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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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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CC-90009


str1

2-(4-Chlorophenyl)-N-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methyl]-2,2-difluoroacetamide.png

CC-90009

CC-90009-AML-001

CAS 1860875-51-9

461.8 g/mol, C22H18ClF2N3O4

2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

  • 4-Chloro-N-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α,α-difluorobenzeneacetamide
  • Benzeneacetamide, 4-chloro-N-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α,α-difluoro-

Phase 1 Clinical, Acute myelogenous leukemia, Protein cereblon modulator

Useful for treating chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia or acute myeloid leukemia.

Celgene is developing CC-90009, a cereblon E3 ligase modulator, for treating AML; in January 2019, data from a phase I trial were expected later that year.

  • 0iginator Celgene Corporation
  • Class Antineoplastics
  • Mechanism of Action CRBN protein modulators; Ubiquitin protein ligase complex modulators
  • Phase I Acute myeloid leukaemia
  • 28 Mar 2019 No recent reports of development identified for clinical-Phase-Unknown development in Acute-myeloid-leukaemia in USA (IV)
  • 01 Sep 2016 Phase-I clinical trials in Acute myeloid leukaemia (Second-line therapy or greater) in Canada (IV) (NCT02848001)
  • 04 Aug 2016 Celgene plans a phase I trial for Acute Myeloid Leukaemia in USA and Canada (NCT02848001)

In September 2016, Celgene initiated a phase I dose-finding trial of CC 90009 in patients with relapsed or refractory acute myeloid leukaemia (NCT02848001; CC-90009-AML-001). The open-label study intends to enrol 60 patients in the US and Canada

CC-90009 is a cereblon modulator. CC-90009 specifically binds to CRBN, thereby affecting the activity of the ubiquitin E3 ligase complex. This leads to the ubiquitination of certain substrate proteins and induces the proteasome-mediated degradation of certain transcription factors, including Ikaros (IKZF1) and Aiolos (IKZF3), which are transcriptional repressors in T-cells. This reduces the levels of these transcription factors, and modulates the activity of the immune system, which may include the activation of T-lymphocytes. .

Development Overview

cereblon modulator CC-90009A modulator of cereblon (CRBN), which is part of the cullin 4-RING E3 ubiquitin ligase complex (CRL4-CRBN E3 ubiquitin ligase; CUL4-CRBN E3 ubiquitin ligase), with potential immunomodulating and pro-apoptotic activities. Upon administration, CC-90009 specifically binds to CRBN, thereby affecting the activity of the ubiquitin E3 ligase complex. This leads to the ubiquitination of certain substrate proteins and induces the proteasome-mediated degradation of certain transcription factors, including Ikaros (IKZF1) and Aiolos (IKZF3), which are transcriptional repressors in T-cells. This reduces the levels of these transcription factors, and modulates the activity of the immune system, which may include the activation of T-lymphocytes. In addition, this downregulates the expression of other proteins, including interferon regulatory factor 4 (IRF4) and c-myc, which plays a key role in the proliferation of certain cancer cell types. CRBN, the substrate recognition component of the E3 ubiquitin ligase complex, plays a key role in the ubiquitination of certain proteins. Check for active clinical trials using this agent. (NCI Thesaurus)

WO 2017120446,

PATENT

WO2016007848

US 20170348298

WO 2017120415

WO 2017120446

WO 2017120437

PATENT

WO2017214014

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017214014&tab=PCTDESCRIPTION

Provided herein are methods of treating, preventing, managing, and/or ameliorating a hematologic malignancy with 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of

stereoisomers, an isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Further provided is a compound for use in methods of treating, preventing, managing, and/or ameliorating a hematologic malignancy, wherein the compound is 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers, an isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

The term Compound 1 refers to”2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide” having the structure:

and its stereoisomers or mixture of stereoisomers, isotopologues, pharmaceutically acceptable salts, tautomers, solvates, hydrates, co-crystals, clathrates, or polymorphs thereof. In certain embodiments, Compound 1 refers to 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide and its tautomers. In certain embodiments, Compound 1 refers to a polymorph of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-

oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide. In certain embodiments, Compound 1 refers to polymorph Form C of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide. In one embodiment, the stereoisomer is an enantiomer.

PATENT

WO-2019136016

Novel isotopologs of the compound presumed to be CC-90009 , processes for their preparation and compositions comprising them are claimed.

str2

Patent ID Title Submitted Date Granted Date
US2017199193 METHODS FOR TREATING CANCER AND THE USE OF BIOMARKERS AS A PREDICTOR OF CLINICAL SENSITIVITY TO THERAPIES 2017-01-06
US2018224435 METHODS FOR MEASURING SMALL MOLECULE AFFINITY TO CEREBLON 2018-02-02
US2018353496 FORMULATIONS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE 2018-07-19
US2017196847 FORMULATIONS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE 2017-01-06
US2017348298 TREATMENT OF A HEMATOLOGIC MALIGNANCY WITH 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE 2017-06-05
Patent ID Title Submitted Date Granted Date
US2018221361 ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF 2018-04-09
US9968596 Antiproliferative compounds and methods of use thereof 2017-10-02 2018-05-15
US2017197934 SOLID FORMS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE, AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES 2017-01-06
US9499514 ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF 2015-07-09 2016-01-14
US9808451 ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF 2016-09-23

////////CC-90009 , CC 90009  , CC90009, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, phase I, CANCER, CC-90009-AML-001

Clc1ccc(cc1)C(F)(F)C(=O)NCc2ccc3C(=O)N(Cc3c2)C4CCC(=O)NC4=O

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Selinexor


Skeletal formula of selinexor

Selinexor.png

Selinexor

セリネクソル

KPT-330

UNII-31TZ62FO8F

(Z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-N‘-pyrazin-2-ylprop-2-enehydrazide

Formula
C17H11F6N7O
CAS
1393477-72-9
Mol weight
443.306

FDA, APPROVED 2019/7/3, Xpovio

CAS : 1393477-72-9 (free base)   1421923-86-5 (E-isomer)   1621865-82-4 (E-isomer)   Unknown (HCl)

Treatment of cancer, Antineoplastic, Nuclear export inhibitor

Selinexor (INN, trade name Xpovio; codenamed KPT-330) is a selective inhibitor of nuclear export used as an anti-cancer drug. It works by quasi-irreversibly binding to exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis.[1] It is the first drug with this mechanism of action.[2][3]

Selinexor was granted accelerated approval by the U.S. Food and Drug Administration in July 2019, for use as a drug of last resort in people with multiple myeloma. In clinical trials, it was associated with a high incidence of severe side effects, including low platelet counts and low blood sodium levels.[3][4]

Selinexor is an orally available, small molecule inhibitor of CRM1 (chromosome region maintenance 1 protein, exportin 1 or XPO1), with potential antineoplastic activity. Selinexor modifies the essential CRM1-cargo binding residue cysteine-528, thereby irreversibly inactivates CRM1-mediated nuclear export of cargo proteins such as tumor suppressor proteins (TSPs), including p53, p21, BRCA1/2, pRB, FOXO, and other growth regulatory proteins. As a result, this agent, via the approach of selective inhibition of nuclear export (SINE), restores endogenous tumor suppressing processes to selectively eliminate tumor cells while sparing normal cells. CRM1, the major export factor for proteins from the nucleus to the cytoplasm, is overexpressed in a variety of cancer cell types.

Selinexor has been used in trials studying the treatment of AML, Glioma, Sarcoma, Leukemia, and Advanced, among others.

 Selinexor, also known as KPT-330, is an orally bioavailable, potent and selective XPO1/CRM1 Inhibitor. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Selinexor potentiates the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, depletion of the antiapoptotic proteins, and induction of apoptosis. Selinexor has strong activity against primary AML cells while sparing normal stem and progenitor cells.

SYN

Medical uses

Selinexor is restricted for use in combination with the steroid dexamethasone in people with relapsed or refractory multiple myelomawhich has failed to respond to at least four or five other therapies (so-called “quad-refractory” or “penta-refractory” myeloma),[5] for whom no other treatment options are available.[3][4] It is the first drug to be approved for this indication.[6]

Adverse effects

In the clinical study used to support FDA approval, selinexor was associated with high rates of pancytopenia, including leukopenia(28%), neutropenia (34%, severe in 21%), thrombocytopenia (74%, severe in 61% of patients), and anemia (59%).[4][7] The most common non-hematological side effects were gastrointestinal reactions (nausea, anorexia, vomiting, and diarrhea), hyponatremia (low blood sodium levels, occurring in up to 40% of patients), and fatigue.[7][8] More than half of all patients who received the drug developed infections, including fatal cases of sepsis.[7] However, these data are from an open-label trial, and thus cannot be compared to placebo or directly attributed to treatment.

Mechanism of action

Schematic illustration of the Ran cycle of nuclear transport. Selinexor inhibits this process at the nuclear export receptor (upper right).

Like other so-called selective inhibitors of nuclear export (SINEs), selinexor works by binding to exportin 1 (also known as CRM1). CRM1 is a karyopherin which performs nuclear transport of several proteins, including tumor suppressorsoncogenes, and proteins involved in governing cell growth, from the cell nucleus to the cytoplasm; it is often overexpressed and its function misregulated in several types of cancer.[1] By restoring nuclear transport of these proteins to normal, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell proliferation. This ultimately leads to cell cycle arrest and death of cancer cells by apoptosis.[1][2][7] In vitro, this effect appeared to spare normal (non-malignant) cells.[1][8]

Because CRM1 is a pleiotropic gene, inhibiting it affects many different systems in the body, which explains the high incidence of adverse reactions to selinexor.[2] Thrombocytopenia, for example, is a mechanistic and dose-dependent effect, occurring because selinexor causes a buildup of the transcription factor STAT3 in the nucleus of hematopoietic stem cells, preventing their differentiation into mature megakaryocytes (platelet-producing cells) and thus slowing production of new platelets.[2]

Chemistry

Selinexor is a fully synthetic small-molecule compound, developed by means of a structure-based drug design process known as induced-fit docking. It binds to a cysteine residue in the nuclear export signal groove of exportin 1. Although this bond is covalent, it is not irreversible.[1]

History

Selinexor was developed by Karyopharm Therapeutics of Newton, Massachusetts, a pharmaceutical company devoted entirely to the development of drugs that target nuclear transport. It was approved by the FDA on July 3, 2019, on the basis of a single uncontrolled clinical trial. The decision was controversial, and overruled the previous recommendation of an FDA Advisory Panel which had voted 8–5 against approving the drug, due to concerns about efficacy and toxicity.[3]

Research

Under the codename KPT-330, selinexor was tested in several preclinical animal models of cancer, including pancreatic cancerbreast cancernon-small-cell lung cancerlymphomas, and acute and chronic leukemias.[9] In humans, early clinical trials (phase I) have been conducted in non-Hodgkin lymphomablast crisis, and a wide range of advanced or refractory solid tumors, including colon cancerhead and neck cancermelanomaovarian cancer, and prostate cancer.[9] Compassionate use in patients with acute myeloid leukemia has also been reported.[9]

The pivotal clinical trial which served to support approval of selinexor for people with relapsed/refractory multiple myeloma was an open-label study of 122 patients known as the STORM trial.[7] In all of the enrolled patients, selinexor was used as fifth-line or sixth-line therapy after conventional chemotherapytargeted therapy with bortezomibcarfilzomiblenalidomidepomalidomide, and a monoclonal antibody (daratumumab or isatuximab)[5]; nearly all had also undergone hematopoietic stem cell transplantation to no effect.[7] The overall response rate was 25%, and no patients had a complete response.[7] However, the response rate was higher in patients with high-risk myeloma (cytogenetic abnormalities associated with a worse prognosis).[5] The median time to progression was 2.3 months overall and 5 months in patients who responded to the drug.[2]

As of 2019, phase I/II and III trials are ongoing,[3][9] including the use of selinexor in other cancers and in combinations with other drugs used for multiple myeloma.[2]

PATENT

WO 2013019561

WO 2013019548

US 9079865

PATENT

WO 2016025904 A

https://patents.google.com/patent/WO2016025904A1/tr

International Publication No. WO 2013/019548 describes a series of compounds that are indicated to have inhibitory activity against chromosomal region maintenance 1 (CRM1, also referred to as exportin 1 or XPO1) and to be useful in the treatment of disorders associated with CRM1 activity, such as cancer. (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N’-(pyrazin-2-yl)acrylohydrazide (also referred to as selinexor) is one of the compounds disclosed in International Publication No. WO 2013/019548. Selinexor has the chemical structure shown in Structural Formula I:

Example 1. Preparation of Selinexor Lot No.1305365 (Form A).

[00274] Selinexor for Lot No. 1305365 was made in accordance with the following reaction scheme:

[00275] A solution of propane phosphonic acid anhydride (T3P®, 50% in ethyl acetate, 35Kg) in THF (24.6Kg) was cooled to about -40 °C. To this solution was added a solution of KG1 (13.8Kg) and diisopropylethylamine (12.4Kg) in tetrahydrofuran (THF, 24.6Kg). The resulting mixture was stirred at about -40°C for approximately 2.5 hours.

[00276] In a separate vessel, KJ8 (4.80Kg) was mixed with THF (122.7Kg), and the resulting mixture cooled to about -20°C. The cold activated ester solution was then added to the KJ8 mixture with stirring, and the reaction was maintained at about -20°C. The mixture was warmed to about 5°C, water (138.1Kg) was added and the temperature adjusted to about 20°C. After agitating for about an hour, the lower phase was allowed to separate from the mixture and discarded. The upper layer was diluted with ethyl acetate (EtOAc). The organic phase was then washed three times with potassium phosphate dibasic solution (~150Kg), then with water (138.6Kg).

[00277] The resulting organic solution was concentrated under reduced pressure to 95L, EtOAc (186.6Kg) was added and the distillation repeated to a volume of 90L. Additional EtOAc (186.8Kg) was added and the distillation repeated a third time to a volume of 90L. The batch was filtered to clarify, further distilled to 70L, then heated to about 75°C, and slowly cooled to 0 to 5°C. The resulting slurry was filtered and the filter cake washed with a mixture of EtOAc (6.3Kg) and toluene (17.9Kg) before being dried in a vacuum oven to provide selinexor designated Lot No. 1305365 (Form A).

Example 2. Preparation of Selinexor Lot No.1341-AK-109-2 (Form A).

[00278] The acetonitrile solvate of selinexor was prepared in accordance with Example 6.

[00279] The acetonitrile solvate of selinexor (2.7g) was suspended in a mixture of isopropanol (IPA, 8mL) and water (8mL), and the resulting mixture heated to 65 to 70 °C to effect dissolution. The solution was cooled to 45 °C, and water (28mL) was added over 15 minutes, maintaining the temperature between 40 and 45 °C. The slurry was cooled to 20 to 25 °C over an hour, then further cooled to 0 to 5 °C and held at that temperature for 30 minutes before being filtered. The filter cake was washed with 20% v/v IPA in water and the product dried under suction overnight, then in vacuo (40°C).

Example 3. Preparation of SelinexorSelinexorSelinexor Lot No. PC-14-005 (Form A).

[00280] The acetonitrile solvate of selinexor (Form D) was prepared in accordance with the procedure described in Example 6.

[00281] The acetonitrile solvate of selinexor (1.07Kg) was suspended in a mixture of IPA (2.52Kg) and water (3.2Kg) and the mixture heated to 70 to 75 °C to dissolve. The temperature was then adjusted to 40 to 45 °C and held at that temperature for 30 minutes. Water (10.7Kg) was added while maintaining the temperature at 40 to 45 °C, then the batch was cooled to 20 to 25 °C and agitated at that temperature for 4 hours before being further cooled to 0 to 5 °C. After a further hour of agitation, the slurry was filtered and the filter cake washed with a cold mixture of IPA (0.84Kg) and water (4.28Kg) before being dried.

Example 4. Preparation of SelinexorSelinexorSelinexor Lot No. PC-14-009 (Form A).

[00282] The acetonitrile solvate of selinexor (Form D) was prepared in accordance with the procedure described in Example 6.

[00283] The acetonitrile solvate of selinexor (1.5Kg) was suspended in IPA (3.6Kg) and water (4.5Kg) and warmed to 37 to 42 °C with gentle agitation. The suspension was agitated at that temperature for 4 hours, and was then cooled to 15 to 20 °C over 1 hour. Water (15.1Kg) was added, maintaining the temperature, then the agitation was continued for 1 hour and the batch was filtered. The filter cake was washed with a mixture of IPA (1.2Kg) and water (6Kg), then dried under a flow of nitrogen.

Example 5. Preparation of Selinexor Lot Nos.1339-BS-142-1, 1339-BS-142-2 and PC-14-008 (Form A).

[00284] A reactor, under nitrogen, was charged with KG1 (1Kg, 1.0 Eq), KJ8 (0.439 Kg, 1.4 Eq) and MeTHF (7L, 7 parts with respect to KG1). Diisopropylethylamine (0.902Kg, 2.45 Eq with respect to KG1) was added to the reaction mixture at -20 °C to -25 °C with a MeTHF rinse. To the reaction mixture, 50% T3P® in ethyl acetate (2.174Kg, 1.2 Eq with respect to KG1) was then charged, maintaining the temperature at -20 °C to -25 °C with a MeTHF rinse. After the completion of the addition, the reaction mixture was stirred briefly

and then warmed to 20 °C to 25 °C. Upon completion, the reaction mixture was washed first with water (5L, 5 parts with respect to KG1) and then with dilute brine (5L, 5 parts with respect to KG1). The organic layer was concentrated by vacuum distillation to a volume of 5 L (5 parts with respect to KG1), diluted with acetonitrile (15L, 15 parts with respect to KG1) at approximately 40 °C and concentrated again (5L, 5 parts with respect to KG1). After solvent exchange to acetonitrile, the reaction mixture was then heated to approximately 60 °C to obtain a clear solution. The reaction mixture was then cooled slowly to 0-5 °C, held briefly and filtered. The filter cake was washed with cold acetonitrile (2L, 5 parts with respect to KG1) and the filter cake was then dried under a stream of nitrogen to provide the acetonitrile solvate of selinexor (Form D) as a slightly off-white solid.

[00285] Form D of selinexor (0.9Kg) was suspended in IPA (2.1Kg, 2.7L, 3 parts with respect to Form D) and water (2.7Kg, 2.7L, 3 parts with respect to Form D) and warmed to approximately 40 °C. The resulting suspension was agitated for about 4 hours, selinexor, cooled to approximately 20 °C, and diluted with additional water (9Kg, 10 parts with respect to Form D). The mixture was stirred for a further 4-6 hours, then filtered, and the cake washed with a mixture of 20% IPA and water (4.5L, 5 parts with respect to Form D). The filter cake was then dried under vacuum to provide selinexor designated Lot No. PC-14-008 as a white crystalline powder with a >99.5% a/a UPLC purity (a/a=area to area of all peaks; UPLC-ultra performance HPLC).

Example 6. Preparation of Selinexor Lot No.1405463 (Form A).

[00286] Selinexor Lot No. 1405463 was prepared in accordance with the following reaction scheme:

 .

[00287] A reactor was charged with KG1 (15.8Kg), KJ8 (6.9Kg) and MeTHF (90Kg). Diisopropylethylamine (14.2Kg) was added to the reaction mixture over approximately 35 minutes at about -20 °C. Following the addition of the diisopropylethylamine, T3P® (50%

solution in EtAOc, 34.4Kg) was added maintaining the temperature at -20 °C. The mixture stirred to complete the reaction first at -20 °C, then at ambient temperature.

[00288] Upon completion of the reaction, water (79Kg) was added over about 1 hour. The layers were separated and the organic layer was washed with a mixture of water (55Kg) and brine (18Kg), The mixture was filtered, and the methyl-THF/ethyl acetate in the mixture distillatively replaced with acetonitrile (volume of approximately 220L). The mixture was warmed to dissolve the solids, then slowly cooled to 0 to 5 °C before being filtered. The filter cake was washed with acetonitrile to provide the acetonitrile solvate of

selinexorSelinexorSelinexor (Form D).

[00289] The acetonitrile solvate of selinexorSelinexorSelinexor was dried, then mixed with isopropanol (23Kg) and water (55Kg). The slurry was warmed to about 38 °C and held at that temperature for approximately 4 hours before being cooled to 15 to 20 °C. Water (182Kg) was added. After a further 5 hours of agitation, the mixture was filtered and the filter cake washed with a mixture of isopropanol (14Kg) and water (73Kg), before being dried under vacuum (45 °C). The dried product was packaged to provide

selinexorSelinexorSelinexor Lot No. 1405463 (Form A).

Example 7. Polymorphism Studies of Selinexor.

[00290] A comprehensive polymorphism assessment of selinexor was performed in a range of different solvents, solvent mixtures and under a number of experimental conditions based on the solubility of selinexor. Three anhydrous polymorphs of

selinexorSelinexorSelinexor were observed by XRPD investigation, designated Form A, Form B and Form C. Form A is a highly crystalline, high-melting form, having a melting point of 177 °C, and was observed to be stable from a physico-chemical point of view when exposed for 4 weeks to 25 °C/97% relative humidity (RH) and to 40 °C/75% RH. A solvated form of selinexor was also observed in acetonitrile, designated Form D. A competitive slurry experiment confirmed Form A as the stable anhydrous form under the conditions investigated, except in acetonitrile, in which solvate formation was observed. It was further found that in acetonitrile, below 50 °C, only Form D is observed, at 50 °C both Form A and Form D are observed, and at 55 °C, Form A is observed .

PATENT

CN 106831731

https://patents.google.com/patent/CN106831731A/en

Selinexor is an orally bioavailable selective nuclear export inhibitors, 2012 for the first time in clinical, so far carried out a total of 21 trials, indications include chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphatic leukemia, prostate cancer, melanoma, non-small cell lung cancer, glioma, neuroblastoma into, gynecological cancer, diffuse large B-cell lymphoma, squamous cell carcinoma, colorectal cancer and the like. May 2014, FDA granted orphan drug designation Selinexor treatment of acute myeloid leukemia and diffuse large B-cell lymphoma, in June 2014, EMA is also granted orphan drug designation Selinexor treatment of both diseases. January 2015, received FDA orphan drug to treat multiple myeloma identified.

[0003] Currently, the synthesis process has been disclosed, the following reaction equation:

Figure CN106831731AD00041

[0006] wherein the compound is 5 Selinexor drug.

[0007] In this method, however, easy to produce Intermediate 1-2 double bond is easily reversed when synthetically produced from trans impurities, in addition to more difficult to impact yield; Intermediate 3 Intermediate 4 Synthesis APIs 5 when required ultra-low temperature, and the product was purified by column required, only a yield of 20%.

SUMMARY

[0008] The object of the present invention to provide a novel compound Selinexor drug synthesis of 5, in order to solve technical problems.

[0009] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0010] A, Compound 7

[0011] Compound 6, dichloromethane and ethyl acetate mixture, stirred and dissolved, compound 4, T3P (n-propyl phosphoric anhydride) and DIPEA (N, N- diisopropylethylamine) at a low temperature; the reaction was stirred for 25-35min at a low temperature, dichloromethane and water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0012] B, Synthesis of Compound 8

[0013] the compound obtained in Step 7, and mixed sodium iodide acetic acid, warmed to 110-120 ° C, the reaction 2.5-3.5h; After completion of the reaction, the system cooled to room temperature, water and dichloromethane were added, stirred for 8 after -15min, standing layered organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in DMF (dimethyl fumarate) to give compound in DMF 8;

Synthesis [0014] C, of Compound 5

[0015] Compound 1, DBAC0 (triethylenediamine), the DMF mixed and dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring was continued for 3-4 hours; the reaction after completion, water and ethyl acetate were added to the system, the organic phase is evaporated to dryness and petroleum ether and recrystallized from ethyl acetate to give compound 5.

[0016] Preferably, said step A, the low temperature is 0-2 ° C.

[0017] Preferably, said step B in DMF, the crude compound 8 concentration of less than 1%.

[0018] The novel synthetic methods of the present invention Selinexor drug, the chemical equation is as follows:

Figure CN106831731AD00051

[0020] The present invention has the following advantages: novel synthetic method Selinexor drug of the present invention to overcome the conventional synthesis process, is easy to produce trans impurities, more difficult in addition, the influence the yield and the need for ultra-low temperature, and the product requires problems purified by column, the yield is very low, reducing the synthetic steps, increased yield, there is provided a new process for the synthesis of the drug Selinexor.

[0021] In addition to the above-described objects, features and advantages of the present invention as well as other objects, features and advantages. Below the invention will be described in further detail present.

Example 1

[0024] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0025] A, Compound 7

[0026] 50ml three □ flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 0 ° C; the system at 0 ° C the reaction was stirred for 30min, 50ml of dichloromethane and 30ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0027] B, Synthesis of Compound 8

[0028] 50ml three-necked flask, added the compound obtained in Step 7,40ml of glacial acetic acid and 1.38g of sodium iodide was heated to 115. (:, The reaction 3H; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 50ml of water was added and IOOml dichloromethane, after stirring IOmin, standing separation, the organic phase was washed with saturated sodium bicarbonate and saturated washed with sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in IOmL DMF to give DMF solution of compound 8;

Synthesis [0029] C, of Compound 5

[0030] After 50ml 3-necked flask was added 0.2g compound 1,0.24gDBAC0,20mlDMF, dissolved with stirring, dropwise adding to the reaction system in DMF compound obtained in Step 8, after the addition was complete, stirring continued for 3.5 hours; after completion of the reaction, 20ml water was added to the system and 50ml ethyl acetate, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.158g of compound 5, yield 50.9%.

[0031] Example 2

[0032] – new type Se Iinexor drug synthesis, comprising the steps of:

Synthesis [0033] A, Compound 7

[0034] 50ml three □ flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 1 ° C; system at 1 ° C the reaction was stirred for 35min, 50ml of dichloromethane and 30ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0035] B, Synthesis of Compound 8

Three-neck flask [0036] 50ml of addition of the compound obtained in Step 7,40ml glacial acetic acid and 1.38g of sodium iodide was heated to 120. (:, The reaction for 2.5 h; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 60ml water and 120ml dichloromethane was added, after stirring for 15min, allowed to stand for separation, the organic phase was washed with saturated sodium bicarbonate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, 12mLDMF was dissolved in DMF to give a solution of compound 8;

Synthesis [0037] C, of Compound 5

[0038] After 50ml 3-necked flask was added 0.2g compound 1,0.24gDBAC0,20mlDMF, dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring continued for 3 hours; after completion of the reaction, 25ml of water and 50ml of ethyl acetate was added to the system, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.152g of compound 5, yield 49.0% billion

[0039] Example 3

[0040] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0041] A, Compound 7

Three [0042] 50ml of flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 2 ° C; system from 0 ° C the reaction was stirred for 25min, 40ml of dichloromethane and 35ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0043] B, Synthesis of Compound 8

Three-neck flask [0044] 50ml of addition of the compound obtained in Step 7,35ml glacial acetic acid and 1.38g of sodium iodide was heated to 110. (:, The reaction for 3.5 h; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 50ml of water was added and dichloromethane IOOml After Smin of stirring, standing separation, the organic phase was washed with saturated sodium bicarbonate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in IOmL DMF to give DMF solution of compound 8;

Synthesis [0045] C, of Compound 5

[0046] 50ml three-neck flask was added 0.2g compound 1,0.24gDBA⑶, 20mlDMF, and dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring was continued for 4 hours; after completion of the reaction, 20ml of water and 40ml ethyl acetate were added to the system, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.155g of compound 5, yield 49.9% billion

PATENT

WO 2017118940

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017118940&tab=PCTDESCRIPTION

The drug compound having the adopted name “Selinexor” has chemical name:(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-IH-l,2,4-triazol-1 -yl)-N’-(pyrazin-2yl) acrylohydrazide as below.

Figure imgf000003_0001

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE™ compound. Selinexor functions by binding with and inhibiting the nuclear export protein XP01 (also called CRM1 ), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. Over 1 ,200 patients have been treated with Selinexor in company and investigator-sponsored Phase 1 and Phase 2 clinical trials in advanced hematologic malignancies and solid tumors. Karyopharm has initiated four later-phase clinical trials of Selinexor, including one in older patients with acute myeloid leukemia (SOPRA), one in patients with Richter’s transformation (SIRRT), one in patients with diffuse large B-cell lymphoma (SADAL) and a single-arm trial of Selinexor and lose-dose dexamethasone in patients with multiple myeloma (STORM). Patients may receive a twice-weekly combination of Selinexor in combination with low dose dexamethasone. Randomized 1 :1 , Selinexor will be dosed either at 60mg + dexamethasone or at 100 mg + dexamethasone.

US 8999996 B2 discloses Selinexor and a pharmaceutically acceptable salt thereof, pharmaceutical compositions and use for treating disorders associated with CRM1 activity. Further, it discloses preparative methods for the preparation of compounds disclosed therein including Selinexor by reacting (Z)-3-(3- (3,5-

bis(trifluoromethyl)phenyl)-IH-l,2,4-triazol-l-yl)acrylic acid in 1 :1 CH2CI2: AcOEt with 2-Hydrazinopyrazine at -40 °C followed by addition of T3P[Propylphosphonic anhydride] (50%) and DIPEA. After 30 minutes, the reaction mixture was concentrated and the crude oil was purified by preparative TLC using 5% MeOH in CH2CI2 as mobile phase (under ammonia atmosphere) to afford 40 mg of Selinexor with purity: 95.78%. However, it is not disclosed about the nature of the compound obtained therein.

WO 2016025904 A1 discloses various crystalline forms of Selinexor namely Form A, Form B, Form C, Form D, compositions and MoU thereof for the treatment of disorder associated with CRM1 activity and their preparative processes.

Prior art process for the preparation of Selinexor suffers from disadvantages interms of process such as the use of lengthy procedures to practice and resulting in low yields, which may not be viable at industrial scale. Synthetic product obtained therein has very low purity and contains significant amounts of unreacted starting materials and trans-isomer of Selinexor, which are further purified by time consuming and expensive chromatographic separations leading to loss of yield. Hence, there remains a need for improved process for the preparation of Selinexor which is industrially viable and reproducible. Particularly, it is desirable to have a process avoiding purification steps still meeting desired pharmaceutical quality.

EXAMPLES

Example-1 : Preparation of isopropyl (Z)-3-(3-(3,5-bis(trifluoromethyl) phenyl)-1 H- -triazol-1 -yl)acrylate

Figure imgf000061_0001

3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazole (250 g) was dissolved in tetrahydrofuran (2 I) under nitrogen atmosphere at 27°C and cooled to -5°C. 1 ,4- diazabicyclo[2.2.2]octane (DABCO, 1 99.5 g) was added to the reaction mixture at -5°C and stirred at the same temperature for 40 minutes. Isopropyl (Z)-3- iodoacrylate (234.8 g in 500 mL of tetrahydrofuran) was added drop wise to the reaction mixture in 1 hour 1 0 minutes at -5°C and stirred at the same temperature for 2 hours. After the completion of the reaction, the reaction mixture was added to ice cold water (2 I) and separated the organic layer. The aqueous layer was extracted with ethyl acetate (2 x 1 I). The combined organic layer was washed with brine solution (1 I) and dried over sodium sulphate. The dried solution was evaporated completely under vacuum at 40°C to obtain crude product with HPLC purity of 93.53% The crude product was triturated with hexane (700 mL) and stirred for 20 minutes at -30°C and filtered the solid. Trituration of crude product with hexane was repeated for three times and dried under vacuum to obtain the title compound with HPLC purity of 97.46% and trans-isomer content of 0.66%. Yield: 297 g Example-2: Preparation of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4- triazol-1 -yl)acr lic acid.

Figure imgf000062_0001

To a mixture of tetrahydrofuran (300 mL) and water (300 mL), Isopropyl (Z)-3-(3- (3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylate (30 g) was added and cooled to 0°C. Lithium hydroxide monohydrate (16.03 g) under cooling condition at 0°C was added to the reaction mixture and stirred the reaction mixture at same temperature for 7 hours. After completion of the reaction, 2 N HCI (180 mL) was added to adjust the pH of the reaction mixture to 2 and extracted it with ethyl acetate (300 mL). Organic layer was dried over sodium sulphate and evaporated under vacuum at 40°C. The crude compound was stirred with hexane (150 mL) and filtered the solid. Dried the compound under vacuum at 40°C for 0.5 hour to obtain the title compound with HPLC purity of 97.25% with trans-isomer content of 3 %. Yield: 24 g

Example-3: Purification of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4- tria

Figure imgf000062_0002

A mixture of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid (24 g) and acetone (240 mL) was stirred for complete dissolution at 30°C. Dicyclohexyl amine (1 5 mL) was added drop wise for 20 minutes under stirring at the same temperature. Acetone (50 mL) was added to the reaction mixture and stirred for 2 hours at 27°C. Filtered the solid and washed with hot acetone (150 mL) and dried in vacuum drier at 30°C for 1 hour to obtain the Dicyclohexyl amine salt of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid. To the above salt, dichloromethane (150 mL) and water (1 00 mL) was added and stirred for complete dissolution at 30and adjusted the pH of the solution with 2 N sulphuric acid (100 mL) to 2. Filtered the reaction mixture and washed the product with water (1 00 mL) and then with hexane (150 mL). The solid was dried under vacuum at 40°C for 0.5 hour to obtain title compound with HPLC purity 99.98% with no detectable content of trans-isomer. Yield: 17 g

Example-4: Preparation of Selinexor

Figure imgf000063_0001

(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid (10 g) was combined with a mixture of acetonitrile (1 00 mL) and ethyl acetate (50 mL) then added the 2-hydrazinylpyrazine (3.76 g) and stirred for 5 min. Reaction mixture was cooled to 0°C and diisopropyl ethyl amine (16.63 ml) and then Propylphosphonic anhydride (T3P, 33.31 mL) was added at 0°C and stirred the reaction mixture for 2.5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with cold water (100 mL) and extracted the product with ethyl acetate (2 x 150 mL). The combined organic layer was dried over sodium sulphate and evaporated the solvent under vacuum at 40°C to obtain the crude product as yellow syrup. The obtained crude product was combined with dichloromethane (1 00 mL) and filtered the solid and washed with dichloromethane (2 x 50 mL). The solid was dried under vacuum at 40°C to obtain the title compound with purity by HPLC of 99.86%. Yield : 7 g

PATENT
WO 2018129227

References

  1. Jump up to:a b c d e Fung HY, Chook YM (2014). “Atomic basis of CRM1-cargo recognition, release and inhibition”Semin Cancer Biol27: 52–61. doi:10.1016/j.semcancer.2014.03.002PMC 4108548PMID 24631835.
  2. Jump up to:a b c d e f Gandhi UH, Senapedis W, Baloglu E, Unger TJ, Chari A, Vogl D; et al. (2018). “Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma”. Clin Lymphoma Myeloma Leuk18 (5): 335–345. doi:10.1016/j.clml.2018.03.003PMID 29610030.
  3. Jump up to:a b c d e Feuerstein, Adam (2019-07-03). “FDA approves new multiple myeloma drug despite toxicity concerns”STAT. Retrieved 2019-07-06.
  4. Jump up to:a b c Mulcahy, Nick (2019-07-03). “FDA Approves Selinexor for Refractory Multiple Myeloma”Medscape. Retrieved 2019-07-06.
  5. Jump up to:a b c Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA; et al. (2018). “Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond”Leukemia32 (2): 252–262. doi:10.1038/leu.2017.329PMC 5808071PMID 29257139.
  6. ^ Barrett, Jennifer (2019-07-03). “New Treatment for Refractory Multiple Myeloma Granted FDA Approval”Pharmacy Times. Retrieved 2019-07-07.
  7. Jump up to:a b c d e f g “XPOVIO Prescribing Information” (PDF). Newton, MA: Karyopharm Therapeutics. 2019-07-03. Retrieved 2019-07-06.
  8. Jump up to:a b Chen C, Siegel D, Gutierrez M, Jacoby M, Hofmeister CC, Gabrail N (2018). “Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia”. Blood131 (8): 855–863. doi:10.1182/blood-2017-08-797886PMID 29203585.
  9. Jump up to:a b c d Parikh K, Cang S, Sekhri A, Liu D; et al. (2014). “Selective inhibitors of nuclear export (SINE)—a novel class of anti-cancer agents”J Hematol Oncol7: 78. doi:10.1186/s13045-014-0078-0PMC 4200201PMID 25316614.

REFERENCES

1: Wang AY, Weiner H, Green M, Chang H, Fulton N, Larson RA, Odenike O, Artz AS, Bishop MR, Godley LA, Thirman MJ, Kosuri S, Churpek JE, Curran E, Pettit K, Stock W, Liu H. A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia. J Hematol Oncol. 2018 Jan 5;11(1):4. doi: 10.1186/s13045-017-0550-8. PubMed PMID: 29304833.

2: Crochiere ML, Hannus S, Hansen K, Becker F, Baloglu E, Lee M, Kauffman M, Shacham S, Landesman Y. XPO1 target occupancy measurements confirm the selinexor recommended phase 2 dose. Oncotarget. 2017 Nov 30;8(66):110503-110516. doi: 10.18632/oncotarget.22801. eCollection 2017 Dec 15. PubMed PMID: 29299164; PubMed Central PMCID: PMC5746399.

3: Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA, Giralt S, Mateos MV, Leleu X, Anderson KC. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia. 2017 Jan 16. doi: 10.1038/leu.2017.329. [Epub ahead of print] Review. PubMed PMID: 29257139.

4: Bobillo S, Abrisqueta P, Carpio C, Raheja P, Castellví J, Crespo M, Bosch F. Promising activity of selinexor in the treatment of a patient with refractory diffuse large B-cell lymphoma and central nervous system involvement. Haematologica. 2017 Dec 14. pii: haematol.2017.181636. doi: 10.3324/haematol.2017.181636. [Epub ahead of print] PubMed PMID: 29242296.

5: Chen C, Siegel D, Gutierrez M, Jacoby M, Hofmeister CC, Gabrail N, Baz R, Mau-Sorensen M, Berdeja JG, Savona M, Savoie L, Trudel S, Areethamsirikul N, Unger TJ, Rashal T, Hanke T, Kauffman M, Shacham S, Reece D. Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom’s macroglobulinemia. Blood. 2017 Dec 4. pii: blood-2017-08-797886. doi: 10.1182/blood-2017-08-797886. [Epub ahead of print] PubMed PMID: 29203585.

6: Corno C, Stucchi S, De Cesare M, Carenini N, Stamatakos S, Ciusani E, Minoli L, Scanziani E, Argueta C, Landesman Y, Zaffaroni N, Gatti L, Perego P. FoxO-1 contributes to the efficacy of the combination of the XPO1 inhibitor selinexor and cisplatin in ovarian carcinoma preclinical models. Biochem Pharmacol. 2018 Jan;147:93-103. doi: 10.1016/j.bcp.2017.11.009. Epub 2017 Nov 16. PubMed PMID: 29155058.

7: Azmi AS, Li Y, Muqbil I, Aboukameel A, Senapedis W, Baloglu E, Landesman Y, Shacham S, Kauffman MG, Philip PA, Mohammad RM. Exportin 1 (XPO1) inhibition leads to restoration of tumor suppressor miR-145 and consequent suppression of pancreatic cancer cell proliferation and migration. Oncotarget. 2017 Jul 17;8(47):82144-82155. doi: 10.18632/oncotarget.19285. eCollection 2017 Oct 10. PubMed PMID: 29137251; PubMed Central PMCID: PMC5669877.

8: Chen Y, Zhang L, Huang J, Hong X, Zhao J, Wang Z, Zhang K. Dasatinib and chemotherapy in a patient with early T-cell precursor acute lymphoblastic leukemia and NUP214-ABL1 fusion: A case report. Exp Ther Med. 2017 Nov;14(5):3979-3984. doi: 10.3892/etm.2017.5046. Epub 2017 Aug 28. PubMed PMID: 29067094; PubMed Central PMCID: PMC5647690.

9: Body S, Esteve-Arenys A, Miloudi H, Recasens-Zorzo C, Tchakarska G, Moros A, Bustany S, Vidal-Crespo A, Rodriguez V, Lavigne R, Com E, Casanova I, Mangues R, Weigert O, Sanjuan-Pla A, Menéndez P, Marcq B, Picquenot JM, Pérez-Galán P, Jardin F, Roué G, Sola B. Cytoplasmic cyclin D1 controls the migration and invasiveness of mantle lymphoma cells. Sci Rep. 2017 Oct 24;7(1):13946. doi: 10.1038/s41598-017-14222-1. PubMed PMID: 29066743; PubMed Central PMCID: PMC5654982.

10: Broccoli A, Argnani L, Zinzani PL. Peripheral T-cell lymphomas: Focusing on novel agents in relapsed and refractory disease. Cancer Treat Rev. 2017 Nov;60:120-129. doi: 10.1016/j.ctrv.2017.09.002. Epub 2017 Sep 18. Review. PubMed PMID: 28946015.

11: Soung YH, Kashyap T, Nguyen T, Yadav G, Chang H, Landesman Y, Chung J. Selective Inhibitors of Nuclear Export (SINE) compounds block proliferation and migration of triple negative breast cancer cells by restoring expression of ARRDC3. Oncotarget. 2017 May 18;8(32):52935-52947. doi: 10.18632/oncotarget.17987. eCollection 2017 Aug 8. PubMed PMID: 28881784; PubMed Central PMCID: PMC5581083.

12: Garg M, Kanojia D, Mayakonda A, Ganesan TS, Sadhanandhan B, Suresh S, S S, Nagare RP, Said JW, Doan NB, Ding LW, Baloglu E, Shacham S, Kauffman M, Koeffler HP. Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin. Sci Rep. 2017 Aug 29;7(1):9749. doi: 10.1038/s41598-017-10325-x. PubMed PMID: 28852098; PubMed Central PMCID: PMC5575339.

13: Conforti F, Zhang X, Rao G, De Pas T, Yonemori Y, Rodriguez JA, McCutcheon JN, Rahhal R, Alberobello AT, Wang Y, Zhang YW, Guha U, Giaccone G. Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors. Cancer Res. 2017 Oct 15;77(20):5614-5627. doi: 10.1158/0008-5472.CAN-17-1323. Epub 2017 Aug 17. PubMed PMID: 28819023.

14: Arango NP, Yuca E, Zhao M, Evans KW, Scott S, Kim C, Gonzalez-Angulo AM, Janku F, Ueno NT, Tripathy D, Akcakanat A, Naing A, Meric-Bernstam F. Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer. Breast Cancer Res. 2017 Aug 15;19(1):93. doi: 10.1186/s13058-017-0878-6. PubMed PMID: 28810913; PubMed Central PMCID: PMC5557476.

15: Schaffer M, Chaturvedi S, Davis C, Aquino R, Stepanchick E, Versele M, Liu Y, Yang J, Lu R, Balasubramanian S. Identification of potential ibrutinib combinations in hematological malignancies using a combination high-throughput screen. Leuk Lymphoma. 2017 Jul 28:1-10. doi: 10.1080/10428194.2017.1349899. [Epub ahead of print] PubMed PMID: 28750570.

16: Muz B, Azab F, de la Puente P, Landesman Y, Azab AK. Selinexor Overcomes Hypoxia-Induced Drug Resistance in Multiple Myeloma. Transl Oncol. 2017 Aug;10(4):632-640. doi: 10.1016/j.tranon.2017.04.010. Epub 2017 Jun 29. PubMed PMID: 28668761; PubMed Central PMCID: PMC5496204.

17: Gupta A, Saltarski JM, White MA, Scaglioni PP, Gerber DE. Therapeutic Targeting of Nuclear Export Inhibition in Lung Cancer. J Thorac Oncol. 2017 Sep;12(9):1446-1450. doi: 10.1016/j.jtho.2017.06.013. Epub 2017 Jun 21. PubMed PMID: 28647672; PubMed Central PMCID: PMC5572747.

18: Machlus KR, Wu SK, Vijey P, Soussou TS, Liu ZJ, Shacham E, Unger TJ, Kashyap T, Klebanov B, Sola-Visner M, Crochiere M, Italiano JE Jr, Landesman Y. Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis. Blood. 2017 Aug 31;130(9):1132-1143. doi: 10.1182/blood-2016-11-752840. Epub 2017 Jun 19. PubMed PMID: 28630120; PubMed Central PMCID: PMC5580272.

19: Podar K, Pecherstorfer M. Current and developing synthetic pharmacotherapy for treating relapsed/refractory multiple myeloma. Expert Opin Pharmacother. 2017 Aug;18(11):1061-1079. doi: 10.1080/14656566.2017.1340942. Epub 2017 Jul 5. Review. PubMed PMID: 28604120.

20: Tandon N, Kumar SK. Highlights of Multiple Myeloma at the Annual Meeting of American Society of Hematology, 2016. Indian J Hematol Blood Transfus. 2017 Jun;33(2):153-158. doi: 10.1007/s12288-017-0796-x. Epub 2017 Feb 28. Review. PubMed PMID: 28596644; PubMed Central PMCID: PMC5442069.

Selinexor
Skeletal formula of selinexor
Clinical data
Trade names Xpovio
Pregnancy
category
  • Known to cause fetal harm
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Protein binding 95%
Metabolism Hepatic oxidation, glucuronidation, and conjugation, by CYP3A4UGTand GST
Elimination half-life 6–8 h
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
Chemical and physical data
Formula C17H11F6N7O
Molar mass 443.313 g·mol−1
3D model (JSmol)

Karyopharm’s Selinexor Receives Fast Track Designation from FDA for the Treatment of Patients with Penta-Refractory Multiple Myeloma

NEWTON, Mass., April 10, 2018 (GLOBE NEWSWIRE) — Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to the Company’s lead, oral Selective Inhibitor of Nuclear Export (SINE) compound selinexor for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy.  The FDA’s statement, consistent with the design of Karyopharm’s Phase 2b STORM study, noted that the three prior lines of therapy include regimens comprised of an alkylating agent, a glucocorticoid, Velcade® (bortezomib), Kyprolis® (carfilzomib), Revlimid® (lenalidomide), Pomalyst® (pomalidomide) and Darzalex® (daratumumab).  In addition, the patient’s disease must be refractory to at least one proteasome inhibitor (Velcade or Kyprolis), one immunomodulatory agent (Revlimid or Pomalyst), glucocorticoids and to Darzalex, as well as to the most recent therapy.  The Company expects to report top-line data from the STORM study at the end of April 2018.

ChemSpider 2D Image | selinexor | C17H11F6N7O

The FDA’s Fast Track program facilitates the development of drugs intended to treat serious conditions and that have the potential to address unmet medical needs.  A drug program with Fast Track status is afforded greater access to the FDA for the purpose of expediting the drug’s development, review and potential approval.  In addition, the Fast Track program allows for eligibility for Accelerated Approval and Priority Review, if relevant criteria are met, as well as for Rolling Review, which means that a drug company can submit completed sections of its New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be submitted for review.

“The designation of Fast Track for selinexor represents important recognition by the FDA of the potential of this anti-cancer agent to address the significant unmet need in the treatment of patients with penta-refractory myeloma that has continued to progress despite available therapies,” said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm.  “We are fully committed to working closely with the FDA as we continue development of this potential new, orally-administered treatment for patients who currently have no other treatment options of proven benefit.”

About the Phase 2b STORM Study

In the multi-center, single-arm Phase 2b STORM (Selinexor Treatment oRefractory Myeloma) study, approximately 122 patients with heavily pretreated, penta-refractory myeloma receive 80mg oral selinexor twice weekly in combination with 20mg low-dose dexamethasone, also dosed orally twice weekly.  Patients with penta-refractory disease are those who have previously received an alkylating agent, a glucocorticoid, two immunomodulatory drugs (IMiDs) (Revlimid® (lenalidomide) and Pomalyst® (pomalidomide)), two proteasome inhibitors (PIs) (Velcade® (bortezomib) and Kyprolis® (carfilzomib)), and the anti-CD38 monoclonal antibody Darzalex® (daratumumab), and their disease is refractory to at least one PI, at least one IMiD, Darzalex, glucocorticoids and their most recent anti-myeloma therapy.  Overall response rate is the primary endpoint of the study, with duration of response and clinical benefit rate being secondary endpoints.  All responses will be adjudicated by an Independent Review Committee (IRC).

About Selinexor

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,300 patients have been treated with selinexor, and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade® (bortezomib) and low-dose dexamethasone (BOSTON), in combination with low-dose dexamethasone (STORM) and as a potential backbone therapy in combination with approved therapies (STOMP), and in diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

About Karyopharm Therapeutics

Karyopharm Therapeutics Inc. (Nasdaq:KPTI) is a clinical-stage pharmaceutical company focused on the discovery, development and subsequent commercialization of novel first-in-class drugs directed against nuclear transport and related targets for the treatment of cancer and other major diseases. Karyopharm’s SINE compounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). In addition to single-agent and combination activity against a variety of human cancers, SINE compounds have also shown biological activity in models of neurodegeneration, inflammation, autoimmune disease, certain viruses and wound-healing. Karyopharm, which was founded by Dr. Sharon Shacham, currently has several investigational programs in clinical or preclinical development.

/////////Selinexor, FDA 2019, セリネクソル  ,KPT-330, KPT 330 , KPT330,  AML, Glioma, Sarcoma, Leukemia, Fast Track, CANCER

Picropodophyllin


Picropodophyllin.png

Image result for Picropodophyllin

2D chemical structure of 477-47-4

Picropodophyllin

Picropodophyllotoxin

CAS 477-47-4

AXL1717, NSC 36407, BRN 0099161

414.4 g/mol, C22H22O8

(5R,5aR,8aS,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one

Furo(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6(5aH)-one, 5,8,8a,9-tetrahydro-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-, (5R-(5-alpha,5a-alpha,8a-alpha,9-alpha))-

5-19-10-00665 (Beilstein Handbook Reference)

Axelar is developing picropodophyllin, a small-molecule IGF-1 receptor antagonist for the treatment of cancer including NSCLC and malignant astrocytoma. In February 2019, a phase Ia study was planned to initiate for solid tumor in March 2019.

Picropodophyllin is a cyclolignan alkaloid found in the mayapple plant family (Podophyllum peltatum), and a small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF1R) with potential antineoplastic activity. Picropodophyllin specifically inhibits the activity and downregulates the cellular expression of IGF1R without interfering with activities of other growth factor receptors, such as receptors for insulin, epidermal growth factor, platelet-derived growth factor, fibroblast growth factor and mast/stem cell growth factor (KIT). This agent shows potent activity in the suppression o f tumor cell proliferation and the induction of tumor cell apoptosis. IGF1R, a receptor tyrosine kinase overexpressed in a variety of human cancers, plays a critical role in the growth and survival of many types of cancer cells.

Picropodophyllotoxin is an organic heterotetracyclic compound that has a furonaphthodioxole skeleton bearing 3,4,5-trimethoxyphenyl and hydroxy substituents. It has a role as an antineoplastic agent, a tyrosine kinase inhibitor, an insulin-like growth factor receptor 1 antagonist and a plant metabolite. It is a lignan, a furonaphthodioxole and an organic heterotetracyclic compound.

Picropodophyllin has been investigated for the treatment of Non Small Cell Lung Cancer.

One of the largest challenges in pharmaceutical drug development is that drug compounds often are poorly soluble, or even insoluble, in aqeous media. Insufficient drug solubility means insufficient bioavailability, as well as poor plasma exposure of the drug when administered to humans and animals. Variability of plasma exposure in humans is yet a problem when developing drugs which are poorly soluble, or even insoluble, in aqeous media.

It is estimated that between 40% and 70 % of all new chemical entities identified in drug discovery programs, are insufficiently soluble in aqeous media (M. Lindenberg, S et al: European Journal of Pharmaceutics and Biopharmaceuticals, vol. 58, no.2, pp. 265-278, 2004). Scientists have investigated various ways of solving the problem with poor drug solubility in order to enhance bioavailability of poorly absorbed drugs, aiming at increasing their clinical efficacy when administered orally.

Technologies such as increase of the surface area and hence dissolution may sometimes solve solubility problems. Other techniques that may also solve bioavailability problems are addition of surfactants and polymers. However, each chemical compound has its own unique chemical and physical properties, and hence has its own unique challenges when being formulated into a pharmaceutical product that can exert its clinical efficacy.

Picropodophyllin is an insulin-like growth factor-1 receptor inhibitor fiGF-lR inhibitor) small-molecule compound belonging to the class of compounds denominated cyclolignans, having the chemical structure:

The patent applicant is presently entering clinical phase II development with its development compound picropodophyllin (AXL1717). However, picropodophyllin is poorly soluble in aqueous media. In a phase I clinical study performed by the applicant in 2012 (Ekman S et al; Acta Oncologica, 2016; 55: pp. 140-148), it was discovered that picropodophyllin, when administered as an oral suspension to lung cancer patients, resulted in unacceptable variability in drug exposure. A large variability in plasma exposure of the active drug picropodophyllin occurred not only within certain patients, but also between several patients.

Yet a problem with administering picropodophyllin as an aqeous solution, is that due to the poor solubility in aqueous media, it is difficult or even impossible to reach the required therapeutic doses.

The compound picropodophyllin is furthermore physically unstable, and transforms from amorphous picropodophyllin into crystalline picropodophyllin. Yet a stability problem with picropodophyllin is that it is chemically unstable in solution.

Image result for Picropodophyllin AND podophyllotoxin

Product case, WO02102804

Patent

WO-2019130194

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019130194&tab=PCTDESCRIPTION&_cid=P10-JXYAA3-53049-1

Novel amorphous forms of picropodophyllin , processes for their preparation and compositions comprising them are claimed. Also claims are their use for treating cancers, such as neurologic cancer, lung cancer, breast cancer, head and neck cancer, gastrointestinal cancer, genitourinary cancer, gynecologic cancer, hematologic cancer, musculoskeletal cancer, skin cancer, endocrine cancer, and eye cancers. , claiming picropodophyllin derivatives as modulators of insulin-like growth factor-1 receptor (IGF-1), useful for treating cancers, assigned to Axelar AB ,

CLIP

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CLIP

https://pubs.rsc.org/en/content/articlelanding/2004/cc/b312245j/unauth#!divAbstract

Image result for Picropodophyllin

http://www.rsc.org/suppdata/cc/b3/b312245j/b312245j.pdf

dH(CDCl3; 300 MHz; Me4Si): 2.64-2.78 (1 H, m, 3-H), 3.23 (1 H, dd, J 4.4 and 8.2, 2-H), 3.81 (6 H, s, 2 x OMe), 3.85 (3 H, s, OMe), 4.09 (1 H, d, J 4.4, 1-H), 4.38–4.59 (3 H, m, 11-H2 and 4-H), 5.91 (1 H, d, J 1.5, OCH2O), 5.93 (1 H, d, J 1.5, OCH2O), 6.35 (1 H, s, 5-H/8-H), 6.46 (1 H, s, 2’-H and 6’-H) and 7.07 (1 H, s, 5-H/8-H).

CLIP

Image result for Picropodophyllin

PAPER

Organic Letters (2018), 20(6), 1651-1654

https://pubs.acs.org/doi/abs/10.1021/acs.orglett.8b00408

Abstract Image

A nickel-catalyzed reductive cascade approach to the efficient construction of diastereodivergent cores embedded in podophyllum lignans is developed for the first time. Their gram-scale access paved the way for unified syntheses of naturally occurring podophyllotoxin and other members.

Synthesis of (−)-Podophyllotoxin (1)

https://pubs.acs.org/doi/suppl/10.1021/acs.orglett.8b00408/suppl_file/ol8b00408_si_001.pdf

The residue was purified by flash column chromatography (petroleum ether/EtOAc = 4 : 1 → petroleum ether/EtOAc = 2 : 1) on silica gel to afford 1 (8.6 mg, 87% yield) as a white solid; Rf = 0.23 (petroleum ether/EtOAc = 1 : 1); [α]20 D = –115.00 (c = 1.00, CHCl3) [ref.13: [α]20 D = –101.7 (c = 0.55, EtOH)]; Mp. 167–168 °C; 1H NMR (400 MHz, CDCl3): δ = 7.11 (s, 1H), 6.51 (s, 1H), 6.37 (s, 2H), 5.98 (s, 1H), 5.96 (s, 1H), 4.77 (t, J = 8.4 Hz, 1H), 4.60 (t, J = 8.0 Hz, 1H), 4.59 (d, J = 4.4 Hz, 1H), 4.08 (dd, J = 9.6, 8.8 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 6H), 2.84 (dd, J = 14.0, 4.4 Hz, 1H), 2.83−2.74 (m, 1H), 2.13 (d, J = 8.0 Hz, 1H, −OH) ppm; 13C NMR (100 MHz, CDCl3): δ = 174.6, 152.5 (2C), 147.7, 147.6, 137.1, 135.5, 133.3, 131.0, 109.7, 108.4 (2C), 106.3, 101.4, 72.6, 71.4, 60.7, 56.2 (2C), 45.2, 44.1, 40.6 ppm.

https://pubs.acs.org/doi/suppl/10.1021/acs.orglett.8b00408/suppl_file/ol8b00408_si_002.pdf

PAPER

Organic Letters (2017), 19(24), 6530-6533

https://pubs.acs.org/doi/abs/10.1021/acs.orglett.7b03236

Abstract Image

he first catalytic enantioselective total synthesis of (−)-podophyllotoxin is accomplished by a challenging organocatalytic cross-aldol Heck cyclization and distal stereocontrolled transfer hydrogenation in five steps from three aldehydes. Reversal of selectivity in hydrogenation led to the syntheses of other stereoisomers from the common precursor.

https://pubs.acs.org/doi/suppl/10.1021/acs.orglett.7b03236/suppl_file/ol7b03236_si_001.pdf

(-)-Picropodophyllin 4. The lactone 5 (0.2 g, 0.38 mmol) was taken in 1-pentanol (5 mL) in a double neck RB flask at rt. Water (0.14 mL, 7.6 mmol) was added to above mixture and it was then degassed with argon followed by addition of Pd/C (0.04 g, 20% by wt.) and HCO2Na (0.78g, 11.4 mmol). The reaction mixture was heated at 40 °C for 12 h. On completion, the reaction mixture was diluted with EtOAc (200 mL), filtered through a celite pad and solvent was removed under vacuum. This crude mixture was dissolved in THF (3.8 mL), TBAF (1.9 mL, 1.9 mmol, 1M in THF) was added and stirred for 6 h at 27 °C. On completion, EtOAc (250 mL) was added, washed with water (100 mL), brine and dried over Na2SO4. After removal of solvent, the crude product was purified by column chromatography (hexanes-EtOAc, 3:2) to get the title compound as a white solid (0.082 g, 52%): Rf 0.32 (hexanes/EtOAc, 1:1); [α]25 D = -10.6 (c = 0.4, CHCl3) [lit. -10 (c = 0.3, CHCl3), -11 (c = 0.41, CHCl3)]3a,b;

Mp 214-216 °C; 1H NMR (600 MHz, CDCl3) δ 7.05 (s, 1H), 6.47 (s, 2H), 6.41 (s, 1H), 5.95 (d, J = 14.1 Hz, 2H), 4.5 (m, 2H), 4.44 (t, J = 8.0 Hz, 1H), 4.15 (d, J = 4.1 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 6H), 3.24 (dd, J = 8.7, 5.0 Hz, 1H), 2.75 (m, 1H), 2.12 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 177.6, 153.7, 147.5, 147.1, 139.3, 137.4, 131.9, 130.6, 109.3, 105.9, 105.5, 101.2, 69.8, 69.6, 60.9, 56.3, 45.4, 44.1, 42.7; HRMS (ESI-TOF) m/z 437.1219 [(M+Na)+ ; calcd for C22H22O8Na+ : 437.1212].

PAPER

The Journal of organic chemistry (2000), 65(3), 847-60.

https://pubs.acs.org/doi/abs/10.1021/jo991582+

Abstract Image

REF

Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1932), 65B, 1846.

Justus Liebigs Annalen der Chemie (1932), 499, 59-76.

Justus Liebigs Annalen der Chemie (1932), 494, 126-42.

Journal of the American Chemical Society (1954), 76, 5890-1

Helvetica Chimica Acta (1954), 37, 190-202.

 Journal of the American Chemical Society (1988), 110(23), 7854-8.

//////////////Picropodophyllin, AXL1717, NSC 36407, BRN 0099161, Picropodophyllotoxin, AXELAR, PHASE 1, CANCER, neurologic cancer, lung cancer, breast cancer, head and neck cancer, gastrointestinal cancer, genitourinary cancer, gynecologic cancer, hematologic cancer, musculoskeletal cancer, skin cancer, endocrine cancer, eye cancers,  NSCLC, malignant astrocytoma, SOLID TUMOUR

COC1=CC(=CC(=C1OC)OC)C2C3C(COC3=O)C(C4=CC5=C(C=C24)OCO5)O

Podofilox, Podophyllotoxin, Wartec, Condyline, Condylox

J Org Chem 2000,65(3),847

The formylation of 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) with BuLi and DMF gives the 6-formyl derivative (II), which is reduced with NaBH4 in ethanol to yield the corresponding carbinol (III). The cyclization of (III) with dimethyl acetylenedicarboxylate (V) in hot acetic acid (through the nonisolated intermediate (IV)) affords dimethyl 1,4-epoxy-6,7-(methylenedioxy)naphthalene-2,3-dicarboxylate (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the (1R*,2S*,3R*,4S*)-tetrahydro derivative (VII). The reduction of (VII) with LiAlH4 in refluxing ethyl ether affords the corresponding bis carbinol (VIII), which is treated with acetic anhydride to afford the diacetate (IX). The enzymatic monodeacetylation of (VIII) with PPL enzyme in DMSO/buffer gives (1R,2R,3S,4S)-2-(acetoxymethyl)-1,4-epoxy-3-(hydroxymethyl)-6,7-(methylenedioxy)-1,2,3,4-tetrahydronaphthalene (X), which is silylated with TBDMS-Cl and imidazole in DMF yielding the silyl ether (XI). The hydrolysis of the acetoxy group of (XI) with K2CO3 in methanol affords the carbinol (XII), which is oxidized with oxalyl chloride in dichloromethane affording the carbaldehyde (XIII). The exchange of the silyl protecting group of (XIII) (for stability problems) provided the triisopropylsilyl ether (XIV), which is treated with sodium methoxide in methanol to open the epoxide ring yielding the hydroxy aldehyde (XV). The protection of the hydroxy group of (XV) with 2-(trimethylsilyl)ethoxymethyl chloride and DIEA in dichloromethane provides the corresponding ether (XVI). The carbinol (III) can also be obtained directly from 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) by reaction with formaldehyde and BuLi in THF.

The oxidation of the aldehyde group of (XVI) with NaClO2 in tert-butanol affords the corresponding carboxylic acid (XVII), which is condensed with 2-oxazolidinone (XVIII) by means of carbonyldiimidazole (CDI) in THF to give the acyl imidazolide (XIX). The arylation of (XIX) with 3,4,5-trimethoxyphenylmagnesium bromide (XX) in THF yields the expected addition product (XXI), which is cyclized by means of TBAF in hot THF to afford the tetracyclic intermediate (XXII). Isomerization of the cis-lactone ring of (XXII) with LDA in THF affords intermediate (XXIII) with its lactone ring with the correct trans-conformation. Finally, this compound is deprotected with ethyl mercaptane and MgBr2 in ethyl ether to provide the target compound.

Synthesis 1992,719

The intermediate trans-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetra-hydronaphtho[2,3-d][1,3]benzodioxole-6-carboxylic acid ethyl ester (XI) has been obtained by several different ways: (a) The condensation of benzophenone (XXXVIII) with diethyl malonate (XXXIX) by means of t-BuOK gives the alkylidenemalonate (XL), which is hydrogenated with H2 over Pd/C to the alkylmalonate hemiester (XLI). The reaction of (XLI) with acetyl chloride affords the mixed anhydride (XLII), which is finally cyclized to the target (XI) by means of SnCl4. (b) The cyclization of the malonic ester derivative (XLIII) by means of Ti(CF3–CO2)3 gives the 5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho [2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLIV), which is finally oxidized and decarboxylated with NBS and NaOH in methanol to afford the target intermediate (XI). (c) The cyclization of the benzylidenemalonate (XLV) with the aryllithium derivative (XLVI) gives the 8-methoxy-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLVII), which is demethylated with TFA and oxidized with CrO3 and pyridine to the target compound (XI). (d) The cyclopropanation of the chalcone (XLVIII) with (ethoxycarbonyl) (dimethylsulfonium)methylide (XLIX) gives the cyclopropanecarboxylate (L), which is finally rearranged with BF3/Et2O to the target intermediate (IX).

The cyclization of 3,4,5-trimethoxycinnamic acid ethyl ester (LI) with malonic acid ethyl ester potassium salt (LII) by means of Mn(OAc)3 gives the tetrahydrofuranone (LIII), which is acylated with 1,3-benzodioxol-5-ylcarbonyl chloride (LIV) yielding the tetrahydrofuranone (LV). Finally, this compound is rearranged and decarboxylated with SnCl4 to the target intermediate (XI).

The cyclization of 6-[1-hydroxy-1-(3,4,5-trimethoxyphenyl)methyl]-1,3-benzodioxol-5-carbaldehyde dimethylacetal (LVI) by means of AcOH gives 5-(3,4,5-trimethoxyphenyl)-1,3-dioxolo[4,5-f]isobenzofuran (LVII), which is submitted to a Diels-Alder cyclization with acetylenedicarboxylic acid dimethyl ester (LVIII) yielding the epoxy derivative (LIX). The selective reduction of (LIX) with LiBEt3H and H2 affords the carbinol (LX), which is treated with H2 over RaNi in order to open the epoxide ring to give the diol (LXI) with the wrong configuration at the secondary OH group. The treatment of (LXI) with aqueous acid isomerizes the secondary OH group to (LXII) with the suitable configuration. Finally, this compound is cyclized with DCC to the desired target compound.

The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with dimethyl maleate (LXIII) gives the expected adduct (LXIV), which by thermal extrusion of CO2 yields the dihydronaphthodioxole (LXV). This compound is then converted to dihydroxycompound (X), which is finally cyclized by means of ZnCl2 to provide the target compound. The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with dimethyl fumarate (LXVI) gives the expected adduct (LXVII), which by hydrogenation with H2 over Pd/C yields the tricarboxylic acid derivative (LXVIII). The reaction of (LXVIII) with Pb(OAc)4 affords the acetoxy derivative (LXIX), which is selectively reduced with LiBEt3H providing the diol (LXI) with the wrong configuration at the secondary OH group. The treatment of (LXI) with aqueous acid isomerizes the secondary OH group to give the previously described (X) with the suitable configuration.

The reaction of benzocyclobutane derivative (LXX) with isocyanate (LXXI) by means of Ph3SnOAc gives the carbamate (LXXII), which is cyclized by a thermal treatment with LiOH yielding the tetracyclic carboxylic acid (LXXIII). The opening of the oxazinone ring of (LXXIII) in basic medium affords the tricyclic amino acid (LXXIV), which is finally cyclized to the target compound by reaction with sodium nitrite in acidic medium (pH = 4).

J Chem Soc Chem Commun 1993,1200

The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with the chiral dihydrofuranone (II) in hot acetonitrile gives the pentacyclic anhydride (III), which is opened with warm acetic acid yielding the carboxylic acid (IV). Hydrogenation of the benzylic double bond of (IV) with H2 over Pd/C affords (V), which is treated with lead tetraacetate and acetic acid in THF to give the acetoxy compound (VI). The hydrolysis of the acetoxy group and the menthol hemiacetal group with HCl in hot dioxane yields the diol (VII), which is treated with diazomethane in ether/methanol affording the aldehyde (VIII). The reduction of the aldehyde group of (VIII) with LiEt3BH in THF gives the diol (IX) as a diastereomeric mixture, which is treated with HCl in THF to afford the diol (X) with the right conformation. Finally, this compound is lactonized to the target compound with ZnCl2 in THF.

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SELPERCATINIB


img

Selpercatinib.png

SELPERCATINIB

LOXO 292

CAS: 2152628-33-4
Chemical Formula: C29H31N7O3
Molecular Weight: 525.613

CEGM9YBNGD

UNII-CEGM9YBNGD

 6-(2-hydroxy-2-methylpropoxy)-4-(6-{6-[(6-methoxypyridin- 3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Selpercatinib is a tyrosine kinase inhibitor with antineoplastic properties.

A phase I/II trial is also under way in pediatric patients and young adults with activating RET alterations and advanced solid or primary CNS tumors.

Loxo Oncology (a wholly-owned subsidiary of Eli Lilly ), under license from Array , is developing selpercatinib, a lead from a program of RET kinase inhibitors, for treating cancer, including non-small-cell lung cancer, medullary thyroid cancer, colon cancer, breast cancer, pancreatic cancer, papillary thyroid cancer, other solid tumors, infantile myofibromatosis, infantile fibrosarcoma and soft tissue sarcoma

In 2018, the compound was granted orphan drug designation in the U.S. for the treatment of pancreatic cancer and in the E.U. for the treatment of medullary thyroid carcinoma.

Trk is a high affinity receptor tyrosine kinase activated by a group of soluble growth factors called neurotrophic factor (NT). The Trk receptor family has three members, namely TrkA, TrkB and TrkC. Among the neurotrophic factors are (1) nerve growth factor (NGF) which activates TrkA, (2) brain-derived neurotrophic factor (BDNF) and NT4/5 which activate TrkB, and (3) NT3 which activates TrkC. Trk is widely expressed in neuronal tissues and is involved in the maintenance, signaling and survival of neuronal cells.
The literature also shows that Trk overexpression, activation, amplification and/or mutations are associated with many cancers including neuroblastoma, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, multiple myeloma, astrocytoma. And medulloblastoma, glioma, melanoma, thyroid cancer, pancreatic cancer, large cell neuroendocrine tumor and colorectal cancer. In addition, inhibitors of the Trk/neurotrophin pathway have been shown to be effective in a variety of preclinical animal models for the treatment of pain and inflammatory diseases.
The neurotrophin/Trk pathway, particularly the BDNF/TrkB pathway, has also been implicated in the pathogenesis of neurodegenerative diseases, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. The modulating neurotrophic factor/Trk pathway can be used to treat these and related diseases.
It is believed that the TrkA receptor is critical for the disease process in the parasitic infection of Trypanosoma cruzi (Chagas disease) in human hosts. Therefore, TrkA inhibitors can be used to treat Chagas disease and related protozoal infections.
Trk inhibitors can also be used to treat diseases associated with imbalances in bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastasis. Bone metastases are a common complication of cancer, up to 70% in patients with advanced breast or prostate cancer and about 15 in patients with lung, colon, stomach, bladder, uterine, rectal, thyroid or kidney cancer Up to 30%. Osteolytic metastases can cause severe pain, pathological fractures, life-threatening hypercalcemia, spinal cord compression, and other neurostress syndromes. For these reasons, bone metastases are a serious cancer complication that is costly. Therefore, an agent that can induce apoptosis of proliferating bone cells is very advantageous. Expression of the TrkA receptor and TrkC receptor has been observed in the osteogenic region of the fractured mouse model. In addition, almost all osteoblast apoptosis agents are very advantageous. Expression of the TrkA receptor and TrkC receptor has been observed in the osteogenic region of the fractured mouse model. In addition, localization of NGF was observed in almost all osteoblasts. Recently, it was demonstrated that pan-Trk inhibitors in human hFOB osteoblasts inhibit tyrosine signaling activated by neurotrophic factors that bind to all three Trk receptors. This data supports the theory of using Trk inhibitors to treat bone remodeling diseases, such as bone metastases in cancer patients.
Developed by Loxo Oncology, Larotrectinib (LOXO-101) is a broad-spectrum antineoplastic agent for all tumor patients expressing Trk, rather than tumors at an anatomical location. LOXO-101 chemical name is (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)pyrazolo[1,5-a] Pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, the structural formula is as follows. LOXO-101 began treatment of the first patient in March 2015; on July 13, 2016, the FDA granted a breakthrough drug qualification for the inoperable removal or metastatic solid tumor of adults and children with positive Trk fusion gene mutations; Key entry was completed in February 2017; in November 2018, the FDA approved the listing under the trade name Vitrakvi.
Poor absorption, distribution, metabolism, and/or excretion (ADME) properties are known to be the primary cause of clinical trial failure in many drug candidates. Many of the drugs currently on the market also limit their range of applications due to poor ADME properties. The rapid metabolism of drugs can lead to the inability of many drugs that could be effectively treated to treat diseases because they are too quickly removed from the body. Frequent or high-dose medications may solve the problem of rapid drug clearance, but this approach can lead to problems such as poor patient compliance, side effects caused by high-dose medications, and increased treatment costs. In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites.
Although LOXO-101 is effective as a Trk inhibitor in the treatment of a variety of cancers and the like, it has been found that a novel compound having a good oral bioavailability and a drug-forming property for treating a cancer or the like is a challenging task. Thus, there remains a need in the art to develop compounds having selective inhibitory activity or better pharmacodynamics/pharmacokinetics for Trk kinase mediated diseases useful as therapeutic agents, and the present invention provides such compounds.
SYN
WO 2018071447

PATENT

WO2018071447

PATENT

US 20190106438

PATENT

WO 2019075108

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019075108&tab=PCTDESCRIPTION

Compounds of Formula I-IV, 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula I); 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula II); 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula III); and 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula IV) are inhibitors of RET kinase, and are useful for treating diseases such as proliferative diseases, including cancers.

[0007] Accordingly, provided herein is a compound of Formula I-IV:

and pharmaceutically acceptable salts, amorphous, and polymorph forms thereof.

PATENT

WO 2019075114

PATENT

WO-2019120194

Novel deuterated analogs of pyrazolo[1,5-a]pyrimidine compounds, particularly selpercatinib , processes for their preparation and compositions comprising them are claimed. Also claims are their use for treating pain, inflammation, cancer and certain infectious diseases.

Example 2(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl-2,3,3-d 3)-pyrazolo[ 1,5-a] pyrimidin-3-yl) -3-hydroxypyrazole prepared pyrrolidine-1-carboxamide (compound L-2) a.

[0163]

[0164]
Use the following route for synthesis:

[0165]
Patent ID Title Submitted Date Granted Date
US10137124 Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors 2018-01-03
US10172851 Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors 2018-01-03
US10112942 Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors 2017-12-29

/////////////SELPERCATINIB, non-small-cell lung cancer, medullary thyroid cancer, colon cancer, breast cancer, pancreatic cancer, papillary thyroid cancer, other solid tumors, infantile myofibromatosis, infantile fibrosarcoma, soft tissue sarcoma, LOXO, ELI LILY,  ARRAY, LOXO 292, orphan drug designation

N#CC1=C2C(C3=CC=C(N4CC(C5)N(CC6=CC=C(OC)N=C6)C5C4)N=C3)=CC(OCC(C)(O)C)=CN2N=C1

Ceralasertib, AZD 6738


Image result for azd 6738

Image result for azd 6738

Image result for azd 6738

AZD-6738, Ceralasertib

  • Molecular Formula C20H24N6O2S
  • Average mass 412.509 Da
CAS 1352226-88-0 [RN]
1H-Pyrrolo[2,3-c]pyridine, 4-[4-[(3R)-3-methyl-4-morpholinyl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]-2-pyrimidinyl]-
4-{4-[(3R)-3-Methyl-4-morpholinyl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]-2-pyrimidinyl}-1H-pyrrolo[2,3-c]pyridine
1H-Pyrrolo(2,3-b)pyridine, 4-(4-(1-((S(R))-S-methylsulfonimidoyl)cyclopropyl)-6-((3R)-3-methyl-4-morpholinyl)-2-pyrimidinyl)-
imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-λ6-sulfane
85RE35306Z
AZD-6738
UNII:85RE35306Z
CAS : 1352226-88-0 (free base)   1352280-98-8 (formic acid)   1352226-97-1 (racemic)
  • 4-[4-[1-[[S(R)]-S-Methylsulfonimidoyl]cyclopropyl]-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinyl]-1H-pyrrolo[2,3-b]pyridine
  • AZD 6738
  • Ceralasertib
  • Originator AstraZeneca; University of Pennsylvania
  • Class Antineoplastics; Morpholines; Pyrimidines; Small molecules
  • Mechanism of Action ATR protein inhibitors
  • Phase II Breast cancer; Gastric cancer; Non-small cell lung cancer; Ovarian cancer
  • Phase I/II Chronic lymphocytic leukaemia; Solid tumours
  • Phase I Non-Hodgkin’s lymphoma
  • Preclinical Diffuse large B cell lymphoma
  • No development reported B-cell lymphoma; Lymphoid leukaemia
  • 26 Mar 2019 National Cancer Institute plans a phase II trial for Cholangiocarcinoma (Combination therapy, Second-line therapy or greater) and Solid tumours (Combination therapy, Second-line therapy or greater) in March 2019 (NCT03878095)
  • 18 Mar 2019 Royal Marsden NHS Foundation Trust and AstraZeneca re-initiate the phase I PATRIOT trial in Solid tumours (Second-line therapy or greater) in United Kingdom (NCT02223923)
  • 25 Dec 2018 University of Michigan Cancer Center plans the phase II TRAP trial for Prostate cancer (Combination therapy; Metastatic disease; Second-line therapy or greater) in February 2019 (NCT03787680)

Inhibits ATR kinase.

Ceralasertib, also known as AZD6738, is an orally available morpholino-pyrimidine-based inhibitor of ataxia telangiectasia and rad3 related (ATR) kinase, with potential antineoplastic activity. Upon oral administration, ATR kinase inhibitor Ceralasertib selectively inhibits ATR activity by blocking the downstream phosphorylation of the serine/threonine protein kinase CHK1. This prevents ATR-mediated signaling, and results in the inhibition of DNA damage checkpoint activation, disruption of DNA damage repair, and the induction of tumor cell apoptosis.

ATR (also known as FRAP-Related Protein 1; FRP1; MEC1; SCKL; SECKL1) protein kinase is a member of the PI3 -Kinase like kinase (PIKK) family of proteins that are involved in repair and maintenance of the genome and its stability (reviewed in Cimprich K.A. and Cortez D. 2008, Nature Rev. Mol. Cell Biol. 9:616-627). These proteins co-ordinate response to DNA damage, stress and cell-cycle perturbation. Indeed ATM and ATR, two members of the family of proteins, share a number of downstream substrates that are themselves recognised components of the cell cycle and DNA-repair machinery e.g. Chkl, BRCAl, p53 (Lakin ND et al,1999, Oncogene; Tibbets RS et al, 2000, Genes & Dev.). Whilst the substrates of ATM and ATR are to an extent shared, the trigger to activate the signalling cascade is not shared and ATR primarily responds to stalled replication forks (Nyberg K.A. et al., 2002, Ann. Rev.

Genet. 36:617-656; Shechter D. et al. 2004, DNA Repair 3:901-908) and bulky DNA damage lesions such as those formed by ultraviolet (UV) radiation (Wright J. A. et al, 1998, Proc. Natl. Acad. Sci. USA, 23:7445-7450) or the UV mimetic agent, 4-nitroquinoline-1-oxi-e, 4NQO (Ikenaga M. et al. 1975, Basic Life Sci. 5b, 763-771). However, double strand breaks (DSB) detected by ATM can be processed into single strand breaks (SSB) recruiting ATR; similarly SSB, detected by ATR can generate DSB, activating ATM. There is therefore a significant interplay between ATM and ATR.

Mutations of the ATR gene that result in complete loss of expression of the ATR protein are rare and in general are not viable. Viability may only result under heterozygous or hypomorphic conditions. The only clear link between ATR gene mutations and disease exists in a few patients with Seckel syndrome which is characterized by growth retardation and microcephaly (O’Driscoll M et al, 2003 Nature Genet. Vol3, 497-501). Cells from patients with hypomorphic germline mutations of ATR (seckel syndrome) present a greater susceptibility to chromosome breakage at fragile sites in presence of replication stress compared to wild type cells (Casper 2004). Disruption of the ATR pathway leads to genomic instability. Patients with Seckel syndrome also present an increased incidence of cancer,suggestive of the role of ATR in this disease in the maintenance of genome stability .

Moreover, duplication of the ATR gene has been described as a risk factor in rhabdomyosarcomas (Smith L et al, 1998, Nature Genetics 19, 39-46). Oncogene-driven tumorigenesis may be associated with ATM loss-of- function and therefore increased reliance on ATR signalling (Gilad 2010). Evidence of replication stress has also been reported in several tumour types such as colon and ovarian cancer, and more recently in glioblastoma, bladder, prostate and breast (Gorgoulis et al, 2005; Bartkova et al. 2005a; Fan et al., 2006; Tort et al, 2006; Nuciforo et al, 2007; Bartkova et al., 2007a). Loss of Gl checkpoint is also frequently observed during tumourigenesis. Tumour cells that are deficient in Gl checkpoint controls, in particular p53 deficiency, are susceptible to inhibition of ATR activity and present with premature chromatin condensation (PCC) and cell death (Ngheim et al, PNAS, 98, 9092-9097).

ATR is essential to the viability of replicating cells and is activated during S-phase to regulate firing of replication origins and to repair damaged replication forks (Shechter D et al, 2004, Nature cell Biology Vol 6 (7) 648-655). Damage to replication forks may arise due to exposure of cells to clinically relevant cytotoxic agents such as hydroxyurea (HU) and platinums (O’Connell and Cimprich 2005; 118, 1-6). ATR is activated by most cancer chemotherapies (Wilsker D et al, 2007, Mol. Cancer Ther. 6(4) 1406-1413). Biological assessment of the ability of ATR inhibitors to sensitise to a wide range of chemotherapies have been evaluated. Sensitisation of tumour cells to chemotherapeutic agents in cell growth assays has been noted and used to assess how well weak ATR inhibitors (such as Caffeine) will sensitise tumour cell lines to cytotoxic agents. (Wilsker D .et al, 2007, Mol Cancer Ther. 6 (4)1406-1413; Sarkaria J.N. et al, 1999, Cancer Res. 59, 4375-4382). Moreover, a reduction of ATR activity by siRNA or ATR knock-in using a dominant negative form of ATR in cancer cells has resulted in the sensitisation of tumour cells to the effects of a number of therapeutic or experimental agents such as antimetabolites (5-FU, Gemcitabine, Hydroxyurea, Metotrexate, Tomudex), alkylating agents (Cisplatin, Mitomycin C, Cyclophosphamide, MMS) or double-strand break inducers (Doxorubicin, Ionizing radiation) (Cortez D. et al. 2001, Science, 294:1713-1716; Collis S.J. et al, 2003, Cancer Res. 63:1550-1554; Cliby W.A. et al, 1998, EMBO J. 2:159-169) suggesting that the combination of ATR inhibitors with some cytotoxic agents might be therapeutically beneficial.

An additional phenotypic assay has been described to define the activity of specific ATR inhibitory compounds is the cell cycle profile (PJ Hurley, D Wilsker and F Bunz, Oncogene, 2007, 26, 2535-2542). Cells deficient in ATR have been shown to have defective cell cycle regulation and distinct characteristic profiles, particularly following a cytotoxic cellular insult. Furthermore, there are proposed to be differential responses between tumour and normal tissues in response to modulation of the ATR axis and this provides further potential for therapeutic intervention by ATR inhibitor molecules (Rodnguez-Bravo V et al, Cancer Res., 2007, 67, 11648-11656).

Another compelling utility of ATR-specific phenotypes is aligned with the concept of synthetic lethality and the observation that tumour cells that are deficient in G1 checkpoint controls, in particular p53 deficiency, are susceptible to inhibition of ATR activity resulting in premature chromatin condensation (PCC) and cell death (Ngheim et al, PNAS, 98, 9092-9097). In this situation, S-phase replication of DNA occurs but is not completed prior to M-phase initiation due to failure in the intervening checkpoints resulting in cell death from a lack of ATR signalling. The G2/M checkpoint is a key regulatory control involving ATR (Brown E. J. and Baltimore D., 2003, Genes Dev. 17, 615-628) and it is the compromise of this checkpoint and the prevention of ATR signalling to its downstream partners which results in PCC. Consequently, the genome of the daughter cells is compromised and viability of the cells is lost (Ngheim et al, PNAS, 98, 9092-9097).

It has thus been proposed that inhibition of ATR may prove to be an efficacious approach to future cancer therapy (Collins I. and Garret M.D., 2005, Curr. Opin. Pharmacol., 5:366-373; Kaelin W.G. 2005, Nature Rev. Cancer, 5:689-698) in the appropriate genetic context such as tumours with defects in ATM function or other S-phase checkpoints. Until recently, There is currently no clinical precedent for agents targeting ATR, although agents targeting the downstream signalling axis i.e. Chk1 are currently undergoing clinical evaluation (reviewed in Janetka J.W. et al. Curr Opin Drug Discov Devel, 2007, 10:473-486). However, inhibitors targeting ATR kinase have recently been described (Reaper 2011, Charrier 2011).

In summary ATR inhibitors have the potential to sensitise tumour cells to ionising radiation or DNA-damage inducing chemotherapeutic agents, have the potential to induce selective tumour cell killing as well as to induce synthetic lethality in subsets of tumour cells with defects in DNA damage response.

PAPER

Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent

  • Kevin M. Foote
Cite This:J. Med. Chem.201861229889-9907
Publication Date:October 22, 2018
https://doi.org/10.1021/acs.jmedchem.8b01187
The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2(AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.
 ATR Inhibitors
4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (2)
2 (139 g, 42%) as a white crystalline solid.
1H NMR (400 MHz, DMSO-d6): 1.19 (3H, d), 1.29–1.50 (3H, m), 1.61–1.72 (1H, m), 3.01 (3H, s), 3.22 (1H, d), 3.43 (1H, td), 3.58 (1H, dd), 3.68–3.76 (2H, m), 3.87–3.96 (1H, m), 4.17 (1H, d), 4.60 (1H, s), 6.98 (1H, s), 7.20 (1H, dd), 7.55–7.58 (1H, m), 7.92 (1H, d), 8.60 (1H, d), 11.67 (1H, s).
13C NMR (176 MHz, DMSO-d6) 11.29, 12.22, 13.39, 38.92, 41.14, 46.48, 47.81, 65.97, 70.19, 101.54, 102.82, 114.58, 117.71, 127.21, 136.70, 142.21, 150.12, 161.88, 162.63, 163.20.
HRMS-ESI m/z 413.17529 [MH+]; C20H24N6O2S requires 413.1760.
Chiral HPLC: (HP1100 system 4, 5 μm Chiralpak AS-H (250 mm × 4.6 mm) column, eluting with isohexane/EtOH/MeOH/TEA 50/25/25/0.1) Rf = 8.252, >99%. Anal. Found (% w/w): C, 58.36; H, 5.87; N, 20.20; S, 7.55; H2O, <0.14. C20H24N6O2S requires C, 58.23; H, 5.86; N, 20.37; S, 7.77.

Patent

WO 2011154737

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=CF8CA857FDD8BF59DA9F336056132BB7.wapp2nA?docId=WO2011154737&tab=PCTDESCRIPTION

Example 1.01

4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[((R)-S-methylsulfonimidoyl)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine

(R)-3-Methyl-4-(6-((R)-S-methylsulfonimidoylmethyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (98 mg, 0.18 mmol) was dissolved in MeOH (10 ml) and DCM (10 ml) and heated to 50 °C. Sodium hydroxide, 2M aqueous solution (0.159 ml, 0.32 mmol) was then added and heating continued for 5 hours. The reaction mixture was evaporated and the residue dissolved in DME: water :MeCN 2: 1 : 1 (4 ml) and then purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated and the residue trituated with Et2O

(1 ml) to afford the title compound (34.6 mg, 49%); 1HNMR (400 MHz, CDCl3) 1.40 (3H, d), 3.17 (3H, s), 3.39 (1H, tt), 3.62 (1H, td), 3.77 (1H, dd), 3.85 (1H, d), 4.08 (1H, dd), 4.18 (1H, d), 4.37 – 4.48 (2H, q), 4.51 (1H, s), 6.59 (1H, s), 7.35 (1H, t), 7.46 (1H, d), 8.06 (1H, d), 8.42 (1H, d), 10.16 (1H, s); m/z: (ES+) MH+, 387.19.

The (R)-3-methyl-4-(6-((R)-S-methylsulfonimidoylmethyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine, used as starting material, can be prepared as follows:

a) (R)-3-methylmorpholine (7.18 g, 71.01 mmol) and triethylamine (12.87 ml, 92.31 mmol) were added to methyl 2,4-dichloropyrimidine-6-carboxylate (14.70 g, 71.01 mmol) in DCM (100 ml). The resulting mixture was stirred at RT for 18 hours. Water (100 ml) was added, the layers separated and extracted with DCM (3 × 75 ml). The combined organics were

dried over MgSO4, concentrated in vacuo and the residue triturated with Et2O to yield (R)-methyl 2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylate (14.77 g, 77%); 1H NMR (400 MHz, CDCl3) 1.35 (3H, d), 3.34 (1H, td), 3.55 (1H, td), 3.70 (1H, dd), 3.81 (1H, d), 3.97 (3H, s), 4.03 (1H, dd), 4.12 (1H, br s), 4.37 (1H, br s), 7.15 (1H, s); m/z: (ESI+) MH+, 272.43. The liquors were concentrated onto silica and purified by chromatography on silica eluting with a gradient of 20 to 40% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford (R)-methyl 2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylate (1.659 g, 9%); 1H NMR (400 MHz, CDCl3) 1.35 (3H, d), 3.33 (1H, td), 3.55 (1H, td), 3.69 (1H, dd), 3.80 (1H, d), 3.97 (3H, s), 4.03 (1H, dd), 4.12 (1H, br s), 4.36 (1H, br s), 7.15 (1H, s); m/z: (ESI+) MH+, 272.43.

b) Lithium borohydride, 2M in THF (18 ml, 36.00 mmol) was added dropwise to (R)-methyl 2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylate (16.28 g, 59.92 mmol) in THF (200 ml) at 0°C over a period of 20 minutes under nitrogen. The resulting solution was stirred at 0 °C for 30 minutes and then allowed to warm to RT and stirred for a further 18 hours. Water (200 ml) was added and the THF evaporated. The aqueous layer was extracted with EtOAc (2 × 100 ml) and the organic phases combined, dried over MgSO4 and then evaporated to afford (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (14.54 g, 100%) which was used in the next step without purification; 1HNMR (400 MHz, CDCl3) 1.32 (3H, d), 2.65 (1H, br s), 3.25 – 3.32 (1H, m), 3.51 – 3.57 (1H, m), 3.67 – 3.70 (1H, m), 3.78 (1H, d), 3.98 – 4.09 (2H, m), 4.32 (1H, br s), 4.59 (2H, s), 6.44 (1H, s); m/z: (ESI+) MH+, 244.40.

c) Methanesulfonyl chloride (4.62 ml, 59.67 mmol) was added dropwise to (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (14.54 g, 59.67 mmol) and triethylamine (8.32 ml, 59.67 mmol) in DCM (250 ml) at 25 °C over a period of 5 minutes. The resulting solution was stirred at 25 °C for 90 minutes. The reaction mixture was quenched with water (100 ml) and extracted with DCM (2 × 100 ml). The organic phases were combined, dried over MgSO4, filtered and evaporated to afford (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (20.14 g, 105%) which was used in the next step without further purification; 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.13 (3H, s), 3.27 – 3.34 (1H, m), 3.51 -3.57 (1H, m), 3.66 – 3.70 (1H, m), 3.79 (1H, d), 3.99 – 4.03 (2H, m), 4.34 (1H, br s), 5.09 (2H, d) , 6.52 (1H, s); m/z: (ESI+) MH+, 322.83.

Alternatively, this step can be carried out as follows:

In a 3 L fixed reaction vessel with a Huber 360 heater / chiller attached, under a nitrogen atmosphere, triethylamine (0.120 L, 858.88 mmol) was added in one go to a stirred solution of (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (161 g, 660.68 mmol) in DCM (7.5vol) (1.2 L) at 20°C (3°C exotherm seen). The mixture was cooled to 5°C and then methanesulfonyl chloride (0.062 L, 792.81 mmol) was added dropwise over 15 minutes, not allowing the internal temperature to exceed 15°C. The reaction mixture was stirred at 15°C for 2 hours and then held (not stirring) overnight at RT under a nitrogen atmosphere. Water (1.6 L, 10 vol) was added and the aqueous layer was separated and then extracted with DCM (2 × 1.6 L, 2 × 10 vol). The organics were combined, washed with 50% brine / water (1.6 L, 10 vol), dried over magnesium sulphate, filtered and then evaporated to afford a mixture of

approximately two thirds (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate and one third (R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine (216 g) which was used in the next step without further purification, d) Lithium iodide (17.57 g, 131.27 mmol) was added to (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (19.2 g, 59.67 mmol) in dioxane (300 ml) and heated to 100 °C for 2 hours under nitrogen. The reaction mixture was quenched with water (200 ml) and extracted with EtOAc (3 × 200 ml). The organic layers were combined and washed with 2M sodium bisulfite solution (400 ml), water (400 ml), brine (400 ml) dried over MgSO4 and then evaporated. The residue was triturated with Et2O to afford (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (13.89 g, 66%); 1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98 -4.02 (2H, m), 4.21 (2H, s), 4.29 (1H, br s), 6.41 (1H, s); m/z: (ESI+) MH+ 354.31.

The mother liquors were concentrated down and triturated with Et2O to afford a further crop of (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (2.46 g, 12%); 1HNMR (400 MHz, CDCI3) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98 – 4.02 (2H, m), 4.21 (2H, s), 4.30 (1H, s), 6.41 (1H, s); m/z: (ESI+) MH+, 354.31.

Alternatively, this step can be carried out as follows:

(R)-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (80 g, 248.62 mmol) and lithium iodide (83 g, 621.54 mmol) were dissolved in dioxane (300 ml) and then heated at 107 °C for 1 hour. The reaction mixture was quenched with water (250 ml), extracted with EtOAc (3 × 250 ml), the organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and Et2O was added, the mixture was passed through silica (4 inches) and eluted with Et2O. Fractions containing product were evaporated and the residue was then triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to afford (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (75 g, 86%) ; m/z: (ESI+) MH+, 354.27.

e) (R)-4-(2-Chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (17.0 g, 48.08 mmol) was dissolved in DMF (150 ml), to this was added sodium methanethiolate (3.37 g, 48.08 mmol) and the reaction was stirred for 1 hour at 25 °C. The reaction mixture was quenched with water (50 ml) and then extracted with Et2O (3 × 50 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by flash

chromatography on silica, eluting with a gradient of 50 to 100% EtOAc in iso-hexane. Pure fractions were evaporated to afford (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (12.63 g, 96%); m/z: (ES+) MH+, 274.35.

Alternatively, (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine, may be prepared as follows:

In a 3 L fixed vessel, sodium thiomethoxide (21% in water) (216 g, 646.69 mmol) was added dropwise over 5 minutes to a stirred solution of a mixture of approximately two thirds (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate and one third (R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine (130.2 g, 431 mmol) and sodium iodide (1.762 ml, 43.11 mmol) in MeCN (1 L) at RT (temperature dropped from 20 °C to 18 °C over the addition and then in the next 5 minutes rose to 30 °C). The reaction mixture was stirred for 16 hours and then diluted with EtOAc (2 L), and washed sequentially with water (750 ml) and saturated brine (1 L). The organic layer was dried over MgSO4, filtered and then evaporated to afford (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (108 g, 91%); 1H NMR (400 MHz, DMSO- d6) 1.20 (3H, d), 2.07 (3H, s), 3.11 – 3.26 (1H, m), 3.44 (1H, td), 3.53 (2H, s), 3.59 (1H, dd), 3.71 (1H, d), 3.92 (1H, dd), 3.92 – 4.04 (1H, br s), 4.33 (1H, s), 6.77 (1H, s); m/z: (ES+) MH+, 274.36.

f) (R)-4-(2-Chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (12.63 g, 46.13 mmol) was dissolved in DCM (100 ml), to this was added mCPBA (7.96 g, 46.13 mmol) in one portion and the reaction mixture was stirred for 10 minutes at 25 °C. An additional portion of mCPBA (0.180 g) was added. The reaction mixture was quenched with saturated Na2CO3 solution (50 ml) and extracted with DCM (3 × 50 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was dissolved in DCM (80 ml) in a 150

ml conical flask which was placed into a beaker containing Et2O (200 ml) and the system covered with laboratory film and then left for 3 days. The obtained crystals were filtered, crushed and sonicated with Et2O. The crystallisation procedure was repeated to afford (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine as white needles (3.87 g, 29%); 1HNMR (400 MHz, CDCl3) 1.33 (3H, d), 2.62 (3H, s), 3.30 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d), 4.00 (1H, dd), 4.02 (1H, s), 4.32 (1H, s), 6.42 (1H, s).

The remaining liquour from the first vapour diffusion was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to afford (R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine as an orange gum (5.70 g, 43%); 1 HNMR (400 MHz, CDCl3) 1.33 (3H, d), 2.62 (3H, d), 3.29 (1H, td), 3.54 (1H, td), 3.68 (1H, dd), 3.73 – 3.82 (2H, m), 3.94 (1H, dd), 4.00 (2H, dd), 4.33 (1H, s), 6.42 (1H, s).

Alternatively, this step can be carried out as follows:

Sodium meta-periodate (64.7 g, 302.69 mmol) was added in one portion to (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (82.87 g, 302.69 mmol) in water (500 ml), EtOAc (1000 ml) and MeOH (500 ml). The resulting solution was stirred at 20 °C for 16 hours. Sodium metabisulfite (50 g) was added and the mixture stirred for 30 minutes. The reaction mixture was filtered and then partially evaporated to remove the MeOH. The organic layer was separated, dried over MgSO4, filtered and then evaporated. The aqueous layer was washed with DCM (3 x 500 ml). The organic layers were combined, dried over MgSO4, filtered and then evaporated. The residues were combined and dissolved in DCM (400 ml) and purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Fractions containing product were evaporated and the residue was dissolved in DCM (400 ml) and then divided into four 450 ml bottles. An aluminium foil cap was placed over the top of each bottle and a few holes made in each cap. The bottles were placed in pairs in a large dish containing Et2O (1000 ml), and then covered and sealed with a second glass dish and left for 11 days. The resultant white needles were collected by filtration and dried under vacuum. The crystals were dissolved in DCM (200 ml) and placed into a 450 ml bottle. An aluminium foil cap was placed over the top of the bottle and a few holes made in the cap. The bottle was placed in a large dish containing Et2O (1500 ml) and then covered and sealed with a second glass dish and left for 6 days. The resultant crystals were collected by filtration and dried under vacuum to afford (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (16.53 g, 19%); 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 2.61 (3H, s),

3.29 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d), 3.99 (1H, dd), 4.02 (1H, s), 4.31 (1H, s), 6.41 (1H, s). Chiral HPLC: (HP1100 System 5, 20μm Chiralpak AD-H (250 mm × 4.6 mm) column eluting with Hexane/EtOH/TEA 50/50/0.1) Rf, 12.192 98.2%.

The filtrate from the first vapour diffusion was concentrated in vacuo to afford an approximate

5:2 mixture of (R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine and (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (54.7 g, 62%).

Alternatively, this step can be carried out as follows:

Sodium meta-periodate (2.87 g, 13.44 mmol) was added in one portion to (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (3.68 g, 13.44 mmol) in water (10.00 ml), EtOAc (20 ml) and MeOH (10.00 ml). The resulting solution was stirred at 20 °C for 16 hours. The reaction mixture was diluted with DCM (60 ml) and then filtered. The DCM layer was separated and the aqueous layer washed with DCM (3 × 40 ml). The organics were combined, dried over MgSO4, filtered and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. Pure fractions were evaporated to afford (R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (2.72 g, 70%); 1H NMR (400 MHz, DMSO-d6) 1.22 (3H, d), 2.64 (3H, d), 3.14 – 3.26 (1H, m), 3.45 (1H, td), 3.59 (1H, dd), 3.73 (1H, d), 3.88 – 3.96 (2H, m), 4.00 (1H, d), 4.07 (1H, dt), 4.33 (1H, s), 6.81 (1H, s); m/z: (ESI+) MH+, 290.43.

The (3R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (2.7 g, 9.32 mmol) was purified by preparative chiral chromatography on a Merck 100 mm 20 μm Chiralpak AD column, eluting isocratically with a 50:50:0.1 mixture of iso-Hexane:EtOH:TEA as eluent. The fractions containing product were evaporated to afford (R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (1.38 g, 51%) as the first eluting compound; 1HNMR (400 MHz, CDCl3) 1.29 (3H, dd), 2.56 (3H, s), 3.15 – 3.33 (1H, m), 3.46 (1H, tt), 3.55 – 3.83 (3H, m), 3.85 – 4.06 (3H, m), 4.31 (1H, s), 6.37 (1H, s). Chiral HPLC: (HP1100 System 6, 20μm Chiralpak AD (250 mm × 4.6 mm) column eluting with iso-Hexane/EtOH/TEA 50/50/0.1) Rf, 7.197 >99%.

and (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (1.27 g, 47 %) as the second eluting compound; 1H NMR (400 MHz, CDCl3) 1.28 (3H, d), 2.58 (3H, s),

3.26 (1H, td), 3.48 (1H, td), 3.62 (1H, dt), 3.77 (2H, dd), 3.88 – 4.13 (3H, m), 4.28 (1H, s), 6.37 (1H, s). Chiral HPLC: (HP1100 System 6, 20μm Chiralpak AD (250 mm × 4.6 mm) column eluting with iso-Hexane/EtOH/TEA 50/50/0.1) Rf, 16.897 >99%.

g) Iodobenzene diacetate (18.98 g, 58.94 mmol) was added to (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (17.08 g, 58.94 mmol), 2,2,2-trifluoroacetamide (13.33 g, 117.88 mmol), magnesium oxide (9.50 g, 235.76 mmol) and rhodium(II) acetate dimer (0.651 g, 1.47 mmol) in DCM (589 ml) under air. The resulting suspension was stirred at 20 °C for 24 hours. Further 2,2,2-trifluoroacetamide (13.33 g, 117.88 mmol), magnesium oxide (9.50 g, 235.76 mmol), iodobenzene diacetate (18.98 g, 58.94 mmol) and rhodium(II) acetate dimer (0.651 g, 1.47 mmol) were added and the suspension was stirred at 20 °C for 3 days. The reaction mixture was filtered and then silica gel (100 g) added to the filtrate and the solvent removed in vacuo. The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to afford N-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-(R)-sulfanylidene]-2,2,2-trifluoroacetamide (19.39 g, 82%); 1H NMR (400 MHz, DMSO-d6) 1.22 (3H, d), 3.17 – 3.27 (1H, m), 3.44 (1H, td), 3.59 (1H, dd), 3.62 (3H, s), 3.74 (1H, d), 3.95 (1H, dd), 4.04 (1H, br s), 4.28 (1H, s), 5.08 (2H, q), 6.96 (1H, s); m/z: (ESI+) MH+, 401.12 and 403.13.

h) Dichlorobis(triphenylphosphine)palladium(II) (8.10 mg, 0.01 mmol) was added in one portion to N-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-(R)-sulfanylidene]-2,2,2-trifluoroacetamide (185 mg, 0.46 mmol), 2M aqueous Na2CO3 solution (0.277 ml, 0.55 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (193 mg, 0.48 mmol) in DME:water 4: 1 (5 ml) at RT. The reaction mixture was stirred at 90 °C for 1 hour, filtered and then purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to afford (R)-3-methyl-4-(6-((R)-S-methylsulfonimidoylmethyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (102 mg, 41%); 1HNMR (400 MHz, CDCl3) 1.33 (3H, d), 3.21 – 3.38 (1H, m), 3.42 (3H, d), 3.45 – 3.57 (1H, m), 3.61 – 3.70 (1H, m), 3.78 (1H, d), 4.01 (1H, dd), 3.90 -4.15 (1H, br s), 4.30 (1H, s), 4.64 (1H, dd), 4.84 (1H, dd), 6.49 (1H, d); m/z: (ESI+) MH+, 541.35

The 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, used as starting material, can be prepared as follows:

a) To a 3L fixed vessel was charged 3-chlorobenzoperoxoic acid (324 g, 1444.67 mmol) portionwise to 1H-pyrrolo[2,3-b]pyridine (150 g, 1244.33 mmol) in DME (750 ml) and heptane (1500 ml) at 20°C over a period of 1 hour under nitrogen. The resulting slurry was stirred at 20 °C for 18 hours. The precipitate was collected by filtration, washed with DME / heptane (1/2 5 vol) (750 ml) and dried under vacuum at 40°C to afford 1H-pyrrolo[2,3-b] pyridine 7-oxide 3-chlorobenzoate (353 g, 97%) as a cream solid, which was used without further purification; 1H NMR (400 MHz, DMSO-d6) 6.59 (1H, d), 7.07 (1H, dd), 7.45 (1H, d), 7.55 (1H, t), 7.65 (1H, dd), 7.70 (1H, ddd), 7.87 – 7.93 (2H, m), 8.13 (1H, d), 12.42 (1H, s), 13.32 (1H, s).

b) A 2M solution of potassium carbonate (910 ml, 1819.39 mmol) was added dropwise to a stirred slurry of 1H-pyrrolo[2,3-b]pyridine 7-oxide 3-chlorobenzoate (352.6 g, 1212.93 mmol) in water (4.2 vol) (1481 ml) at 20°C, over a period of 1 hour adjusting the pH to 10. To the resulting slurry was charged water (2 vol) (705 ml) stirred at 20 °C for 1 hour. The slurry was cooled to 0°C for 1 hour and the slurry filtered, the solid was washed with water (3 vol 1050ml) and dried in a vacuum oven at 40°C over P2O5 overnight to afford 1H-pyrrolo[2,3-b] pyridine 7-oxide (118 g, 73%); 1H NMR (400 MHz, DMSO-d6) 6.58 (1H, d), 7.06 (1H, dd), 7.45 (1H, d), 7.64 (1H, d), 8.13 (1H, d), 12.44 (1H, s); m/z: (ES+) (MH+MeCN)+, 176.03. c) To a 3L fixed vessel under an atmosphere of nitrogen was charged methanesulfonic anhydride (363 g, 2042.71 mmol) portionwise to 1H-pyrrolo[2,3-b]pyridine 7-oxide (137 g, 1021.36 mmol), and tetramethylammonium bromide (236 g, 1532.03 mmol) in DMF (10 vol) (1370 ml) cooled to 0°C over a period of 30 minutes under nitrogen. The resulting suspension was stirred at 20 °C for 24 hours. The reaction mixture was quenched with water (20 vol, 2740 ml) and the reaction mixture was adjusted to pH 7 with 50% sodium hydroxide (approx 200 ml). Water (40 vol, 5480 ml) was charged and the mixture cooled to 10°C for 30 minutes. The solid was filtered, washed with water (20 vol, 2740 ml) and the solid disssolved into

DCM/methanol (4: 1, 2000 ml), dried over MgSO4 and evaporated to provide a light brown solid. The solid was taken up in hot methanol (2000 ml) and water added dropwise until the solution went turbid and left overnight. The solid was filtered off and discarded, the solution was evaporated and the solid recrystallised from MeCN (4000 ml). The solid was filtered and washed with MeCN to afford 4-bromo-1H-pyrrolo[2,3-b]pyridine (68.4 g, 34%) as a pink

solid; 1H NMR (400 MHz, OMSO-d6) 6.40 – 6.45 (1H, m), 7.33 (1H, d), 7.57 – 7.63 (1H, m), 8.09 (1H, t), 12.02 (1H, s); m/z: (ES+) MH+, 198.92. The crude mother liquors were purified by Companion RF (reverse phase CI 8, 415g column), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents (starting at 26% upto 46% MeCN). Fractions containing the desired compound were evaporated to afford 4-bromo-1H-pyrrolo[2,3-b]pyridine (5.4 g, 3%) as a pink solid; 1H NMR (400 MHz, DMSO-d6) 6.43 (1H, dd), 7.33 (1H, d), 7.55 – 7.66 (1H, m), 8.09 (1H, d), 12.03 (1H, s); m/z: (ES+) MH+, 199.22.

d) Sodium hydroxide (31.4 ml, 188.35 mmol) was added to 4-bromo-1H-pyrrolo[2,3-b]pyridine (10.03 g, 50.91 mmol), tosyl chloride (19.41 g, 101.81 mmol) and

tetrabutylammonium hydrogensulfate (0.519 g, 1.53 mmol) in DCM (250 ml) at RT. The resulting mixture was stirred at RT for 1 hour. The reaction was quenched through the addition of saturated aqueous NH4Cl, the organic layer removed and the aqueous layer further extracted with DCM (3 × 25 ml). The combinbed organics were washed with brine (100 ml), dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to afford 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (14.50 g, 81%); 1H NMR (400 MHz, CDCl3) 2.38 (3H, s), 6.64 (1H, d), 7.28 (2H, d), 7.36 (1H, d), 7.78 (1H, d), 8.06 (2H, d), 8.22 (1H, d); m/z: (ES+) MH+, 353.23.

e) 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (3.37 g, 4.13 mmol) was added in one portion to 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (14.5 g, 41.28 mmol), bis(pinacolato)diboron (20.97 g, 82.57 mmol) and potassium acetate (12.16 g, 123.85 mmol) in anhydrous DMF (300 ml) at RT. The resulting mixture was stirred under nitrogen at 90 °C for 24 hours. After cooling to RT, 1N aqueous NaOH was added untill the aqueous layer was taken to pH 10. The aqueous layer was washed with DCM (1L), carefully acidified to pH 4 with 1 N aqueous HCl, and then extracted with DCM (3 × 300 ml). The organic layer was concentrated under reduced pressure to afford a dark brown solid. The solid was triturated with diethyl ether, filtered and dried to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (7.058 g, 43%); 1H NMR (400 MHz, CDCl3) 1.36 (12H, s), 2.35 (3H, s), 7.01 (1H, d), 7.22 (2H, d), 7.52 (1H, d), 7.74 (1H, d), 8.03 (2H, m), 8.42 (1H, d); m/z: (ES+) MH+, 399.40. The mother liquors were concentrated in vacuo and the residue triturated in isohexane, filtered and dried to afford a further sample of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (3.173 g, 19%); 1H NMR (400 MHz,

CDCI3) 1.36 (12H, s), 2.35 (3H, s), 7.01 (1H, d), 7.23 (2H, d), 7.52 (1H, d), 7.74 (1H, d), 8.03 (2H, d), 8.42 (1H, d); m/z: (ES+) MH+, 399.40.

Example 2.01 and example 2.02

4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-blpyridine, and

4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-blpyridine


(3R)-3-Methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine (1.67 g, 2.95 mmol) was dissolved in DME:water 4: 1 (60 ml) and heated to 50 °C. Sodium hydroxide, 2M aqueous solution (2.58 ml, 5.16 mmol) was then added and heating continued for 18 hours. The reaction mixture was acidified with 2M H Cl (~2 ml) to pH5. The reaction mixture was evaporated to dryness and the residue dissolved in EtOAc (250 ml), and washed with water (200 ml). The organic layer was dried over MgSO4, filtered and evaporated onto silica gel (10 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 7% MeOH in DCM. Pure fractions were evaporated and the residue was purified by preparative chiral chromatography on a Merck 50mm, 20μm ChiralCel OJ column, eluting isocratically with 50% isohexane in EtOH/MeOH (1 : 1) (modified with TEA) as eluent. The fractions containing the desired compound were evaporated to dryness to afford the title compound: 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (0.538g, 44%) as the first eluting compound; 1H NMR (400 MHz,

DMSO-d6) 1.29 (3H, d), 1.51 (3H, m), 1.70 – 1.82 (1H, m), 3.11 (3H, s), 3.28 (1H, m, obscured by water peak), 3.48 – 3.60 (1H, m), 3.68 (1H, dd), 3.75 – 3.87 (2H, m), 4.02 (1H, dd), 4.19 (1H, d), 4.60 (1H, s), 7.01 (1H, s), 7.23 (1H, dd), 7.51 – 7.67 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.76 (1H, s); m/z: (ES+) MH+, 413.12. Chiral HPLC: (HP1100 System 4, 5μm Chiralcel OJ-H (250 mm × 4.6 mm) column eluting with iso-Hexane/EtOH/MeOH/TEA 50/25/25/0.1) Rf, 9.013 >99%. Crystals were grown and isolated by slow evaporation to dryness in air from EtOAc. These crystals were used to obtain the structure shown in Fig 1 by X-Ray diffraction (see below). Example 2.02: 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (326 mg, 0.79 mmol) was dissolved in DCM (3 ml). Silica gel (0.5 g) was added and the mixture concentrated in vacuo. The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness and the residue was crystallized from EtOAc/n-heptane to afford 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (256 mg, 79%) as a white crystalline solid; 1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.39 – 1.60 (3H, m), 1.71 – 1.81 (1H, m), 3.10 (3H, d), 3.21 – 3.29 (1H, m), 3.52 (1H, td), 3.67 (1H, dd), 3.80 (2H, t), 4.01 (1H, dd), 4.19 (1H, d), 4.59 (1H, s), 7.01 (1H, s), 7.23 (1H, dd), 7.54 – 7.62 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.75 (1H, s). DSC (Mettler-Toledo DSC 820, sample run at a heating rate of 10°C per minute from 30°C to 350°C in a pierced aluminium pan) peak, 224.1 FC.

and the title compound: 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (0.441 g, 36%) as the second eluting compound; 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.40 – 1.58 (3H, m), 1.70 – 1.80 (1H, m), 3.10 (3H, d), 3.23 – 3.27 (1H, m), 3.51 (1H, dt), 3.66 (1H, dd), 3.80 (2H, d), 4.01 (1H, dd), 4.21 (1H, d), 4.56 (1H, s), 6.99 (1H, s), 7.22 (1H, dd), 7.54 – 7.61 (1H, m), 7.94 (1H, d), 8.33 (1H, d), 11.75 (1H, s); m/z: (ES+) MH+, 413.12. Chiral HPLC: (HP1100 System 4, 5μm Chiralcel OJ-H (250 mm × 4.6 mm) column eluting with iso-Hexane/EtOH/MeOH/TEA 50/25/25/0.1) Rf, 15.685 >99%. Example 2.01 : 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (66.5 mg) was purified by crystallisation from EtOH/water to afford 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (0.050 g); 1H NMR (400 MHz, CDCl3) 1.40 (3H, d), 1.59 (2H, s), 1.81 (2H, s), 2.41 (1H, s), 3.16 (3H, s), 3.39 (1H, td), 3.59 – 3.67 (1H, m), 3.77 (1H, dd), 3.86 (1H, d), 4.07 (1H, dd), 4.17 (1H, d), 4.54 (1H, s), 6.91 (1H, s), 7.34 (1H, t), 7.43 (1H, t), 8.05 (1H, d), 8.41 (1H, d), 9.14 (1H, s).

Scheme 1. Medicinal Chemistry Route to AZD6738

Reagent and conditions:

(a) (3R)-3-methylmorpholine, TEA, DCM, 77%;

(b) LiBH4, THF, 100%;

(c) MsCl, TEA, DCM, 100%;

(d) LiI, dioxane, 78%;

(e) NaSMe, DMF, 96%;

(f) m-CPBA, DCM;

(g) crystallization or chromatography, 40% (two steps);

(h) IBDA, trifluoroacetamide, MgO, DCM, Rh2(OAc)4 82%;

(i) 1,2-dibromoethane, sodium hydroxide, TOAB, 2-MeTHF, 47%;

(j) TsCl, tetrabutylammonium hydrogen sulfate, sodium hydroxide, DCM, 92%;

(k) bis(pinacolato)diboron, potassium acetate, 1,1′-bis(diphenylphosphino)ferrocene dichloro palladium(II), DMF, 62%;

(l) Pd(II)Cl2(PPh3)2, Na2CO3, DME, water, 80%;

(m) 2 N NaOH, DME, water, 92%.

Foote, K. M. N.Johannes, W. M.Turner, P.Morpholino Pyrimidines and their use in therapyWO 2011/154737 A1, 15 December 2011.

PAPER

Development and Scale-up of a Route to ATR Inhibitor AZD6738

  • William R. F. Goundry et al
Cite This:Org. Process Res. Dev.2019XXXXXXXXXX-XXX
Publication Date:June 21, 2019
https://doi.org/10.1021/acs.oprd.9b00075
AZD6738 is currently being tested in multiple phase I/II trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine, and an azaindole, make it a challenging molecule to synthesize on a large scale. We describe the evolution of the chemical processes, following the manufacture of AZD6738 from the initial scale-up through to multikilos on plant scale. During this evolution, we developed a biocatalytic process to install the sulfoxide with high enantioselectivity, followed by introduction of the cyclopropyl group first in batch, then in a continuous flow plate reactor, and finally through a series of continuous stirred tank reactors. The final plant scale process to form AZD6738 was operated on 46 kg scale with an overall yield of 18%. We discuss the impurities formed throughout the process and highlight the limitations of this route for further scale-up.
Abstract Image
imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-λ6-sulfane (1) (30.0 g) were added at 75 °C, and the reaction mixture was held for 2 h. The mixture was cooled to 20 °C, and n-heptane (141.9 kg) was added at the rate of 40 kg/h. The solid was collected by filtration, washed with a mixture of 1-butanol and n-heptane (9.3 and 22.4 kg respectively), and then given a further wash with n-heptane (32.2 kg). The solid was dried at 40 °C to give imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-λ6-sulfane (1) as a whit  solid (41.4 kg, 92% yield): Assay (HPLC) 99.9%; Assay (NMR) 99% wt/wt.

REFERENCES

1: Vendetti FP, Karukonda P, Clump DA, Teo T, Lalonde R, Nugent K, Ballew M, Kiesel BF, Beumer JH, Sarkar SN, Conrads TP, O’Connor MJ, Ferris RL, Tran PT, Delgoffe GM, Bakkenist CJ. ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation. J Clin Invest. 2018 Jun 28. pii: 96519. doi: 10.1172/JCI96519. [Epub ahead of print] PubMed PMID: 29952768.

2: Wallez Y, Dunlop CR, Johnson TI, Koh SB, Fornari C, Yates JWT, Bernaldo de Quirós Fernández S, Lau A, Richards FM, Jodrell DI. The ATR Inhibitor AZD6738 Synergizes with Gemcitabine In Vitro and In Vivo to Induce Pancreatic Ductal Adenocarcinoma Regression. Mol Cancer Ther. 2018 Jun 11. doi: 10.1158/1535-7163.MCT-18-0010. [Epub ahead of print] PubMed PMID: 29891488.

3: Fròsina G, Profumo A, Marubbi D, Marcello D, Ravetti JL, Daga A. ATR kinase inhibitors NVP-BEZ235 and AZD6738 effectively penetrate the brain after systemic administration. Radiat Oncol. 2018 Apr 23;13(1):76. doi: 10.1186/s13014-018-1020-3. PubMed PMID: 29685176; PubMed Central PMCID: PMC5914052.

4: Zhang J, Dulak AM, Hattersley MM, Willis BS, Nikkilä J, Wang A, Lau A, Reimer C, Zinda M, Fawell SE, Mills GB, Chen H. BRD4 facilitates replication stress-induced DNA damage response. Oncogene. 2018 Jul;37(28):3763-3777. doi: 10.1038/s41388-018-0194-3. Epub 2018 Apr 11. PubMed PMID: 29636547.

5: Jin J, Fang H, Yang F, Ji W, Guan N, Sun Z, Shi Y, Zhou G, Guan X. Combined Inhibition of ATR and WEE1 as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer. Neoplasia. 2018 May;20(5):478-488. doi: 10.1016/j.neo.2018.03.003. Epub 2018 Mar 30. PubMed PMID: 29605721; PubMed Central PMCID: PMC5915994.

6: Henssen AG, Reed C, Jiang E, Garcia HD, von Stebut J, MacArthur IC, Hundsdoerfer P, Kim JH, de Stanchina E, Kuwahara Y, Hosoi H, Ganem NJ, Dela Cruz F, Kung AL, Schulte JH, Petrini JH, Kentsis A. Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors. Sci Transl Med. 2017 Nov 1;9(414). pii: eaam9078. doi: 10.1126/scitranslmed.aam9078. PubMed PMID: 29093183; PubMed Central PMCID: PMC5683417.

7: Jones BC, Markandu R, Gu C, Scarfe G. CYP-Mediated Sulfoximine Deimination of AZD6738. Drug Metab Dispos. 2017 Nov;45(11):1133-1138. doi: 10.1124/dmd.117.077776. Epub 2017 Aug 23. PubMed PMID: 28835442.

8: Dunne V, Ghita M, Small DM, Coffey CBM, Weldon S, Taggart CC, Osman SO, McGarry CK, Prise KM, Hanna GG, Butterworth KT. Inhibition of ataxia telangiectasia related-3 (ATR) improves therapeutic index in preclinical models of non-small cell lung cancer (NSCLC) radiotherapy. Radiother Oncol. 2017 Sep;124(3):475-481. doi: 10.1016/j.radonc.2017.06.025. Epub 2017 Jul 8. PubMed PMID: 28697853.

9: Kiesel BF, Shogan JC, Rachid M, Parise RA, Vendetti FP, Bakkenist CJ, Beumer JH. LC-MS/MS assay for the simultaneous quantitation of the ATM inhibitor AZ31 and the ATR inhibitor AZD6738 in mouse plasma. J Pharm Biomed Anal. 2017 May 10;138:158-165. doi: 10.1016/j.jpba.2017.01.055. Epub 2017 Feb 4. PubMed PMID: 28213176; PubMed Central PMCID: PMC5357441.

10: Ma J, Li X, Su Y, Zhao J, Luedtke DA, Epshteyn V, Edwards H, Wang G, Wang Z, Chu R, Taub JW, Lin H, Wang Y, Ge Y. Mechanisms responsible for the synergistic antileukemic interactions between ATR inhibition and cytarabine in acute myeloid leukemia cells. Sci Rep. 2017 Feb 8;7:41950. doi: 10.1038/srep41950. PubMed PMID: 28176818; PubMed Central PMCID: PMC5296912.

11: Vendetti FP, Leibowitz BJ, Barnes J, Schamus S, Kiesel BF, Abberbock S, Conrads T, Clump DA, Cadogan E, O’Connor MJ, Yu J, Beumer JH, Bakkenist CJ. Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation. Sci Rep. 2017 Feb 1;7:41892. doi: 10.1038/srep41892. PubMed PMID: 28145510; PubMed Central PMCID: PMC5286430.

12: Min A, Im SA, Jang H, Kim S, Lee M, Kim DK, Yang Y, Kim HJ, Lee KH, Kim JW, Kim TY, Oh DY, Brown J, Lau A, O’Connor MJ, Bang YJ. AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells. Mol Cancer Ther. 2017 Apr;16(4):566-577. doi: 10.1158/1535-7163.MCT-16-0378. Epub 2017 Jan 30. PubMed PMID: 28138034.

13: Dillon MT, Barker HE, Pedersen M, Hafsi H, Bhide SA, Newbold KL, Nutting CM, McLaughlin M, Harrington KJ. Radiosensitization by the ATR Inhibitor AZD6738 through Generation of Acentric Micronuclei. Mol Cancer Ther. 2017 Jan;16(1):25-34. doi: 10.1158/1535-7163.MCT-16-0239. Epub 2016 Nov 9. PubMed PMID: 28062704; PubMed Central PMCID: PMC5302142.

14: Kim H, George E, Ragland R, Rafial S, Zhang R, Krepler C, Morgan M, Herlyn M, Brown E, Simpkins F. Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in BRCA-Mutant Ovarian Cancer Models. Clin Cancer Res. 2017 Jun 15;23(12):3097-3108. doi: 10.1158/1078-0432.CCR-16-2273. Epub 2016 Dec 19. PubMed PMID: 27993965; PubMed Central PMCID: PMC5474193.

15: Kim HJ, Min A, Im SA, Jang H, Lee KH, Lau A, Lee M, Kim S, Yang Y, Kim J, Kim TY, Oh DY, Brown J, O’Connor MJ, Bang YJ. Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells. Int J Cancer. 2017 Jan 1;140(1):109-119. doi: 10.1002/ijc.30373. Epub 2016 Oct 21. PubMed PMID: 27501113.

16: Biskup E, Naym DG, Gniadecki R. Small-molecule inhibitors of Ataxia Telangiectasia and Rad3 related kinase (ATR) sensitize lymphoma cells to UVA radiation. J Dermatol Sci. 2016 Dec;84(3):239-247. doi: 10.1016/j.jdermsci.2016.09.010. Epub 2016 Sep 16. PubMed PMID: 27743911.

17: Checkley S, MacCallum L, Yates J, Jasper P, Luo H, Tolsma J, Bendtsen C. Corrigendum: Bridging the gap between in vitro and in vivo: Dose and schedule predictions for the ATR inhibitor AZD6738. Sci Rep. 2016 Feb 9;6:16545. doi: 10.1038/srep16545. PubMed PMID: 26859465; PubMed Central PMCID: PMC4747154.

18: Kwok M, Davies N, Agathanggelou A, Smith E, Oldreive C, Petermann E, Stewart G, Brown J, Lau A, Pratt G, Parry H, Taylor M, Moss P, Hillmen P, Stankovic T. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood. 2016 Feb 4;127(5):582-95. doi: 10.1182/blood-2015-05-644872. Epub 2015 Nov 12. PubMed PMID: 26563132.

19: Vendetti FP, Lau A, Schamus S, Conrads TP, O’Connor MJ, Bakkenist CJ. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget. 2015 Dec 29;6(42):44289-305. doi: 10.18632/oncotarget.6247. PubMed PMID: 26517239; PubMed Central PMCID: PMC4792557.

20: Karnitz LM, Zou L. Molecular Pathways: Targeting ATR in Cancer Therapy. Clin Cancer Res. 2015 Nov 1;21(21):4780-5. doi: 10.1158/1078-0432.CCR-15-0479. Epub 2015 Sep 11. Review. PubMed PMID: 26362996; PubMed Central PMCID: PMC4631635.

//////AZD6738AZD-6738AZD 6738, AstraZeneca,  University of Pennsylvania, Phase II,  Breast cancer, Gastric cancer, Non-small cell lung cancer, Ovarian cancer, Ceralasertib
C[C@@H]1COCCN1c2cc(nc(n2)c3cncc4[nH]ccc34)C5(CC5)[S@](=N)(=O)C

HS 10340


HS-10340

CAS 2156639-66-4

MF C26 H31 N7 O5
MW 521.57
1,8-Naphthyridine-1(2H)-carboxamide, N-[5-cyano-4-[[(1R)-2-methoxy-1-methylethyl]amino]-2-pyridinyl]-7-formyl-3,4-dihydro-6-[(tetrahydro-2-oxo-1,3-oxazepin-3(2H)-yl)methyl]-
(R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl)-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide

CAS 2307670-65-9

Jiangsu Hansoh Pharmaceutical Group Co Ltd

Being investigated by Jiangsu Hansoh, Shanghai Hansoh Biomedical and Changzhou Hengbang Pharmaceutical ; in June 2018, the product was being developed as a class 1 chemical drug in China.

Useful for treating liver cancer, gastric cancer and prostate cancer.

Use for treating cancers, liver cancer, gastric cancer, prostate cancer, skin cancer, ovary cancer, lung cancer, breast cancer, colon cancer, glioma and rhabdomyosarcoma

The fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase transmembrane receptor and includes four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and adult body functions. FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor-targeted therapeutic research.
FGFR4, a member of the FGFR receptor family, forms dimers on the cell membrane by binding to its ligand, fibroblast growth factor 19 (FGF19), and the formation of these dimers can cause critical tyrosine in FGFR4’s own cells. The phosphorylation of the amino acid residue activates multiple downstream signaling pathways in the cell, and these intracellular signaling pathways play an important role in cell proliferation, survival, and anti-apoptosis. FGFR4 is overexpressed in many cancers and is a predictor of malignant invasion of tumors. Decreasing and reducing FGFR4 expression can reduce cell proliferation and promote apoptosis. Recently, more and more studies have shown that about one-third of liver cancer patients with continuous activation of FGF19/FGFR4 signaling pathway are the main carcinogenic factors leading to liver cancer in this part of patients. At the same time, FGFR4 expression or high expression is also closely related to many other tumors, such as gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and the like.
The incidence of liver cancer ranks first in the world in China, with new and dead patients accounting for about half of the total number of liver cancers worldwide each year. At present, the incidence of liver cancer in China is about 28.7/100,000. In 2012, there were 394,770 new cases, which became the third most serious malignant tumor after gastric cancer and lung cancer. The onset of primary liver cancer is a multi-factor, multi-step complex process with strong invasiveness and poor prognosis. Surgical treatments such as hepatectomy and liver transplantation can improve the survival rate of some patients, but only limited patients can undergo surgery, and most patients have a poor prognosis due to recurrence and metastasis after surgery. Sorafenib is the only liver cancer treatment drug approved on the market. It can only prolong the overall survival period of about 3 months, and the treatment effect is not satisfactory. Therefore, it is urgent to develop a liver cancer system treatment drug targeting new molecules. FGFR4 is a major carcinogenic factor in liver cancer, and its development of small molecule inhibitors has great clinical application potential.
At present, some FGFR inhibitors have entered the clinical research stage as anti-tumor drugs, but these are mainly inhibitors of FGFR1, 2 and 3, and the inhibition of FGFR4 activity is weak, and the inhibition of FGFR1-3 has hyperphosphatemia. Such as target related side effects. Highly selective inhibitor of FGFR4 can effectively treat cancer diseases caused by abnormal FGFR4 signaling pathway, and can avoid the side effects of hyperphosphatemia caused by FGFR1-3 inhibition. Highly selective small molecule inhibitors against FGFR4 in tumor targeted therapy The field has significant application prospects.
SYN

PATENT

WO2017198149

where it is claimed to be an FGFR-4 inhibitor for treating liver and prostate cancers, assigned to Jiangsu Hansoh Pharmaceutical Group Co Ltd and Shanghai Hansoh Biomedical Co Ltd .

PATENT

WO2019085860

Compound (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-) 1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (shown as Formula I). The compound of formula (I) is disclosed in Hausen Patent PCT/CN2017/084564, the compound of formula I is a fibroblast growth factor receptor inhibitor, and the fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase transmembrane receptor. The body includes four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and adult body functions. FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor-targeted therapeutic research.

[0003]
Example 1: Preparation of a compound of formula (I)

[0048]
First step 4-(((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butane Preparation of 1-propanol

[0049]

[0050]
2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-carbaldehyde (1.0 g, 4.2 mmol), 4-aminobutyl at room temperature l-ol (0.45g, 5.1mmol) was dissolved in DCE (15mL), stirred for 2 hours, followed by addition of NaBH (OAc) . 3 (1.35 g of, 6.4 mmol), stirred at room temperature overnight. The reaction was treated with CH 2 CI 2 was diluted (100 mL), the organic phase was washed with water (10mL) and saturated brine (15mL), and dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 4 – (((2- ( Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butan-1-ol (0.9 g, 69%) .

[0051]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.13 (S, IH), 5.17 (S, IH), 4.84 (S, IH), 3.73 (S, 2H), 3.66-3.49 (m, 2H), 3.42 ( s, 6H), 3.40-3.36 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.68-2.56 (m, 2H), 1.95-1.81 (m, 2H), 1.74-1.55 (m, 4H);

[0052]
MS m/z (ESI): 310.2 [M+H] + .

[0053]
The second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone

[0054]

[0055]
4-(((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino) in an ice water bath Butan-1-ol (0.6 g, 1.94 mmol) was dissolved in DCE (15 mL), then bis(trichloromethyl) carbonate (0.22 g, 0.76 mmol) was added and triethylamine (0.78 g, 7.76) was slowly added dropwise. Methyl) and then stirred at room temperature for 3 hours. The reaction temperature was raised to 80 ° C, and the reaction was carried out at 80 ° C for 6 hours. After the reaction was cooled to room temperature, it was diluted with CH 2 Cl 2 (100 mL), and the organic phase was washed sequentially with water (10 mL) and brine (15 mL) Drying with sodium sulfate, concentration and column chromatography to give the compound 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) )methyl)-1,3-oxazepin-2-one (0.37 g, 57%).

[0056]
MS m/z (ESI): 336.2 [M+H] + .

[0057]
The third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate

[0058]

[0059]
3-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3-oxan -2-one (670mg, 2mmol), diphenyl carbonate (643mg, 3mmol) mixing in of THF (15 mL), N 2 in an atmosphere, cooled to -78 deg.] C, was added dropwise LiHMDS in THF (4mL, 4mmol) was Naturally, it was allowed to react to room temperature overnight. After adding saturated aqueous NH 4 Cl (100 mL), ethyl acetate (100 mL×2), EtOAc. Methyl)-6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (432 mg, 47%) .

[0060]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.56 (S, IH), 7.38 (m, 2H), 7.21 (m, 3H), 5.22 (S, IH), 4.77 (S, 2H), 4.16 (m, 2H), 3.95 (m, 2H), 3.39 (s, 6H), 3.25 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 4H);

[0061]
MS m/z (ESI): 456.2 [M+H] + .

[0062]
The fourth step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide synthesis

[0063]

[0064]
(R)-6-Amino-4-((1-methoxypropan-2-yl)amino) nicotinenitrile (30 mg, 0.14 mmol), phenyl 7-(dimethoxymethyl)-6- ( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (60 mg, 0.13 Methyl acetate was dissolved in THF (5 mL), cooled to -78 ° C under N 2atmosphere, and a solution of THF (0.3 mL, 0.3 mmol) of LiHMDS was added dropwise to the reaction mixture. After adding a saturated aqueous solution of NH 4 Cl (50 mL), EtOAc (EtOAc) (5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-carbonyl-1) 3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 86%).

[0065]
1H NMR (400MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 7.60 (s, 2H), 5.41 (s, 1H), 5.12 (d, J = 7.8 Hz, 1H), 4.73 (s, 2H), 4.20-4.11 (m, 2H), 4.06-3.99 (m, 2H), 3.93 (s, 1H), 3.52-3.48 (m, 7H), 3.46-3.42 (m, 1H), 3.39 (s, 3H), 3.26-3.21 (m, 2H), 2.83 (t, J = 6.2 Hz, 2H), 2.03-1.95 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1.62 (m , 2H), 1.31 (d, J = 6.6 Hz, 3H);

[0066]
MS m/z (ESI): 568.3 [M+H] + .

[0067]
Step 5: (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide

[0068]

[0069]
(R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 0.12 mmol) Dissolved in THF/water (volume ratio: 11/4, 4.5 mL), concentrated HCl (0.45 mL, 5.4 mmol), and allowed to react at room temperature for 2 h. Saturated NaHC03 . 3 solution (50mL), (50mL × 2 ) and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound (R) -N- ( 5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1,3-oxazepine) 3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)-carboxamide (30 mg, 51%).

[0070]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 13.57 (S, IH), 10.26 (S, IH), 8.17 (S, IH), 7.71 (S, IH), 7.63 (S, IH), 5.27 (S, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H) , 3.33 – 3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m , 3H);

[0071]
MS m/z (ESI): 522.2 [M+H] + .

PATENT

WO-2019085927

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019085927&tab=FULLTEXT

Novel crystalline salt (such as hydrochloride, sulfate, methane sulfonate, mesylate, besylate, ethanesulfonate, oxalate, maleate, p-toluenesulfonate) forms of FGFR4 inhibitor, particularly N-[5-cyano-4-[[(1R)-2-methoxy-1-methyl-ethyl]amino]-2-pyridyl]-7-formyl-6-[(2-oxo-1,3-oxazepan-3-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide (designated as Forms I- IX), compositions comprising them and their use as an FGFR4 inhibitor for the treatment of cancer such as liver cancer, gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and glioma or rhabdomyosarcoma are claimed.

Example 1: Preparation of a compound of formula (I)
First step 4-(((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butane Preparation of 1-propanol
2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-carbaldehyde (1.0 g, 4.2 mmol), 4-aminobutyl at room temperature l-ol (0.45g, 5.1mmol) was dissolved in DCE (15mL), stirred for 2 hours, followed by addition of NaBH (OAc) . 3 (1.35 g of, 6.4 mmol), stirred at room temperature overnight. The reaction was treated with CH 2 CI 2 was diluted (100 mL), the organic phase was washed with water (10mL) and saturated brine (15mL), and dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 4 – (((2- ( Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butan-1-ol (0.9 g, 69%) .
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.13 (S, IH), 5.17 (S, IH), 4.84 (S, IH), 3.73 (S, 2H), 3.66-3.49 (m, 2H), 3.42 ( s, 6H), 3.40-3.36 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.68-2.56 (m, 2H), 1.95-1.81 (m, 2H), 1.74-1.55 (m, 4H);
MS m/z (ESI): 310.2 [M+H] + .
The second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone
4-(((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino) in an ice water bath Butan-1-ol (0.6 g, 1.94 mmol) was dissolved in DCE (15 mL), then bis(trichloromethyl) carbonate (0.22 g, 0.76 mmol) was added and triethylamine (0.78 g, 7.76) was slowly added dropwise. Methyl) and then stirred at room temperature for 3 hours. The reaction temperature was raised to 80 ° C, and the reaction was carried out at 80 ° C for 6 hours. After the reaction was cooled to room temperature, it was diluted with CH 2 Cl 2 (100 mL), and the organic phase was washed sequentially with water (10 mL) and brine (15 mL) Drying with sodium sulfate, concentration and column chromatography to give the compound 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) )methyl)-1,3-oxazepin-2-one (0.37 g, 57%).
MS m/z (ESI): 336.2 [M+H] + .
The third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate
3-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3-oxan -2-one (670mg, 2mmol), diphenyl carbonate (643mg, 3mmol) mixing in of THF (15 mL), N 2 in an atmosphere, cooled to -78 deg.] C, was added dropwise LiHMDS in THF (4mL, 4mmol) was Naturally, it was allowed to react to room temperature overnight. After adding saturated aqueous NH 4 Cl (100 mL), ethyl acetate (100 mL×2), EtOAc. Methyl)-6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (432 mg, 47%) .
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.56 (S, IH), 7.38 (m, 2H), 7.21 (m, 3H), 5.22 (S, IH), 4.77 (S, 2H), 4.16 (m, 2H), 3.95 (m, 2H), 3.39 (s, 6H), 3.25 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 4H);
MS m/z (ESI): 456.2 [M+H] + .
The fourth step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide synthesis
(R)-6-Amino-4-((1-methoxypropan-2-yl)amino) nicotinenitrile (30 mg, 0.14 mmol), phenyl 7-(dimethoxymethyl)-6- ( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (60 mg, 0.13 Methyl acetate was dissolved in THF (5 mL), cooled to -78 ° C under N 2atmosphere, and a solution of THF (0.3 mL, 0.3 mmol) of LiHMDS was added dropwise to the reaction mixture. After adding a saturated aqueous solution of NH 4 Cl (50 mL), EtOAc (EtOAc) (5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-carbonyl-1) 3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 86%).
1H NMR (400MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 7.60 (s, 2H), 5.41 (s, 1H), 5.12 (d, J = 7.8 Hz, 1H), 4.73 (s, 2H), 4.20-4.11 (m, 2H), 4.06-3.99 (m, 2H), 3.93 (s, 1H), 3.52-3.48 (m, 7H), 3.46-3.42 (m, 1H), 3.39 (s, 3H), 3.26-3.21 (m, 2H), 2.83 (t, J = 6.2 Hz, 2H), 2.03-1.95 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1.62 (m , 2H), 1.31 (d, J = 6.6 Hz, 3H);
MS m/z (ESI): 568.3 [M+H] + .
Step 5: (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide
(R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 0.12 mmol) Dissolved in THF/water (volume ratio: 11/4, 4.5 mL), concentrated HCl (0.45 mL, 5.4 mmol), and allowed to react at room temperature for 2 h. Saturated NaHC03 . 3 solution (50mL), (50mL × 2 ) and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound (R) -N- ( 5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1,3-oxazepine) 3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)-carboxamide (30 mg, 51%).
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 13.57 (S, IH), 10.26 (S, IH), 8.17 (S, IH), 7.71 (S, IH), 7.63 (S, IH), 5.27 (S, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H) , 3.33 – 3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m , 3H);
MS m/z (ESI): 522.2 [M+H] + .

///////////HS-10340 , HS 10340 , HS10340, CANCER, Jiangsu Hansoh, Shanghai Hansoh Biomedical,  Changzhou Hengbang, CHINA,  liver cancer, gastric cancer, prostate cancer, skin cancer, ovary cancer, lung cancer, breast cancer, colon cancer, glioma,  rhabdomyosarcoma

C[C@H](COC)Nc1cc(ncc1C#N)NC(=O)N4CCCc3cc(CN2CCCCOC2=O)c(C=O)nc34

CCS(=O)(=O)O.C[C@H](COC)Nc1cc(ncc1C#N)NC(=O)N4CCCc3cc(CN2CCCCOC2=O)c(C=O)nc34

TL 487


str1

TL-487

CAS  1469746-55-1
2-Butenamide, N-[3-cyano-7-ethoxy-4-[(4-phenoxyphenyl)amino]-6-quinolinyl]-4-(dimethylamino)-, (2E)-
Molecular Weight, 507.58, MF C30 H29 N5 O3

Teligene Inc(2E)-N-[3-Cyano-7-ethoxy-4-[(4-phenoxyphenyl)amino]-6-quinolinyl]-4-(dimethylamino)-2-butenamide

(E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide

Maleate in anhydrous or monohydrate CAS, 2326561-36-6, AND 2326561-38-8 form are BTK and HER-2 kinase inhibitor useful for treating cancer

Useful for treating breast cancer, ovary cancer and colon cancer. are BTK and HER-2 kinase inhibitor useful for treating cancer.

Anticancer protein kinase inhibitor

The compound was originally claimed in WO2013152135 , and may provide the structure of TL-487 , a small molecule inhibitor to HERs, being investigated by Teligene for the treatment of breast cancer; in July 2016, the company intended to develop the product as a class 1.1 chemical drug in China.

PATENT

US 20150057312

PATENT

WO2013152135

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013152135&tab=PCTDESCRIPTION&queryString=%28ET%2Fkinase%29+&recNum=8&maxRec=4574

PATENT

WO-2019096327

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019096327&redirectedID=true

Novel crystalline maleate salt of (E)-N-(3-cyano-7-ethoxy-4-((4-phenoxyphenyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide (first disclosed in WO2013152135) and its hydrates (monohydrate) and anhydrates, process for its preparation, composition comprising it and its use for treating cancers such as breast cancer, ovary cancer, colon cancer, prostate cancer, kidney cancer, bladder cancer, stomach cancer, lung cancer, mantle cell lymphoma and multiple myeloma are claimed. The compound is disclosed to be an irreversible inhibitor to BTK and Her-2 (also known as Erb-2 or neu).

(E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide is mentioned in WO2013152135 and corresponds to the compound of the Formula I:
Formula I
Compounds derived from 3-cyanoquinoline have been shown to have anti-tumor activity, which may make them useful as chemotherapeutic agents in treating various cancers, including but not limited to, pancreatic cancer, melanoma, lymphatic cancer, parotid tumors, Barrett’s esophagus, esophageal carcinomas, head and neck tumors, ovarian cancer, breast cancer, epidermoid tumors, cancers of major organs, such as kidney, bladder, larynx, stomach, and lung, colonic polyps and colorectal cancer and prostate cancer. Examples of compounds derived from 3-cyanoquinoline are disclosed and shown to possess anti-tumor activity in many literatures. One limitation of certain 3-cyanoquinoline compounds is that they are not water soluble in a free base form.
The crystalline form of a particular drug as a salt, a hydrate and/or any polymorph thereof is often one important determinant of the drug’s ease of preparation, stability, water solubility, storage stability, ease of formulation and in-vivo pharmacology. It is possible that one crystalline form is preferable over another where certain aspects such as ease of preparation, stability, water solubility and/or superior pharmacokinetics are deemed to be critical. Crystalline forms of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide salts that possess a higher degree of water solubility than the free base but are stable fulfill an unmet need for stable, crystalline, water-solubl
Example 1. (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide sulfate
95%ethanol (4.0 ml) was added to (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (500 mg, 0.99 mmol, 1.0 eq) , followed sulfuric acid (101.9 mg, 1.04 mmol, 1.05 eq) in 95%ethanol (1.0 ml) was added dropwise to the reaction mixture. Then an amount of precipitate was founded. Another 95% (60 ml) was added to the reaction mixture and the reaction mixture was heated to 70℃. Filtered and the filtrate was heated to 70℃ again. Then the reaction mixture was cooled to room temperature and The reaction mixture was crystallized at -10℃ for 41.5h. Filtered the precipitated solid and dried at 40℃ under vacuum for 1 hour to get the title compound (260 mg) as a yellow solid.
X-ray detection shows an amorphous structure to the compound as FIG. 9.
Example 2. Synthesis of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide hydrochloride
95%ethanol (5.0 ml) was added to (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (500 mg, 0.99 mmol, 1.0 eq) , followed hydrochloric acid (38.0 mg, 1.04 mmol, 1.05 eq) in 95%ethanol (1.0 ml) was added dropwise to the reaction mixture. The reaction mixture was heated to 70℃. Filtered and the filtrate was crystallized under -10℃ for 44.5h. Filtered the precipitated solid and dried at 40℃ under vacuum for 1 hour to get the title compound (96 mg) as a yellow solid.
X-ray detection shows an amorphous structure to the compound in FIG. 6.
Example 3. Synthesis of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide malate
(E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (500 mg, 0.99 mmol, 1.0 eq) , L-malic acid (139.4 mg, 1.04 mmol, 1.05 eq) and 95%ethanol (5.0 ml) was added to a 50 ml round-bottom flask. The reaction mixture was heated to 70℃. Filtered and the filtrate was crystallized under -10℃ for 45.5h. A little of precipitate was founded and then the reaction mixture was evaporated under vacuum at 40℃ to give the target (370 mg) as a yellow solid.
X-ray detection shows an amorphous structure to the compound in FIG. 8
Example 4: synthesis of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide citrate
To a solution of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (500 mg, 0.99 mmol, 1.0 eq) , citric acid (198.8 mg, 1.04 mmol, 1.05 eq) and 95%ethanol (5.0 ml) . The reaction mixture was heated to 70℃. Filtered and the filtrate was crystallized under -10℃ for 45h. A little of precipitate was founded and then the reaction mixture was evaporated under vacuum at 40℃ to give the target compound (610 mg) as a yellow solid.
X-ray detection shows an crystalline structure to the compound in FIG. 7.
Example 5: Preparation of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate monohydrate.
(E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide free base (0.091 kg) is rinsed with a 10%solution of USP purified water in n-propanol (0.082 kg, 0.10 L) followed by the addition of water: n-propanol solution (0.74 kg, 0.90 L) . Maleic acid is added (1.01 equiv) and the mixture is rinsed with 10%water: n-propanol (0.082 kg, 0.10 L) . The mixture is quickly heated to 50-60 ℃ and held for a minimum of 15 min. until a solution is obtained. The hot solution is clarified through a pre-heated 50-60 ℃, 0.2 Mm filter cartridge and the filtrates are collected in a preheated 45-55℃, 2 L multi-neck flask. The filter cartridge is rinsed through with 10%water: n-propanol pre-heated to 45-55 ℃ (0.082 kg, 0.10 L) . The solution is cooled over at least one hour to 40 ℃ and held at that temperature for 12 hours then cooled to room temperature (25 ℃) over a minimum of four hours and held at that temperature for at least two hours. The mixture is filtered on a 12.5 cm diameter Buchner funnel for 5 min., then rinsed and washed with prefiltered10%water: n-propanol solution (2 x 0.12 kg, 2 x 0.15 L) . The cake is dammed and suction maintained until dripping essentially stops, about 1 h.
PXRD is shown in FIG. 1.
Example 6: The product from Example 1 is dried (50 ℃, 10 mm Hg, 24 h) to give crystalline, anhydrous (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate.
PXRD is shown in FIG. 3.
Example 7: Preparation of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate monohydrate.
To a solution of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (38.0 g, 75.0 mmol, 1.0 eq) and n-propanol/H 2O (380 ml, V: V=9: 1) . maleic acid (8.7 g, 75.0 mmol, 1.0 eq) in n-propanol/H 2O (76 ml, V: V=9: 1) was added to the reaction mixture. An amount of precipitate was founded, then the reaction mixturewas heated to 65 ℃. The solid was dissolved completely, then the reaction mixture was cooled to room temperature and stand for 20 hours. Filtered and filtrate was evaporated under vacuum to get the crude product.
The crude product (14.0 g) was recrystallized in n-propanol/H 2O (240 ml, V: V=9: 1) at 70℃. The solid was dissolved completely, then the reaction mixture was cooled to room temperature and stand for 20.5 hours. Filtered and wash the cake with n-propanol/H 2O (20 ml, V: V=9: 1) to get target product (12.9 g, wet) .
PXRD as FIG. 1.
Example 8: crystalline, anhydrous (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide maleate.
To a solution of (E) -N- (3-cyano-7-ethoxy-4- ( (4-phenoxyphenyl) amino) quinolin-6-yl) -4- (dimethylamino) but-2-enamide (21.5 g, 42.4 mmol, 1.0 eq) and ethanol (300 ml) . maleic acid (5.2 g, 44.8 mmol, 1.05 eq) was added to the reaction mixture. An amount of precipitate was founded, then the reaction mixture was heated to 70 ℃. Another ethanol (1980 ml) was added to the reaction mixture in several times and the reaction temperature was keep at 70 ℃. Filtered and filtrate was cooled to room temperature, stop stirring and stand for 16-20 hours. Filtered and the solid was dried at room temperature for 24 hours to get the title compound.

///////////////TL-487, PRECLINICAL, CHINA, breast cancer, ovary cancer, olon cancer,  BTK, HER-2 kinase inhibitor,

CN(C)C\C=C\C(=O)Nc3cc4c(Nc2ccc(Oc1ccccc1)cc2)c(cnc4cc3OCC)C#N

GFH 018


(E)-3-[6-[2-(6-Methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,2,4]triazolo[1,5-a]pyridin-5-yl]prop-2-enamide.png

GFH-018

CAS 2169299-67-4

C21 H19 N7 O, 385.42
(E)-3-[6-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,2,4]triazolo[1,5-a]pyridin-5-yl]prop-2-enamide
2-Propenamide, 3-[6-[5,6-dihydro-2-(6-methyl-2-pyridinyl)-4H-pyrrolo[1,2-b]pyrazol-3-yl][1,2,4]triazolo[1,5-a]pyridin-5-yl]-, (2E)-

GenFleet Therapeutics

Advanced solid tumor; Cancer

TGF-beta Receptor Type-1 (TGFBR1; ALK5; SKR4; TbetaR-I) Inhibitors

Signal Transduction Modulators

GFH-018 , a TGFBR1 inhibitor, being investigated by GenFleet as an oral tablet formulation, for the treatment of cancer, including advanced solid tumors and hepatocellular carcinoma,  in March 2019, the company was developing GFH-018 as a class 1 chemical drug in China, with a clinical trial expected to begin in the second half of 2019.

Transforming growth factor-β (TGF-β) is a multifunctional growth factor superfamily with extensive biological activity, involved in early embryonic development, cartilage and bone formation, extracellular matrix synthesis, inflammation, Interstitial fibrosis, regulation of immune and endocrine functions, tumor formation and development.
The TGF-β superfamily consists of a class of structural and functionally related polypeptide growth factors, including TGF-βs (ie, narrowly defined TGF-β), activins (axivins), inhibins, and bone morphogenetic proteins (BMPs). Müllerian inhibitors (mullerian), etc., TGF-β is one of the important members of this family. In mammals, TGF-β mainly exists in three forms of TGF-β1, TGF-β2 and TGF-β3, which are located on different chromosomes, and TGF-β1 accounts for the highest proportion (>90%) in somatic cells. It has the strongest activity, the most functions, and the widest distribution. The newly synthesized TGF-β appears as an inactive precursor consisting of a signal peptide, a latent-associated polypeptide (LAP) and a mature TGF-β. After enzymatic hydrolysis, it forms active TGF-β, and then Receptor binding exerts a biological effect.
TGF-[beta] signaling molecules signal through a transmembrane receptor complex. TGF-β receptor is a transmembrane protein present on the cell surface and is divided into type I receptor (TGF-βRI), type II receptor (TGF-βRII) and type III receptor (TGF-βRIII), of which TGF- βRI is also known as activin receptor-like kinase 5 (ALK5). TGF-βRIII lacks intrinsic activity and is primarily involved in the storage of TGF-β. TGF-βRI and TGF-βRII belong to the serine/threonine kinase family. Type II receptors bind to TGF-β ligands with higher affinity and form heterologous receptor complexes with type I receptors. Phosphorylation of a region rich in glycine and serine residues (GS domain) of the proximal membrane of the receptor initiates an intracellular signal cascade reaction.
Smads are important TGF-β signal transduction and regulatory molecules in cells, which can directly transduce TGF-β signaling from the cell membrane, such as the nucleus. TGF-β/Smads signaling pathway plays an important role in the occurrence and development of tumors. . In TGF-β/Smads signal transduction, activated TGF-β first binds to TGF-βRII on the cell membrane surface to form a heterodimeric complex, and TGF-βRI recognizes and binds to the binary complex.
TGF-βRII phosphorylates serine/threonine in the GS domain of the cytoplasmic domain of TGF-βRI, thereby activating TGF-βRI; activated TGF-βRI further phosphorylates R-Smads (Smad2/Smad3) protein, which in turn Co-Smad (Smad4) binds to a heterotrimeric complex that enters the nucleus and acts synergistically with other co-activators and co-inhibitors to regulate transcription of target genes. . Any change in any part of the TGF-β/Smads signaling pathway leads to abnormalities in the signal transduction pathway.
Current research indicates that in tumor cells, TGF-β can directly affect tumor growth (non-inherent effects of TGF-β signaling), or by inducing epithelial-mesenchymal transition, blocking anti-tumor immune responses, and increasing tumor-associated fibrosis And enhanced angiogenesis indirectly affects tumor growth (the intrinsic effect of TGF-β). At the same time, TGF-β has a strong fibrotic induction, which is an activator of tumor-associated fibroblasts. These fibroblasts are a major source of collagen type I and other fibrotic factors. Induction products of fibroblasts and other fibrotic factors may continue to develop a microenvironment that reduces immune responses, increases drug resistance, and enhances tumor angiogenesis. In addition, TGF-β affects blood vessels during individual development and tumor growth. Raw regeneration. For example, TGF-βRI-deficient mouse embryos show severe vascular development defects, demonstrating that the TGF-β signaling pathway is a key regulator in vascular endothelium and smooth muscle cell development.
In 2013, the FDA awarded Lilly’s small molecule TGF-βRI inhibitor LY2157299 (WO 2002/094833) for the treatment of glioma and liver cancer. LY2157299 is an orphan drug under research, named Galunisertib. Galunisertib inhibits tumor cell invasion and metastasis while inhibiting the infiltration of tumor cells into blood vessels. In the phase 2 clinical trial of patients with liver cancer, about 23% of patients treated with Galunisertib had a decrease in serum alpha-fetoprotein (AFP) levels of more than 20%. Compared with patients without AFP response, these patients had slower tumor progression and longer survival, and increased expression of cadherin in epithelial cells was also observed in these patients, suggesting that Galunisertib can be regulated by inhibiting TGF-β signaling pathway. EMT, thereby inhibiting the progression of liver cancer, the structure of Galunisertib (LY2157299) is shown in formula (II):
Background research and development materials refer to the following documents:
WO2009/009059; WO2007/076127; WO2004/026306; WO2004/072033; WO2002/094833.
Synthesis
WO2017215506

PATENT

WO2017215506

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017215506

Example 1
Preparation of intermediates 1-6:
Step A: Ethyl acetate (291.41 ml, 2.98 mol) was dissolved in toluene (750.00 ml), and then sodium ethoxide (135.06 g, 1.98 mol) was added portionwise at room temperature, and the mixture was stirred at room temperature for 1 hour. Methyl 6-methylpyridine-2-carboxylate (150.00 g, 992.33 mmol) was added to the above reaction solution at 25 ° C, then heated to 95 ° C and stirred for 15 hours. The reaction mixture was cooled to 30 ° C, the pH was adjusted to 7 with acetic acid, diluted with water (500 ml), and ethyl acetate (500 ml). The organic phase was dried with anhydrous sodium s The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc Rate: 58.35%).
Step B: Ethyl 3-(6-methyl-2-pyridine)-3-oxo-propanoate (120.00 g, 579.07 mmol) was dissolved in pyridine (300 mL) then 1-aminopyrrolidine- 2-keto-p-toluenesulfonate (172.01 g, 631.66 mmol). The reaction mixture was stirred at 25 ° C for 16 hours and then concentrated under reduced pressure to remove solvent. The residue was diluted with water (300 ml) and then extracted with ethyl acetate (300 ml). The combined organic phases were dried with anhydrous sodium s , yield: 90.28%).
Step C: Dissolving 3-(6-methyl-2-pyridine)-3-(2-carbonyl-pyrrolidine)imino-propionic acid ethyl ester (155.00 g, 535.72 mmol) in toluene and then adding ethanol Sodium (72.91 g, 1.07 mol). The reaction mixture was heated to 100 ° C and stirred for 16 hours, then cooled to room temperature. It was slowly diluted with water (1.5 liters), adjusted to pH 4 with concentrated hydrochloric acid, and extracted with dichloromethane / isopropyl alcohol (10/1) (1 liter x 7). The combined organic layers were dried with anhydrous sodium s The residue was triturated with petroleum ether / ethyl acetate = 10/1 (200 mL). The solid was dried under reduced pressure to give 2-(6-methyl-2-pyridine)-5,6-dihydro-4H-pyrrole[1,2-b]pyrazole-3-carboxylic acid (52.80 g, yield : 40.52%).
Step D: Dissolving 2-(6-methyl-2-pyridyl)-5,6-dihydro-4H-pyrrole[1,2-b]pyrazole-3-carboxylic acid (45.00 g, 184.99 mmol) In N,N-dimethylformamide (650.00 ml), then NBS (49.09 g, 258.99 mmol). The reaction mixture was stirred at 30-40 ° C for 60 hours, then diluted with water (600 mL) and extracted with dichloromethane / isopropyl alcohol (10/1) (500 mL × 3). The combined organic phases were washed with EtOAc (EtOAc m. The resulting solid was slurried with EtOAc/EtOAc =EtOAc (EtOAc). The solid was dried under reduced pressure to give 3-bromo-2-(6-methyl-2-pyridine)-5,6-dihydro-4H-pyrrole[1,2-b]pyrazole (33.00 g, yield: 64.13%).
Step E: 3-Bromo-2-(6-methyl-2-pyridyl)-5,6-dihydro-4H-pyrrole [1,2-b]pyrazole (1.00 g, 3.60 mmol) and boric acid Triisopropyl ester (1.79 g, 9.54 mmol) was dissolved in tetrahydrofuran (20.00 mL). The reaction mixture was cooled to minus 70 ° C, then n-butyllithium (2.5 M, 3.74 mL) was then added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at 25 ° C for 1 hour, and then the pH was adjusted to 7 with aqueous hydrochloric acid (0.5 mol / liter). The tetrahydrofuran was then concentrated under reduced pressure and cooled to 15 °C. The mixture was filtered, and the filtered cake was purified with EtOAc EtOAc EtOAc (EtOAc) 5,6-Dihydro-4H-pyrrole[1,2-b]pyrazol-3-yl]boronic acid (750 mg, yield: 85.71%).
Preparation of Example 1:
Step A: 6-Iodo-[1,2,4]triazolo[1,5-a]pyridine (16.00 g, 65.30 mmol) was dissolved in tetrahydrofuran (800.00 mL) and cooled to below 60-70 ° C. Thereafter, lithium hexamethyldisilazide (1 mol/liter, 130.60 ml, 65.30 mmol) was added dropwise. The reaction mixture was stirred at minus 60-70 ° C for 15 minutes and N,N-dimethylformamide (14.32 g, 195.90 mmol, 15.07 mL). Stirring was then continued at minus 60 to 70 degrees C for 15 minutes and then quenched with saturated aqueous ammonium chloride (500 mL). The reaction mixture was warmed to room temperature and then extracted with ethyl acetate (500 ml). The combined organic layers were washed with EtOAc EtOAc m. The residue was purified with a silica gel column (eluent: methylene chloride / ethyl acetate = 10/1) to afford 6-iodo-[1,2,4]triazolo[1,5-a]pyridine-5- Formaldehyde (6.40 g, yield: 35.90%). . 1H NMR (400 MHz, DMSO-d6) 10.46 (S, IH), 8.62 (S, IH), 8.16 (D, J = 9.3Hz, IH), 7.88 (D, J = 9.3Hz, IH).
Step B: To a 500 ml three-necked flask equipped with a thermometer and a nitrogen balloon, 2-diethoxyphosphorylacetonitrile (3.83 g, 21.61 mmol, 3.48 ml) and tetrahydrofuran (80 ml) were added. The mixture was cooled to 0.degree. C. and then potassium tert-butoxide (2.42 g, 21.61 mmol). The reaction mixture was stirred at 0 ° C for 15 minutes and then added dropwise to another suspension through a dropping funnel (dispersing 6-iodo-[1,2,4]triazolo[1,5-a]pyridine-5-carbaldehyde In tetrahydrofuran (120 ml) and cooled to 0 ° C). The reaction mixture was stirred at 0<0>C for 15 min then EtOAc (EtOAc)EtOAc. The combined organic layers were washed with EtOAc EtOAc m. The residue was purified with a silica gel column (eluent: methylene chloride / ethyl acetate = 200/1 to 10/1) to afford (E)-3-(6-iodo-[1,2,4]triazole. [1,5-a]pyridin-5-yl)prop-2-enenitrile (4.2 g, yield: 65.66%). . 1 H NMR (400 MHz, CHLOROFORM-D) [delta] 8.42 (S, IH), 8.03 (D, J = 9.3Hz, IH), 7.98-7.91 (m, IH), 7.85-7.78 (m, IH), 7.60 (d, J = 9.2 Hz, 1H).
Step C: (E)-3-(6-Iodo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)prop-2-enenitrile (4.50 g, 15.20 m Mole), [2-(6-methyl-2-pyridyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]boronic acid (4.43 g, 18.24 m Mole), sodium carbonate (4.83 g, 45.60 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (556.07 mg, 759.96 μmol), 2-dicyclohexylphosphine- 2′,6′-dimethoxybiphenyl (311.98 mg, 759.96 μmol) and [2-(2-aminophenyl)phenyl]-chloro-palladium-cyclohexyl-[2-(2,6- Dimethoxyphenyl)phenyl]phosphine (547.64 mg, 759.96 μmol) was added to a mixed solvent of dioxane (100 ml) and water (20 ml). It was replaced with nitrogen 3 times and then heated to 90-100 ° C and stirred for 2 hours. The reaction mixture was poured into water (200 ml) and evaporated and evaporated. The combined organic layers were washed with EtOAc EtOAc m. The residue was purified with EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The solid was concentrated and dried under reduced pressure to give (E)-3-[6-[2-(6-methyl-2-pyridyl)-5,6-dihydro-4H-pyrrolo[1,2-b] Pyrazol-3-yl]-[1,2,4]triazolo[1,5-a]pyridin-5-yl]prop-2-enenitrile (5.37 g, yield: 96.16%). . 1 H NMR (400 MHz, CHLOROFORM-D) [delta] 8.49 (S, IH), 7.82-7.74 (m, 2H), 7.59-7.46 (m, 4H), 6.99 (dd, J = 2.6,6.1Hz, IH) , 4.39 (d, J = 6.3 Hz, 2H), 2.90 – 2.70 (m, 4H), 2.20 (s, 3H).
Step D: (E)-3-[6-[2-(6-Methyl-2-pyridyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3 -yl]-[1,2,4]triazolo[1,5-a]pyridin-5-yl]prop-2-enenitrile (5.37 g, 14.62 mmol) dissolved in dichloromethane (20 mL) , a mixed solvent of dimethyl sulfoxide (70 ml) and water (20 ml), then separately added hydrogen peroxide (8.29 g 73.10 mmol, 7.02 ml, 30%) and sodium hydroxide (2 mol / liter, 14.62 ml) ). The mixture was stirred at 15-20 degrees Celsius for 12 hours. The mixture was poured into water (200 ml), and extracted with a mixture solvent of dichloromethane/isopropanol (3/1) (200 ml × 1). The organic layer was washed with EtOAc EtOAc m. The residue was purified by preparative high performance liquid chromatography (column: Phenomenex Gemini C18 250 x 50 mm x 10 μm; mobile phase: [water (0.05% ammonia v/v)-acetonitrile]; gradient: 5%-32%, 33 80% min) Example 1 (3.6 g, yield: 63.82%) was obtained. . 1 H NMR (400 MHz, CHLOROFORM-D) [delta] 8.45 (S, IH), 8.09 (D, J = 15.6Hz, IH), 7.85 (D, J = 15.6Hz, IH), 7.69 (D, J = 9.2 Hz, 1H), 7.55-7.45 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 5.93-5.65 (m, 2H), 4.35 (br .s., 2H), 2.99-2.64 (m, 4H), 2.33 (s, 3H).

PATENT

WO-2019114792

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019114792&tab=FULLTEXT&maxRec=1000

Novel crystalline and salt (hydrochloride, sulfate and mesylate) forms of a TGF-βRI inhibitor, designated as Forms A and B, processes for their preparation and compositions comprising them are claimed for treating cancers. The compound was originally claimed in WO2017215506 , assigned to Medshine Discovery Inc alone.

Example 1 Preparation of a compound of formula (I)
Preparation of intermediates 1-6:
Step A: Ethyl acetate (291.41 ml, 2.98 mol) was dissolved in toluene (750.00 ml), and then sodium ethoxide (135.06 g, 1.98 mol) was added portionwise at room temperature, and the mixture was stirred at room temperature for 1 hour. 1-1 (150.00 g, 992.33 mmol) was added to the above reaction liquid at 25 ° C, and then heated to 95 ° C and stirred for 15 hours. The reaction mixture was cooled to about 30 ° C, and the pH was adjusted to 7 with acetic acid, diluted with water (500 ml), and ethyl acetate (500 ml). The organic phase was dried with anhydrous sodium s The residue was purified with a silica gel column (eluent: petroleum ether/ethyl acetate v/v = 50/1) to afford 1-2.
Step B: Dissolve 1-2 (120.00 g, 579.07 mmol) in pyridine (300 mL), then add 1-aminopyrrolidin-2-one p-toluenesulfonate (172.01 g, 631.66 mmol) ). The reaction mixture was stirred at 25 ° C for 16 hours and then concentrated under reduced vacuo. The residue was diluted with water (300 ml) and then extracted with ethyl acetate (300 ml). The combined organic layers were dried with anhydrous sodium s
Step C: 1-3 (155.00 g, 535.72 mmol) was dissolved in toluene then sodium ethoxide (72.91 g, 1.07 mol). The reaction mixture was heated to 100 ° C and stirred for 16 hours, then cooled to room temperature. It was slowly diluted with water (1.5 liters), adjusted to pH 4 with concentrated hydrochloric acid, and extracted with dichloromethane/isopropanol (v/v = 10/1, 1 liter x 7). The combined organic layers were dried with anhydrous sodium s The residue was triturated with petroleum ether / ethyl acetate (v/v = 10/1, 200 mL). The solid was dried under reduced pressure to give 1-4.
Step D: 1-4 (45.00 g, 184.99 mmol) was dissolved in N,N-dimethylformamide (650.00 ml), then NBS (49.09 g, 258.99 mmol). The reaction mixture was stirred at 30 to 40 ° C for 60 hours, then diluted with water (600 ml), and extracted with dichloromethane / isopropyl alcohol (v / v = 10 / 1,500 ml × 3). The combined organic phases were washed with EtOAc (EtOAc m. The resulting solid was slurried with EtOAc/EtOAc (EtOAc/EtOAc) The solid was dried under reduced pressure to give 1-5.
Step E: 1-5 (1.00 g, 3.60 mmol) and triisopropyl borate (1.79 g, 9.54 mmol) were dissolved in tetrahydrofuran (20.00 mL). The reaction mixture was cooled to minus 70 ° C, then n-butyllithium (2.5 M, 3.74 mL) was added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at 25 ° C for 1 hour, and then the pH was adjusted to 7 with aqueous hydrochloric acid (0.5 mol / liter). It was then concentrated under reduced pressure to remove tetrahydrofuran and cooled to 15 °C. The mixture was filtered, and the EtOAc EtOAc m.
Preparation of the compound of formula (I):
Step A: 1-7 (16.00 g, 65.30 mmol) was dissolved in tetrahydrofuran (800.00 ml), cooled to minus 60-70 ° C, and lithium hexamethyldisilazide (1 mol/L, 130.60) was added dropwise. ML, 65.30 mmol). The reaction mixture was stirred at -60 to 70 ° C for 15 minutes, and N,N-dimethylformamide (14.32 g, 195.90 mmol, 15.07 ml) was added. Stirring was then continued at minus 60-70 ° C for 15 minutes and then quenched with saturated aqueous ammonium chloride (500 mL). The reaction mixture was warmed to room temperature and then extracted with ethyl acetate (500 ml). The combined organic layers were washed with EtOAc EtOAc m. The residue was purified with a silica gel column (eluent: methylene chloride / ethyl acetate v/v = 10/1) to afford 1-8. . 1 H NMR (400 MHz, DMSO-d6) 10.46 (S, IH), 8.62 (S, IH), 8.16 (D, J = 9.3Hz, IH), 7.88 (D, J = 9.3Hz, IH).
Step B: To a 500 ml three-necked flask equipped with a thermometer and a nitrogen balloon, 2-diethoxyphosphorylacetonitrile (3.83 g, 21.61 mmol, 3.48 ml) and tetrahydrofuran (80 ml) were added. The mixture was cooled to 0 ° C then potassium tert-butoxide (2.42 g, 21.61 mmol). The reaction mixture was stirred at 0<0>C for 15 min then added dropwise to a further suspension (1~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The reaction mixture was stirred at 0<0>C for 15 min then EtOAc (EtOAc)EtOAc. The combined organic layers were washed with EtOAc EtOAc m. The residue was purified with a silica gel column (eluent: methylene chloride/ethyl acetate v/v = 200/1 to 10/1) to afford 1-9. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 8.42 (S, IH), 8.03 (D, J = 9.3Hz, IH), 7.98-7.91 (m, IH), 7.85-7.78 (m, IH), 7.60 ( d, J = 9.2 Hz, 1H).

Step C: 1-9 (4.50 g, 15.20 mmol), 1-6 (4.43 g, 18.24 mmol), sodium carbonate (4.83 g, 45.60 mmol), [1,1′-bis (diphenyl) Phosphine) ferrocene] palladium dichloride (556.07 mg, 759.96 μmol), 2-biscyclohexylphosphine-2′, 6′-dimethoxybiphenyl (311.98 mg, 759.96 μmol) and [2-( 2-Aminophenyl)phenyl]-chloro-palladium-cyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphine (547.64 mg, 759.96 μmol) was added to the dioxane (100 ml) and water (20 ml) in a mixed solvent. It was replaced with nitrogen three times and then heated to 90 to 100 ° C and stirred for 2 hours. The reaction mixture was poured into water (200 ml) and evaporated and evaporated. The combined organic layers were washed with EtOAc EtOAc m. The residue was purified on a silica gel column (eluent: methylene chloride/methanol, v/v=30/1) to afford crude crude product in petroleum ether/ethyl acetate (v/v=5/1) After stirring for 12 hours, the solid was collected by filtration, and the solid was concentrated and dried under reduced pressure to give 1-10. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 8.49 (S, IH), 7.82-7.74 (m, 2H), 7.59-7.46 (m, 4H), 6.99 (dd, J = 2.6,6.1Hz, IH), 4.39 (d, J = 6.3 Hz, 2H), 2.90 – 2.70 (m, 4H), 2.20 (s, 3H).

Step D: 1-10 (5.37 g, 14.62 mmol) was dissolved in a mixed solvent of dichloromethane (20 ml), dimethyl sulfoxide (70 ml) and water (20 ml), and then hydrogen peroxide ( 8.29 g 73.10 mmol, 7.02 mL, 30%) and sodium hydroxide (2 mol/L, 14.62 mL). The mixture was stirred at 15 to 20 ° C for 12 hours. The mixture was poured into water (200 ml), and extracted with a mixture solvent of dichloromethane/isopropanol (3/1) (200 ml × 1). The organic layer was washed with EtOAc EtOAc m. The residue was purified by preparative high performance liquid chromatography (column: Phenomenex Gemini C18 250 x 50 mm x 10 μm; mobile phase: [water (0.05% ammonia v/v)-acetonitrile]; gradient: 5%-32%, 33 80% minute) to give a compound of formula (I). . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 8.45 (S, IH), 8.09 (D, J = 15.6Hz, IH), 7.85 (D, J = 15.6Hz, IH), 7.69 (D, J = 9.2Hz , 1H), 7.55-7.45 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 5.93-5.65 (m, 2H), 4.35 (br. s., 2H), 2.99-2.64 (m, 4H), 2.33 (s, 3H).
Example 2 Preparation of a compound of formula (II)
115 mg of the compound of formula (I) was added to an 8 ml glass vial, 4 ml of tetrahydrofuran was added, and the solution was sonicated by ultrasonication; then 1.05 equivalent of p-toluenesulfonic acid monohydrate was slowly added. The suspension sample was placed on a magnetic stirrer (40 ° C) and stirred for 16 hours. The sample solution was centrifuged, and the solid was taken out and dried in a vacuum oven at 35 ° C for 16 hours to obtain a compound of the formula (II). 1 H NMR (400 MHz, CD 3 OD) δ 8.61 (s, 1H), 8.14 (t, J = 8.0 Hz, 1H), 8.05 (d, J = 15.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.70 (dd, J=8.4, 15.6 Hz, 4H), 7.54 (d, J = 15.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.6) Hz, 2H), 4.42 (m, 2H), 3.05-2.87 (m, 2H), 2.82 (s, 3H), 2.81-2.74 (m, 2H), 2.35 (s, 3H).
Example 3 Preparation of a compound of formula (IV)
115 mg of the compound of formula (I) was added to an 8 ml glass vial, 4 ml of tetrahydrofuran was added, and the solution was sonicated by ultrasonication; then 1.05 equivalent of hydrochloric acid was slowly added. The suspension sample was placed on a magnetic stirrer (40 ° C) and stirred for 16 hours. The sample solution was centrifuged, and the solid was taken out and dried in a vacuum oven at 35 ° C for 16 hours. The obtained solid was added to an appropriate amount of acetone to prepare a suspension and stirred at 40 ° C, and the supernatant was discarded by centrifugation, and the solid sample was drained with an oil pump at room temperature to obtain a compound of the formula (IV).
Example 4 Preparation of a compound of formula (V)
115 mg of the compound of formula (I) was added to an 8 ml glass vial, 4 ml of tetrahydrofuran was added, and the solution was sonicated by ultrasonication; then 1.05 equivalent of sulfuric acid was slowly added. The suspension sample was placed on a magnetic stirrer (40 ° C) and stirred for 16 hours. The sample solution was centrifuged, and the solid was taken out and dried in a vacuum oven at 35 ° C for 16 hours to obtain a compound of the formula (V).
Example 5 Preparation of a compound of formula (VI)
115 mg of the compound of formula (I) was added to an 8 ml glass vial, 4 ml of tetrahydrofuran was added, and the solution was sonicated by ultrasonication; then 1.05 equivalent of methanesulfonic acid was slowly added. The suspension sample was placed on a magnetic stirrer (40 ° C) and stirred for 16 hours. The sample solution was centrifuged, and the solid was taken out and dried in a vacuum oven at 35 ° C for 16 hours to obtain a compound of the formula (VI).
Example 6 Preparation of Form A of Compound of Formula (I)
10 g of the compound of the formula (I) was placed in a mixed solvent of ethanol (80 ml) and water (40 ml), heated to 70-75 ° C and stirred until clarified, and filtered while hot, and the filtrate was distilled under reduced pressure to a volume of the remaining solution. 50 ml, followed by cooling to stand for crystallisation, filtration, and the resulting filter cake was dried under reduced pressure to give a solid of the compound of formula (I).
Example 7 Preparation of Form B of Compound of Formula (II)

192 mg of the compound of formula (I) was weighed into a glass bottle. 10 ml of a tetrahydrofuran:acetic acid (v/v=9/1) mixed solvent was added, and after ultrasonic assisted for 30 minutes, the sample was dissolved into a clear solution. Stir on a magnetic stirrer (40 ° C). After 1.05 equivalents of p-toluenesulfonic acid monohydrate was slowly added, the sample was stirred overnight. After naturally cooling to room temperature, the supernatant was discarded by centrifugation, stirred for 10 hours by adding 10 ml of tetrahydrofuran, and the supernatant was discarded by centrifugation, and the same procedure was repeated twice more. The obtained solid was dried in a vacuum oven at 40 ° C for 1 hour, and after milling, it was further dried in a vacuum oven at 30 ° C for 16 hours to obtain a crystal form B of the compound of the formula (II).

.///////////////////GFH-018, GFH 018, GenFleet Therapeutics, Advanced solid tumor,  Cancer, PRECLINICAL

NC(=O)/C=C/c4n5ncnc5ccc4c2c3CCCn3nc2c1cccc(C)n1

SEVITERONEL, севитеронел , سيفيتيرونيل , 赛维罗奈 ,


VT-464.svg

SEVITERONEL

CAS Registry Number 1610537-15-9

Molecular formulaC18 H17 F4 N3 O3, MW 399.34

1H-1,2,3-Triazole-5-methanol, α-[6,7-bis(difluoromethoxy)-2-naphthalenyl]-α-(1-methylethyl)-, (αS)-

(αS)-α-[6,7-Bis(difluoromethoxy)-2-naphthalenyl]-α-(1-methylethyl)-1H-1,2,3-triazole-5-methanol

8S5OIN36X4

севитеронел [Russian] [INN]
سيفيتيرونيل [Arabic] [INN]
赛维罗奈 [Chinese] [INN]
  • Mechanism of ActionAndrogen receptor antagonists; Estrogen receptor antagonists; Steroid 17-alpha-hydroxylase inhibitors; Steroid 17-alpha-hydroxylase modulators
  • WHO ATC codeL01 (Antineoplastic Agents)L01X-X (Other antineoplastic agents)
  • EPhMRA codeL1 (Antineoplastics)L1X9 (All other antineoplastics)

1H-1,2,3-Triazole-5-methanol, alpha-(6,7-bis(difluoromethoxy)-2-naphthalenyl)-alpha-(1-methylethyl)-, (alphaS)-

Seviteronel (developmental codes VT-464 and, formerly, INO-464) is an experimental cancer medication which is under development by Viamet Pharmaceuticals and Innocrin Pharmaceuticals for the treatment of prostate cancer and breast cancer.[1] It is a nonsteroidalCYP17A1 inhibitor and works by inhibiting the production of androgens and estrogens in the body.[1] As of July 2017, seviteronel is in phase II clinical trials for both prostate cancer and breast cancer.[1] In January 2016, it was designated fast-track status by the United States Food and Drug Administration for prostate cancer.[1][2] In April 2017, seviteronel received fast-track designation for breast cancer as well.[1]

  • Originator Viamet Pharmaceuticals
  • Developer Innocrin Pharmaceuticals
  • Clas sAntiandrogens; Antineoplastics; Fluorine compounds; Naphthalenes; Propanols; Small molecules; Triazoles
  • Mechanism of Action Androgen receptor antagonists; Estrogen receptor antagonists; Steroid 17-alpha-hydroxylase inhibitors; Steroid 17-alpha-hydroxylase modulators
  • Phase II Breast cancer; Prostate cancer; Solid tumours
  • 31 Jan 2019 Innocrin Pharmaceutical completes a phase II trial in Prostate Cancer (Second-line therapy or greater, Hormone refractory) in the US (NCT02445976)
  • 31 Jan 2019 Innocrin Pharmaceutical completes a phase II trial for Prostate Cancer (Hormone refractory) in the US, UK, Switzerland and Greece (NCT02012920)
  • 31 Jan 2019 Innocrin Pharmaceuticals completes the phase I/II CLARITY-01 trial for Breast cancer (Late stage disease) in USA (NCT02580448)
  • CYP-17 useful for treating fungal infections, prostate cancer, and polycystic ovary syndrome, assigned to Viamet Pharmaceuticals Inc , naming Hoekstra and Rafferty. Innocrin Pharmaceuticals , a spin-out of Viamet is developing oral seviteronel, the lead dual selective inhibitors of the 17,20-lyase activity of P450c17 (CYP17) and androgen receptor antagonist, which also includes VT-478 and VT-489, developed using the company’s Metallophile technology, for treating castration-resistant prostate cancer (CRPC) in men, breast cancer and androgen (AR) related cancers.

Pharmacology

Pharmacodynamics

Seviteronel is a nonsteroidal antiandrogen, acting specifically as an androgen synthesis inhibitor via inhibition of the enzyme CYP17A1, for the treatment of castration-resistant prostate cancer.[3][4][5][6][7][8] It has approximately 10-fold selectivity for the inhibition of 17,20-lyase (IC50 = 69 nM) over 17α-hydroxylase (IC50 = 670 nM), which results in less interference with corticosteroid production relative to the approved CYP17A1 inhibitor abiraterone acetate (which must be administered in combination with prednisone to avoid glucocorticoid deficiency and mineralocorticoid excess due to 17α-hydroxylase inhibition) and hence may be administerable without a concomitant exogenous glucocorticoid.[4][5][6][7][8] Seviteronel is 58-fold more selective for inhibition of 17,20-lyase than abiraterone (the active metabolite of abiraterone acetate), which has IC50 values for inhibition of 17,20-lyase and 17α-hydroxylase of 15 nM and 2.5 nM, respectively.[7] In addition, in in vitro models, seviteronel appears to possess greater efficacy as an antiandrogen relative to abiraterone.[6] Similarly to abiraterone acetate, seviteronel has also been found to act to some extent as an antagonist of the androgen receptor.[6]

Society and culture

Generic names

Seviteronel is the generic name of the drug and its INN.[9]

PATENT

WO2012064943

PATENT

WO-2019113312

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019113312&redirectedID=true

The present invention relates to a process for preparing compound 1 that is useful as an anticancer agent. In particular, the invention seeks to provide a new methodology for preparing compound 1 and substituted derivatives thereof.

Living organisms have developed tightly regulated processes that specifically import metals, transport them to intracellular storage sites and ultimately transport them to sites of use. One of the most important functions of metals such as zinc and iron in biological systems is to enable the activity of metalloenzymes. Metalloenzymes are enzymes that incorporate metal ions into the enzyme active site and utilize the metal as a part of the catalytic process. More than one-third of all characterized enzymes are metalloenzymes.

The function of metalloenzymes is highly dependent on the presence of the metal ion in the active site of the enzyme. It is well recognized that agents which bind to and inactivate the active site metal ion dramatically decrease the activity of the enzyme. Nature employs this same strategy to decrease the activity of certain metalloenzymes during periods in which the enzymatic activity is undesirable. For example, the protein TIMP (tissue inhibitor of metalloproteases) binds to the zinc ion in the active site of various matrix metalloprotease enzymes and thereby arrests the enzymatic activity. The pharmaceutical industry has used the same strategy in the design of therapeutic agents. For example, the azole antifungal agents fluconazole and voriconazole contain a l-( 1,2, 4-triazole) group that binds to the heme iron present in the active site of the target enzyme lanosterol demethylase and thereby inactivates the enzyme.

In the design of clinically safe and effective metalloenzyme inhibitors, use of the most appropriate metal-binding group for the particular target and clinical indication is critical. If a weakly binding metal-binding group is utilized, potency may be suboptimal. On the other hand, if a very tightly binding metal-binding group is utilized, selectivity for the target enzyme versus related metalloenzymes may be suboptimal. The lack of optimal selectivity can be a cause for clinical toxicity due to unintended inhibition of these off-target metalloenzymes.

One example of such clinical toxicity is the unintended inhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19 and CYP3A4 by the currently-available azole antifungal agents such as fluconazole and voriconazole. It is believed that this off-target inhibition is caused primarily by the indiscriminate binding of the currently utilized l-(l,2,4-triazole) to iron in the active site of CYP2C9, CYP2C19 and CYP3A4. Another example of this is the joint pain that has been observed in many clinical trials of matrix metalloproteinase inhibitors. This toxicity is considered to be related to inhibition of off-target metalloenzymes due to indiscriminate binding of the hydroxamic acid group to zinc in the off-target active sites.

Therefore, the search for metal-binding groups that can achieve a better balance of potency and selectivity remains an important goal and would be significant in the realization of therapeutic agents and methods to address currently unmet needs in treating and preventing diseases, disorders and symptoms thereof. Similarly, methods of synthesizing such therapeutic agents on the laboratory and, ultimately, commercial scale is needed. Addition of metal-based nucleophiles (Zn, Zr, Ce, Ti, Mg, Mn, Li) to azole-methyl substituted ketones have been effected in the synthesis of voriconazole (M. Butters, Org. Process Res. Dev. 2001, 5, 28-36). The nucleophile in these examples was an ethyl-pyrimidine substrate. Similarly, optically active azole-methyl epoxide has been prepared as precursor electrophile toward the synthesis of ravuconazole (A. Tsuruoka, Chem. Pharm. Bull. 1998, 46, 623-630). Despite this, the development of methodology with improved efficiency and selectivity is desirable

Preparation of Compound 4:

de 

Acetone (850 L), 2,3-dihydroxynaphthalene (85.00 kg, 530.7 moles), and potassium carbonate (219.3 kg, 1,586.7 moles) were charged to a clean, fixed reactor with stirring and with the temperature maintained at 20 – 35 °C. Dimethyl sulfate (200.6 kg, 2131.09) was added to the stirred reaction at a rate that maintains the internal temperature of the exothermic reaction below 60 °C. This addition typically requires about 3 hours. At the end of the dimethyl sulfate addition, the reaction is continued to allow to stir while maintaining the internal temperature at 50 – 60 °C. After about 3 hours, the reaction was analyzed by HPLC. The reaction was concentrated by atmospheric pressure distillation of acetone. The distillation was continued until 340 – 425 L of distillate was collected. This represents 40 – 50 % of the initial charge of acetone. At the end of the distillation, the reaction mass is present as a thick suspension. While maintaining the internal temperature below 60 °C, the reactor contents were slowly diluted with water (850 L). When the addition is complete, the reaction was cooled to an internal temperature of 25 – 35 °C and stirring was continued for 1 – 2 hours after the designated internal temperature was reached. Compound 2 was isolated by filtration and the cake was washed with water (at least 3 X 85 L). Compound 2 was dried at 40 – 45 °C and full vacuum until the water content by Karl Fisher titration is found to be NMT 2.0 %. Typically, greater than 90 kg of dry product is obtained with an assay of >99.5% AUC by HPLC.

Dichloromethane (with a water content by Karl Fisher Titration of NMT 0.50%) (928 L) and 2,3-dimethoxynaphthalene (2, 116.00 kg, 616.3 moles) were charged to a clean, fixed reactor with stirring and with the temperature maintained at 20 – 35 °C. The reactor contents were cooled to an internal temperature of -5 to 0 °C. Aluminum chloride (164.72 kg, 1235.3 moles, 2.00 molar equivalents) was carefully added in portions to the reaction, while maintaining the internal temperature at -5 to +5 °C. This addition typically requires 5 – 6 hours. At the end of the addition, the reactor contents were cooled to an internal temperature of -15 to -5 °C. Isobutyryl chloride (102.08 kg, 958.05 moles, 1.55 molar equivalents) was slowly added to the reaction while maintaining the internal temperature at -15 to -5 °C. The addition typically requires about 3 hours. At the end of the isobutyryl chloride addition, the reaction was warmed to an internal temperature of 20 – 35 °C. When the temperature was reached, these conditions were maintained for 2 – 3 hours until the IPC indicated a level of residual starting material of NMT 2.0 % AUC by HPLC. The reactor contents were then cooled to 0 – 5 °C. The reaction was quenched by adding the reaction to a precooled (0 – 5 °C) 3M aqueous solution of hydrochloric hcid (Water, 754 L: cone. HC1, 406 L). The mixture was vigorously stirred for 15 – 20 minutes then the layers were allowed to settle. The lower, dichloromethane, product-containing layer was washed sequentially with 10 % aqueous sodium bicarbonate (1044 L), water (1160 L), then 10 % aqueous sodium chloride (1044 L). The reaction was concentrated by distillation under full vacuum and at an internal temperature of NMT 40 °C. The reaction concentrate was cooled to 20 – 35 °C and diluted with hexanes (812 L). The resultant slurry was warmed to 45 – 50 °C and these conditions were maintained for 1 – 2 hours. The reactor contents were cooled to 20 – 35 °C for 1 – 2 hours. Compound 3 was isolated by filtration. The cake was washed with fresh hexanes (232 L) twice, the filter was cooled, and the cake was washed an additional two times with hexanes. Compound 3 was dried under full vacuum at a jacket temperature of 45 °C. Typically, about 95 kg of dry product was isolated with a product purity of >90% by HPLC.

Acetic acid (212.5 L L) and l-(6,7-dimethoxynaphthalene-2-yl)-2-methylpropane-l- one (42.5 kg, 164.5 moles) were charged to a clean, fixed reactor with stirring and with the temperature maintained at 25 – 45 °C. Concentrated hydrochloric acid (425.0 L) was added carefully to the stirring reactor contents while maintaining reactor contents at an internal temperature of 25 – 45 °C. When the addition was complete, the internal temperature of the reaction was raised to 100 – 105 °C. Note that the reaction is a heterogeneous mixture. The reaction was stirred under these conditions for 6 – 8 hours. The reaction was cooled to 85 – 90 °C to which was carefully added a fresh portion of hydrochloric acid (127.5 L). The reaction was warmed to 100 – 105 °C and stirred for another 6 – 8 hours. The reaction was cooled to 85 – 90 °C. The reaction was cooled further to 70 – 80 °C. Water (212.5 L) was added to the well stirred reaction and the reactor contents were cooled to an internal temperature of 35 – 45 °C and stirred for 3 – 4 hours. Compound 4 was collected by filtration. The wet cake was washed with water (212.5 L). The wet cake was added to a clean reactor with a 5% aqueous sodium bicarbonate solution and stirred at an internal temperature of 35 – 45 °C for 1 – 2 hours.

Compound 4 was collected by filtration and washed with water (212.5 L). Compound 4 was dried under full vacuum and a temperature of < 50 °C until the water content of the dried material was found to be NMT 5.0% by Karl Fisher Titration. The yield is typically >31 kg with a purity >99.5 %.

Preparation of Compound 5:

The following difluoromethylation conditions listed in Table 1 were investigated:

Preparation 1:

The reaction flask was dried under an argon flow at 120 °C. (lS,2R)-l-Phenyl-2-(l- pyrrolidinyl)propan-l-ol (ligand 45) (196.6 g, 0.96 mol, 2.2 eq.) was added into the flask and then toluene (195 mL) was added. The solution was cooled to <12 °C. A solution of diethyl zinc (716.4 g, 0.87 mol, 15 wt%, 2 eq.) in toluene was added through a septum over 30 min at 0-10 °C. Further, a solution of ((Trimethylsilyl)ethynyl)-magnesium bromide in THF (1.81 kg; 0.87 mol, 9.7 wt%, 2 eq.) was added over 30 min at 0-10 °C. Finally, trifluoroethanol (87.0 g; 0.87 mol; 2 eq.) was added over 10 min at 0-10 °C. The reaction solution was stirred at 10-12 °C for 3 h. Compound 5 (143.4 g; 0.434 mol; 1 eq.) was added (as a solid) at room

temperature. The reaction mixture was stirred at room temperature for 1 h and at 55 °C for 17 h. The reaction solution was cooled to room temperature and dosed with aqueous HC1 (3600 mL; 7.5 wt%) within 20 min. The temperature of the mixture was kept below 25 °C. Toluene (1250 mL) was added and the mixture was stirred at room temperature for 5 min. The aqueous phase was separated and stored for the recycling of ligand 45. The organic phases were washed with water (638 mL) and concentrated via distillation under reduced pressure (50 mbar). The residue (approx. 184 g) was treated with heptane (200 mL), which was removed

via distillation. The residue was dissolved in heptane (2050 mL) at 50 °C. The mixture was cooled to room temperature and subsequently to -8 °C within 2 hours. The obtained suspension was stirred at -8 °C for 1 h. Crystallized compound 5 (20.0 g; 14%) was isolated via filtration, washed twice with cold (0 °C) heptane (2×20 mL) and dried under vacuum at 50 °C for 12 hours. The combined heptane phases were concentrated under reduced pressure to obtain a 48 wt% solution of compound 18b in heptane (yield: 83.0%). The solution was directly used for the next step.

1H-NMR (600.6 MHz, DMSO-D6) d: 0.23 (s, 9H), 0.77 (d, J = 6.7 Hz, 3H), 0.93 (d, 7 = 6.7 Hz, 3H), 2.04 (sept., 7 = 6.7 Hz, 1H), 6.11 (s, 1H), 7.32 (t, 27H,F = 73.4 Hz, 1H), 7.35 (t, 27H,F = 73.4 Hz, 1H), 7.68 (dd, 7 = 8.6, 1.5 Hz, 1H), 7.84 (s, 1H), 7.87 (s, 1H), 7.93 (d, 7 = 8.6 Hz, 1H), 8.03 (s (broad), 1H);

HPLC (purity): 94%;

chiral HPLC: e.r. = 18:82.

Preparation 2:

(7S,2R)-l-Phenyl-2-(l-pyrrolidinyl)propan-l-ol (ligand 45) (13.0 kg, 63.3 mol, 2.2 eq.) was charged into the reactor and toluene (60 L) was added. The solution was cooled to < 12 °C. A solution of diethyl zinc (35.6 kg, 57.3 mol, 20 wt%, 2 eq.) in toluene was added via mass flow controller at 8-16 °C. Further, a solution of ((trimethylsilyl)ethynyl)-magnesium bromide in THF (11.5 kg; 57.3 mol, 9.7 wt%, 2 eq.) was added at 8-16 °C. Finally, trifluoroethanol (5.7 kg; 57.3 mol; 2 eq.) was added over 10 min at 8-16 °C.The reaction solution was stirred at 22-25 °C for 3 h. A solution of compound 5 (9.5 kg; 28.7 mol; 1 eq.) in toluene (20 L) was added at room temperature. The reaction mixture was stirred at 25 °C for 1 h and at 55 °C for 17 h. The reaction solution was cooled to room temperature and dosed in aqueous HC1 (225L; 7.5 wt%) within 20 min. The temperature of the mixture should be kept below 25 °C. Toluene (80 L) was added and the mixture was stirred at room temperature for 5 min. The organic phases was washed with water (50 L) and concentrated via distillation under reduced pressure (50 mbar). The residue was treated with heptane (100 L), which was removed via distillation. The residue was dissolved in heptane (100 L) at 50°C, which was removed via distillation. The residue was dissolved in heptane (25 L). Heptane (110 L) was added, the mixture was cooled to room temperature and subsequently to 0-5 °C and seeded with compound 5 (0.15 kg). The obtained suspension was cooled to -8 °C within 1 h and stirred at this temperature for 2 h. Crystallized compound 5 was removed via filtration. The filtrate was concentrated under reduced pressure to obtain a 48 wt% solution of compound 18b in heptane (calculated 8.8 kg, 71.6%). This solution was directly used for the next step.

1H-NMR (600.6 MHz, DMSO-D6) d: 0.23 (s, 9H), 0.77 (d, J = 6.7 Hz, 3H), 0.93 (d, 7 = 6.7 Hz, 3H), 2.04 (sept., 7 = 6.7 Hz, 1H), 6.11 (s, 1H), 7.32 (t, 27H,F = 73.4 Hz, 1H), 7.35 (t, 27H,F = 73.4 Hz, 1H), 7.68 (dd, 7 = 8.6, 1.5 Hz, 1H), 7.84 (s, 1H), 7.87 (s, 1H), 7.93 (d, 7 = 8.6 Hz, 1H), 8.03 (s (broad), 1H);

HPLC (purity): 94%;

chiral HPLC: e.r. = 18:82.

Recovery of the chiral ligand ( lS,2R)-l-Phenvl-2- 
-l-ol from the

Preparation 1:

The above acidic aqueous phase was diluted with toluene (1000 mL) and the mixture was treated with sodium hydroxide (50 wt% solution) to adjust the pH to 12. The mixture was warmed to 50 °C and sodium chloride (100 g) was added. The aqueous phase was separated and washed with toluene (1000 mL). The combined organic phases were washed with water (200 mL). The combined toluene phases were treated with water (1000 mL) and the pH was adjusted to 2 by the addition of a cone. HC1 solution. The aqueous phase was separated and the mixture was treated with sodium hydroxide (50 wt% solution) at 5 °C to adjust the pH to 12. After seeding, the suspension was stirred at 5 °C for 30 min. The solids were isolated, washed with cold (0 °C) water (4×100 mL) and dried under vacuum at 30 °C for 24 hours. Ligand 45 (178.9g; 91%) was obtained as slightly yellow crystalline solid.

HPLC (purity): 99%.

Preparation 2:

The acidic aqueous phase containing ligand 45 (500 L) was diluted with toluene (125 L) and treated with“Kieselgur” (20 L). The mixture was treated with sodium hydroxide (40 L; 50 wt% solution) to adjust the pH to 12 whereas the temperature was kept <55 °C. The suspension was stirred for 15-20 min and filtered to remove all solids. Toluene (80 L) was added and the aqueous phase was separated. The organic phase was treated with water (150 mL) and the pH was adjusted to 1.5-2 by the addition of an aqueous HC1 solution (10 L; 32 wt%). The aqueous phase was separated, toluene (150 L) was added, and the mixture was treated with sodium hydroxide (5 L; 50 wt% solution) at 5 °C to adjust the pH to 12-12.5. The organic phase was separated, washed with water (30 L), and concentrated under reduced

pressure at 50 °C. Approx. 100L of distillate was removed. A sample of the solution of ligand 45 in toluene was analyzed:

The NMR results indicated a 21.6 wt% solution of ligand 45 in toluene which corresponds to a calculated amount of 118.4 kg (83.6%) of ligand 45.

Preparation of Compound 18a

Preparation 1:

A solution of tertiary alcohol 18b (320 g; 48 wt%; 0.36 mol; 1 eq.) in heptane was dissolved in methanol (800 mL). Potassium carbonate (219 g; 1.58 mol; 4.4 eq.) was added (temperature was kept < 30 °C) and the suspension was stirred at room temperature for 3 h. Water (1250 mL) was added and the mixture was treated with a cone. HC1 solution (approx. 130 mL) to adjust the pH to 7.8. The reaction mixture was extracted twice with methyl- /-butyl ether (MTBE; 2×465 mL). The combined MTBE phases were washed with water (155 mL). Water (190 mL) was added to the MTBE phase and the organic solvent was distilled off under reduced pressure (50 mbar). The obtained emulsion of compound 18a (yield: 99%) was directly used for the next step.

1H-NMR (600.6 MHz, CDC13) d: 0.87 (d, J = 6.8 Hz, 3H), 1.09 (d, / = 6.8 Hz, 3H), 2.20 (sept. / = 6.8 Hz, 1H), 2.47 (s, 1H), 2.77 (s, 1H), 6.63 (t, 27H,F = 73.5 Hz, 1H), 6.63 (t, 2/H,F = 73.5 Hz, 1H), 7.65 (s, 1H), 7.69 (s, 1H), 7.74 (dd, 7 = 8.6, 1.7 Hz, 1H), 7.79 (d, / =

8.6 Hz, 1H), 8.06 (s (broad), 1H);

HPLC (purity): 95%.

Preparation 2:

The solution of tertiary alcohol 18b (48 wt%; 57.5 mol; 1 eq.) in heptane was dissolved in methanol (128 L). Potassium carbonate (35.0 kg; 253 mol; 4.4 eq.) was added (temperature was kept < 30 °C) and the suspension was stirred at 20-30 °C for 3 h. Water (200 L) was added and the mixture was treated with an aqueous HC1 solution (approx. 25 L; 32 wt%) to adjust the pH to 7.5 – 7.8. The reaction mixture was extracted twice with MTBE

(2×66.6 L). The combined MTBE phases were washed with water (25 L). Water (30 L) was added to the MTBE phase and the organic solvent was distilled off under reduced pressure (<80 mbar; 55°C). The residue was dissolved in tert-butanol (25 L). The resulting 18a was cooled to <30°C and used directly in the next step.

^-NMR (600.6 MHz, CDC13) d: 0.87 (d, / = 6.8 Hz, 3H), 1.09 (d, / = 6.8 Hz, 3H), 2.20 (sept. / = 6.8 Hz, 1H), 2.47 (s, 1H), 2.77 (s, 1H), 6.63 (t, 27H,F = 73.5 Hz, 1H), 6.63 (t, 2/H,F = 73.5 Hz, 1H), 7.65 (s, 1H), 7.69 (s, 1H), 7.74 (dd, 7 = 8.6, 1.7 Hz, 1H), 7.79 (d, / = 8.6 Hz, 1H), 8.06 (s (broad), 1H);

HPLC (purity): 95%.

Preparation of Compound 31

Preparation 1:

Benzyl bromide (39.4 g; 0.23 mol; 1 eq.) was dissolved in water (177 mL) and t-BuOH (200 mL). Diisopropylethylamine (DIPEA; 59.4 g; 0.46 mol; 2 eq.) and sodium azide (15.0 g; 0.23 mol; 1 eq.) were added. The suspension was stirred for 5 min at room temperature. A suspension of compound 18a (82 g; 0.23 mol; 1 eq.) in water (123 mL) was treated with t-BuOH (100 mL) and copper (I) iodide (8.8 g; 46 mmol; 0.2 eq.) was added and the temperature was kept below 30 °C. The yellow-brown suspension was stirred for 5 h at room temperature. Zinc powder (5.0 g; 76 mmol) and ammonium chloride (7.4 g; 0.14 mol) were added and the reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with MTBE (800 mL), water (280 mL), and an aqueous ammonia solution (120 g; 25 wt%). Solids were removed by filtration and additional MTBE (200 mL) and brine (200 mL) were added. The aqueous phase was separated and extracted with MTBE (400 mL). The combined organic phases were treated with water (150 mL) and MTBE was distilled off under reduced pressure (100 mbar). The obtained suspension of compound 31 (113 g; 50 wt%) in water (approx. 113 mL) was directly used for the next step.

Ή-NMEI (600.6 MHz, DMSO-D6) d: 0.66 (d, / = 6.8 Hz, 3H), 0.83 (d, / = 6.7 Hz, 3H), 2.78 (sept. / = 6.8 Hz, 1H), 5.55 (s, 2H), 5.68 (s, 1H), 7.29 (t, 27H,F = 73.4 Hz, 1H), 7.32 (t, 27H,F = 73.4 Hz, 1H), 7.36 – 7.26 (m, 5H), 7.79 (s, 1H), 7.82 (s, 1H), 7.82 (dd, 7 = 8.8, 1.7 Hz, 1H), 7.86 (d, / = 8.8 Hz, 1H), 7.94 (s, 1H), 8.10 (s (broad), 1H);

HPLC (purity): 87%.

Preparation 2:

Benzyl bromide (11.0 kg g; 64.4 mol; 1,12 eq.) was dissolved in water (40 L) and t-BuOH (60 L). DIPEA (16.4 kg; 126.5 mol; 2,2 eq.) and sodium azide (4.12 kg; 63.3 mol; 1 eq.) were added. The suspension was stirred 5 min at room temperature. A mixture of compound 18a (20.5 kg; 57.5 mol; 1 eq.) in ieri-butanol (see previous step) was added together with water (5 L) and copper (I) iodide (2.2 kg; 11.5 mol; 0.2 eq.) at a temperature < 30 °C. The yellow-brown suspension was stirred for 5 h at room temperature. Zinc powder (1.25 kg; 19 mol, 0.33 eq.) and an aqueous solution of ammonium chloride (2.14 kg; 20 wt%; 40 mol; 0.7 eq.) were added and the reaction mixture was stirred at 20-30 °C for 2 hours. The reaction mixture was concentrated under vacuum (<200 mbar, 55 °C). The residue was diluted with MTBE (200 L), water (30 L), and an aqueous ammonia solution (30 kg; 25 wt%). Solids were removed by filtration over a pad of“Kieselgur NF” (2 kg). Brine (50 L) was added for a better phase separation. The aqueous phase was separated and washed with MTBE (200 L). The combined organic phases were washed with an aqueous HC1 solution (1 N, 52 L) and water (50 L). MTBE was distilled off under reduced pressure (<400 mbar, 55°C; distillate min. 230L). The oily residue was dissolved in ethanol (150 L), which was distilled off under reduced pressure (<300 mbar; 55°C; distillate min. 150-155L) and the residue was dissolved in additional ethanol (60 L). To the resulting solution of compound 31 was added water (24 L) and the mixture was warmed to 50-55 °C. The mixture was cooled to 30 °C and crystallization started. The suspension was stirred at 30 °C for 1 h, cooled to <0 °C within 2 hours, and stirred at -5-0 °C for an additional 2 hours. The solids were isolated and washed with ethanol/water (1/1; v/v) (2 x 12 L). The wet product was dissolved in ethanol (115L) at 60 °C and water (24 L) was added. The mixture was cooled to 40 °C and the crystallization started. The suspension was stirred at 30 °C for 1 h, cooled to <0 °C within 2 hours, and stirred at -5-0 °C for additional 2 hours. The solids were isolated and washed (without stirring) with ethanol/water (1/1; v/v) (3 x 8 L). Pure, wet compound 31 was isolated as a white solid, which was used for the next step without drying. 14.0 kg of wet 31 were obtained with a 31 content of 81.6 wt%. Based on the determined content, the calculated amount of pure 31 was 11.4 kg with a yield of 41% over two steps (from 18b).

1H-NMR (600.6 MHz, DMSO-D6) d: 0.66 (d, J = 6.8 Hz, 3H), 0.83 (d, / = 6.7 Hz, 3H), 2.78 (sept. / = 6.8 Hz, 1H), 5.55 (s, 2H), 5.68 (s, 1H), 7.29 (t, 27H,F = 73.4 Hz, 1H), 7.32 (t, 27H,F = 73.4 HZ, 1H), 7.36 – 7.26 (m, 5H), 7.79 (s, 1H), 7.82 (s, 1H), 7.82 (dd, 7 = 8.8, 1.7 Hz, 1H), 7.86 (d, / = 8.8 Hz, 1H), 7.94 (s, 1H), 8.10 (s (broad), 1H);

HPLC (purity): 87%.

Preparation 3: Synthesis of compound 31 directly from compound 18b

Benzyl bromide (1.64 g, 9.59 mmol, 1.12 eq) was dissolved in water (2.4 mL) and

MeOH (2.4 mL). K2CO3 (2.38 g, 17.2 mmol, 2.00 eq), sodium ascorbate (0.34 g, 1.72 mmol, 0.20 eq) and finally sodium azide (0.62 g, 9.40 mmol, 1.10 eq.) were added. The suspension was stirred for 5 min at room temperature. A suspension of 18b (3.08 g; 8.64 mmol, 1.00 eq) in water (2.5 mL) and MeOH (2.5 mL) and the resulting mixture was stirred for 10 min.

CuS04 (0.21 g, 1.30 mmol, 0.15 eq) were added (slightly exothermic reaction). The reaction mixture was stirred for 19 h and the conversion was determined by HPLC (conv. 100%, purity of compound 31 by HPLC: 83 area%). To the yellow-green suspension was added zinc powder (0.24 g, 4.13 mmol, 0.43 eq) and ammonium chloride (0.34 g, 6.36 mmol, 0.74 eq) were added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure (150 mbar, 50 °C). The mixture was diluted with MTBE (40 mL), water (15 mL), and an aqueous ammonia solution (6.5 mL). Solids were removed by filtration and brine (5.5 mL) was added. The aqueous phase was separated and extracted with MTBE (20 mL). The combined organic phases were treated with water (10 mL) and the pH was adjusted to a pH of 1 by addition of cone. HC1. After phase separation, the organic layer was washed with water (10 mL). MTBE was distilled off under reduced pressure (100 mbar, 50°C) to give the crude compound 31 as an oil. Water (2.5 mL) and EtOH (30 mL) were added and the mixture was warmed to 50 °C. After cooling to 30 °C, the mixture was seeded with compound 31 and compound 31 started to precipitate. The mixture was kept for 1 h at 30 °C, then cooled to 0 °C over 2 h and kept at 0 °C for 2 h. The resulting product, 31, was collected by filtration and the filter cake was washed with small portions of EtOH/water (1:1). After drying, the product (2.97 g) was obtained as a pale yellow, crystalline solid with an HPLC purity of 79 area% and a NMR content of ca. 70 wt%.

Recrystallization of 
31

Preparation 1:

To a suspension of compound 31 (96 g; 0.196 mol; 50 wt%) in water (96 mL) was added ethanol (480 mL) and the mixture was warmed to 50 °C. The mixture was cooled to 30 °C and crystallization started. The suspension was stirred at 30 °C for 1 h, cooled to 0 °C within 2 hours and stirred at 0 °C for additional 2 hours. The solids were isolated and washed with ethanol/water (1/1; v/v) (3 x 40 mL). The wet product was dissolved in ethanol (280 mL) at 60 °C and water (56 mL) was added. The mixture was cooled to 40 °C and crystallization started. The suspension was stirred at 30 °C for 1 h, cooled to 0 °C within 2 hours, and stirred at 0 °C for an additional 2 hours. The solids were isolated and washed with ethanol/water (1/1; v/v) (3 x 28 mL). Pure, wet compound 31 (46.8 g on dried basis; 49 % over 2 steps) was isolated as a white solid, which was used for the next step without drying.

1H-NMR (600.6 MHz, DMSO-D6) d: 0.66 (d, J = 6.8 Hz, 3H), 0.83 (d, / = 6.7 Hz, 3H), 2.78 (sept. / = 6.8 Hz, 1H), 5.55 (s, 2H), 5.68 (s, 1H), 7.29 (t, 27H,F = 73.4 Hz, 1H), 7.32 (t, 27H,F = 73.4 HZ, 1H), 7.36 – 7.26 (m, 5H), 7.79 (s, 1H), 7.82 (s, 1H), 7.82 (dd, 7 = 8.8, 1.7 Hz, 1H), 7.86 (d, / = 8.8 Hz, 1H), 7.94 (s, 1H), 8.10 (s (broad), 1H);

HPLC (purity): 99.5%;

chiral HPLC: e.r.: 0.2:99.8%.

mp of dried product: 110 °C.

Preparation 2:

14 kg of ethanol-wet 31 (content 81.6 wt%, calculated 11.4 kg, 23.7 mol) were suspended in ethanol (46 L) and the mixture was warmed to 50-55 °C, forming a homogenous solution at this temperature. Water (9 L) was added at 50-55 °C and the mixture was cooled to 40-45 °C. After the crystallization had started, the suspension was stirred at 40-45 °C for 1 h, cooled to 0 °C within 2 hours, and stirred at 0 °C for additional 2 hours. The solids were isolated and washed with ethanol/water (1/1; v/v) (3 x 8 L). Pure, wet compound 31 (14.5 kg) was isolated as a white solid, which was used for the next step without drying.

1H-NMR (600.6 MHz, DMSO-D6) d: 0.66 (d, / = 6.8 Hz, 3H), 0.83 (d, / = 6.7 Hz, 3H), 2.78 (sept. / = 6.8 Hz, 1H), 5.55 (s, 2H), 5.68 (s, 1H), 7.29 (t, 27H,F = 73.4 Hz, 1H), 7.32 (t, 27H,F = 73.4 Hz, 1H), 7.36 – 7.26 (m, 5H), 7.79 (s, 1H), 7.82 (s, 1H), 7.82 (dd, 7 = 8.8, 1.7 Hz, 1H), 7.86 (d, / = 8.8 Hz, 1H), 7.94 (s, 1H), 8.10 (s (broad), 1H);

HPLC (purity): 99.8%;

chiral HPLC: e.r.: 0.2:99.8%.

mp of dried product: 110 °C.

Preparation of Azidomethyl Pivalate Protected Triazole (6) from Compound 18a

1

Azidomethyl pivalate (1.42 g, 9.00 mmol, 1.05 eq) was suspended in water (6.0 mL) and t-BuOH (7.2 mL) and the suspension was stirred for 5 min. Compound 18a (theor. 3.08 g, 8.64 mmol, 1.00 eq), sodium ascorbate (0.48 g, 2.4 mmol, 0.30 eq), and CuS04 (0.08 g, 0.40 mmol, 0.05 eq.) were added. The reaction mixture was stirred for 19 h and conversion was determined by HPLC (conv. 98%, purity of the product by HPLC: 81 area%). To the green suspension was added MTBE (20 mL), water (10 mL), and an aqueous ammonia solution (2 g). A biphasic turbid mixture was formed. To improve phase separation, additional MTBE (20 mL) and water (10 mL) were added. The aqueous phase was separated and extracted with MTBE (20 mL). The combined organic phases were concentrated under reduced pressure (100 mbar, 50 °C) to give the crude product as a brown oil that solidified upon standing. HPLC purity: ca. 65 area%; NMR content of ca. 73 wt%.

1H-NMR (600.6 MHz, CDCL) d: 0.79 (d, 3H), 0.93 (d, 3H), 1.15 (s. 9H), 2.86 (sept, 1H), 3.12 (s, 1H), 6.20 (s, 2H), 6.59 (t/t, 27H,F = 73.5 Hz, 2H), 7.61 (1, 1H), 7.64 (s, 1H), 7.70 – 7.82 (m, 3H), 8.04 (s, 1H).

Preparation of Azidomethyl Pivalate Protected Triazole (6) from 18b

In a reaction flask, sodium ascorbate (277 mg, 1.4 mmol, 1.20 eq) and CuS04 (37 mg, 0.23 mmol, 0.20 eq.) were suspended in MeOH (11 mL). Azidomethyl pivalate (183 mg, 1.16 mmol, 1.00 eq) and 18b (183 mg, 1.16 mmol, 1.00 eq) were added and the mixture was warmed to 60 °C. The reaction mixture was stirred for 19 h and worked up. To the green suspension was added an aq NH4Cl solution (2 mL) and zinc powder, and the mixture was stirred for 2 h. MTBE (2 mL) was added and the aqueous phase was separated and extracted with MTBE (2 mL). The combined organic phases were concentrated under reduced pressure (100 mbar, 50 °C) to give 6 as a brown oil that solidified upon standing. HPLC purity: ca. 81 area%; NMR content of ca. 57 wt%.

1H-NMR (600.6 MHz, CDCL) d: 0.79 (d, 3H), 0.93 (d, 3H), 1.15 (s. 9H), 2.86 (sept, 1H), 3.12 (s, 1H), 6.20 (s, 2H), 6.59 (t/t, 27H,F = 73.5 Hz, 2H), 7.61 (1, 1H), 7.64 (s, 1H), 7.70 – 7.82 (m, 3H), 8.04 (s, 1H).

Preparation of Compound 1

Preparation 1:

Compound 31 (26 g; 53 mmol; 1 eq.) was dissolved in ethanol (260 mL) and Noblyst Pl 155 (2.2 g; 10 % Pd; 54 wt% water) was added. The autoclave was flushed with nitrogen and hydrogen (5 bar) was added. The reaction mixture was stirred at room temperature for 32 hours. The reaction mixture was treated with charcoal (2 g), stirred for 15 min, and the charcoal was filtered off. The filtrate was concentrated via distillation and the residue (approximately 42 g) was diluted with heptane (200 mL). The mixture was heated to reflux to

obtain a clear solution. The solution was cooled to room temperature within 1 h and the resulting suspension was cooled to 0 °C and stirred for 2 hours at 0 °C. The solids were isolated via filtration and washed with heptane/ethanol (10:1; v/v; 3×10 mL). Compound 1 (18.0 g; 85 %) was dried under vacuum at 60 °C for 24 hours and obtained as a white, crystalline solid.

1H-NMR (600 MHz) d: 0.80 (d, J = 6.8 Hz, 3H), 0.97 (d, / = 6.7 Hz, 3H), 2.83 (sept. / = 6.8 Hz, 1H), 6.60 (t, 27H,F = 73.5 Hz, 1H), 6.61 (t, 27H,F = 73.5 Hz, 1H), 7.61 (s, 1H), 7.65 (s, 1H), 7.68 (dd, / = 8.7, 1.6 Hz, 1H), 7.74 (s, 1H), 7.75 (d, / = 8.7 Hz, 1H), 8.02 (s (broad), 1H); HPLC (purity): 100%.

Preparation 2:

Compound 31 (26.5 kg; 53.5 mol; 1 eq.) was dissolved in ethanol (265 L) and Pd/C (2.0 kg; 10 % Pd; 54 wt% water) was added. The reactor was flushed with nitrogen, and hydrogen (4.5 bar) was added. The reaction mixture was stirred at 28-32 °C until the reaction was complete. The reaction mixture was treated with charcoal (1.3 kg) at a temperature of <

33 °C, stirred for 10 min, and the charcoal was filtered off, and the filter was washed with ethanol (10 L).The filtrates from two reactions were combined and concentrated via distillation under reduced pressure (max. 65 °C; distillate: min 480 L). The residue (approx. 50-60 L) was diluted with isopropylacetate (250 L). The mixture was again concentrated via distillation under reduced pressure (max. 65 °C; distillate: min 240-245 L). The residue (approx. 60-70 L) was cooled to 35-40 °C and isopropylacetate (125 L) and heptane (540 L) were added. The suspension was heated to reflux (approx. 88 °C) and stirred under reflux for 15-20 min. Subsequently, the mixture was cooled to 0-5 °C within 2 h and stirred at 0-5 °C for 2 hours. The solids were isolated via filtration and washed with heptane/isopropylacetate (5:1; v/v; 2×30 L; 0-5 °C). Wet 1 was dried under vacuum at 60 °C and was obtained as a white, crystalline solid (35.4 kg, 81.9%).

1H-NMR (600 MHz) d: 0.80 (d, / = 6.8 Hz, 3H), 0.97 (d, / = 6.7 Hz, 3H), 2.83 (sept. / = 6.8 Hz, 1H), 6.60 (t, 27H,F = 73.5 Hz, 1H), 6.61 (t, 27H,F = 73.5 Hz, 1H), 7.61 (s, 1H), 7.65 (s, 1H), 7.68 (dd, / = 8.7, 1.6 Hz, 1H), 7.74 (s, 1H), 7.75 (d, / = 8.7 Hz, 1H), 8.02 (s (broad), 1H); HPLC (purity): 100%.

Preparation 3: Preparation of Compound 1 from Compound 6

At room temperature, 6 (3.00 g, 5.84 mmol) was dissolved in MeOH (19.8 mL). NaOH (1.0 M, 19.8 mL) was added in one portion and the reaction mixture was stirred for 1 h at room temperature. The reaction progress was monitored by HPLC, which showed 98% conversion after 1 h. Aq. HC1 (19.8 mL) was added and the mixture was diluted with water (120 mL) and MTBE (60 mL), resulting in a clear biphasic solution. After phase separation, the organic phase was washed with aq NaHC03 (20 mL). The organic layer was concentrated under high vacuum (25 mbar, 45 °C) to yield 2.77 g of 1 as a greenish oil. The identity was confirmed by comparison of HPLC retention time with an authentic sample of 1 as well as by 1H NMR.

Recrystallization of Compound 1

Wet 1 (40 kg; isopropylacetate/heptane wet) was treated with isopropylacetate (110 L) and heptane (440 L). The suspension was heated to reflux (approx. 88 °C) and stirred under reflux for 15-20 min. Subsequently, the mixture was cooled to 0-5 °C within 2 h and stirred at 0-5 °C for 2 hours. The solids were isolated via filtration and washed with

heptane/isopropylacetate (5:1; v/v; 2×30 L; 0-5 °C). A sample was taken for analysis

(criterion: a) purity; NLT 99.0 A% by HPLC; b) single impurities, NMT 0.15 A% by HPLC; c) enantiomer VT-463, NMT 1.0 A% by HPLC). Wet 1 was dried under vacuum at 60 °C for not less than 12 h. A sample was taken for analysis: criterion: a) LOD; NMT 0.5 wt% by gravimetry; b) residual toluene, NMT 890 ppm by HS-GC. 1 was obtained as a white, crystalline solid (28.5 kg, 66.7% from 31).

PAPER

 Bioorganic & Medicinal Chemistry Letters (2014), 24(11), 2444-2447.

https://www.sciencedirect.com/science/article/pii/S0960894X14003606

PATENT

WO 2016040896

https://patents.google.com/patent/WO2016040896A1/en

References

  1. Jump up to:a b c d e http://adisinsight.springer.com/drugs/800035241
  2. ^ http://www.pharmaceutical-technology.com/news/newsfda-grants-fast-track-status-innocrins-seviteronel-treat-metastatic-crpc-4770025
  3. ^ Yin L, Hu Q, Hartmann RW (2013). “Recent progress in pharmaceutical therapies for castration-resistant prostate cancer”Int J Mol Sci14 (7): 13958–78. doi:10.3390/ijms140713958PMC 3742227PMID 23880851.
  4. Jump up to:a b Stein MN, Patel N, Bershadskiy A, Sokoloff A, Singer EA (2014). “Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer”Asian J. Androl16 (3): 387–400. doi:10.4103/1008-682X.129133PMC 4023364PMID 24759590.
  5. Jump up to:a b Rafferty SW, Eisner JR, Moore WR, Schotzinger RJ, Hoekstra WJ (2014). “Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors”. Bioorg. Med. Chem. Lett24 (11): 2444–7. doi:10.1016/j.bmcl.2014.04.024PMID 24775307.
  6. Jump up to:a b c d Toren PJ, Kim S, Pham S, Mangalji A, Adomat H, Guns ES, Zoubeidi A, Moore W, Gleave ME (2015). “Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer”. Mol. Cancer Ther14 (1): 59–69. doi:10.1158/1535-7163.MCT-14-0521PMID 25351916.
  7. Jump up to:a b c Stephen Neidle (30 September 2013). Cancer Drug Design and Discovery. Academic Press. pp. 341–342. ISBN 978-0-12-397228-6.
  8. Jump up to:a b Wm Kevin Kelly; Edouard J. Trabulsi, MD; Nicholas G. Zaorsky, MD (17 December 2014). Prostate Cancer: A Multidisciplinary Approach to Diagnosis and Management. Demos Medical Publishing. pp. 342–. ISBN 978-1-936287-59-8.
  9. ^ http://www.who.int/medicines/publications/druginformation/innlists/RL76.pdf

Further reading

External links[

Seviteronel
VT-464.svg
Clinical data
Synonyms VT-464; INO-464
Routes of
administration
By mouth
Drug class Androgen biosynthesis inhibitorNonsteroidal antiandrogen
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C18H17F4N3O3
Molar mass 399.339 g/mol g·mol−1
3D model (JSmol)

References

  1. Innocrin Pharmaceuticals Created as a Spin-out of the Prostate Cancer Program from Viamet Pharmaceuticals.

    Media Release 

  2. Viamet Pharmaceuticals and the Novartis Option Fund Enter Agreement for Development of Novel Metalloenzyme Inhibitors.

    Media Release 

  3. Innocrin Pharmaceuticals, Inc. Granted SME Status Designation by the European Medicines Agency.

    Media Release 

  4. A Single arm, open label, signal seeking, Phase II a trial of the activity of seviteronel in patients with androgen receptor (AR) positive solid tumours

    ctiprofile 

  5. Innocrin Pharmaceuticals and the Prostate Cancer Foundation (PCF) Join Forces for Innovative Phase 2 Clinical Study.

    Media Release 

  6. A Phase 2 Open-label Study to Evaluate the Efficacy and Safety of Seviteronel in Subjects With Castration-Resistant Prostate Cancer Progressing on Enzalutamide or Abiraterone

    ctiprofile 

  7. Innocrin Pharmaceuticals, Inc. Granted Fast Track Designation by FDA for VT-464 Treatment of Patients with Metastatic Castrate-resistant Prostate Cancer.

    Media Release 

  8. Innocrin Pharmaceuticals, Inc. Begins Phase 2 Study of Seviteronel in Women with Estrogen Receptor-positive or Triple-negative Breast Cancer and Expands Two Phase 2 Studies of Seviteronel in Men with Metastatic Castrate-resistant Prostate Cancer.

    Media Release 

  9. A Phase 2 Open-Label Study to Evaluate the Efficacy and Safety of VT-464 in Patients With Metastatic Castration Resistant Prostate Cancer Who Have Previously Been Treated With Enzalutamide, Androgen Receptor Positive Triple-Negative Breast Cancer Patients, and Men With ER Positive Breast Cancer

    ctiprofile 

  10. Innocrin Pharmaceuticals Inc. to Present Interim Results from Its Phase 1/2 Prostate Cancer Clinical Study and Preclinical Results That Demonstrate VT-464 Efficacy in a Clinically-Relevant Enzalutamide-Resistant Mouse Model.

    Media Release 

  11. A Phase 1/2 Open-Label Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Seviteronel in Subjects With Castration-Resistant Prostate Cancer

    ctiprofile 

  12. A Phase 1/2 Open-Label, Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Once-Daily VT-464 in Patients With Castration-Resistant Prostate Cancer

    ctiprofile 

  13. Viamet Pharmaceuticals Appoints Former Novartis Executive Marc Rudoltz, M.D. as Chief Medical Officer.

    Media Release 

  14. VIAMET PHARMACEUTICALS AND THE NATIONAL INSTITUTES OF HEALTH TO JOINTLY DEVELOP NOVEL VIAMET COMPOUND.

    Media Release 

  15. Viamet Pharmaceuticals Initiates Phase 1/2 Clinical Trial of Novel Prostate Cancer Therapy, VT-464.

    Media Release 

  16. Viamet Pharmaceuticals to Present at the 32nd Annual J.P. Morgan Healthcare Conference.

    Media Release 

  17. VIAMET PHARMACEUTICALS TO PRESENT AT THE 31st Annual J.P. MORGAN HEALTHCARE CONFERENCE.

    Media Release 

  18. Innocrin Pharmaceuticals, Inc. Initiates Phase 2 Castration-Resistant Prostate Cancer (CRPC) Study in Men Who Have Failed Enzalutmaide or Abiraterone.

    Media Release 

  19. Innocrin Pharmaceuticals Appoints Fred Eshelman, PharmD as CEO and is Granted Fast Track Designation by FDA for Seviteronel Treatment of Women with Triple-negative Breast Cancer and Women or Men with Estrogen Receptor-positive Breast Cancer.

    Media Release 

  20. Gucalp A, Bardia A, Gabrail N, DaCosta N, Danso M, Elias AD, et al. Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC). SABCS-2016 2016; abstr. P2-08-04.

    Available from: URL:http://www.abstracts2view.com/sabcs/view.php?nu=SABCS16L_1479

  21. Innocrin Pharmaceuticals Presents Data from the Ongoing Phase 2 Trial of Seviteronel in Estrogen Receptor-positive or Triple-negative Breast Cancer (CLARITY-01) at the San Antonio Breast Cancer Symposium.

    Media Release 

  22. Innocrin Pharmaceuticals, Inc. Appoints Edwina Baskin-Bey, MD as Chief Medical Officer and Expands the Ongoing Phase 2 Study of Seviteronel in Women with Estrogen Receptor-positive or Triple-negative Breast Cancer (TNBC).

    Media Release 

  23. Innocrin Pharmaceuticals, Inc. Raises $28 Million in Series D Financing.

    Media Release 

  24. A Phase 1/2 Open-Label Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of Seviteronel in Subjects With Advanced Breast Cancer

    ctiprofile 

  25. Speers CW, Chandler B, Zhao S, Liu M, Wilder-Romans K, Olsen E, et al. Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (SEVI), a selective CYP17 lyase and AR inhibitor. ASCO-2017 2017; abstr. e12102.

    Available from: URL: http://abstracts.asco.org/199/AbstView_199_193240.html

  26. Innocrin Pharmaceuticals, Inc. Appoints Charles F. Osborne Jr. as its Chief Financial Officer.

    Media Release 

  27. Viamet Pharmaceuticals Secures $18 Million Financing.

    Media Release 

  28. Viamet Pharmaceuticals Raises $4 Million Round of Financing.

    Media Release 

///////////SEVITERONEL, VT-464, INO-464, VT 464, INO 464, Phase II,  Breast cancer,  Prostate cancer,  Solid tumours, viamet, CANCER, севитеронел سيفيتيرونيل 赛维罗奈 

C1(=CN=NN1)C(C1=CC2=C(C=C1)C=C(C(=C2)OC(F)F)OC(F)F)(C(C)C)O

NASTORAZEPIDE


imgNastorazepide.png

Nastorazepide (Z-360)
CAS: 209219-38-5
Chemical Formula: C29H36N4O5
Molecular Weight: 520.61994

UNII-R22TMY97SG; 209219-38-5;

Phase II, treatment of pancreatic cancer.

(R)-3-(3-(5-cyclohexyl-1-(3,3-dimethyl-2-oxobutyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)ureido)benzoic acid

Image result

Nastorazepide, also known as Z-360, is a selective, orally available, 1,5-benzodiazepine-derivative gastrin/cholecystokinin 2 (CCK-2) receptor antagonist with potential antineoplastic activity. Z-360 binds to the gastrin/CCK-2 receptor, thereby preventing receptor activation by gastrin, a peptide hormone frequently associated with the proliferation of gastrointestinal and pancreatic tumor cells.

In January 2018, Zeria is developing nastorazepide calcium (phase II clinical trial), a CCK2 receptor antagonist, for the treatment of pancreatic cancer.

Zeria is developing nastorazepide calcium (Z-360), an oral CCK2 receptor (gastrin receptor) antagonist, for the potential treatment of pancreatic cancer. In September 2005, a phase Ib/IIa trial began in the UK for pancreatic cancer ,  in February 2008, the trial was completed ; in June 2008, data were presented . In March 2010, the drug was listed as being in phase II preparation in Europe ; in August 2011, this was still the case . In April 2014, a phase II trial began in patients with metastatic pancreatic adenocarcinoma in Japan, Korea and Taiwan. In November 2015, the drug was listed as being in phase II development

343326-69-2

Nastorazepide (calcium salt)

CAS No. : 343326-69-2

M.Wt:540.62Formula:C29H36N4O5Ca0.5

Cholecystokinin (CK) is a digestive hormone produced and released in the duodenum, jejunal membrane and is known to have actions such as secretion of secretion, constriction of the gallbladder, stimulation of insulin secretion and the like. C CK is also known to exist in high concentrations in the cerebral cortex, hypothalamus and hippocampus, and it is also known that it has actions such as suppression of food intake, memory enhancement, anxiety action and the like. On the other hand, gastrin is a gastrointestinal hormone produced and released in G cells distributed in the pyloric region of the stomach, and it is known that it has gastric acid secretion action, contraction action of the gastric pyloric part and gallbladder, and the like. These C CK and gastrin have the same 5 amino acids at the C-terminus, and all express the action through the receptor. C CK receptors are classified into peripheral type C CK – A distributed in the ile, gall bladder and intestinal tract and central type C CK – B distributed in the brain. The gastrin receptor and the CKK – B receptor show similar properties in receptor binding experiments and sometimes called C CK 1 B / gastrin receptor due to high homology. These receptors, such as gastrin or a CCK-B receptor antagonist compound, are useful in the treatment of gastric ulcers, duodenal ulcers, gastritis, reflux esophagitis, splenitis, Zollinger-EUison syndrome, cavitary G cell hyperplasia, basal hyperplasia, Choleditis, gallstone stroke, gastrointestinal motility disorder, sensitive bowel syndrome, certain tumors, eating disorders, anxiety, panic disorder, depression, schizophrenia, Parkinson’s disease, late onset dyskinesia, It is expected to be useful for treatment and prevention of La Tourette’s syndrome, addiction due to drug ingestion, and withdrawal symptoms. It is also expected that the induction of analgesia or the enhancement of induction of analgesia by opioid drugs is expected (Journal of Pharmacology, Vol. 106, 171-180 (1995), Drugs of the Future, Vol. 18, 919-931 (1993), American Journal of Physiology, Vol.

As a gastrin receptor antagonist already, prolumide is known as a therapeutic agent for gastric ulcer and gastritis. However, proglumide has considerably low affinity for gastrin or CKK-B receptor and its therapeutic effect is weak. In addition, L – 3 6 4, 7 1 8 (Dibazepide, Japanese Unexamined Patent Publication No. 616366), L -3 6 5, 2 6 0 (Japanese Patent Laid-Open No. 6 3- 9), and the like, have been reported to exhibit either CKK-A receptor antagonism or CKK-B receptor antagonism. Furthermore, it is disclosed that a compound having a strong C 4 C – – B receptor antagonistic effect suppresses gastric acid secretion by pentagastrin stimulation (International Patent Publication WO 94/438, International Patent Publication WO 95/18110) , It is not always satisfactory and clinically applicable gastrin or CKK-B receptor antagonist has not yet been provided.

Compounds capable of strongly binding to gastrin or cholecystokinin receptors are expected for the prevention and treatment of diseases involving their respective receptors in the digestive tract and the central nervous system.

PRODUCT PATENT WO1998025911

Inventors Katsuo ShinozakiTomoyuki YonetaMasakazu MurataNaoyoshi MiuraKiyoto MaedaLess «
Applicant Zeria Pharmaceutical Co., Ltd.

SYNTHESIS WO 2017030859

PATENT

WO 9825911

https://www.google.co.in/patents/WO1998025911A1?cl=und

PATENT

WO2017175854

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017175854&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Compound A ((R) – (-) – 3- [3- (1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl- 1,3,4,5-tetrahydro- 2H- 1,5-benzodiazepine -3-yl) ureido] benzoate) has the following structural formula and can be produced by the method described in Patent Document 1.
[Chemical formula 1]
Example 1
Compound A 20.0 g of amorphous substance was suspended in 253 mL of methanol. After dissolving by heating, it was cooled and the precipitated crystals were collected by filtration and washed with methanol. The obtained wet crystals were dried under reduced pressure.
1 H-NMR (DMSO-d 6 ) δ: 1.18 (18H, s), 1.10-2.03 (20H, m), 3.17 (12H, d), 3.19-3.29 (4H, m), 3.37-3.44 (2H, (2H, m), 7.07-7.12 (2H, m), 4.07-4.16 (4H, br)
IR (KBr) cm -1 : 2935 (2H, m), 7.15 (2H, t), 7.22-7.29 (4H, m), 7.50-7.56 (4H, m), 7.88 , 2361, 1648, 1553, 1497, 1388, 1219, 776
 The powder X-ray diffraction spectrum of the obtained crystal is shown in FIG. 2. From NMR, IR and FIG. 2, the obtained crystals were Compound AI type crystals.
Example 5
Compound A 50.0 g of amorphous material was suspended in 380 mL of isopropanol (IPA). After dissolving by heating, it was cooled and precipitated. Precipitated crystals were collected by filtration and washed with IPA to obtain wet crystals. This was dried under reduced pressure. The powder X-ray diffraction spectrum of the obtained crystal is shown in FIG.
1 H-NMR (DMSO-d 6 ) [delta]: 1.04 (24H, d), 1.18 (18H, s), 1.10-2.03 (20H, m), 3.16-3.28 (4H, m), 3.37-3.45 (2H, (2H, m), 7.07-7.12 (2H, m), 3.72-3.83 (4H, m), 4.33-4.43 (8H, m), 5.13 (2H, d), 6.71
IR (KBr) cm -1 : 2933 (2H, m), 7.15 (2H, t), 7.21-7.30 (4H, m), 7.48-7.54 (4H, m), 7.84 , 2361, 1653, 1553, 1498, 1394, 1219, 769
 From NMR, IR and FIG. 4, the obtained crystals were Compound AIII type crystals.

PATENT

WO-2018008569

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018008569&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Process for producing a calcium salt of a 1,5-benzodiazepine compound – nastorazepide calcium – a cholecystokinin CCK2 receptor antagonist. Useful for the treatment of gastritis, reflux esophagitis, Zollinger-Ellison syndrome.

Example 1
(1) (R) – (-) – 2-Oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (compound 2)), 139.3 g of 1-chloropinacolone and 8.3 g of tetrabutylammonium bromide in 1432 ml of toluene was added dropwise 461 g of 30% sodium hydroxide aqueous solution at 10 ° C. or lower. After stirring for 1 hour, the aqueous layer was removed. To the toluene layer, 620 ml of water was added and the liquid was separated, and the toluene layer was used for the next step.
(2) 628.9 g of hydrochloric acid was added dropwise to the toluene layer obtained in the previous step at 30 ° C. or lower. After stirring for 30 minutes, liquid separation was carried out, and the aqueous layer was separated. It was neutralized with 908.5 g of 30% sodium hydroxide aqueous solution and extracted with 1432 ml of toluene. The toluene layer was separated with 620 g of a 20% sodium chloride aqueous solution, and toluene was distilled off under reduced pressure. (R) – (-) – 1 -tert-butylcarbonylmethyl-2-oxo-3-amino-5- cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (Compound (6) ) Was obtained.
(3) The (R) – (-) – 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1 , 5-benzodiazepine (Compound (6)), 221.8 g of 3-phenyloxycarbonylaminobenzoic acid, 174.5 g of triethylamine and 77.7 g of water were added and the mixture was stirred at 45 to 50 ° C. for 2 hours. To the reaction solution were added 1375 ml of ethanol and 930 ml of water, and 62.9 g of hydrochloric acid was added dropwise at 30 ° C. or lower. The precipitated crystals were centrifuged.
The obtained crystals were heated to dissolve in 4714 ml of ethanol at 60 ° C., and 2790 ml of water was added dropwise to precipitate crystals. The precipitated crystals were separated by centrifugation and dried under reduced pressure to give (R) – (-) – 3- [3- (1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl- 5-tetrahydro-2H-1,5-benzodiazepin-3-yl) ureido] benzoic acid (Compound (5)) 0.5 ethanolate monohydrate 430.2 g.
(4) (R) – (-) – 3- [3- (1-tert-Butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H- 1,5-benzodiazepine -3-yl) ureido] benzoic acid (Compound (5)) 0.5 Ethanol solvate monohydrate 430.3 g was suspended in 1645 ml of isopropyl alcohol (IPA), sodium hydroxide 31.6 g / A solution of 934 ml of water was added dropwise to dissolve (a).
112.7 g of calcium chloride dihydrate was dissolved in 3012 ml of water. Here, the solution of (a) was added dropwise at 10 ° C. or lower. After dropping, the temperature was raised to 50 ° C., after stirring for 2 hours, it was cooled to 10 ° C. or lower. The precipitated powder was centrifuged and washed with a mixed solution of IPA 658 ml / water 2065 ml, followed by 4303 ml of water and dried under reduced pressure to give (R) – (-) – 3- [3- (1-tert- Oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl) ureido] benzoate (compound (1)). The powder X-ray diffraction spectrum was measured (as 7% water content), and the obtained compound (1) was amorphous.
Example 2 In
step (4) of Example 1, investigation was carried out by changing the amount of the solvent and sodium hydroxide.
First, when the IPA / water ratio is 1 / 2.5 to 1/10, preferably 1 / 2.75 to 1/8, more preferably 1 / 2.75 to 1/5, the compound (1 ) Amorphous can be stably obtained.
Next, when the amount of sodium hydroxide is 1.0 to 1.10 mol with respect to the compound (1) and the amount of calcium chloride is 0.5 to 1.5 mol with respect to the compound (1), the amount of the compound 1) can be obtained in high yield.
Further, it was found that impurities are not produced when the reaction temperature of the compound (1) and sodium hydroxide in the step (4) is 20 ° C. or less, more preferably 10 ° C. or less, further preferably 0 to 10 ° C.
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US2008161293 Antitumor Agent
2008-07-03
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US2015038495 THERAPEUTIC AGENT FOR PAIN
2014-09-24
2015-02-05
US2011059956 THERAPEUTIC AGENT FOR PAIN
2011-03-10
US2017151256 ANTITUMOR AGENT
2017-02-10
US2010143366 ANTITUMOR AGENT
2010-06-10
US2010086553 ANTITUMOR AGENT
2010-04-08
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US6747022 Calcium salts of 1, 5-benzodiazepine derivatives, process for producing the salts and drugs containing the same
2003-05-22
2004-06-08
US6239131 1, 5 Benzodiazepine derivatives
2001-05-29
EP0945445 1, 5-BENZODIAZEPINE DERIVATIVES 1, 5-BENZODIAZEPINE DERIVATIVES
1999-09-29
2005-12-28
US2015050212 CHOLECYSTOKININ B RECEPTOR TARGETING FOR IMAGING AND THERAPY
2013-02-22
2015-02-19
US2012010401 METHOD FOR MANUFACTURING 1, 5-BENZODIAZEPINE DERIVATIVE
2012-01-12

1: Kato H, Seto K, Kobayashi N, Yoshinaga K, Meyer T, Takei M. CCK-2/gastrin receptor signaling pathway is significant for gemcitabine-induced gene expression of VEGF in pancreatic carcinoma cells. Life Sci. 2011 Oct 24;89(17-18):603-8. doi: 10.1016/j.lfs.2011.07.019. Epub 2011 Aug 3. PubMed PMID: 21839751.

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