrobromic acid (20 ml). The reaction solution was reacted at 80 ° C for 3 hours, and distilled under normal pressure. The 60-70 ° C fraction was collected to obtain a colorless liquid. 6.2g, yield 65%.

[0192]
Step 2 Synthesis of Compound A-4

[0193]
Compound A-3 (3.0 g, 27.8 mmol) was added to a DMF (20 ml) solution, the solution was lowered to 0 ° C, K 2 CO 3 (4.6 g, 33.3 mmol, 10 ml) was added, and the mixture was stirred at low temperature for 0.5 h. Then compound A-2 (4.3g, 33.3mmol) was slowly added dropwise. After the dropwise addition, the temperature was raised to 90 ° C for 10 hours. The reaction solution was extracted with DCM (50ml × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1) to obtain 3.1 g of a white solid in a yield of 72%. LC-MS (APCI): m / z = 158.21.06 (M + 1) + .

[0194]
Step 3 Synthesis of Compound A-5

[0195]
Under nitrogen protection, compound A-4 (3.0 g, 19.1 mmol) was added to a solution of anhydrous THF (40 ml), and the temperature was lowered to -5 ° C, and CH 3 MgBr (19.1 ml, 57.3 mmol, 3 ml / L) was added dropwise . Anhydrous THF solution. After the dropwise addition was completed, the temperature was gradually raised to reflux for 4 h. The reaction was quenched with saturated ammonium chloride, then the pH was adjusted to neutral with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (50 ml × 3). The phases were dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 2: 3) to obtain 2.0 g of a yellow solid with a yield of 61%. LC-MS (APCI): m / z = 175.21.06 (M + 1) + .

[0196]
Step 4 Synthesis of Compound A-6

[0197]
Compound A-5 (2.0g, 11.5mmol), PTSA (4.2g, 23.0mmol) were added to the acetonitrile (15ml) solution, and after dropping to 0 ° C, sodium nitrite (1.43g, 20.7mmol) and Aqueous solution (5 ml) of potassium iodide (3.82 g, 23.0 mmol). The reaction solution was reacted at room temperature for 3 hours, and extracted with ethyl acetate (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain 2.5 g of an orange solid with a yield of 75%.

[0198]
Step 5 Synthesis of Compound A-8

[0199]
Under nitrogen protection, compound A-6 (2.0 g, 7.01 mmol) was added to a DMF (15 ml) solution, and the temperature was raised to 120 ° C. Then compound A-7 (1.9 g, 10.5 mmol, 10 ml) was added at 120 ° C. The reaction was stirred for 0.5h. Dichloromethane (30ml × 3) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was separated by column. ) To obtain 1.9 g of the product in a yield of 80%. LC-MS (APCI): m / z = 341.06 (M + 1) + .

[0200]
Step 6 Synthesis of Compound A-9

[0201]
Under nitrogen protection, compound A-8 (1.9 g, 5.6 mmol) and guanidine carbonate (1.6 g, 12.8 mmol) were sequentially added to the NMP (20 ml) solution. At the same time, a water separation device was set up to raise the solution to 130 ° C. The reaction was stirred at 130 ° C for 10 hours. After the reaction was completed, dichloromethane (30ml × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was separated by column (eluent: petroleum ether / ethyl acetate (v / v) = 2: 3), 1.5 g of product was obtained with a yield of 81%. LC-MS (APCI): m / z = 336.86 (M + 1) + .

[0202]
Step 7 Synthesis of Compound A-10

[0203]
Compound A-9 (1.5 g, 4.5 mmol) was added to the TFA (15 ml) solution. After reducing to 0 ° C, sodium nitrite (0.93 g, 13.4 mmol) was added as a solid. The reaction solution was reacted at room temperature for 1 h. Extract with ethyl acetate (30ml × 3), combine the organic phases, dry over anhydrous sodium sulfate, spin dry the oil with MTBE (10ml), and filter to obtain 1.3g of white solid, 87% yield, LC-MS (APCI) : m / z = 338.15 (M + 1) + .

[0204]
Step 8 Synthesis of intermediate compound A

[0205]
Compound A-10 (1.3 g, 3.86 mmol) was added to a solution of POCl 3 (15 ml), and the temperature was raised to 110 ° C., and the reaction was refluxed at this temperature for 10 h. After the reaction was completed, the reaction solution was spin-dried and dichloromethane (30 ml × 2) Extraction, combined organic phases, dried over anhydrous sodium sulfate, and column separation of the concentrated solution (eluent: petroleum ether / ethyl acetate (v / v) = 4: 1), 1.0 g of product was obtained, yield 73% . LC-MS (APCI): m / z = 356.32 (M + 1) + .

[0206]
Preparation of intermediate B (S)-(methyl-d 3) (1-aminoprop-2-yl) aminocarbonate.

[0208]
Use the following route for synthesis:

[0209]

[0207]
WO2020011141 / pic / -0strXxact6b2WUIRF3g-qYghbCelI38aof_aRxWyEeaR72see_zBNkAfrwxU-jzi8mdXg4_x4dVwb8bvcLmC0ELLoGLnitco1K2i6cFdUmLPY-LVCRcRcRiOsrQrCsIrOc

[0208]
Use the following route for synthesis:

[0209]
WO2020011141 / pic / luvqF_emaX_eXgTd5ug-arAL8ywwxiu1gGgclql8FZMllvX_6O0eC2cCrB0EEspypcf5ZTRPbOib3MqPf8rPV8752UgYWY2ZwOYZY

[0210]
Step 1 Synthesis of Compound B-2

[0211]
Compound B-1 (1.3 g, 4.5 mmol) was dissolved in a toluene (15 ml) solution, the temperature was lowered to 0 ° C, and CD 3 OD (0.5 g, 15 mmol) and triethylamine (1.7 g, 17 mmol) in toluene were added dropwise . (10ml) solution, reacted at room temperature for 2h after the dropwise addition, washed three times with ice water, dried over anhydrous sodium sulfate, filtered to obtain a toluene solution of compound B-2, and directly used in the next step.

[0212]
Step 2 Synthesis of Compound B-4

[0213]
At 0 ° C, the hydrochloride (0.5 g, 2.4 mmol) and triethylamine (0.73 g, 7.2 mmol) of compound B-3 were added to a solution of dichloromethane (10 ml) in this order, and one step of compound B was added dropwise. -2 toluene solution, reacted for 5 hours at room temperature after the addition, quenched by adding water (10ml), extracted with dichloromethane (20ml × 3), combined organic phases, dried over anhydrous sodium sulfate, and concentrated the column for separation (elution Agent: petroleum ether / ethyl acetate (v / v) = 4: 1), 0.45 g of white solid product was obtained with a yield of 80%.

[0214]
Step 3 Synthesis of intermediate compound B

[0215]
At 0 ° C, a solution of 4M hydrochloric acid in dioxane (4ml) was slowly added to a solution of compound B-4 (0.45g, 1.9mmol) in dichloromethane (10ml), and the reaction was continued at room temperature for 6h. After the reaction was completed, the solution was spin-dried, petroleum ether (10 ml) was slurried, and 0.2 g of the product was obtained by suction filtration with a yield of 77%.

[0216]
Preparation of intermediate C (1-aminoprop-2-yl-1,1,3,3,3-d 5) carbamate.

[0218]
Use the following route for synthesis:

[0219]

[0217]
WO2020011141 / pic / bZLBsYoBZtulvxpYYI8e5PX_miQYNGkgLgTUstJSMH5SqupQ2PJkQONEOn2GgxHGWmCDZMa-2G5AAvETeF0Qc5Isx_T67ZCJL4_fm2

[0218]
Use the following route for synthesis:

[0219]
WO2020011141 / pic / NoYKNLy2Fhdd3EaVaPfdnESILNKxV3p8R23Zhj7ewo2iRP1aX1fafA7EijayZQiw1sBGSuhkSMC5kcA3OJoo4VaSIpow2Qpww2wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwzw

[0220]
Step 1 Synthesis of compound C-3

[0221]
A mixture of compound C-2 (4.6 g, 61.8 mmol), compound C-1 (11.5 g, 67.6 mmol) and sodium hydroxide (7.16 g, 67.7 mmol) in water (60 ml) was stirred and reacted at 0 ° C for 3 h. After the reaction was completed, water (60 ml) was added, and the mixture was extracted with ethyl acetate (60 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 10: 1), 11.2 g of an oily substance was obtained, and the yield was 88%.

[0222]
Step 2 Synthesis of Compound C-4

[0223]
Under a nitrogen atmosphere, DMSO (4.8 g, 61.5 mmol) was slowly added to a solution of oxalyl chloride (6.0 g, 47.2 mmol) in DCM (60 ml) at -78 ° C, and the mixture was stirred at -78 ° C for half an hour. Then, a solution of compound C-3 (8.0 g, 38.2 mmol) in DCM (20 ml) was added to the mixture, and the mixture was further stirred at -78 ° C for 1 h, and then triethylamine (16 ml) was added to the mixture, and the mixture was raised to At room temperature, it was washed with 1N hydrochloric acid (50ml) and sodium bicarbonate aqueous solution (50ml) successively. The organic phase was dried over anhydrous sodium sulfate, heat-shrinked, and then slurried with a volume ratio of PE: EA = 8: 1 to obtain 5.3g of a white solid product. The rate is 87%.

[0224]
Step 3 Synthesis of Compound C-5

[0225]
1,5,7-Triazabicyclo [4.4.0] dec-5-ene (0.27 g, 1.9 mmol) was added to a solution of compound C-4 (4.0 g, 19.3 mmol) in deuterated chloroform (30 ml) After the reaction solution was stirred at room temperature for 30 hours, water (10 ml) was added to quench the reaction, and the organic phase was separated and washed with saturated sodium chloride. The organic phase was dried and spin-dried to obtain 3.9 g of an oil with a yield of 98%.

[0226]
Step 4 Synthesis of compound C-6

[0227]
Under a nitrogen atmosphere, compound C-5 (4.0 g, 18.9 mmol) and tert-butylsulfinamide (2.7 g, 22.6 mmol) were added to the THF (60 ml) solution, and tetraisopropyl titanate was added at room temperature. Ester (11.8 g, 41.5 mmol), and then heated to 60 ° C for 3 h. The reaction solution was cooled to room temperature, quenched by adding water, and extracted with ethyl acetate (60 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate ( v / v) = 4: 1), 3.5 g of product was obtained with a yield of 58%. LC-MS (APCI): m / z = 315.80 (M + 1) + .

[0228]
Step 5 Synthesis of compound C-7

[0229]
At -50 ° C, NaBH 4 (0.73 g, 19.1 mmol) was added to a solution of compound C-6 (2.0 g, 6.3 mmol) in methanol (20 ml), and then the reaction was continued at low temperature for 1 h. 1M hydrochloric acid was added to quench the reaction, and the mixture was extracted with dichloromethane (30 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain 2.1 g of an oily product.

[0230]
Step 6 Synthesis of compound C-8

[0231]
A solution of 4M hydrochloric acid in dioxane (10 ml) was slowly added to a solution of compound C-7 (2.0 g, 6.3 mmol) in dichloromethane (20 ml) at 0 ° C, and the reaction was continued at 0 ° C for 6 h. After the reaction is completed, the solvent is spin-dried and directly used in the next step without further processing.

[0232]
Step 7 Synthesis of compound C-9

[0233]
Triethylamine (1.43 g, 14.1 mmol) was added to a solution of compound C-8 (1.5 g, 7.0 mmol) in dichloromethane (20 ml) at 0 ° C, and methyl chloroformate was added dropwise to the mixture. (0.8g, 8.5mmol), and react at room temperature for 5 hours after the addition. After the reaction is complete, water (10ml) is added to quench the reaction. The reaction solution is extracted with dichloromethane (20ml × 2). Sodium was dried, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 4: 1) to obtain 1.1 g of a white solid product with a yield of 58%.

[0234]
Step 8 Synthesis of intermediate compound C

[0235]
Under a hydrogen atmosphere, Pd-C (0.2g, 10%) was added to the compound C-9 (1.0g, 3.7mmol) in ethanol (5ml) and a 1N hydrochloric acid solution (5ml), and the reaction was stirred for 5h. After the reaction was completed, It was filtered and the filtrate was directly concentrated to obtain 0.4 g of the product.

[0236]
Example 1 (S) -methyl- (1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (propan-2-yl -d 7) Preparation of 1H-pyrazol-4-yl) pyrimidin-2-yl) amino) propan-2-yl) carbamate (compound L-1).

[0238]
Use the following route for synthesis:

[0239]

[0237]
WO2020011141 / pic / 3xtiuTx657XV12_fky8oaKP_xXwX4wCXzmrOFYj-6WrLGfn7RokqPCy3lz6vK0t_oUjqoYktURzPEI8R4Z4fga0Yw0QXQQWYQZYUZTYWYQT

[0238]
Use the following route for synthesis:

[0239]
WO2020011141 / pic / kZCwkP7P-x1L3nCmUBMv9tcq80zMDMHYE9GLLB13iwjtMkE58H7GHYCHtBFrk_OoAPcX1xuC9dLyLTpjsyBA2GaUqv2D2XU2C2R2C2R2C2R2C2B2C2D2C2C2B2

[0240]
Step 1 Synthesis of Compound 2

[0241]
Under nitrogen protection, intermediate compound A (1.0 g, 2.8 mmol), compound 1 (0.52 g, 3.1 mmol), and sodium carbonate (1.2 g, 11.2 mmol) were sequentially added to the DMSO (20 ml) solution, and the temperature was raised to 90 ° C. The reaction was stirred at this temperature for 16h. After the reaction was completed, DCM (30ml × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was separated by column (eluent: petroleum ether / ethyl acetate (v / v) = 1: 2), 0.8 g of product was obtained with a yield of 63%. LC-MS (APCI): m / z = 452.33 (M + 1) + .

[0242]
Step 2 Synthesis of Compound 4

[0243]
Under nitrogen protection, compound 2 (0.5 g, 1.11 mmol), compound 3 (0.5 g, 1.33 mmol), sodium carbonate (0.47 g, 4.43 mmol), and Pd (dppf) Cl2 (0.09 g, 0.11 mmol) were added in this order. Into a mixed solution of toluene (20 ml) and water (4 ml), heated to 80 ° C. for 2 h. The reaction solution was cooled to room temperature, extracted with ethyl acetate (30 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1) 0.2 g of product was obtained with a yield of 31%. LC-MS (APCI): m / z = 569.09 (M + 1) + .

[0244]
Step 3 Synthesis of Compound 5

[0245]
At 0 ° C, a solution of 4M hydrochloric acid in dioxane (4ml) was slowly added to a solution of compound 4 (0.2g, 0.35mmol) in DCM (10ml), and the reaction mixture was warmed to room temperature for 6h. After the reaction is complete, the solution is spin-dried and directly sent to the next step without further processing. LC-MS (APCI): m / z = 469.27 (M + 1) + .

[0246]
Step 4 Synthesis of Compound L-1

[0247]
Compound 5 (0.15 g, 0.32 mmol) and triethylamine (0.16 g, 1.6 mmol) were sequentially added to the DCM (10 ml) solution. After the temperature was lowered to 0 ° C, MsCl (0.11 g, 1.0 mmol) was slowly added dropwise. After the addition was completed, the reaction temperature was raised to room temperature for 5 hours. After the reaction was completed, the reaction solution was spin-dried to obtain a residue. Toluene (9 ml), methanol (1 ml), water (10 ml), and sodium carbonate (2 g) were sequentially added to the residue. The reaction temperature was raised to 85 ° C for 10 hours, cooled to room temperature, and extracted with ethyl acetate (20ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: dichloromethane / methanol (v / v) = 20: 1), 50 mg of product was obtained with a yield of 35%. LC-MS (APCI): m / z = 547.31 (M + 1) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.08 (d, J = 11.4 Hz, 2H), 7.61 (d, J = 6.3 Hz, 1H), 7.42 (d, J = 5.6 Hz, 1H), 6.48 (d , J = 5.1 Hz, 1H), 5.32 (d, J = 18.8 Hz, 1H), 5.17 (s, 1H), 4.59 (d, J = 13.2 Hz, 1H), 3.79 (s, 1H), 3.61 (s , 3H), 3.24 (s, 1H), 2.98 (d, J = 16.6Hz, 3H), 2.01 (s, 1H), 1.31 (s, 3H).

[0248]
Example 2 (S)-(methyl-d 3)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1-iso Preparation of propyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) propan-2-yl) carbamate (compound L-2).

[0249]
WO2020011141 / pic / tVDfDEoOqWI5X7v8Kaju3q5h9JqkTve6llLuavobFC_1bh4Bp_PcG7AbdlZy5eFwRexqa8OY2mQ_WQBTMQu5Ce-x7qWisFmuvIijUJGQ7JhMqHf6vDSCLDW8ySQjx0v3LUA6YMGFZwOYZJznC59drnUBFfVdu6tdIqqvonWRiGg “>

[0250]
Use the following route for synthesis:

[0251]
WO2020011141 / pic / m9mXD-mrSGFj20R47ROzFF6keVQ70kCzBace3esKjuDXwTUrjQQweunbgPzPIPpGrRj1It6FgZXqv5ywjyC2eHI6VD0F0D0f0FJ1DKfY1D1KVFY1D1F1D1F2D2F2D2F2D2D2D2F2D2D2D2D2D2D2D2D2D2D2D2D2D2D2D2D2D2D2D2d2d2d2d2d2ddffd1d2d2dffd2d2dffd2ddfffd1d2d2dffd1ddffj1nKixYeQ2ohmGYVDVF7F7R2

[0252]
Step 1 Synthesis of compound 7

[0253]
Under nitrogen protection, compound 6 (0.5 g, 1.5 mmol), intermediate compound B (0.2 g, 1.5 mmol), and sodium carbonate (0.63 g, 6.0 mmol) were sequentially added to the DMSO (20 ml) solution, and the temperature was raised to 90 ° C. The reaction was stirred at this temperature for 16h. After the reaction was completed, DCM (30ml × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was separated by column (eluent: petroleum ether / ethyl acetate (v / v) = 1: 2), 0.42 g of product was obtained in a yield of 65%. LC-MS (APCI): m / z = 447.80 (M + 1) + .

[0254]
Step 2 Synthesis of Compound 8

[0255]
Under nitrogen protection, compound 7 (0.4 g, 0.90 mmol), compound 3 (0.4 g, 1.07 mmol), sodium carbonate (0.38 g, 3.6 mmol), and Pd (dppf) Cl2 (0.07 g, 0.09 mmol) were added in this order. Into a mixed solution of toluene (20 ml) and water (4 ml), the mixture was heated to 80 ° C. and reacted for 2 h. The reaction solution was cooled to room temperature, extracted with ethyl acetate (30 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1) 0.2 g of product was obtained with a yield of 40%. LC-MS (APCI): m / z = 565.03 (M + 1) + .

[0256]
Step 3 Synthesis of Compound 9

[0257]
At 0 ° C, a solution of 4M hydrochloric acid in dioxane (4 ml) was slowly added to a solution of compound 8 (0.2 g, 0.35 mmol) in DCM (10 ml), and the reaction mixture was warmed to room temperature and continued to react for 6 h. After the reaction is complete, the solution is spin-dried and directly sent to the next step without further processing. LC-MS (APCI): m / z = 465.27 (M + 1) + .

[0258]
Step 4 Synthesis of Compound L-2

[0259]
Compound 9 (0.2 g, 0.43 mmol) and triethylamine (0.22 g, 2.1 mmol) were sequentially added to the DCM (10 ml) solution. After lowering to 0 ° C, MsCl (0.15 g, 1.3 mmol) was slowly added dropwise. After the addition was completed, the reaction temperature was raised to room temperature for 5 hours. After the reaction was completed, the reaction solution was spin-dried to obtain a residue. Toluene (9 ml), methanol (1 ml), water (10 ml), and sodium carbonate (2 g) were sequentially added to the residue. The reaction temperature was raised to 85 ° C for 10 hours, cooled to room temperature, and extracted with ethyl acetate (20ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: dichloromethane / methanol (v / v) = 20: 1), 70 mg of product was obtained with a yield of 30%. LC-MS (APCI): m / z = 543.21 (M + 1) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.01 (d, J = 11.4 Hz, 2H), 7.63 (d, J = 6.3 Hz, 1H), 7.40 (d, J = 5.8 Hz, 1H), 6.58 (d , J = 6.1 Hz, 1H), 5.47 (d, J = 18.8 Hz, 1H), 5.17 (s, 1H), 4.59 (d, J = 12.2, Hz, 1H), 3.80 (s, 1H), 3.61 ( s, 1H) 3.24 (s, 1H), 3.10 (d, J = 16.6 Hz, 3H), 2.21 (s, 1H), 1.35 (s, 3H), 1.27 (d, 6H).

[0260]
Example 3 (S)-(methyl-d 3)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- ( Preparation of prop-2-yl-d 7) -1H-pyrazol-4 -yl) pyrimidin-2-yl) amino) prop-2-yl) carbamate (compound L-3).

[0261]
WO2020011141 / pic / iqj6pvdjjM4HOwS5mON3pOQ9HR7saOazmNYNpzaiXojjcGBiI6WDlFm3cKezb4yS-LlWgLP3UOsiRLU-U82AHxNXxfErtH82vSuy7aRZyypOhFxSIKcmsU1IrgUTfZfHvHyV7GUrqgilmX3Uhs5HqB4J8lAtCQzt3Usg8oMeezs “>

[0262]
Take the following synthetic route:

[0263]
WO2020011141 / pic / YwVS_N4uouPkEHjeYuqZOHrNDrfCXIg0xzYvgPjs2CnKzWkQFiTy2WMm9EsgMfhElppKsKCS5sgXcDsnhYWWYWWYWWYVWYWYWW

[0264]
Step 1 Synthesis of compound 10

[0265]
Under nitrogen protection, intermediate compound A (0.6 g, 1.7 mmol), intermediate compound B (0.23 g, 1.7 mmol), and sodium carbonate (0.71 g, 6.8 mmol) were added to the DMSO (20 ml) solution in this order, and the temperature was raised to The reaction was stirred at 90 ° C for 16h at this temperature. After the reaction was completed, DCM (30ml × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate ( v / v) = 1: 2), 0.65 g of product was obtained with a yield of 84%. LC-MS (APCI): m / z = 454.92 (M + 1) + .

[0266]
Step 2 Synthesis of Compound 11

[0267]
Under nitrogen protection, compound 10 (0.6 g, 1.3 mmol), compound 3 (0.59 g, 1.6 mmol), sodium carbonate (0.56 g, 5.3 mmol), and Pd (dppf) Cl2 (0.10 g, 0.13 mmol) were added in this order. Into a mixed solution of toluene (20 ml) and water (4 ml), heated to 80 ° C. for 2 h. The reaction solution was cooled to room temperature, extracted with ethyl acetate (30 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1) 0.32 g of the product was obtained with a yield of 43%. LC-MS (APCI): m / z = 572.10 (M + 1) + .

[0268]
Step 3 Synthesis of Compound 12

[0269]
At 0 ° C, a solution of 4M hydrochloric acid in dioxane (4 ml) was slowly added to a solution of compound 11 (0.3 g, 0.52 mmol) in DCM (10 ml), and the reaction mixture was warmed to room temperature and continued to react for 6 h. After the reaction is complete, the solution is spin-dried and directly sent to the next step without further processing. LC-MS (APCI): m / z = 472.09 (M + 1) + .

[0270]
Step 4 Synthesis of Compound L-3

[0271]
Compound 12 (0.25 g, 0.53 mmol) and triethylamine (0.27 g, 2.6 mmol) were sequentially added to the DCM (10 ml) solution. After dropping to 0 ° C, MsCl (0.18 g, 1.6 mmol) was slowly added dropwise. After the addition was completed, the reaction temperature was raised to room temperature for 5 hours. After the reaction was completed, the reaction solution was spin-dried to obtain a residue. Toluene (9 ml), methanol (1 ml), water (10 ml), and sodium carbonate (2 g) were sequentially added to the residue. The reaction temperature was raised to 85 ° C for 10 hours, cooled to room temperature, and extracted with ethyl acetate (20ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: dichloromethane / methanol (v / v) = 20: 1), 75 mg of product was obtained with a yield of 26%. LC-MS (APCI): m / z = 550.29 (M + 1) + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, J = 11.4 Hz, 2 H), 7.63 (d, J = 6.3 Hz, 1 H), 7.40 (d, J = 5.8 Hz, 1 H), 6.65 (d , J = 6.1 Hz, 1H), 5.47 (d, J = 18.8 Hz, 1H), 5.17 (s, 1H), 4.63 (d, J = 12.2, Hz, 1H), 3.70 (s, 1H), 3.54 ( s, 1H), 3.16 (d, J = 16.6 Hz, 3H), 2.11 (s, 1H), 1.38 (s, 3H).

[0272]
Example 4 (1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl) -1H-pyrazole- 4- yl) pyrimidin-2-yl) amino ) propan-2-yl -1,1,3,3,3-d 5) carbamate (compound L-4),

[0273]
(S)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl) -1H-pyrazole 4-yl) pyrimidin-2-yl) amino) propan-2- yl-1,1,3,3,3-d 5) methyl carbamate (compound L-4-S) and

[0274]
(R)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl) -1H-pyrazole 4-yl) pyrimidin-2-yl) amino) propan-2- yl-1,1,3,3,3-d 5) Preparation of methyl carbamate (compound L-4-R).

[0275]
WO2020011141 / pic / m0IN31dnhItfm5H-dGFizFalHv9quUKvHfmY4zFpAaHFgTp-0iUzxdHuZwlvRxqTStKdio_PlNaIPfHi8pthED3hbMalT8GyFmZ1tCDOIKmutZCiuLJ4FJW4WY

[0276]
Take the following synthetic route:

[0277]
WO2020011141 / pic / fjV2PIKmugqfUgshQfiVwrkjSTGfhIl9ZWz96JIiDMEhwjAlTOxFStuhxFFooUqAr0FVv7GXsyKUDxeLYZl-uQQWMt1C9_9Zi9U9U9Zi9U9U

[0278]
Step 1 Synthesis of compound 13

[0279]
Under nitrogen protection, compound 6 (0.4 g, 1.1 mmol), intermediate compound C (0.16 g, 1.1 mmol), and sodium carbonate (0.50 g, 4.6 mmol) were sequentially added to the DMSO (15 ml) solution, and the solution was raised to The reaction was stirred at 90 ° C at this temperature for 16 hours. After the reaction was completed, the reaction solution was extracted with dichloromethane (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether). / Ethyl acetate (v / v) = 1: 2) to obtain 0.40 g of the product in a yield of 75%. LC-MS (APCI): m / z = 449.53 (M + 1) + .

[0280]
Step 2 Synthesis of Compound 14

[0281]
Under a nitrogen atmosphere, compound 13 (0.4 g, 0.9 mmol), compound 3 (0.5 g, 1.4 mmol), sodium carbonate (0.40 g, 3.56 mmol), and Pd (dppf) Cl 2 (0.08 g, 0.1 mmol) were added in this order. Into a mixed solution of toluene (20 ml) and water (4 ml), heated to 80 ° C. for 2 h. The reaction solution was cooled to room temperature, and then extracted with ethyl acetate (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1), 0.28 g of product was obtained with a yield of 55%. LC-MS (APCI): m / z = 567.12 (M + 1) + .

[0282]
Step 3 Synthesis of Compound 15

[0283]
At 0 ° C, a solution of 4M hydrochloric acid in dioxane (2ml) was slowly added to a solution of compound 14 (0.28g, 0.50mmol) in dichloromethane (10ml), and the reaction was continued at room temperature for 6h. After the reaction is completed, the solution is directly spin-dried and directly sent to the next step without further processing. LC-MS (APCI): m / z = 467.29 (M + 1) + .

[0284]
Step 4 Synthesis of compound L-4

[0285]
Triethylamine (0.13 g, 1.28 mmol) was added to a solution of compound 15 (0.2 g, 0.43 mmol) in dichloromethane (10 ml). After the solution was lowered to 0 ° C, methanesulfonyl chloride (0.15 g, 1.3 mmol) was slowly added dropwise to the upper solution. The reaction solution was reacted at room temperature for 5 hours. After the reaction was completed, the reaction solution was spin-dried. To the residue were added toluene (9 ml), methanol (1 ml), and water (10 ml). Sodium carbonate (2g), the solution was reacted at 85 ° C for 10h, the reaction solution was cooled to room temperature, and then extracted with ethyl acetate (20ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation ( Eluent: dichloromethane / methanol (v / v) = 20: 1) to obtain 65 mg of the product with a yield of 27%. LC-MS (APCI): m / z = 545.08 (M + 1) + . 1 H NMR (400MHz, CDCl 3 ) δ8.05 (d, 2H), 7.61 (d, 1H), 7.45 (d, 1H), 6.40 (d, 1H), 5.29 (d, 1H), 5.18 (s, 1H), 4.62 (d, 1H), 3.89 (d, 1H), 3.58 (s, 3H), 3.10 (d, 3H), 2.05 (s, 1H), 1.29 (d, 6H).

[0286]
Step 5 Synthesis of compounds L-4-S and L-4-R

[0287]
The racemic compound L-4 was separated using a chiral preparative column to obtain compounds L-4-S and L-4-R.

[0288]
Example 5 (1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl-d 7))-1H -Pyrazol-4-yl) pyrimidin-2-yl) amino) propan-2-yl-1,1,3,3,3-d 5) methyl carbamate (compound L-5),

[0289]
(S)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl-d 7))- 1H-pyrazol-4-yl) pyrimidin-2-yl) amino) propan-2-yl-1,1,3,3,3-d 5) methyl carbamate (compound L-5-S) and

[0290]
(R)-(1-((4- (3- (5-chloro-2-fluoro-3- (methylsulfonylamino) phenyl) -1- (prop-2-yl-d 7))- 1H-pyrazol-4-yl) pyrimidin-2-yl) amino) propan-2-yl-1,1,3,3,3-d 5) Preparation of methyl carbamate (compound L-5-R) .

[0291]
WO2020011141 / pic / 4br07jLUTScNPUcnWdxxTyAAMGS9P15P0yXUsyhcCny-ABv5BZExa5YOY-Hj3wTZWdByUUB-EQbGG-h4QuoddgCTRMClBcl1WY1TjnTsnDDYTZxC6-taMQZYW1Z1WY

[0292]
WO2020011141 / pic / By6lfXwpBcoklf-47-VujG_XNVWV7ZjYOo73wMiKwo9v4cKff0K2As3lqLKG1kFOYG87EWp6SIobdq2gtEFMnxfVVVJVYVZGYZFYZVYG-ZVY-ZFY-ZF

[0293]
Take the following synthetic route:

[0294]
WO2020011141 / pic / dMfm7g9kIiR87Eo-VsdQ2-2wcdHuYsfKuUWOyKuR4SUJ3Kmoy907w2C1tLHvEDhc4vBBT2l48TSysgdivcFJmRqGQNZWYQZNYWQD

[0295]
Step 1 Synthesis of compound 16

[0296]
Under nitrogen protection, intermediate compound A (0.5 g, 1.5 mmol), intermediate compound C (0.2 g, 1.5 mmol), and sodium carbonate (0.63 g, 6.0 mmol) were added to the DMSO (20 ml) solution in this order. The temperature was raised to 90 ° C, and the reaction was stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was extracted with dichloromethane (30ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: Petroleum ether / ethyl acetate (v / v) = 1: 2) to obtain 0.45 g of the product with a yield of 68%. LC-MS (APCI): m / z = 456.68 (M + 1) + .

[0297]
Step 2 Synthesis of Compound 17

[0298]
Under a nitrogen atmosphere, compound 16 (0.45 g, 0.98 mmol), compound 3 (0.55 g, 1.54 mmol), sodium carbonate (0.42 g, 3.95 mmol), and Pd (dppf) Cl 2 (0.08 g, 0.1 mmol) were sequentially added Into a mixed solution of toluene (20 ml) and water (4 ml), heated to 80 ° C. for 2 h. The reaction solution was cooled to room temperature, and then extracted with ethyl acetate (30 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (eluent: petroleum ether / ethyl acetate (v / v) = 1: 1), 0.40 g of the product was obtained in a yield of 70%. LC-MS (APCI): m / z = 574.16 (M + 1) + .

[0299]
Step 3 Synthesis of Compound 18

[0300]
A solution of 4M hydrochloric acid in dioxane (2 ml) was slowly added to a solution of compound 17 (0.40 g, 0.70 mmol) in dichloromethane (10 ml) at 0 ° C, and the reaction was allowed to proceed to room temperature for 6 h. After the reaction is completed, the solution is directly spin-dried and directly sent to the next step without further processing. LC-MS (APCI): m / z = 474.21 (M + 1) + .

[0301]
Step 4 Synthesis of Compound L-5

[0302]
Triethylamine (0.23 g, 2.21 mmol) was added to a solution of compound 18 (0.35 g, 0.74 mmol) in dichloromethane (10 ml). After the solution was lowered to 0 ° C, methanesulfonyl chloride (0.25 g, 2.2 mmol) was slowly added dropwise to the upper solution. The reaction solution was reacted at room temperature for 5 hours. After the reaction was completed, the reaction solution was spin-dried. To the residue were added toluene (9 ml), methanol (1 ml), and water (10 ml). Sodium carbonate (2g), the solution was reacted at 85 ° C for 10h, the reaction solution was cooled to room temperature, and then extracted with ethyl acetate (20ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation Eluent: dichloromethane / methanol (v / v) = 20: 1) to obtain 120 mg of the product in a yield of 30%. LC-MS (APCI): m / z = 552.33 (M + 1) + . 1 H NMR (400MHz, CDCl 3 ) δ 8.02 (d, 2H), 7.61 (d, 1H), 7.45 (d, 1H), 6.40 (d, 1H), 5.22 (d, 1H), 5.18 (s, 1H), 4.59 (d, 1H), 3.58 (s, 3H), 2.98 (d, 3H), 2.05 (s, 1H).

[0303]
Step 5 Synthesis of compounds L-5-S and L-5-R

[0304]
The racemic compound L-4 was separated using a chiral preparative column to obtain compounds L-5-S and L-5-R.

GRAPIPRANT


Grapiprant.svg

Grapiprant.png

ChemSpider 2D Image | grapiprant | C26H29N5O3S

Structure of GRAPIPRANT

GRAPIPRANT

  • Molecular FormulaC26H29N5O3S
  • Average mass491.605 Da

CAS 415903-37-6

UNII-J9F5ZPH7NB, CJ 023423, CJ-023423,

Phase II, Arrys Therapeutics, CANCER,

PAIN, AskAt Phase II, 

N-{2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}-N’-[(4-methylphenyl)sulfonyl]urea
RQ-00000007, MR10A7
9763
AAT-007
Benzenesulfonamide, N-[[[2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]amino]carbonyl]-4-methyl-
CJ-023,423
  • N-[[[2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]amino]carbonyl]-4-methylbenzenesulfonamide
  • 1-[2-[4-(2-Ethyl-4,6-dimethylimidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]-3-(4-methylphenyl)sulfonylurea
  • 2-Ethyl-4,6-dimethyl-1-[4-[2-[[[[(4-methylphenyl)sulfonyl]amino]carbonyl]amino]ethyl]phenyl]-1H-imidazo[4,5-c]pyridine
  • AAT 007
  • CJ 023423
  • Grapiprant
  • MR 10A7
  • RQ 00000007
  • RQ 7

Synonyms and Mappings

  • 415903-37-6
  • GRAPIPRANT [GREEN BOOK]
  • CJ-023
  • GRAPIPRANT [INN]
  • GRAPIPRANT [WHO-DD]
  • MR-10A7
  • AAT-007
  • MR10A7
  • RQ-00000007
  • RQ-7
  • GRAPIPRANT [USAN]
  • GRAPIPRANT
  • 2-ETHYL-4,6-DIMETHYL-1-(4-(2-(((((4-METHYLPHENYL)SULFONYL)AMINO)CARBONYL)AMINO)ETHYL)PHENYL)-1H-IMIDAZO(4,5-C)PYRIDINE
  • N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYLBENZENESULFONAMIDE
  • CJ 023423
  • BENZENESULFONAMIDE, N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYL-
  • CJ-023,423
  • N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYL-BENZENESULFONAMIDE
  • CJ-023423

SYN

Arrys Therapeutics (under license from AskAt ) and affiliate Ikena Oncology (formerly known as Kyn Therapeutics ) are developing ARY-007 , an oral formulation of grapiprant, for treating cancers; in December 2019, preliminary data were expected in 2020

Grapiprant (trade name Galliprant) is a small molecule drug that belongs in the piprant class. This analgesic and anti-inflammatory drug is primarily used as a pain relief for mild to moderate inflammation related to osteoarthritis in dogs. Grapiprant has been approved by the FDA’s Center  for Veterinary  Medicine  and was  categorized  as a  non-cyclooxygenase inhibiting non-steroidal anti-inflammatory drug (NSAID) in March 2016.[1]

Preclinical studies also indicate that grapiprant is not only efficacious as a acute pain but also in chronic pain relief and inflammation drug. The effect of the drug is directly proportional to the dosage and its effects were comparable to human medication such as rofecoxib and piroxicam.[2]

Grapiprant, a prostanoid EP4 receptor antagonist, is in phase II clinical trials at AskAt for the treatment of chronic pain. Phase I/II clinical trials are ongoing at Arrys Therapeutics in combination with pembrolizumab for the treatment of patients with microsatellite stable colorectal cancer and in patients with advanced or metastatic PD-1/L1 refractory non-small cell lung cancer (NSCLC).

Grapiprant  is also  used  in humans,  and  was researched  to be  used  as a pain  control  and inflammation associated with osteoarthritis. The effect of grapiprant could be explained through the function of prostaglandin E2, in which acts as a pro-inflammatory mediator of redness of the skin, edema and pain which are the typical signs of inflammation. The effect of PGE2 stems from its action through the four prostaglandin receptor subgroups EP1, EP2, EP3 and EP4, in which the prostaglandin EP4 receptor acts as the main intermediary of the prostaglandin-E2-driven inflammation. Grapiprant is widely accepted in veterinary medicine due to its specific and targeted approach to pain management in dogs. The serum concentration of grapiprant is increased when used in conjunction with other drugs such as acetaminophenalbendazole, and alitretinoin.

Common side effects are intestinal related effects such as mild diarrhea, appetite loss, and vomiting.[3] Additionally, it is found that it might lead to reduced tear production due to it being a sulfa-based medication and also reduced albumin levels.

Grapiprant, a prostanoid EP4 receptor antagonist, is in phase II clinical trials at AskAt for the treatment of chronic pain. Phase I/II clinical trials are ongoing at Arrys Therapeutics in combination with pembrolizumab for the treatment of patients with microsatellite stable colorectal cancer and in patients with advanced or metastatic PD-1/L1 refractory non-small cell lung cancer (NSCLC).

Medical uses

Grapiprant is used once a day as an oral pain relief for dogs with inflammation-related osteoarthritis. It is a non-steroidal anti-inflammatory (NSAID) that functions as a targeted action to treat osteoarthritis pain and inflammation in dogs.

Mechanism of action

Grapiprant acts as a specific antagonist that binds and blocks the prostaglandin EP4 receptor, one out of the four prostaglandin E2 (PGE2) receptor subgroups. The EP4 receptor then mediates the prostaglandin-E2-elicited response to pain, and hence grapiprant was proven to be effective in the decrease of pain in several inflammatory pain models of rats. It was also proven to be effective in reducing osteoarthritis-related pain in humans, which serves as a proof for its mechanism of action. The approximate calculation for  canine efficacy  dose  is between the range of 1.3 and 1.7 mg/kg, in conjunction with a methylcellulose suspending agent. Based on the calculations from the comparisons of binding affinity of grapiprant to the EP4 receptors of  dogs, rats, and humans, the study of plasma and serum protein binding determinations, the effective doses determined in inflammation pain models of rats, and  human-related clinical  studies, it  is  evaluated that  Grapiprant should be administered just once a day. The approved dose of the commercial Grapiprant tablet by the FDA for the pain relief and inflammation associated with osteoarthritis to dogs is reported to be 2 mg/kg a day.[4]

Absorption

Studies in animals such as horses have shown the presence of Grapiprant in serum 72 hours with a concentration >0.005 ng/ml after the initial administration of a dose of 2 mg/kg. Grapiprant is expeditiously absorbed and the reported serum concentration was reported to be 31.9 ng/ml in an amount of time of 1.5 hours. The actual body exposure to grapiprant after administration of one dose was shown to be 2000 ng.hr/ml. The degree and rate at which grapiprant is absorbed into the body, presents a mean bioavailability of 39%. A significant reduction in the bioavailability, concentration time and maximal concentration were reported to have occurred after food intake.[1] And thus, grapiprant is usually not administered with food as it will not be as efficient.[5]

Distribution

The volume of distribution in cat studies was reported to be 918 ml/kg.[1]

Route of elimination

Following an oral administration, the majority of the dose was metabolized within the first 72 hours. Equine studies have shown that grapiprant is present in urine 96 hours after the first administration of a dose of 2 mg/kg and has a concentration >0.005 ng/ml. From the excreted dose conducted in horses, it is found that 55%, 15% and 19% of the orally-administered dose was excreted in bile, urine, and faeces respectively.[1]

Toxicity

Safety studies conducted on grapiprant have demonstrated that it generally possesses an exceptional safety profile and a wide safety margin in veterinary studies.[6] In animal studies, a research on 2.5-12 times overdose was conducted for grapiprant and the study resulted in soft-blobs and mucous-filled faeces, occasional bloody stools and emesis.

PATENT

WO-2020014465

Novel crystalline forms of grapiprant and their salts eg HCl (designated as Form A), useful for inhibiting prostaglandin EP4 receptor activity and treating cancers.

Prostaglandins are mediators of pain, fever and other symptoms associated with inflammation. Prostaglandin E2 (PGE2) is the predominant eicosanoid detected in inflammation conditions. In addition, it is also involved in various physiological and/or pathological conditions such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis or the like.

[0003] Four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) displaying different pharmacological properties exist. The EP4 subtype, a Gs-coupled receptor, stimulates cAMP production as well as PI3K and GSK3P signaling, and is distributed in a wide variety of tissue suggesting a major role in PGE2-mediated biological events. Various EP4 inhibitors have been described previously, for example, in WO 2002/032900, WO 2005/021508, EiS 6,710,054, and US 7,238,714, the contents of which are incorporated herein by reference in their entireties.

[0004] Accordingly, there is a need for treating, preventing, and/or reducing severity of a proliferative disorder associated with prostaglandin EP4 receptor activity. The present invention addresses such a need.

It has now been found that compounds of the present invention, and compositions thereof, are useful for treating, preventing, and/or reducing severity of a proliferative disorder associated with prostaglandin EP4 receptor activity. In general, salt forms and co-crystal forms, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of proliferative disorders associated with prostaglandin EP4 receptor activity, as described in detail herein. Such compounds are represented by the chemical structure below, denoted as compound A (also known as grapiprant):

A

or a pharmaceutically acceptable salt thereof.

United States Patent 7,960,407, filed March 1, 2006 and issued June 14, 2011 (“the ‘407 patent,” the entirety of which is hereby incorporated herein by reference), describes certain EP4 inhibitor compounds. Such compounds include compound A:

or a pharmaceutically acceptable salt thereof.

[0037] Compound A, N-[({2-[4-(2-Ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin-l-yl) phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide, is described in detail in the ‘407

patent, including its synthetic route. The ‘407 patent also discloses a variety of physical forms of compound A.

[0038] It would be desirable to provide a solid form of compound A (e.g., as a co-crystal thereof or salt thereof) that imparts characteristics such as improved aqueous solubility, stability and ease of formulation. Accordingly, the present invention provides both co-crystal forms and salt forms of compound A:

A.

PATENT

WO 2002032900

PATENT

WO 2002032422

Family members of the product case ( WO0232422 ) of grapiprant have protection in most of the EU states until October 2021 and expire in the US in October 15, 2021.

PATENT

WO 2003086371

PATENT

WO2020014445 covering combinations of grapiprant and an immuno-oncology agent.

WO 2005102389

WO 2006095268

US 7960407

US 20190314390

References

  1. Jump up to:a b c d “Grapiprant”http://www.drugbank.ca. Retrieved 2019-05-15.
  2. ^ PubChem. “Grapiprant”pubchem.ncbi.nlm.nih.gov. Retrieved 2019-05-15.
  3. ^ Paul Pion, D. V. M.; Spadafori, Gina (2017-08-08). “Veterinary Partner”VIN.com.
  4. ^ Nagahisa, A.; Okumura, T. (2017). “Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs”. Journal of Veterinary Pharmacology and Therapeutics40 (3): 285–292. doi:10.1111/jvp.12349ISSN 1365-2885PMID 27597397.
  5. ^ Paul Pion, D. V. M.; Spadafori, Gina (2017-08-08). “Veterinary Partner”VIN.com.
  6. ^ Kirkby Shaw, Kristin; Rausch-Derra, Lesley C.; Rhodes, Linda (February 2016). “Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation”Veterinary Medicine and Science2 (1): 3–9. doi:10.1002/vms3.13ISSN 2053-1095PMC 5645826PMID 29067176.
Grapiprant
Grapiprant.svg
Clinical data
Trade names Galliprant
Routes of
administration
Oral
ATCvet code
Pharmacokinetic data
Bioavailability 6.6 L/kg, high volume of distribution
Elimination half-life 5.86 hours in horses
Excretion Urine
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C26H29N5O3S
Molar mass 491.61 g·mol−1
3D model (JSmol)

//////////////GRAPIPRANT, 415903-37-6, UNII-J9F5ZPH7NB, CJ 023423, CJ-023423, RQ-00000007, MR10A7, Galliprant, Phase II, Arrys Therapeutics, CANCER, PAIN, AskAt

CCC1=NC2=C(N1C3=CC=C(C=C3)CCNC(=O)NS(=O)(=O)C4=CC=C(C=C4)C)C=C(N=C2C)C

Brilliant blue G , ブリリアントブルーG ,


Brilliant Blue G.png

2D chemical structure of 6104-58-1

Brilliant blue G

FDA 2019, 12/20/2019, TISSUEBLUE, New Drug Application (NDA): 209569
Company: DUTCH OPHTHALMIC, PRIORITY; Orphan

OPQ recommends APPROVAL of NDA 209569 for commercialization of TissueBlue (Brilliant Blue G Ophthalmic Solution), 0.025%

Neuroprotectant

sodium;3-[[4-[[4-(4-ethoxyanilino)phenyl]-[4-[ethyl-[(3-sulfonatophenyl)methyl]azaniumylidene]-2-methylcyclohexa-2,5-dien-1-ylidene]methyl]-N-ethyl-3-methylanilino]methyl]benzenesulfonate

Formula
C47H48N3O7S2. Na
CAS
6104-58-1
Mol weight
854.0197

ブリリアントブルーG, C.I. Acid Blue 90

UNII-M1ZRX790SI

M1ZRX790SI

6104-58-1

Brilliant Blue G

Derma Cyanine G

SYN

////////////Brilliant blue G , ブリリアントブルーG , C.I. Acid Blue 90, FDA 2019, PRIORITY,  Orphan

CCN(CC1=CC(=CC=C1)S(=O)(=O)[O-])C2=CC(=C(C=C2)C(=C3C=CC(=[N+](CC)CC4=CC(=CC=C4)S(=O)(=O)[O-])C=C3C)C5=CC=C(C=C5)NC6=CC=C(C=C6)OCC)C.[Na+]

  • Benzenemethanaminium, N-[4-[[4-[(4-ethoxyphenyl)amino]phenyl][4-[ethyl[(3-sulfophenyl)methyl]amino]-2-methylphenyl]methylene]-3-methyl-2,5-cyclohexadien-1-ylidene]-N-ethyl-3-sulfo-, hydroxide, inner salt, monosodium salt
  • Benzenemethanaminium, N-[4-[[4-[(4-ethoxyphenyl)amino]phenyl][4-[ethyl[(3-sulfophenyl)methyl]amino]-2-methylphenyl]methylene]-3-methyl-2,5-cyclohexadien-1-ylidene]-N-ethyl-3-sulfo-, inner salt, monosodium salt (9CI)
  • Brilliant Indocyanine G (6CI)
  • C.I. Acid Blue 90 (7CI)
  • C.I. Acid Blue 90, monosodium salt (8CI)
  • Acid Blue 90
  • Acid Blue G 4061
  • Acid Blue PG
  • Acid Bright Blue G
  • Acid Brilliant Blue G
  • Acid Brilliant Cyanine G
  • Acidine Sky Blue G
  • Amacid Brilliant Cyanine G
  • Anadurm Cyanine A-G
  • BBG
  • Benzyl Cyanine G
  • Biosafe Coomassie Stain
  • Boomassie blue silver
  • Brilliant Acid Blue G
  • Brilliant Acid Blue GI
  • Brilliant Acid Blue J
  • Brilliant Acid Cyanine G
  • Brilliant Blue G
  • Brilliant Blue G 250
  • Brilliant Blue J
  • Brilliant Indocyanine GA-CF
  • Bucacid Brilliant Indocyanine G
  • C.I. 42655
  • CBB-G 250
  • Colocid Brilliant Blue EG
  • Coomassie Blue G
  • Coomassie Blue G 250
  • Coomassie Brilliant Blue G
  • Coomassie Brilliant Blue G 250
  • Coomassie G 250
  • Cyanine G
  • Daiwa Acid Blue 300
  • Derma Cyanine G
  • Derma Cyanine GN 360
  • Dycosweak Acid Brilliant Blue G
  • Eriosin Brilliant Cyanine G
  • Fenazo Blue XXFG
  • Impero Azure G
  • Kayanol Cyanine G
  • Lerui Acid Brilliant Blue G
  • Milling Brilliant Blue 2J
  • NSC 328382
  • Optanol Cyanine G
  • Orient Water Blue 105
  • Orient Water Blue 105S
  • Polar Blue G
  • Polar Blue G 01
  • Polycor Blue G
  • Sandolan Cyanine N-G
  • Sellaset Blue B
  • Serva Blue G
  • Serva Blue G 250
  • Silk Fast Cyanine G
  • Simacid Blue G 350
  • Sumitomo Brilliant Indocyanine G
  • Supranol Cyanin G
  • Supranol Cyanine G
  • TissueBlue
  • Triacid Fast Cyanine G
  • Water Blue 105
  • Water Blue 105S
  • Water Blue 150
  • Xylene Brilliant Cyanine G

Fluorodopa F 18, フルオロドパ (18F), флуородопа (18F) , فلورودوبا (18F) , 氟[18F]多巴 ,


92812-82-3.png

ChemSpider 2D Image | Fluorodopa F 18 | C9H1018FNO4

Fluorodopa F 18

2019/10/10, fda 2019,

Formula
C9H10FNO4
Cas
92812-82-3
Mol weight
215.1784

Diagnostic aid (brain imaging), Radioactive agent, for use in positron emission tomography (PET)

CAS 92812-82-3

フルオロドパ (18F)

L-6-(18F)Fluoro-DOPA
L-Tyrosine, 2-fluoro-18F-5-hydroxy- [ACD/Index Name]
флуородопа (18F) [Russian] [INN]
فلورودوبا (18F) [Arabic] [INN]
氟[18F]多巴 [Chinese] [INN]
((18)F)FDOPA
2-(fluoro-(18)F)-5-hydroxy-L-tyrosine
2-(Fluoro-18F)-5-hydroxy-L-tyrosine
2-(Fluoro-18F)-L-DOPA
2C598205QX
6-((18)F)fluoro-L-DOPA
6-(18F)Fluoro-L-DOPA
6692
(18F)FDOPA
2-((18)F)fluoro-5-hydroxy-L-tyrosine

Fluorodopa, also known as FDOPA, is a fluorinated form of L-DOPA primarily synthesized as its fluorine-18isotopologue for use as a radiotracer in positron emission tomography (PET).[1] Fluorodopa PET scanning is a valid method for assessing the functional state of the nigrostriatal dopaminergic pathway. It is particularly useful for studies requiring repeated measures such as examinations of the course of a disease and the effect of treatment

In October 2019, Fluorodopa was approved in the United States for the visual detection of certain nerve cells in adult patients with suspected Parkinsonian Syndromes (PS).[2][3]

The U.S. Food and Drug Administration (FDA) approved Fluorodopa F 18 based on evidence from one clinical trial of 56 patients with suspected PS.[2] The trial was conducted at one clinical site in the United States.[2]

PAPER

 Organic & Biomolecular Chemistry (2019), 17(38), 8701-8705

A one-pot two-step synthesis of 6-[18F]fluoro-L-DOPA ([18F]FDOPA) has been developed involving Cu-mediated radiofluorination of a pinacol boronate ester precursor. The method is fully automated, provides [18F]FDOPA in good activity yield (104 ± 16 mCi, 6 ± 1%), excellent radiochemical purity (>99%) and high molar activity (3799 ± 2087 Ci mmol−1), n = 3, and has been validated to produce the radiotracer for human use.

Graphical abstract: One-pot synthesis of high molar activity 6-[18F]fluoro-l-DOPA by Cu-mediated fluorination of a BPin precursor
Radiosynthesis of [ 18F]6F-l-DOPA The synthesis of [ 18F]6F-l-DOPA was fully-automated using a General Electric (GE) TRACERLab FXFN synthesis module (Figure S1) loaded as follows: V1: 500 µL 15mg/mL TBAOTf + 0.2 mg/mL Cs2CO3 in water; V2: 1000 µL acetonitrile; V3: 4 µmol Bpin precursor, 20 µmol Cu2+ , 500 µmol pyridine in 1 mL DMF; V4: 0.2 mL 0.25 M ascorbic acid + 0.6 mL 12.1 N HCl; V6: 3 mL acetonitrile; V7: 10 mL 0.9% saline, USP; V8: 2 mL ethanol, USP; Dilution flask: 100 mL acetonitrile ; F18 separation port: QMA cartridge ; C18 port: Strata cartridge.

PATENT

KR 2019061368

The present invention relates to an L-dopa precursor compd., a method for producing the same, and a method for producing 18F-labeled L-dopa using the same.  The method of prepg. 18F-labeled L-dopa I using the L-dopa precursor II [A = halogen-(un)substituted alkyl; W, X, Y = independently protecting group] can improve the labeling efficiency of 18F.  After the labeling reaction, sepn. and purifn. steps of the product can be carried out continuously and it can be performed with on-column labeling (a method of labeling through the column).  The final product I, 18 F-labeled L-dopa, can be obtained at a high yield relative to conventional methods.  Further, it has an advantage that it is easy to apply various methods such as bead labeling.

PAPER

Science (Washington, DC, United States) (2019), 364(6446), 1170-1174.

PAPER

European Journal of Organic Chemistry (2018), 2018(48), 7058-7065.

PATENT

WO 2018115353

CN 107311877

References

  1. ^ Deng WP, Wong KA, Kirk KL (June 2002). “Convenient syntheses of 2-, 5- and 6-fluoro- and 2,6-difluoro-L-DOPA”. Tetrahedron: Asymmetry13 (11): 1135–1140. doi:10.1016/S0957-4166(02)00321-X.
  2. Jump up to:a b c “Drug Trials Snapshots: Fluorodopa F 18”U.S. Food and Drug Administration (FDA). 27 November 2019. Archived from the original on 27 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.
  3. ^ “Drug Approval Package: Fluorodopa F18”U.S. Food and Drug Administration (FDA). 20 November 2019. Archived from the original on 27 November 2019. Retrieved 26 November 2019. This article incorporates text from this source, which is in the public domain.
Fluorodopa
Fluorodopa.png
Clinical data
Other names 6-fluoro-L-DOPA, FDOPA
License data
Legal status
Legal status
Identifiers
CAS Number
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C9H10FNO4
Molar mass 215.18 g/mol g·mol−1
3D model (JSmol)

//////////////////Fluorodopa F 18, フルオロドパ (18F), FDA 2019, флуородопа (18F) فلورودوبا (18F) 氟[18F]多巴 , radio labelled

N[C@@H](CC1=CC(O)=C(O)C=C1[18F])C(O)=O

Enfortumab vedotin


Image result for enfortumab vedotin

PADCEV™ (enfortumab vedotin-ejfv) Structural Formula - Illustration

Image result for enfortumab vedotin

2D chemical structure of 1346452-25-2

Enfortumab vedotin

Formula
C6642H10284N1742O2063S46
Cas
1346452-25-2
Mol weight
149022.148

AGS-22M6E, enfortumab vedotin-ejfv

Fda approved 2019/12/18, Padcev

Antineoplastic, Nectin-4 antibody, Tubulin polymerization inhibitor, Urothelial cancer

エンホルツマブベドチン (遺伝子組換え);

protein Based Therapies, Monoclonal antibody, mAb, 

UNII DLE8519RWM

Immunoglobulin G1, anti-(human nectin-4) (human monoclonal AGS-22C3 γ1-chain), disulfide with human monoclonal AGS-22C3 κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide

Other Names

  • AGS 22CE
  • AGS 22M6E
  • AGS 22ME
  • Enfortumab vedotin
  • Enfortumab vedotin-ejfv
  • Immunoglobulin G1 (human monoclonal AGS-22M6 γ1-chain), disulfide with human monoclonal AGS-22M6 κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide
  • Padcev

Protein Sequence

Sequence Length: 1322, 447, 447, 214, 214multichain; modified (modifications unspecified)

Enfortumab vedotin is an antibody-drug conjugate used in the treatment of patients with advanced, treatment-resistant urothelial cancers.3 It is comprised of a fully human monoclonal antibody targeted against Nectin-4 and a microtubule-disrupting chemotherapeutic agent, monomethyl auristatin E (MMAE), joined by a protease-cleavable link.3 It is similar to brentuximab vedotin, another antibody conjugated with MMAE that targets CD-30 instead of Nectin-4.

The clinical development of enfortumab vedotin was the result of a collaboration between Astellas Pharma and Seattle Genetics2 and it was first approved for use in the United States in December 2019 under the brand name PadcevTM.3
The most common side effects for patients taking enfortumab vedotin were fatigue, peripheral neuropathy (nerve damage resulting in tingling or numbness), decreased appetite, rash, alopecia (hair loss), nausea, altered taste, diarrhea, dry eye, pruritis (itching) and dry skin. [4]Enfortumab vedotin[1] (AGS-22M6E) is an antibody-drug conjugate[2] designed for the treatment of cancer expressing Nectin-4.[3]Enfortumab refers to the monoclonal antibody part, and vedotin refers to the payload drug (MMAE) and the linker.

The fully humanized antibody was created by scientists at Agensys (part of Astellas) using Xenomice from Amgen; the linker technology holding the antibody and the toxin together was provided by and licensed from Seattle Genetics.[5]

Results of a phase I clinical trial were reported in 2016.[2]

In December 2019, enfortumab vedotin-ejfv was approved in the United States for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy.[4]

Enfortumab vedotin was approved based on the results of a clinical trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy.[4] The overall response rate, reflecting the percentage of patients who had a certain amount of tumor shrinkage, was 44%, with 12% having a complete response and 32% having a partial response.[4] The median duration of response was 7.6 months.[4]

The application for enfortumab vedotin-ejfv was granted accelerated approvalpriority review designation, and breakthrough therapydesignation.[4] The U.S. Food and Drug Administration (FDA) granted the approval of Padcev to Astellas Pharma US Inc.[4]

Indication

Enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.3

Associated Conditions

Pharmacodynamics

Enfortumab vedotin is an anti-cancer agent that destroys tumor cells by inhibiting their ability to replicate.3 Patients with moderate to severe hepatic impairment should not use enfortumab vedotin – though it has not been studied in this population, other MMAE-containing antibody-drug conjugates have demonstrated increased rates of adverse effects in patients with moderate-severe hepatic impairment.3 Enfortumab vedotin may also cause significant hyperglycemia leading, in some cases, to diabetic ketoacidosis, and should not be administered to patients with a blood glucose level >250 mg/dl.3

Mechanism of action

Enfortumab vedotin is an antibody-drug conjugate comprised of multiple components.3 It contains a fully human monoclonal antibody directed against Nectin-4, an extracellular adhesion protein which is highly expressed in urothelial cancers,1 attached to a chemotherapeutic microtubule-disrupting agent, monomethyl auristatin E (MMAE). These two components are joined via a protease-cleavable linker. Enfortumab vedotin binds to cells expressing Nectin-4 and the resulting enfortumab-Nectin-4 complex is internalized into the cell. Once inside the cell, MMAE is released from enfortumab vedotin via proteolytic cleavage and goes on to disrupt the microtubule network within the cell, arresting the cell cycle and ultimately inducing apoptosis.3

PATENT

WO 2016176089

WO 2016138034

WO 2017186928

WO 2017180587

WO 2017200492

US 20170056504

PAPER

Cancer Research (2016), 76(10), 3003-3013.

General References

  1. Hanna KS: Clinical Overview of Enfortumab Vedotin in the Management of Locally Advanced or Metastatic Urothelial Carcinoma. Drugs. 2019 Dec 10. pii: 10.1007/s40265-019-01241-7. doi: 10.1007/s40265-019-01241-7. [PubMed:31823332]
  2. McGregor BA, Sonpavde G: Enfortumab Vedotin, a fully human monoclonal antibody against Nectin 4 conjugated to monomethyl auristatin E for metastatic urothelial Carcinoma. Expert Opin Investig Drugs. 2019 Oct;28(10):821-826. doi: 10.1080/13543784.2019.1667332. Epub 2019 Sep 17. [PubMed:31526130]
  3. FDA Approved Drug Products: Padcev (enfortumab vedotin-ejfv) for IV injection [Link]

References

External links

Enfortumab vedotin
Monoclonal antibody
Type Whole antibody
Source Human
Target Nectin-4
Clinical data
Trade names Padcev
Other names AGS-22M6E, AGS-22CE, enfortumab vedotin-ejfv
License data
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChemSID
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6642H10284N1742O2063S46
Molar mass 149.0 kg/mol g·mol−1

PADCEV™
(enfortumab vedotin-ejfv) for Injection, for Intravenous Use

DESCRIPTION

Enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006). Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1. The molecular weight is approximately 152 kDa.

Figure 1: Structural Formula

PADCEV™ (enfortumab vedotin-ejfv) Structural Formula - Illustration

Approximately 4 molecules of MMAE are attached to each antibody molecule. Enfortumab vedotin-ejfv 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.

PADCEV (enfortumab vedotin-ejfv) for injection is provided as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use. PADCEV is supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL [see DOSAGE AND ADMINISTRATION]. After reconstitution, each vial allows the withdrawal of 2 mL (20 mg) and 3 mL (30 mg). Each mL of reconstituted solution contains 10 mg of enfortumab vedotin-ejfv, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg) and trehalose dihydrate (55 mg) with a pH of 6.0.

///////////////Enfortumab vedotin, AGS-22M6E, エンホルツマブベドチン (遺伝子組換え) , protein Based Therapies, Monoclonal antibody, mAb, FDA 2019

[*]SC1CC(=O)N(CCCCCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(=O)N)C(=O)Nc2ccc(COC(=O)N(C)[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@@H](CC(=O)N3CCC[C@H]3[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c4ccccc4)OC)cc2)C1=O

RESMETIROM


Mgl-3196.png

Image result for resmetirom

2D chemical structure of 920509-32-6

Structure of RESMETIROM

RESMETIROM

C17H12Cl2N6O4

435.2 g/mol

MGL-3196

CAS 920509-32-6, Resmetirom, VIA-3196, UNII-RE0V0T1ES0

Phase III, Non-alcoholic fatty liver disease (NAFLD)

2-[3,5-dichloro-4-[(6-oxo-5-propan-2-yl-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile

2-(3,5-DICHLORO-4-((5-ISOPROPYL-6-OXO-1,6-DIHYDROPYRIDAZIN-3-YL)OXY)PHENYL)-3,5-DIOXO-2,3,4,5-TETRAHYDRO-(1,2,4)TRIAZINE-6-CARBONITRILE

1,2,4-TRIAZINE-6-CARBONITRILE, 2-(3,5-DICHLORO-4-((1,6-DIHYDRO-5-(1-METHYLETHYL)-6-OXO-3-PYRIDAZINYL)OXY)PHENYL)-2,3,4,5-TETRAHYDRO-3,5-DIOXO-

Madrigal Pharmaceuticals , following the merger between Synta and Madrigal Pharmaceuticals (pre-merger) (following the acquisition of  VIA Pharmaceuticals ‘ assets (originally under license from  Roche )), is developing resmetirom (MGL-3196, VIA-3196), the lead from oral capsule formulation thyroid hormone receptor (THR) beta agonists, cholesterol and triglyceride modulators, for the use in the treatment of metabolic disorders including hypercholesterolemia and other dyslipidemias, and non-alcoholic steatohepatitis.

MGL-3196 is a first-in-class, orally administered, small-molecule, liver-directed, THR β-selective agonist. Preclinical, toxicology and Phase 1 clinical data suggest MGL-3196 has an attractive, differentiated profile as a potential treatment for non-alcoholic steatohepatitis (NASH) and dyslipidemias. THR-β selectivity also enhances the safety profile of MGL-3196, compared to non-selective agents. MGL-3196 has shown no suppression of the central thyroid axis, no THR-α effects on heart rate or bone, and no elevation of liver enzymes. These characteristics make MGL-3196 among the most promising molecules in development in this therapeutic area. MGL-3196 is in a Phase 2 clinical trial for the treatment of non-alcoholic steatohepatitis (NASH).

PATENT

WO-2020010068

Novel crystalline salt of resmetirom as thyroid hormone receptor agonists useful for treating obesity, hyperlipidemia, hypercholesterolemia and diabetes. Appears to be the first filing from the assignee and the inventors on this compound,

Thyroid hormones are critical for normal growth and development and for maintaining metabolic homeostasis (Paul M. Yen, Physiological reviews, Vol. 81(3): pp. 1097-1126 (2001)). Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamus/pituitary/thyroid (HPT) axis. Thyroid dysfunction leading to hypothyroidism or hyperthyroidism clearly demonstrates that thyroid hormones exert profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle and behavior.

[0005] The biological activity of thyroid hormones is mediated by thyroid hormone receptors (TRs or THRs) (M. A. Lazar, Endocrine Reviews, Vol. 14: pp. 348-399 (1993)). TRs belong to the superfamily known as nuclear receptors. TRs form heterodimers with the retinoid receptor that act as ligand-inducible transcription factors. TRs have a ligand binding domain, a DNA binding domain, and an amino terminal domain, and regulate gene expression through interactions with DNA response elements and with various nuclear co-activators and co repressors. The thyroid hormone receptors are derived from two separate genes, a and b. These distinct gene products produce multiple forms of their respective receptors through differential RNA processing. The major thyroid receptor isoforms are aΐ, a2, bΐ, and b2. Thyroid hormone receptors aΐ, bΐ, and b2 bind thyroid hormone. It has been shown that the thyroid hormone receptor subtypes can differ in their contribution to particular biological responses. Recent studies suggest that TIIb 1 plays an important role in regulating TRH (thyrotropin releasing hormone) and on regulating thyroid hormone actions in the liver. T11b2 plays an important role in the regulation of TSH (thyroid stimulating hormone) (Abel et. al, J. Clin. Invest., Vol 104: pp. 291-300 (1999)). TIIb 1 plays an important role in regulating heart rate (B. Gloss et. al. Endocrinology, Vol. 142: pp. 544-550 (2001); C. Johansson et. al, Am. J. Physiol., Vol. 275: pp. R640-R646 (1998)).

[0006] Efforts have been made to synthesize thyroid hormone analogs which exhibit increased thyroid hormone receptor beta selectivity and/or tissue selective action. Such thyroid hormone mimetics may yield desirable reductions in body weight, lipids, cholesterol, and lipoproteins, with reduced impact on cardiovascular function or normal function of the hypothalamus/pituitary/thyroid axis (see, e.g., Joharapurkar et al, J. Med. Chem, 2012, 55 (12), pp 5649-5675). The development of thyroid hormone analogs which avoid the undesirable effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones would open new avenues of treatment for patients with metabolic disease such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other disorders and diseases such as liver steatosis and NASH, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, thyroid diseases, a resistance to thyroid hormone (RTH) syndrome, and related disorders and diseases.

PATENT

WO2018075650

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=38F602DAA4A51CA8DF413F1EDBC87DA4.wapp2nB?docId=WO2018075650&recNum=322&office=&queryString=&prevFilter=%26fq%3DICF_M%3A%22A61K%22&sortOption=Pub+Date+Desc&maxRec=1894357

In one embodiment, the metabolite of Compound A comprises a compound

having the following structure: 
(“Ml”).

PATENT

WO 2007009913

PATENT

WO 2014043706

https://patents.google.com/patent/WO2014043706A1/en

Example 3: Preparation of (Z)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6- oxo- l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl)carbamate (Int. 8)

A 2 L, three-neck, round-bottom flask equipped with overhead stirring, a thermocouple, N2 inlet/outlet was charged with Int. 7 (75.0 g, 0.239 mol, 1 wt), acetic acid (600 mL, 8 vol), water (150 mL, 2 vol), and concentrated HC1 (71.3 mL, 0.95 vol). The resulting thin slurry was cooled to 6 °C and a solution of NaN02 (16.8 g, 0.243 mol, 1.02 equiv) in water (37.5 mL, 0.5 vol) was added over a period of 10 min while maintaining a batch temperature below 10 °C. After an additional 10 min of agitation between 5-10 °C, HPLC analysis showed complete conversion of Int. 7 to the diazonium intermediate. A solution of NaOAc (54.5 g, 0.664 mol, 2.78 equiv) in water (225 mL, 3 vol) was added over a period of 6 min while maintaining a batch temperature below 10 °C. N-cyanoacetylurethane (37.9 g, 0.243 mol, 1.02 equiv) was immediately added, the cooling was removed, and the batch naturally warmed to 8 °C over 35 min. HPLC analysis showed complete consumption of the diazonium intermediate and the reaction was deemed complete. The batch warmed naturally to 21 °C and was filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with water (375 mL, 5 vol) twice. The collected orange solid was dried in a 35 °C vacuum oven for 64 h to provide crude Int. 8 (104.8 g, 91%).

A I L, three-neck, round-bottom flask equipped with overhead stirring, a

thermocouple, and N2 inlet/outlet was charged with crude Int. 8 (104.4 g, 1 wt) and acetic acid (522 mL, 5 vol). The resulting slurry was heated to 50 °C and held at that temperature for 1.5 h. The batch cooled naturally to 25 °C over 2 h and was filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with water (522 mL, 5 vol) and the cake conditioned under vacuum for 1.75 h. The light orange solid was dried to constant weight in a 40 °C vacuum oven to provide 89.9 g (78% from Int. 7) of the desired product. 1H NMR (DMSO) was consistent with the assigned structure.

Example 4: Preparation of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine-6-carbonitrile (Compound A)

A 2 L, three-neck, round-bottom flask equipped with overhead stirring, a

thermocouple, N2 inlet/outlet, and reflux condenser was charged with Int. 8 (89.3 g, 0.185 mol, 1 wt), DMAC (446 mL, 5 vol), and KOAc (20.0 g, 0.204 mol, 1.1 equiv). The mixture was heated to 120 °C and held at that temperature for 2 h. HPLC analysis showed complete conversion to Compound A. The batch temperature was adjusted to 18 °C over 1 h, and acetic acid (22.3 mL, 0.25 vol) was added. The batch temperature was adjusted to 8 °C, and water (714 mL, 8 vol) was added over 1 h; an orange slurry formed. The batch was filtered through Sharkskin filter paper and the cake was allowed to condition overnight under N2 without vacuum for convenience. A premixed solution of 1 : 1 acetone/water (445 mL, 5 vol) was charged to the flask and added to the cake as a rinse with vacuum applied. After 2 h of conditioning the cake under vacuum, it was transferred to a clean 1 L, three-neck, round- bottom flask equipped with overhead stirring, a thermocouple, and N2inlet/outlet. Ethanol (357 mL, 4 vol) and acetone (357 mL, 4 vol) were charged and the resulting slurry was heated to 60 °C; dissolution occurred. Water (890 mL, 10 vol) was added over a period of 90 min while maintaining a batch temperature between 55-60 °C. The resulting slurry was allowed to cool to 25 °C and filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with a solution of 1:1 EtOH/water (446 mL, 5 vol). The cake was conditioned overnight under N2 without vacuum for convenience. The cracks in the cake were smoothed and vacuum applied. The cake was washed with water (179 mL, 2 vol) and dried in a 45 °C vacuum oven to a constant weight of 70.5 g (87%, crude Compound A). HPLC analysis showed a purity of 94.8%.

A 500 mL, three-neck, round-bottom flask equipped with overhead stirring, a thermocouple, N2 inlet/outlet, and reflux condenser was charged with crude Compound A (70.0 g) and MIBK (350 mL, 5 vol). The orange slurry was heated to 50 °C and held at that temperature for 2 h. The batch cooled naturally to 23 °C and was filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with MIBK (35 mL, 0.5 vol) twice. The collected solids were dried in a 45 °C vacuum oven to a constant weight of 58.5 g (84%). This solid was charged to a 500 mL, three-neck, round-bottom flask equipped with overhead stirring, a thermocouple, N2 inlet/outlet, and reflux condenser. Ethanol (290 mL, 5 vol) was added and the slurry was heated to reflux. After 3.5 h at reflux, XRPD showed the solid was consistent with Form I, and heating was removed. Upon reaching 25 °C, the batch was filtered through filter paper, and the reactor and cake were washed sequentially with EtOH (174 mL, 3 vol). The tan solid Compound A was dried in a 40 °C vacuum oven to a constant weight of 50.4 g (87%, 64% from Int. 8). HPLC analysis showed a purity of 99.1%. 1H NMR (DMSO) was consistent with the assigned structure.

Example 5: Scaled up preparation of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine-6-carbonitrile (Compound A)

A larger scale batch of Compound A was synthesized according to the scheme below. The conditions in the scheme below are similar to those described in Examples 1-4 above.

Figure imgf000055_0001

6A

Figure imgf000055_0002

Compound A

Synthesis of 4: A 50 L jacketed glass vessel (purged with N2) was charged with 3,6- dichloropyridazine (2.00 kg), 4-amino-2,6-dichlorophenol (2.44 kg) and N,N- dimethylacetamide (10.0 L). The batch was vacuum (26 inHg) / nitrogen (1 PSIG) purged 3 times. Cesium carbonate (5.03 kg) was added and the batch temperature was adjusted from 22.3 °C to 65.0 °C over 3.5 hours. The batch was held at 65.0 °C for 20 hours. At this point,

NMR analysis indicated 3.34% 3.6-dichloropyridazine relative to 2. The batch temperature was adjusted to 21.5 °C and ethyl acetate (4.00 L) was added to the batch. The batch was agitated for 10 minutes and then filtered through a 18″ Nutsche filter equipped with polypropylene filter cloth. The filtration took 15 minutes. Ethyl acetate (5.34 L) was charged to the vessel and transferred to the filter as a rinse. The batch was then manually re- suspended in the filter before re-applying vacuum. This process was repeated 2 more times and the filter cake was conditioned for 10 minutes. The filtrate was charged to a 100-L vessel that contained (16.0 L) of a previously prepared 15% sodium chloride in H20. The batch was agitated for 5 minutes and then allowed to separate for 35 minutes. The interface was not visible, so the calculated 23 L of the lower aqueous phase was removed. 16.0 L of 15% Sodium chloride in H20 was added to the batch. The batch was agitated for 6 minutes and then allowed to separate for 7 minutes. The interface was visible at -19 L and the lower aqueous phase was removed. 17.0 L of 15% Sodium chloride in H20 was added to the batch. The batch was agitated for 7 minutes and then allowed to separate for 11 minutes. The lower aqueous phase was removed. The vessel was set up for vacuum distillation and the batch was concentrated from 17.0 L to 8.0 L over 2 hours 20 minutes with the batch temperature kept around 21 °C. Benzoic anhydride (3.19 kg) and acetic acid (18.0 L) were charged to the vessel. The vessel was set up for vacuum distillation and the batch was concentrated from 28.0 L to 12.0 L over 2 days (overnight hold at 20 °C) with the batch temperature kept between 20 and 55 °C. At this point, JH NMR analysis indicated a mol ratio of acetic acid to ethyl acetate of 1.0:0.015. Acetic acid (4.0 L) was charged to the batch and the batch was distilled to 12 L. JH NMR analysis indicated a mol ratio of acetic acid to ethyl acetate of 1.0:0.0036. Acetic acid (20.0 L) was charged to the batch and the batch temperature was adjusted to 70.0 °C. The batch was sampled for HPLC analysis and 2 was 0.16%. Sodium acetate (2,20 kg) was added to the batch and the batch temperature was adjusted from 72.4 °C to 110.0 °C. After 18.5 hours, HPLC analysis indicated no Int. B detected. The batch temperature was adjusted from 111.3 to 74.7 °C and DI water (30.0 L) was added to the batch over 2 hours. The batch temperature was adjusted to 20 .5 °C and then filtered using a 24″ Haselloy Nutsche filter equipped with polypropylene filter cloth. A previously prepared solution of 1:1 acetic acid in DI H20 (10.0 L) was charged to the vessel and agitated for 5 minutes. The wash was transferred to the filter and the batch was then manually re- suspended in the filter before re-applying vacuum. DI H20 (10.0 L) was charged to the vessel and then transferred to the filter. The batch was manually re-suspended in the filter before re-applying vacuum. DI H20 (10.0 L) was charged directly to the filter and the batch was then manually re-suspended in the filter before re-applying vacuum. The filter cake was allowed to condition for 18 hours to give 14.4 kg of 4. HPLC analysis indicated a purity of 93.7%. This wet cake was carried forward into the purification. A 100 L jacketed glass vessel (purged with N2) was charged with crude 4 (wet cake 14.42 kg), acetic acid (48.8 L) and the agitator was started. DI H20 (1.74 L) was charged. The batch (a slurry) temperature was adjusted from 18.1 to 100.1 °C over 4.25 hours. The batch was held at 100.1 to 106.1 °C for 1 hour and then adjusted to 73.1 °C. DI H20 (28.0 L) was added to the batch over 1 hour keeping the batch temperature between 73.1 and 70.3 °C. The batch temperature was adjusted further from 70.3 °C to 25.0 °C overnight. The batch was filtered using a 24″ Hastelloy Nutsche filter equipped with polypropylene filter cloth. The filtration took 13 minutes. A solution of DI H20 (9.00 L) and acetic acid (11.0 L) was prepared and added to the 100 L vessel. The mixture was agitated for 5 minutes and then transferred to the filter cake. DI H20 (20.0 L) was charged to the vessel, agitated for 6 minutes and then transferred to the filter cake. DI H20 (20.0 L) was charged to the vessel, agitated for 9 minutes and then transferred to the filter cake. The batch was allowed to condition for 3 days and then transferred to drying trays for vacuum oven drying. After 3 days at 50 °C and 28’7Hg, the batch gave a 74% yield (3.7 kg) of4 as an off-white solid. The JH NMR spectrum was consistent with the assigned structure, HPLC analysis indicated a purity of 98.87% and KF analysis indicated 0.14% H20. Synthesis of Int. 7: A 100-L jacketed glass vessel (purged with N2) was charged with tetrahydrofuran (44.4 L). The agitator was started (125 RPM) and 4 (3.67 kg) was charged followed by lithium chloride (1.26 kg). The batch temperature was observed to be 26.7 ° C and was an amber solution. Isopropenylmagnesium bromide 1.64 molar solution in 2-methyl THF (21.29 kg) was added over 2 ½ hours keeping the batch between 24.3 and 33.6 °C. The batch was agitated at 24.5 °C for 17 hours at which point HPLC analysis indicated 9% 4. A 2nd 100-L jacketed glass vessel (purged with N2) was charged with 3N hydrogen chloride (18.3 L). The batch was transferred to the vessel containing the 3N HC1 over 25 minutes keeping the batch temperature between 20 and 46 °C. A bi-phasic solution was observed. The quenched batch was transferred back to the 1st 100-L vessel to quench the small amount of residue left behind. THF (2.00 L) was used as a rinse. The batch temperature was observed to be 40.9 ° C and was agitated at 318 RPM for 45 minutes. The batch temperature was adjusted to 21.8 ° C and the layers were allowed to separate. The separation took 10 minutes. The lower aqueous phase was removed (-26.0 L). A solution of sodium chloride (1.56 kg) in DI water (14.0 L) was prepared and added to the batch. This was agitated at 318 RPM for 10 minutes and agitator was stopped. The separation took 3 minutes. The lower aqueous phase was removed (-16.0 L). The batch was vacuum distilled from 58.0 L to 18.4 L using ~24’7Hg and a jacket temperature of 50 to 55 °C. A solution of potassium hydroxide (2.30 kg) in DI water (20.7 L) was prepared in a 72-L round bottom flask. The vessel was set up for atmospheric distillation using 2 distillation heads and the batch was transferred to the 72-L vessel. THF (0.75 L) was used as a rinse. The batch volume was -41.0 L, the temperature was adjusted to 64.1 °C and distillation started with the aid of a N2 sweep. Heating was continued to drive the batch temperature to 85.4 °C while distilling at which point the 72-L vessel was set up for reflux (batch volume was about 28.0 L at the end of the distillation). The batch was held at 85 °C for 13 hours at which point HPLC analysis indicated 0.3% compound 6A. Heating was stopped and the batch was transferred to a 100-L jacketed glass vessel. Solids were observed. The batch temperature was adjusted from 70.6 °C to 56.7 °C. A previously prepared solution of sodium hydrogen carbonate (2.82 kg) in DI water (35.0 L) was added over 80 minutes keeping the batch temperature between 56.7 and 46.7 °C. The batch pH at the end of the addition was 9.8. The batch was held at

46.7 to 49.0 °C for 40 minutes and then cooled to 25.0 °C. The batch was filtered using a 18″ stainless steel Nutsche filter. DI water (18.4 L) was charged to the vessel and transferred to the filter. The filter cake was manually re-suspended in the filter and then the liquors were removed. This process was repeated once more and the filter cake was 3″ thick. The filter cake was conditioned on the filter for 3 days, was transferred to drying trays and dried in a vacuum oven at 45 °C to provide 2.93 kg Int. 7 (95% yield) with an HPLC purity of 87.6%.

Synthesis of Int. 8: A 100 L jacketed glass vessel (purged with N2 and plumbed to a caustic scrubber) was charged with acidic acid (13.0 L). Int. 7 (2.85 kg) was charged to the vessel and the agitator was started. N-Cyanoacetylurethane (1.56 kg) and DI water (5.70 L) were charged to the vessel. The batch temperature was adjusted from 17.0 °C to 5.5 °C and a thin slurry was observed. At this point 37% hydrogen chloride (2.70 L) was added over 10 minutes keeping the batch temperature between 4.8 °C and 8.8 °C. A previously prepared solution of sodium nitrite (638 g) in DI water (1.42 L) was added over 26 minutes keeping the batch temperature between 5.8 °C and 8.7 °C. A brown gas was observed in the vessel head space during the addition. HPLC analysis indicated no Int. 7 detected. At this point a previously prepared solution of sodium acetate (2.07 kg) in DI water (8.50 L) was added over 47 minutes keeping the batch temperature between 5.5 °C and 9.5 °C. After the addition, a thin layer of orange residue was observed on the vessel wall just above the level of the batch. The batch temperature was adjusted from 9.4 °C to 24.5 °C and held at 25 °C (+ 5 °C) for 12 hours. The batch was filtered using a 24″ Hastelloy Nutsche filter equipped with tight-weave polypropylene filter cloth. The filtration took 30 minutes. The vessel was rinsed with 14.3 L of a 1 : 1 acidic acid / DI water. The orange residue on the reactor washed away with the rinse. The rinse was transferred to the filter where the batch was manually re-suspended. Vacuum was re-applied to remove the wash. A 2nd 1 : 1 acidic acid / DI water wash was performed as above and the batch was conditioned on the filter for 26 hours. HPLC analysis of the wet filter cake indicated purity was 90.4%. The batch was dried to a constant weight of 3.97 kg (91% yield) in a vacuum oven at 45 °C and 287Hg. Preparation of Compound A DMAC Solvate

A 100 L, jacketed, glass vessel purged with N2 was charged with Int. 8 (3.90 kg) and potassium acetate (875 g). N,N-dimethylacetamide (DMAC, 18.3 L) was charged to the vessel and the agitator was started. The batch temperature was adjusted to 115 °C over 2 h. After 2 h at 115 °C, the batch was sampled and HPLC analysis indicated 0.27% Int. 8 remained. The batch temperature was adjusted to 25.0 °C overnight. Acetic acid (975 mL) was added to the batch and the batch was agitated further for 3 h. The batch was transferred to a carboy and the vessel was rinsed clean with 800 mL of DMAC. The batch was transferred back to the 100 L vessel using vacuum through a 10 μιη in-line filter and a DMAC rinse (1.15 L) was used. The filtration was fast at the beginning but slow at the end, plugging up the filter. The batch temperature was adjusted to 11.1 °C and DI water (35.1 L) was added over 2 h 20 min, keeping the batch temperature between 5-15 °C. The batch was held for 1 h and filtered, using an 18″ Nutsche filter equipped with tight-weave

polypropylene cloth. The filtration took 15 h. A 1: 1 ethanol/DI water wash (19.5 L) was charged to the vessel, cooled to 10 °C, and transferred to the filter cake. The cake was allowed to condition under N2 and vacuum for 8 h and transferred to drying trays. The batch was dried in a vacuum oven at 45 °C and 28’7Hg to give 89% yield (3.77 kg) of Compound A DMAC solvate as an orange/tan solid. The 1H NMR spectrum was consistent with the assigned structure and Karl Fischer analysis indicated 0.49% H20. XRPD indicated the expected form, i.e., Compound A DMAC solvate. Thermogravimetric analysis (TGA) indicated 16% weight loss. HPLC analysis indicated a purity of 93.67%.

Preparation of Crude Compound A

A 100 L, jacketed, glass vessel purged with N2 was charged with Compound A

DMAC solvate (3.75 kg) and ethanol (15.0 L). The agitator was started and acetone (15.0 L) was added. The batch temperature was adjusted from 10.6 °C to 60.0 °C over 1 h. At this point, the batch was in solution. DI water was added to the batch over 1.5 h, keeping the batch temperature at 60 + 5 °C. The batch was held at 60 + 5 °C for 1 h and cooled to 23.5 °C. An 18″ Nutsche filter equipped with tight-weave (0.67 CFM) polypropylene cloth was set up and the batch was filtered. The filtration took 15 h. A 1: 1 ethanol/DI water wash (19.5 L) was charged to the vessel and transferred to the filter cake. The cake was allowed to condition under N2 and vacuum for 8 h and transferred to drying trays. The batch was dried in a vacuum oven at 45 °C and 28’7Hg for five days to give a 94% yield (2.90 kg) of Compound A as a powdery tan solid. The NMR spectrum is consistent with the assigned structure and Karl Fischer analysis indicated 6.6% H20. XRPD indicated the expected form of dihydrate. TGA indicated 6.7% weight loss. HPLC analysis indicated a purity of 96.4% (AUC).

Purification of Crude Compound A

A 50 L, jacketed, glass vessel purged with N2 was charged with Compound A crude

(2.90 kg) and methyl isobutyl ketone (14.5 L). The agitator was started and the batch temperature was adjusted from 20.2 °C to 50.4 °C over 1.5 h. The batch was held at 50 °C (+ 5 °C) for 1 h and cooled to 20-25 °C. The batch was held at 20-25 °C for 2.5 h. An 18″ Nutsche filter equipped with tight- weave (0.67 CFM) polypropylene cloth was set up and the batch was filtered. The filtration took 20 min. Methyl isobutyl ketone (MIBK, 1.45 L) was charged to the vessel and transferred to the filter cake. The cake was manually resuspended and the liquors were pulled through with vacuum. Methyl isobutyl ketone (2.90 L) was charged to the filter cake and the cake was manually resuspended. The liquors were pulled through with vacuum and the cake was conditioned with vacuum and nitrogen for 15 h. The filter cake dried into a tan, hard 18″ x 1 ½” disc. This was manually broken up and run through coffee grinders to give a 76% yield (2.72 kg) of MGL-3196 MIBK solvate as a tan, powdery solid. No oven drying was necessary. The NMR spectrum was consistent with the assigned structure and Karl Fischer analysis indicated <0.1 % H20. XRPD indicated the expected form MIBK solvate. TGA indicated 17.3% weight loss. HPLC analysis indicated a purity of 98.5%.

Example 6: Conversion of Compound A to Form I

Purified Compound A (4802 g) as a 1:1 MIBK solvate which was obtained from Int. 8 as described in Example 5 above was added into a jacketed, 100 L reactor along with 24 liters of ethanol. The resulting slurry was heated to 80 + 5 °C (reflux) over 1 h 25 min; the mixture was stirred at that temperature for 4 h 25 min. Analysis of the filtered solids at 2 h 55 min indicated that the form conversion was complete, with the XRPD spectra conforming to Form I. The mixture was cooled to 20 + 5 °C over 45 min and stirred at that temperature for 15 min. The slurry was filtered and the filter cake was washed twice with prefiltered ethanol (2 x 4.8 L). The wet cake (4.28 kg) was dried under vacuum at 40 + 5 °C for 118 h to afford 3390 g of Compound A form I.

PAPER

Journal of Medicinal Chemistry (2014), 57(10), 3912-3923

https://pubs.acs.org/doi/abs/10.1021/jm4019299

The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor β (THR-β) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-β over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.

Abstract Image

//////////////RESMETIROM , MGL-3196, VIA-3196, UNII-RE0V0T1ES0, Phase III

CC(C)C1=CC(=NNC1=O)OC2=C(C=C(C=C2Cl)N3C(=O)NC(=O)C(=N3)C#N)Cl

Avapritinib, アバプリチニブ , авапритиниб , أفابريتينيب ,


Image result for Avapritinib

Avapritinib.png

ChemSpider 2D Image | avapritinib | C26H27FN10

Avapritinib

BLU-285, BLU285

Antineoplastic, Tyrosine kinase inhibitor

アバプリチニブ

авапритиниб [Russian] [INN]
أفابريتينيب [Arabic] [INN]

(1S)-1-(4-fluorophenyl)-1-[2-[4-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl]pyrimidin-5-yl]ethanamine

(1S)-1-(4-Fluorophenyl)-1-(2-{4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl}-5-pyrimidinyl)ethanamine
10613
1703793-34-3 [RN]
513P80B4YJ
5-Pyrimidinemethanamine, α-(4-fluorophenyl)-α-methyl-2-[4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl]-, (αS)-
(S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine
(αS)-(4-fluorophenyl)-α-methyl-2-[4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl]-5-pyrimidinemethanamine
Formula
C26H27FN10
CAS
1703793-34-3
Mol weight
498.558
No. Drug Name Active Ingredient Approval Date FDA-approved use on approval date*
1. Ayvakit avapritinib 1/9/2020 To treat adults with unresectable or metastatic gastrointestinal stromal tumor (GIST)

PRIORITY; Orphan, 

Avapritinib, sold under the brand name Ayvakit, is a medication used for the treatment of tumors due to one specific rare mutation: It is specifically intended for adults with unresectable or metastatic ( y) gastrointestinal stromal tumor (GIST) that harbor a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation.[1]

Common side effects are edema (swelling), nauseafatigue/asthenia (abnormal physical weakness or lack of energy), cognitive impairmentvomitingdecreased appetitediarrhea, hair color changes, increased lacrimation (secretion of tears), abdominal painconstipationrash. and dizziness.[1]

Ayvakit is a kinase inhibitor.[1]

History

The U.S. Food and Drug Administration (FDA) approved avapritinib in January 2020.[1] The application for avapritinib was granted fast track designation, breakthrough therapy designation, and orphan drug designation.[1] The FDA granted approval of Ayvakit to Blueprint Medicines Corporation.[1]

Avapritinib was approved based on the results from the Phase I NAVIGATOR[2][3] clinical trial involving 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 subjects with PDGFRA D842V mutation.[1] Subjects received avapritinib 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity.[1] The recommended dose was determined to be 300 mg once daily.[1] The trial measured how many subjects experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate).[1] For subjects harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response and 77% having a partial response.[1] For the subgroup of subjects with PDGFRA D842V mutations, the overall response rate was 89%, with 8% having a complete response and 82% having a partial response.[1] While the median duration of response was not reached, 61% of the responding subjects with exon 18 mutations had a response lasting six months or longer (31% of subjects with an ongoing response were followed for less than six months).[1]

PATENT

WO 2015057873

https://patents.google.com/patent/WO2015057873A1/en

Example 7: Synthesis of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4- yl)pyrrolo[2, 1 -f\ [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine and (S)- 1 – (4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine (Compounds 43 and 44)

Figure imgf000080_0001
Figure imgf000080_0002

Step 1 : Synthesis of (4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l- f] [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)methanone:

Figure imgf000081_0001

4-Chloro-6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/] [l,2,4]triazine (180 mg, 0.770 mmol), (4-fluorophenyl)(2-(piperazin-l-yl)pyrimidin-5-yl)methanone, HC1 (265 mg, 0.821 mmol) and DIPEA (0.40 mL, 2.290 mmol) were stirred in 1,4-dioxane (4 mL) at room temperature for 18 hours. Saturated ammonium chloride was added and the products extracted into DCM (x2). The combined organic extracts were dried over Na2S04, filtered through Celite eluting with DCM, and the filtrate concentrated in vacuo. Purification of the residue by MPLC (25- 100% EtOAc-DCM) gave (4-fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methanone (160 mg, 0.331 mmol, 43 % yield) as an off-white solid. MS (ES+) C25H22FN90 requires: 483, found: 484 [M + H]+.

Step 2: Synthesis of (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-p razol-4-yl)p rrolo[2, l- ] [l,2,4]triazin-4- l)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide:

Figure imgf000081_0002

(S)-2-Methylpropane-2-sulfinamide (110 mg, 0.908 mmol), (4-fluorophenyl)(2-(4-(6-(l- methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5- yl)methanone (158 mg, 0.327 mmol) and ethyl orthotitanate (0.15 mL, 0.715 mmol) were stirred in THF (3.2 mL) at 70 °C for 18 hours. Room temperature was attained, water was added, and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0- 10% MeOH-EtOAc) gave (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)methylene)-2- methylpropane-2-sulfinamide (192 mg, 0.327 mmol, 100 % yield) as an orange solid. MS (ES+) C29H3iFN10OS requires: 586, found: 587 [M + H]+.

Step 3: Synthesis of (lS’)-N-(l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- l)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-

Figure imgf000082_0001

(lS’,Z)-N-((4-Fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide (190 mg, 0.324 mmol) was taken up in THF (3 mL) and cooled to 0 °C. Methylmagnesium bromide (3 M solution in diethyl ether, 0.50 mL, 1.500 mmol) was added and the resulting mixture stirred at 0 °C for 45 minutes. Additional methylmagnesium bromide (3 M solution in diethyl ether, 0.10 mL, 0.300 mmol) was added and stirring at 0 °C continued for 20 minutes. Saturated ammonium chloride was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave (lS’)-N-(l-(4-fluorophenyl)-l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol, 61.5 % yield) as a yellow solid (mixture of diastereoisomers). MS (ES+) C3oH35FN10OS requires: 602, found: 603 [M + H]+. Step 4: Synthesis of l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l- f\ [ 1 ,2,4] triazin-4- l)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine:

Figure imgf000083_0001

(S)-N- ( 1 – (4-Fluorophenyl)- 1 -(2- (4- (6-( 1 -methyl- 1 H-pyrazol-4-yl)pyrrolo [2,1- /] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol) was stirred in 4 M HCl in 1,4-dioxane (1.5 mL)/MeOH (1.5 mL) at room temperature for 1 hour. The solvent was removed in vacuo and the residue triturated in EtOAc to give l-(4-fluorophenyl)- l-(2-(4-(6-(l -methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4- yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine, HCl (110 mg, 0.206 mmol, 103 % yield) as a pale yellow solid. MS (ES+) C26H27FN10requires: 498, found: 482 [M- 17 + H]+, 499 [M + H]+.

Step 5: Chiral separation of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine and (5)-1-(4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin- 1 -yl)pyrimidin- -yl)ethanamine:

Figure imgf000083_0002

The enantiomers of racemic l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (94 mg, 0.189 mmol) were separated by chiral SFC to give (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH- pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine (34.4 mg, 0.069 mmol, 73.2 % yield) and (lS,)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (32.1 mg, 0.064 mmol, 68.3 % yield). The absolute stereochemistry was assigned randomly. MS (ES+)

C26H27FN10 requires: 498, found: 499 [M + H]+.

References

  1. Jump up to:a b c d e f g h i j k l m “FDA approves the first targeted therapy to treat a rare mutation in patients with gastrointestinal stromal tumors”U.S. Food and Drug Administration (FDA) (Press release). 9 January 2020. Archived from the original on 11 January 2020. Retrieved 9 January 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ “Blueprint Medicines Announces FDA Approval of AYVAKIT (avapritinib) for the Treatment of Adults with Unresectable or Metastatic PDGFRA Exon 18 Mutant Gastrointestinal Stromal Tumor”Blueprint Medicines Corporation (Press release). 9 January 2020. Archived from the original on 11 January 2020. Retrieved 9 January 2020.
  3. ^ “Blueprint Medicines Announces Updated NAVIGATOR Trial Results in Patients with Advanced Gastrointestinal Stromal Tumors Supporting Development of Avapritinib Across All Lines of Therapy”Blueprint Medicines Corporation (Press release). 15 November 2018. Archived from the original on 10 January 2020. Retrieved 9 January 2020.

Further reading

  • Wu CP, Lusvarghi S, Wang JC, et al. (July 2019). “Avapritinib: A Selective Inhibitor of KIT and PDGFRα that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines”. Mol. Pharm16 (7): 3040–3052. doi:10.1021/acs.molpharmaceut.9b00274PMID 31117741.
  • Gebreyohannes YK, Wozniak A, Zhai ME, et al. (January 2019). “Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors”. Clin. Cancer Res25 (2): 609–618. doi:10.1158/1078-0432.CCR-18-1858PMID 30274985.

External links

Avapritinib
Clinical data
Trade names Ayvakit
Other names BLU-285, BLU285
License data
Routes of
administration
By mouth
Drug class Antineoplastic agents
ATC code
  • none
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C26H27FN10
Molar mass 498.570 g·mol−1
3D model (JSmol)

///////Avapritinib, 2020 APPROVALS, PRIORITY, Orphan, BLU-285, BLU285, FDA 2020,  Ayvakit, アバプリチニブ  , авапритиниб أفابريتينيب 

TERIPARATIDE, テリパラチド , терипаратид , تيريباراتيد , 特立帕肽 ,


Teriparatide structure.svg

ChemSpider 2D Image | Teriparatide | C181H291N55O51S2

Teriparatide recombinant human.png

Image result for teriparatide

Image result for teriparatide

TERIPARATIDE

テリパラチド;

терипаратид [Russian] [INN]
تيريباراتيد [Arabic] [INN]
特立帕肽 [Chinese] [INN]
  • PTH 1-34
  • LY 333334 / LY-333334 / LY333334 / ZT-034
Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn
Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His
Asn Phe-OH
  Type
Peptide
Formula
C181H291N55O51S2
CAS
52232-67-4
99294-94-7 (acetate)
Mol weight
4117.7151

(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-methylpentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-4-methylsulfanylbutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-oxobutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]hexanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxypropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(1S)-1-carboxy-2-phenylethyl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-oxopentanoic acid

SVG Image
SVG Image
IUPAC Condensed H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH
Sequence SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF
PLN H-SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF-OH
HELM PEPTIDE1{S.V.S.E.I.Q.L.M.H.N.L.G.K.H.L.N.S.M.E.R.V.E.W.L.R.K.K.L.Q.D.V.H.N.F}$$$$
IUPAC L-seryl-L-valyl-L-seryl-L-alpha-glutamyl-L-isoleucyl-L-glutaminyl-L-leucyl-L-methionyl-L-histidyl-L-asparagyl-L-leucyl-glycyl-L-lysyl-L-histidyl-L-leucyl-L-asparagyl-L-seryl-L-methionyl-L-alpha-glutamyl-L-arginyl-L-valyl-L-alpha-glutamyl-L-tryptophyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-histidyl-L-asparagyl-L-phenylalanine
L-Phenylalanine, L-seryl-L-valyl-L-seryl-L-α-glutamyl-L-isoleucyl-L-glutaminyl-L-leucyl-L-methionyl-L-histidyl-L-asparaginyl-L-leucylglycyl-L-lysyl-L-histidyl-L-leucyl-L-asparaginyl-L-seryl-L-methionyl-L-α-glutamyl-L-arginyl-L-valyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-glutaminyl-L-α-aspartyl-L-valyl-L-histidyl-L-asparaginyl-

Other Names

  • L-Seryl-L-valyl-L-seryl-L-α-glutamyl-L-isoleucyl-L-glutaminyl-L-leucyl-L-methionyl-L-histidyl-L-asparaginyl-L-leucylglycyl-L-lysyl-L-histidyl-L-leucyl-L-asparaginyl-L-seryl-L-methionyl-L-α-glutamyl-L-arginyl-L-valyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-glutaminyl-L-α-aspartyl-L-valyl-L-histidyl-L-asparaginyl-L-phenylalanine
  • (1-34)-Human parathormone
  • (1-34)-Human parathyroid hormone
  • 1-34-Human PTH
  • 1-34-Parathormone (human)
  • 11: PN: WO0039278 SEQID: 17 unclaimed protein
  • 14: PN: WO0181415 SEQID: 16 claimed protein
  • 15: PN: WO0123521 SEQID: 19 claimed protein
  • 1: PN: EP2905289 SEQID: 1 claimed protein
  • 1: PN: WO0198348 SEQID: 13 claimed protein
  • 1: PN: WO2011071480 SEQID: 14 claimed protein
  • 225: PN: US20090175821 SEQID: 272 claimed protein
  • 22: PN: US6110892 SEQID: 22 unclaimed protein
  • 2: PN: US20100261199 SEQID: 4 claimed protein
  • 31: PN: US20070099831 PAGE: 7 claimed protein
  • 32: PN: WO2008068487 SEQID: 32 claimed protein
  • 5: PN: WO2008033473 SEQID: 4 claimed protein
  • 692: PN: WO2004005342 PAGE: 46 claimed protein
  • 69: PN: US20050009742 PAGE: 20 claimed sequence
  • 7: PN: WO0031137 SEQID: 8 unclaimed protein
  • 7: PN: WO0040611 PAGE: 1 claimed protein
  • 93: PN: WO0069900 SEQID: 272 unclaimed protein
  • Forsteo
  • Forteo
  • HPTH-(1-34)
  • Human PTH(1-34)
  • Human parathormone(1-34)
  • Human parathyroid hormone-(1-34)
  • LY 333334
  • Osteotide
  • Parathar
  • Parathormone (human)
  • Teriparatide
  • ZT 034

Product Ingredients

INGREDIENT UNII CAS
Teriparatide acetate 9959P4V12N 99294-94-7

Teriparatide is a form of parathyroid hormone consisting of the first (N-terminus) 34 amino acids, which is the bioactive portion of the hormone. It is an effective anabolic (promoting bone formation) agent[2] used in the treatment of some forms of osteoporosis.[3] It is also occasionally used off-label to speed fracture healing. Teriparatide is identical to a portion of human parathyroid hormone (PTH) and intermittent use activates osteoblasts more than osteoclasts, which leads to an overall increase in bone.

Recombinant teriparatide is sold by Eli Lilly and Company under the brand name Forteo/Forsteo. A synthetic teriparatide from Teva Generics has been authorised for marketing in European territories[4]. Biosimilar product from Gedeon Richter plc has been authorised in Europe[5]. On October 4, 2019 the US FDA approved a recombinant teriparatide product, PF708, from Pfenex Inc. PF708 is the first FDA approved proposed therapeutic equivalent candidate to Forteo.

Teriparatide (recombinant human parathyroid hormone) is a potent anabolic agent used in the treatment of osteoporosis. It is manufactured and marketed by Eli Lilly and Company.

Teriparatide is a recombinant form of parathyroid hormone. It is an effective anabolic (i.e., bone growing) agent used in the treatment of some forms of osteoporosis. It is also occasionally used off-label to speed fracture healing. Teriparatide is identical to a portion of human parathyroid hormone (PTH) and intermittent use activates osteoblasts more than osteoclasts, which leads to an overall increase in bone. Teriparatide is sold by Eli Lilly and Company under the brand name Forteo.

Indication

For the treatment of osteoporosis in men and postmenopausal women who are at high risk for having a fracture. Also used to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture.

Associated Conditions

Pharmacodynamics

Clinical trials indicate that teriparatide increases predominantly trabecular bone in the lumbar spine and femoral neck; it has less significant effects at cortical sites. The combination of teriparatide with antiresorptive agents is not more effective than teriparatide monotherapy. The most common adverse effects associated with teriparatide include injection-site pain, nausea, headaches, leg cramps, and dizziness. After a maximum of two years of teriparatide therapy, the drug should be discontinued and antiresorptive therapy begun to maintain bone mineral density.

Mechanism of action

Teriparatide is the portion of human parathyroid hormone (PTH), amino acid sequence 1 through 34 of the complete molecule which contains amino acid sequence 1 to 84. Endogenous PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney. Daily injections of teriparatide stimulates new bone formation leading to increased bone mineral density.

Medical uses

Teriparatide has been FDA-approved since 2002.[6] It is effective in growing bone (e.g., 8% increase in bone density in the spine after one year)[7] and reducing the risk of fragility fractures.[6][8] When studied, teriparatide only showed bone mineral density (BMD) improvement during the first 18 months of use. Teriparatide should only be used for a period of 2 years maximum. After 2 years, another agent such a bisphosphonate or denosumab should be used in cases of osteoporosis. [9]

Teriparatide cuts the risk of hip fracture by more than half but does not reduce the risk of arm or wrist fracture.[10]

Other

Teriparatide can be used off-label to speed fracture repair and treat fracture nonunions.[11] It has been reported to have been successfully used to heal fracture nonunions.[12] Generally, due to HIPAA regulations, it is not publicized when American athletes receive this treatment to improve fracture recovery.[11] But an Italian football player, Francesco Totti, was given teriparatide after a tibia/fibula fracture, and he unexpectedly recovered in time for the 2006 World Cup.[11] It has been reported that Mark Mulder used it to recover from a hip fracture Oakland A’s for the 2003 MLB playoffs[13] and Terrell Owens to recover from an ankle fracture before the 2005 Super Bowl.[13]

Administration

Teriparatide is administered by injection once a day in the thigh or abdomen.

Contraindications

Teriparatide should not be prescribed for people who are at increased risks for osteosarcoma. This includes those with Paget’s Diseaseof bone or unexplained elevations of serum alkaline phosphate, open epiphysis, or prior radiation therapy involving the skeleton. In the animal studies and in one human case report, it was found to potentially be associated with developing osteosarcoma in test subjects after over 2 years of use. [14]

Patients should not start teriparatide until any vitamin D deficiency is corrected. [15]

Adverse effects

Adverse effects of teriparatide include headache, nausea, dizziness, and limb pain.[6] Teriparatide has a theoretical risk of osteosarcoma, which was found in rat studies but not confirmed in humans.[2] This may be because unlike humans, rat bones grow for their entire life.[2] The tumors found in the rat studies were located on the end of the bones which grew after the injections began.[15]After nine years on the market, there were only two cases of osteosarcoma reported.[7] This risk was considered by the FDA as “extremely rare” (1 in 100,000 people)[6] and is only slightly more than the incidence in the population over 60 years old (0.4 in 100,000).[6]

Mechanism of action

Teriparatide is a portion of human parathyroid hormone (PTH), amino acid sequence 1 through 34, of the complete molecule (containing 84 amino acids). Endogenous PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney. PTH increases serum calcium, partially accomplishing this by increasing bone resorption. Thus, chronically elevated PTH will deplete bone stores. However, intermittent exposure to PTH will activate osteoblasts more than osteoclasts. Thus, once-daily injections of teriparatide have a net effect of stimulating new bone formation leading to increased bone mineral density.[16][17][18]

Teriparatide is the first FDA approved agent for the treatment of osteoporosis that stimulates new bone formation.[19]

FDA approval

Teriparatide was approved by the Food and Drug Administration (FDA) on 26 November 2002, for the treatment of osteoporosis in men and postmenopausal women who are at high risk for having a fracture. The drug is also approved to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture.

Combined teriparatide and denosumab

Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture by increasing BMD. However, there is no evidence of fracture rate reduction in patients taking a teriparatide and denosumab combination. Moreover, the combination therapy group showed a significant decrease in their bone formation marker, indicating that denosumab, an antiresorptive agent, might actually counteract the effect of teriparatide, a bone formation anabolic agent, in bone formation. [20]

PATENT

KR 2011291

WO 2019077432

CN 109897099

CN 109879955

CN 109879954

CN 108373499

PATENT

WO-2020000555

Process for preparing teriparatide as parathyroid hormone receptor agonist, useful for treating osteoporosis in menopausal women. Appears to be the first filing from the assignee and the inventors on this compound, however, this invention was previously seen as a Chinese national filing published in 12/2013. Daiichi Sankyo , through its subsidiary  Asubio Pharma , was developing SUN-E-3001 , a nasally administered recombinant human parathyroid hormone, for the treatment of osteoporosis.

Teriparatide is a 1-34 fragment of human parathyroid hormone, which has the same biological activity as human parathyroid hormone. Hypogonadous osteoporosis and osteoporosis in menopausal women have great market prospects.

The peptide sequence is:
H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu- Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH.
Patent US6590081 uses a method of genetic recombination to obtain teriparatide. However, the genetic recombination method has problems such as complicated process, high cost and serious waste.
Patent CN201510005427 uses Wang resin or 2-Cl-CTC resin to synthesize teriparatide one by one from the C-terminus to the N-terminus, which belongs to the conventional solid-phase synthesis method. However, the reaction is incomplete when the method is coupled to the late stage, which makes purification of the final product difficult and the purity is not high.
Patent CN201310403743 is synthesized by one-by-one coupling method. Unlike patent CN201510005427, this patent ester-condenses the free hydroxyl of Ser at the 17-position with the carboxyl group of Asn at the 16-position, and then obtains teriparatide through O → N acyl transfer. Although this method can reduce the difficulty of coupling at subsequent sites by changing the spatial configuration of the target peptide, it still has the problem of many solid-phase coupling steps and difficult purification.

In patent CN201410262511, a pseudoproline dipeptide Fmoc-Asn (Trt) -Ser (ψ Me, Me Pro) -OH is used instead of the two amino acids at the original 16-17 positions for coupling one by one, and the final cleavage yields teriparatide. This method adopts the method of feeding pseudoproline dipeptide to avoid the generation of oxidative impurities, but it cannot avoid a variety of missing peptides due to the excessively long peptide chain. At the same time, the pseudoproline dipeptide is expensive and difficult to obtain.

Patent CN201511024053 uses multiple di- or tripeptide fragments to replace a single amino acid for coupling, and finally cleavages to obtain teriparatide. This method requires liquid phase synthesis to obtain 11 short peptide fragments, which are complicated in operation and low in production efficiency.
A method for preparing teriparatide includes:

[0016]
Step 1: Coupling 3-Fmoc-4-diaminobenzoic acid with a solid phase carrier, and then sequentially coupling Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc from the C-terminus to the N-terminus according to the peptide sequence -His (Trt) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met -OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and PG- Ser (tBu) -OH, then benzimidazolone is closed by phenyl p-nitrochloroformate, and finally fragmented by salicylaldehyde and TFA to obtain fragment APG-Ser-Val-Ser-Glu-Ile-Gln-Leu- Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL;

[0017]
Step 2: Coupling Fmoc-Phe-OH with a solid support, and then coupling Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Val in sequence from the C-terminus to the N-terminus according to the peptide sequence. -OH, Fmoc-Asp (tBu) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Leu-OH, Fmoc-Lys (Boc) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Arg (Pbf ) -OH, Fmoc-Leu-OH, Fmoc-Trp (Boc) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Val-OH, Fmoc-Arg (Pbf) -OH, Fmoc-Glu (OtBu)- OH, Fmoc-Met-OH and Fmoc-Ser (tBu) -OH, TFA cleavage to obtain fragment B Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp- Val-His-Asn-Phe-OH;

[0018]
Step 3: Coupling Fragment A and Fragment B, and then removing the protecting group of Ser at Fragment A to obtain a crude teriparatide peptide;

[0019]
Step 4: Purifying the teriparatide crude peptide to obtain teriparatide;

[0020]
Step 1 and Step 2 are not in order.

[0021]
Preferably, the solid phase carrier in step 1 is Rink Amide Resin or 2-Cl-CTC Resin.

[0022]
Preferably, the coupling agent in step 1 is HOBt / DIPCDI, HOBt / PyBop / DIPEA, HATU / HOAt / DIPEA, HOAt / PyAop / DIPEA, or HBTU / HOBt / DIPEA.

[0023]
Preferably, the PG of PG-Ser (tBu) -OH in step 1 is a Msz protecting group, a Teoc protecting group, or a Fmoc protecting group.

[0024]
Preferably, the cracking lysing agent in step 1 is a mixed solution of TFA and water.

[0025]
Preferably, the solid phase support in step 2 is Wang Resin.

[0026]
Preferably, the coupling agent in step 2 is HOBt / DIPCDI, HOBt / DMAP / DIPCDI, HOBt / PyBop / DIPEA, HATU / HOAt / DIPEA, HOAt / PyAop / DIPEA, or HBTU / HOBt / DIPEA.

[0027]
Preferably, the lysing lysing agent in step 2 is a mixed solution of TFA and TIS.

[0028]
Preferably, the specific operation of the coupling in step 3 is to dissolve in a pyridine / acetic acid buffer solution for 2-4 hours.

[0029]
Preferably, the specific operation of removing the protecting group of 1-Ser in the fragment A in step 3 is:

[0030]
When the PG of PG-Ser (tBu) -OH in the fragment A is the protecting group of Msz, the coupling of the fragment A and the fragment B is completed by adding TFA / ammonium iodide / dimethylsulfide to remove the protecting group Msz, and the ether precipitates;

[0031]
When the PG of PG-Ser (tBu) -OH in the fragment A is a Teoc protecting group, the fragment A and the fragment B are coupled and tetrabutylammonium fluoride is added to remove the protecting group Teoc;

[0032]
When the PG of PG-Ser (tBu) -OH in the fragment A is a Fmoc protecting group, the fragment A and the fragment B are coupled and diethylamine is added to remove the protecting group Fmoc.

[0033]
The method for preparing teriparatide in the present invention uses fragment condensation to prepare teriparatide. First synthesize the teriparatide peptide sequence 1-16 (fragment A) and the 17-34 peptide sequence (fragment B), and then couple the two fragments to obtain the crude teriparatide peptide. Riparide. The side chain of the fragment in the invention has no protecting group, has good solubility in water, does not have the problem of difficult coupling, simple operation, and high production efficiency. The obtained teriparatide product has high purity and is easy to purify. Experiments show that the crude peptide of teriparatide obtained by the present invention can obtain a purity of 80% and a total yield of 45%. After simple purification, the purity of spermeptide can reach 99.92%, and the single largest impurity is 0.05%. Compared with the prior art, the invention has the characteristics of high product quality, low cost, and suitability for industrial production.
Example 1: Synthesis of fragment one (Msz-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)

[0097]
Weigh 20.0 g (10 mmol) of Rink Amide Resin with a substitution degree of 0.5 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, remove the solution, and weigh 18.7 g (50 mmol) ) 3-Fmoc-4-diaminobenzoic acid and 8.1 g (60 mmol) of HOBt were dissolved in DMF, 8.2 g (65 mmol) of DIPCDI was added under an ice bath, and added to a solid-phase reaction column, and reacted at room temperature for 2 hours. The solution was removed by DMF Wash 3 times. The 20% piperidine solution was used to remove the Fmoc protecting group (reaction time 5 + 7 minutes), and DMF was washed 6 times.

[0098]
According to the peptide sequence of fragment one, the above steps of amino acid coupling and removal of the Fmoc protecting group are repeated, using the coupling agent HOBt / DIPCDI or HOBt / PyBop / DIPEA or HATU / HOAt / DIPEA or HOAt / PyAop / DIPEA or HBTU / HOBt / DIPEA, coupled Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc-His (Trt) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Gly-OH, Fmoc-Leu- OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and Msz-Ser (tBu) -OH.

[0099]
Weigh 10.1 g (50 mmol) of phenyl p-nitrochloroformate in dichloromethane, add it to a solid-phase reaction column, and react at room temperature for 1 hour, then add 12.9 g (100 mol) of DIPEA, react for 30 minutes, and remove the solution. Wash with methyl chloride 6 times. Separately weigh 10.6 g (100 mmol) of sodium carbonate and 100 ml of salicylaldehyde in a mixed solution of DCM / THF (1: 3), add to the peptide resin, react at room temperature overnight, filter, and concentrate the filtrate under reduced pressure to dryness. Finally, it was cleaved with TFA / H 2 O (95: 5) for 2 hours and precipitated with ether to obtain 19.2 g of fragment one.

[0100]
Example 2: Synthesis of fragment two (Teoc-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)

[0101]
Weigh 16.7 g (10 mmol) of 2-Cl-CTC Resin with a substitution degree of 0.6 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, remove the solution, and weigh 7.48 g (20 mmol) of 3-Fmoc-4-diaminobenzoic acid was dissolved in DMF, 5.2 g (40 mmol) of DIPEA was added under an ice bath, and the solid phase reaction column was added, and the reaction was performed at room temperature for 0 hours, and 6 ml of methanol was added to block the resin for 1 hour. The solution was removed and washed 6 times with DMF.

[0102]
Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc-His (Trt) -OH, Fmoc-Lys (Boc) -OH were sequentially coupled according to the peptide sequence of fragment two according to the method in Example 1. , F moc-Gly-OH, Fmoc-Leu-OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and Teoc-Ser (tBu) -OH.

[0103]
Weigh 6.1 g (30 mmol) of phenyl p-nitrochloroformate and dissolve it in dichloromethane, add it to a solid-phase reaction column, and react at room temperature for 1 hour, then add 7.7 g (60 mol) of DIPEA, react for 30 minutes, and remove the solution. Wash with methyl chloride 6 times. Another 6.4 g (60 mmol) of sodium carbonate and 60 ml of salicylaldehyde dissolved in a mixed solution of DCM / THF (1: 1) were added to the peptide resin, reacted at room temperature overnight, filtered, and the filtrate was concentrated under reduced pressure to dryness. Finally, it was cleaved with TFA / H2O (95: 5) for 2 hours and precipitated with ether to obtain 10.5 g of fragment two.

[0104]
Example 3: Synthesis of fragment three (Fmoc-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)

[0105]
Fmoc-Ser (tBu) -OH was used for serine at position 1. Other synthetic methods were the same as in Example 1.

[0106]
Example 4: Synthesis of fragment four (Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH)

[0107]
Weigh 62.5 g (50 mmol) of Wang Resin with a degree of substitution of 0.8 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 3 minutes, then weigh 19.37 g (50 mmol) of Fmoc-Phe- OH, 8.1 g (60 mmol) of HOBt and 6.1 g (5 mmol) of DMAP were dissolved in DMF. 8.2 g (65 mmol) of DIPCDI was added under an ice bath, and the solid phase reaction column was added. The mixture was reacted at room temperature for 2 hours and washed with DMF 6 times. 79.1 g (1000 mmol) of pyridine and 102.1 g (1000 mmol) of acetic anhydride were added to seal the resin for 6 hours, washed with DMF 6 times, and the methanol was shrunk and dried to obtain 71.4 g of Fmoc-Phe-WangResin. .

[0108]
According to the method in Example 1, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Val-OH, Fmoc-Asp (tBu) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Leu-OH, Fmoc-Lys (Boc) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Arg (Pbf) -OH, Fmoc-Leu-OH, Fmoc- Trp (Boc) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Val-OH, Fmoc-Arg (Pbf) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Met-OH and Fmoc-Ser ( tBu) -OH, the obtained peptide resin was cleaved with TFA / TIS (95: 5) for 2 hours, and the ether was precipitated to obtain 23.2 g of fragment four.

[0109]
Example 5: Synthesis of crude teriparatide

[0110]
19.2 g (10 mmol) of fragment 1 obtained in Example 1 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), reacted at room temperature for 2 hours, and concentrated under reduced pressure to Dry, add TFA / ammonium iodide / dimethylsulfide (90: 5: 5) to react for 30 minutes, and diethyl ether precipitates to obtain 37 g of teriparatide crude peptide, purity 80.10%, weight yield 90%. The purity test results are shown in Figure 2 and Table 1.

[0111]
Example 6: Synthesis of crude teriparatide

[0112]
21.9 g (10 mmol) of fragment 2 obtained in Example 2 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), and reacted at room temperature for 3 hours, and then 26.15 g was added. Tetrabutylammonium fluoride (100 mmol) was reacted overnight to obtain the teriparatide crude peptide solution for direct purification. The purity of the crude peptide was 67.97%. The purity test results are shown in Figure 3 and Table 1.

[0113]
Example 7: Synthesis of crude teriparatide

[0114]
21.5 g (10 mmol) of fragment 3 obtained in Example 3 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), reacted at room temperature for 4 hours, and concentrated under reduced pressure to Dry, add methanol to dissolve, then add 14.63 g of diethylamine (200 mmol), react at room temperature for 2 hours, and concentrate to dryness under reduced pressure to obtain 45 g of teriparatide crude peptide, purity 63.22%, weight yield 109%. The purity test results are shown in Figure 4 and Table 1.

[0115]
Example 8: Purification of crude teriparatide

[0116]
The crude teriparatide peptide obtained in Example 5 was purified by HPLC with a wavelength of 220 nm, a chromatographic column was a reversed-phase C18 column, a 0.1% TFA solution, and acetonitrile were used as mobile phases. The target fractions were collected, concentrated by rotary evaporation, and lyophilized. 18.5 g of teriparatide spermidine was obtained, with a purity of 99.92%, a single maximum impurity of 0.05%, and a total yield of 45%. The purity test results are shown in Figure 5 and Table 1.

[0117]
The crude teriparatide peptide obtained in Example 6 was purified under the same conditions as described above to obtain 14.8 g of teriparatide spermeptide with a purity of 99.76%, a single maximum impurity of 0.07%, and a total yield of 36%.

[0118]
The crude teriparatide peptide obtained in Example 7 was purified under the same conditions as described above to obtain 14.0 g of teriparatide spermeptide with a purity of 99.73%, a single maximum impurity of 0.06%, and a total yield of 34%.

References

  1. ^ http://www.minsa.gob.pa/sites/default/files/alertas/nota_seguridad_teriparatida.pdf
  2. Jump up to:a b c Riek AE and Towler DA (2011). “The pharmacological management of osteoporosis”Missouri Medicine108 (2): 118–23. PMC 3597219PMID 21568234.
  3. ^ Saag KG, Shane E, Boonen S, et al. (November 2007). “Teriparatide or alendronate in glucocorticoid-induced osteoporosis”. The New England Journal of Medicine357 (20): 2028–39. doi:10.1056/NEJMoa071408PMID 18003959.
  4. ^ BfArM (2017-05-08). “PUBLIC ASSESSMENT REPORT – Decentralised Procedure – Teriparatid-ratiopharm 20 µg / 80ml, Solution for injection” (PDF).
  5. ^ “Summary of the European public assessment report (EPAR) for Terrosa”. Retrieved 2019-08-14.
  6. Jump up to:a b c d e Rizzoli, R.; Reginster, J. Y.; Boonen, S.; Bréart, G. R.; Diez-Perez, A.; Felsenberg, D.; Kaufman, J. M.; Kanis, J. A.; Cooper, C. (2011). “Adverse Reactions and Drug–Drug Interactions in the Management of Women with Postmenopausal Osteoporosis”Calcified Tissue International89 (2): 91–104. doi:10.1007/s00223-011-9499-8PMC 3135835PMID 21637997.
  7. Jump up to:a b Kawai, M.; Mödder, U. I.; Khosla, S.; Rosen, C. J. (2011). “Emerging therapeutic opportunities for skeletal restoration”Nature Reviews Drug Discovery10 (2): 141–156. doi:10.1038/nrd3299PMC 3135105PMID 21283108.
  8. ^ Murad, M. H.; Drake, M. T.; Mullan, R. J.; Mauck, K. F.; Stuart, L. M.; Lane, M. A.; Abu Elnour, N. O.; Erwin, P. J.; Hazem, A.; Puhan, M. A.; Li, T.; Montori, V. M. (2012). “Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A Systematic Review and Network Meta-Analysis”. Journal of Clinical Endocrinology & Metabolism97(6): 1871–1880. doi:10.1210/jc.2011-3060PMID 22466336.
  9. ^ O’Connor KM. Evaluation and Treatment of Osteoporosis. Med Clin N Am. 2016; 100:807-26
  10. ^ Díez-Pérez A, Marin F, Eriksen EF, Kendler DL, Krege JH, Delgado-Rodríguez M (September 2018). “Effects of teriparatide on hip and upper limb fractures in patients with osteoporosis: A systematic review and meta-analysis”. Bone120: 1–8. doi:10.1016/j.bone.2018.09.020PMID 30268814.
  11. Jump up to:a b c Bruce Jancin (2011-12-12). “Accelerating Fracture Healing With Teriparatide”. Internal Medicine News Digital Network. Retrieved 2013-09-20.
  12. ^ Giannotti, S.; Bottai, V.; Dell’Osso, G.; Pini, E.; De Paola, G.; Bugelli, G.; Guido, G. (2013). “Current medical treatment strategies concerning fracture healing”Clinical Cases in Mineral and Bone Metabolism10 (2): 116–120. PMC 3796998PMID 24133528.
  13. Jump up to:a b William L. Carroll (2005). “Chapter 1: Defining the Issue”The Juice: The Real Story of Baseball’s Drug ProblemsISBN 1-56663-668-X. Retrieved 2013-09-23.
  14. ^ Harper KD, Krege JH, Marcus R, et al. Osteosarcoma and teriparatide? J Bone Miner Res 2007;22(2):334
  15. Jump up to:a b https://www.drugs.com/pro/forteo.html
  16. ^ Bauer, E; Aub, JC; Albright, F (1929). “Studies of calcium and phosphorus metabolism: V. Study of the bone trabeculae as a readily available reserve supply of calcium”J Exp Med49 (1): 145–162. doi:10.1084/jem.49.1.145PMC 2131520PMID 19869533.
  17. ^ Selye, H (1932). “On the stimulation of new bone formation with parathyroid extract and irradiated ergosterol”. Endocrinology16 (5): 547–558. doi:10.1210/endo-16-5-547.
  18. ^ Dempster, D. W.; Cosman, F.; Parisien, M.; Shen, V.; Lindsay, R. (1993). “Anabolic actions of parathyroid hormone on bone”. Endocrine Reviews14 (6): 690–709. doi:10.1210/edrv-14-6-690PMID 8119233.
  19. ^ Fortéo: teriparatide (rDNA origin) injection Archived 2009-12-27 at the Wayback Machine
  20. ^ Tsai, Joy N; Uihlein, Alexander V; Lee, Hang; Kumbhani, Ruchit; Siwila-Sackman, Erica; McKay, Elizabeth A; Burnett-Bowie, Sherri-Ann M; Neer, Robert M; Leder, Benjamin Z (2013). “Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: The DATA study randomised trial”The Lancet382 (9886): 1694–1700. doi:10.1016/S0140-6736(13)60856-9PMC 4010689PMID 24517156.

External links

Teriparatide
Teriparatide structure.svg
Clinical data
Trade names Forteo/Forsteo, Teribone[1]
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • C
Routes of
administration
Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 95%
Metabolism Hepatic (nonspecific proteolysis)
Elimination half-life Subcutaneous: 1 hour
Excretion Renal (metabolites)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ECHA InfoCard 100.168.733 Edit this at Wikidata
Chemical and physical data
Formula C181H291N55O51S2
Molar mass 4117.72 g/mol g·mol−1
3D model (JSmol)

FORTEO (teriparatide [rDNA origin] injection) contains recombinant human parathyroid hormone (1- 34), and is also called rhPTH (1-34). It has an identical sequence to the 34 N-terminal amino acids(the biologically active region) of the 84-amino acid human parathyroid hormone.

Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown below:

FORTEO (teriparatide)Structural Formula Illustration

Teriparatide (rDNA origin) is manufactured using a strain of Escherichia coli modified by recombinant DNA technology. FORTEO is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.

Each cartridge, pre-assembled into a delivery device, delivers 20 mcg of teriparatide per dose each day for up to 28 days.

REFERENCES

1: Lindsay R, Krege JH, Marin F, Jin L, Stepan JJ. Teriparatide for osteoporosis: importance of the full course. Osteoporos Int. 2016 Feb 22. [Epub ahead of print] Review. PubMed PMID: 26902094.

2: Im GI, Lee SH. Effect of Teriparatide on Healing of Atypical Femoral Fractures: A Systemic Review. J Bone Metab. 2015 Nov;22(4):183-9. doi: 10.11005/jbm.2015.22.4.183. Epub 2015 Nov 30. Review. PubMed PMID: 26713309; PubMed Central PMCID: PMC4691592.

3: Babu S, Sandiford NA, Vrahas M. Use of Teriparatide to improve fracture healing: What is the evidence? World J Orthop. 2015 Jul 18;6(6):457-61. doi: 10.5312/wjo.v6.i6.457. eCollection 2015 Jul 18. Review. PubMed PMID: 26191492; PubMed Central PMCID: PMC4501931.

4: Lecoultre J, Stoll D, Chevalley F, Lamy O. [Improvement of fracture healing with teriparatide: series of 22 cases and review of the literature]. Rev Med Suisse. 2015 Mar 18;11(466):663-7. Review. French. PubMed PMID: 25962228.

5: Sugiyama T, Torio T, Sato T, Matsumoto M, Kim YT, Oda H. Improvement of skeletal fragility by teriparatide in adult osteoporosis patients: a novel mechanostat-based hypothesis for bone quality. Front Endocrinol (Lausanne). 2015 Jan 30;6:6. doi: 10.3389/fendo.2015.00006. eCollection 2015. Review. PubMed PMID: 25688232; PubMed Central PMCID: PMC4311704.

6: Wheeler AL, Tien PC, Grunfeld C, Schafer AL. Teriparatide treatment of osteoporosis in an HIV-infected man: a case report and literature review. AIDS. 2015 Jan 14;29(2):245-6. doi: 10.1097/QAD.0000000000000529. Review. PubMed PMID: 25532609; PubMed Central PMCID: PMC4438749.

7: Campbell EJ, Campbell GM, Hanley DA. The effect of parathyroid hormone and teriparatide on fracture healing. Expert Opin Biol Ther. 2015 Jan;15(1):119-29. doi: 10.1517/14712598.2015.977249. Epub 2014 Nov 3. Review. PubMed PMID: 25363308.

8: Yamamoto M, Sugimoto T. [Glucocorticoid and Bone. Beneficial effect of teriparatide on fracture risk as well as bone mineral density in patients with glucocorticoid-induced osteoporosis]. Clin Calcium. 2014 Sep;24(9):1379-85. doi: CliCa140913791385. Review. Japanese. PubMed PMID: 25177011.

9: Chen JF, Yang KH, Zhang ZL, Chang HC, Chen Y, Sowa H, Gürbüz S. A systematic review on the use of daily subcutaneous administration of teriparatide for treatment of patients with osteoporosis at high risk for fracture in Asia. Osteoporos Int. 2015 Jan;26(1):11-28. doi: 10.1007/s00198-014-2838-7. Epub 2014 Aug 20. Review. PubMed PMID: 25138261.

10: Eriksen EF, Keaveny TM, Gallagher ER, Krege JH. Literature review: The effects of teriparatide therapy at the hip in patients with osteoporosis. Bone. 2014 Oct;67:246-56. doi: 10.1016/j.bone.2014.07.014. Epub 2014 Jul 15. Review. PubMed PMID: 25053463.

11: Meier C, Lamy O, Krieg MA, Mellinghoff HU, Felder M, Ferrari S, Rizzoli R. The role of teriparatide in sequential and combination therapy of osteoporosis. Swiss Med Wkly. 2014 Jun 4;144:w13952. doi: 10.4414/smw.2014.13952. eCollection 2014. Review. PubMed PMID: 24896070.

12: Krege JH, Lane NE, Harris JM, Miller PD. PINP as a biological response marker during teriparatide treatment for osteoporosis. Osteoporos Int. 2014 Sep;25(9):2159-71. doi: 10.1007/s00198-014-2646-0. Epub 2014 Mar 6. Review. PubMed PMID: 24599274; PubMed Central PMCID: PMC4134485.

13: Nakano T. [Once-weekly teriparatide treatment on osteoporosis]. Clin Calcium. 2014 Jan;24(1):100-5. doi: CliCa1401100105. Review. Japanese. PubMed PMID: 24369286.

14: Yano S, Sugimoto T. [Daily subcutaneous injection of teriparatide : the progress and current issues]. Clin Calcium. 2014 Jan;24(1):35-43. doi: CliCa14013543. Review. Japanese. PubMed PMID: 24369278.

15: Lewiecki EM, Miller PD, Harris ST, Bauer DC, Davison KS, Dian L, Hanley DA, McClung MR, Yuen CK, Kendler DL. Understanding and communicating the benefits and risks of denosumab, raloxifene, and teriparatide for the treatment of osteoporosis. J Clin Densitom. 2014 Oct-Dec;17(4):490-5. doi: 10.1016/j.jocd.2013.09.018. Epub 2013 Oct 25. Review. PubMed PMID: 24206867.

16: Delivanis DA, Bhargava A, Luthra P. Subungual exostosis in an osteoporotic patient treated with teriparatide. Endocr Pract. 2013 Sep-Oct;19(5):e115-7. doi: 10.4158/EP13040.CR. Review. PubMed PMID: 23757619.

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/////TERIPARATIDE, テリパラチド , терипаратид تيريباراتيد 特立帕肽 PTH 1-34, LY 333334,  LY-333334LY333334,  ZT-034, 52232-67-4, PEPTIDES

Coblopasvir


img

Coblopasvir.png

Coblopasvir
CAS: 1312608-46-0
Chemical Formula: C41H50N8O8
Molecular Weight: 782.89

UNII-67XWL3R65W

methyl {(2S)-1-[(2S)-2-(4-{4-[7-(2-[(2S)-1-{(2S)-2- [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl)-2H-1,3-benzodioxol-4-yl]phenyl}-1Himidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Carbamic acid, N-((1S)-1-(((2S)-2-(5-(4-(7-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methyl-1-oxobutyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-1,3-benzodioxol-4-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)-, methyl ester

hepatitis C virus infection

KW-136

Coblopasvir is an antiviral drug candidate.

Coblopasvir dihydrochloride

CAS 1966138-53-3

C41 H50 N8 O8 . 2 Cl H
 Molecular Weight 855.806
PHASE 3 Beijing Kawin Technology Share-Holding
Hepatitis C virus (HCV), or hepatitis C virus infection, is a chronic blood-borne infection. Studies have shown that 40% of chronic liver diseases are associated with HCV infection, and an estimated 8,000-10,000 people die each year. HCV-related end-stage liver disease is the most common indication for liver transplantation in adults.
In the past ten years, antiviral therapy for chronic liver disease has developed rapidly, and significant improvement has been seen in the treatment effect. However, even with the combination therapy with pegylated IFN-α plus ribavirin, 40% to 50% of patients fail to treat, that is, they are non-responders or relapsers. These patients do not currently have an effective treatment alternative. Because the risk of HCV-related chronic liver disease is related to the duration of HCV infection, and the risk of cirrhosis increases in patients who have been infected for more than 20 years, chronic liver disease often progresses to advanced stages with cirrhosis, ascites, jaundice, and rupture of varicose veins. , Brain disease, and progressive liver failure, and the risk of liver cancer is also significantly increased.
HCV is a enveloped positive-strand RNA virus of the Flaviviridae family. The single-stranded HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) that encodes a single open reading frame (ORF) of approximately 3,000 amino acids. Mostly polyprotein. In infected cells, cellular and viral proteases cleave this polyprotein at multiple sites to produce viral structural and non-structural (NS) proteins. There are two viral proteases that affect the production of mature non-structural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B). The first viral protease is cleaved at the NS2-NS3 junction of the polyprotein; the second viral protease is A “NS3 protease” that mediates all subsequent cleavage events at a site downstream of the NS3 position relative to the polyprotein (ie, the site between the C-terminus of NS3 and the C-terminus of the polyprotein). The NS3 protease exhibits cis-activity at the NS3-NS4 cleavage site and, conversely, exhibits trans-activity at the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B sites. The NS4A protein is thought to provide multiple functions, such as acting as a cofactor for the NS3 protease, and may promote membrane localization of NS3 and other viral replicase components. The formation of a complex between NS3 and NS4A may be necessary for NS3-mediated processing events and improves the proteolytic efficiency at all sites recognized by NS3. NS3 protease may also exhibit nucleotide triphosphatase and RNA helicase activity. NS5B is an RNA-dependent RNA polymerase involved in HCV RNA replication. In addition, compounds that inhibit the effects of NS5A in viral replication may be useful for treating HCV.

Beijing Kawin Technology Share-Holding, in collaboration with Beijing Fu Rui Tiancheng Biotechnology and Ginkgo Pharma , is developing coblopasvir as an oral capsule formulation of dihydrochloride salt (KW-136), for treating hepatitis C virus infection. In June 2018, an NDA was filed in China by Beijing Kawin Technology and Sichuan Qingmu Pharmaceutical . In August 2018, the application was granted Priority Review in China . Also, Beijing Kawin is investigating a tablet formulation of coblopasvir dihydrochloride.

PATENT

WO2011075607 , claiming substituted heterocyclic derivatives as HCV replication inhibitors useful for treating HCV infection and liver fibrosis, assigned to Beijing Kawin Technology Share-Holding Co Ltd and InterMune Inc ,

PATENT

CN 108675998

PATENT

WO-2020001089

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020001089&tab=FULLTEXT&_cid=P22-K53D18-32430-1

Novel crystalline and amorphous forms of methyl carbamate compound, particularly coblopasvir dihydrochloride , (designated as Forms H) processes for their preparation, compositions and combinations comprising them are claimed. Also claim is an article or kit comprising a container and a package insert, wherein the container contains coblopasvir dihydrochloride.

Step 7
To a solution of compound 1-IXf (250 mg, 0.31 mmol) in toluene (10.0 mL) was added NH4OAc (4.0 g, 50 mmol) and the mixture was refluxed for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was removed and the residue was purified by preparative HPLC to give Compound I (43.5 mg, yield 20%) as a white solid. MS (ESI) m / z (M + H) + 783.4.
Example 2 Preparation of a compound of formula II
Compound of formula (I) N-[(2S) -1-[(2S) -2- {4- [7- (4- {2-[(2S) -1-[(2S) -2-[(A Oxycarbonyl) amino] -3-methylbutanoyl] pyrrolidin-2-yl] -1H-imidazol-4-yl} phenyl) -2H-1,3-benzodioxo-4-yl] Preparation of -1H-imidazol-2-yl} pyrrolidin-1-yl] -3-methyl-1-oxobutane-2-yl] carbamate dihydrochloride
At room temperature, a solution of the pure product of structural formula I (800 g, 1.0 eq) and ethyl acetate (8 L) were sequentially added to a 20 L bottle and stirred. A 11.2% HCl / ethyl acetate solution (839 g) was added dropwise to the system, the temperature of the system was controlled at 15 ° C to 25 ° C, and the mixture was stirred for more than 3 hours to stop the reaction. The filter cake was filtered with ethyl acetate (2L). Wash the cake, bake the cake at a controlled temperature of 40-60 ° C, sample and test until the ethyl acetate residue is <0.5%, (about 73 hours of baking), to obtain the compound of formula II, off-white solid powder or granules, 774 g, HPLC Purity: 98.65%, yield: 88.5%, tested XRPD as amorphous.

///////////////Coblopasvir , KW-136, hepatitis C virus infection, CHINA, Beijing Kawin Technology, NDA, Phase III

O=C(OC)N[C@@H](C(C)C)C(N1[C@H](C2=NC(C3=CC=C(C4=C5OCOC5=C(C6=CNC([C@H]7N(C([C@@H](NC(OC)=O)C(C)C)=O)CCC7)=N6)C=C4)C=C3)=CN2)CCC1)=O

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