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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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FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor


FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor 

FDA also approves drug for second indication in a type of lung cancer

The U.S. Food and Drug Administration today granted accelerated approval to Rozlytrek (entrectinib), a treatment for adult and adolescent patients whose cancers have the specific genetic defect, NTRK (neurotrophic tyrosine receptor kinase) gene fusion and for whom there are no effective treatments.

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” said FDA Acting Commissioner Ned Sharpless, M.D. “Using the FDA’s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we’re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. We remain committed to encouraging the advancement of more targeted innovations in oncology treatment and across disease types based on our growing understanding of the underlying biology of diseases.”

This is the third time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated. The approval marks a new paradigm in the development of cancer drugs that are “tissue agnostic.” It follows the policies that the FDA developed in a guidance document released in 2018. The previous tissue agnostic indications approved by the FDA were pembrolizumab for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017 and larotrectinib for NTRK gene fusion tumors in 2018.

“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK-fusion-positive tumors by relying on efficacy information obtained primarily in adults. The FDA continues to encourage the inclusion of adolescents in clinical trials. Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”

The ability of Rozlytrek to shrink tumors was evaluated in four clinical trials studying 54 adults with NTRK fusion-positive tumors. The proportion of patients with substantial tumor shrinkage (overall response rate) was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had tumor shrinkage persist for nine months or longer. The most common cancer locations were the lung, salivary gland, breast, thyroid and colon/rectum.

Rozlytrek was also approved today for the treatment of adults with non-small cell lung cancer whose tumors are ROS1-positive (mutation of the ROS1 gene) and has spread to other parts of the body (metastatic). Clinical studies evaluated 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had tumor shrinkage persist for 12 months or longer.

Rozlytrek’s common side effects are fatigue, constipation, dysgeusia (distorted sense of taste), edema (swelling), dizziness, diarrhea, nausea, dysesthesia (distorted sense of touch), dyspnea (shortness of breath), myalgia (painful or aching muscles), cognitive impairment (confusion, problems with memory or attention, difficulty speaking, or hallucinations), weight gain, cough, vomiting, fever, arthralgia and vision disorders (blurred vision, sensitivity to light, double vision, worsening of vision, cataracts, or floaters). The most serious side effects of Rozlytrek are congestive heart failure (weakening or damage to the heart muscle), central nervous system effects (cognitive impairment, anxiety, depression including suicidal thinking, dizziness or loss of balance, and change in sleep pattern, including insomnia and excessive sleepiness), skeletal fractures, hepatotoxicity (damage to the liver), hyperuricemia (elevated uric acid), QT prolongation (abnormal heart rhythm) and vision disorders. Health care professionals should inform females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with Rozlytrek. Women who are pregnant or breastfeeding should not take Rozlytrek because it may cause harm to a developing fetus or newborn baby.

Rozlytrek was granted accelerated approval. This approval commits the sponsor to provide additional data to the FDA. Rozlytrek also received Priority ReviewBreakthrough Therapy and Orphan Drug designation. The approval of Rozlytrek was granted to Genentech, Inc.

link http://s2027422842.t.en25.com/e/es?s=2027422842&e=244904&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=46563b1749694ceb96d9f79a6d5cd8a7&elqaid=9150&elqat=1

///////////////Rozlytrek, entrectinib, accelerated approval, priority ReviewBreakthrough Therapy,  Orphan Drug designation, fda 2019, Genentech, cancer

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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

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

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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.

//////////

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

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:

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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

Talazoparib, MDV3800


Talazoparib.svg

Talazoparib, BMN-673, MDV-3800

(2S,3S)-methyl-7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

(8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one

CAS 1207456-01-6
Chemical Formula: C19H14F2N6O
Exact Mass: 380.11972

BMN673, BMN673, BMN-673, LT673, LT 673, LT-673,  Talazoparib

BioMarin Pharmaceutical Inc

phase 3

Poly ADP ribose polymerase 2 inhibitor; Poly ADP ribose polymerase 1 inhibitor

cancer

(85,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one toluenesulfonate salt

CAS 1373431-65-2(Talazoparib Tosylate)

1H NMR DMSOD6

str1

13C NMR DMSOD6

str1

HMBC NMR

str1

HSQC NMR

str1

Talazoparib (BMN-673) is an investigational drug that acts as a PARP inhibitor. It is in clinical trials for various cancers.

Talazoparib.png

Medivation, under license from BioMarin Pharmaceuticals, following its acquisition of LEAD Therapeutics, is developing a PARP-1/2 inhibitor, talazoparib, for treating cancer, particularly BRCA-mutated breast cancer. In February 2016, talazoparib was reported to be in phase 3 clinical development

Talazoparib, also known as BMN-673, is an orally bioavailable inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential antineoplastic activity (PARP1 IC50 = 0.57 nmol/L). BMN-673 selectively binds to PARP and prevents PARP-mediated DNA repair of single strand DNA breaks via the base-excision repair pathway. This enhances the accumulation of DNA strand breaks, promotes genomic instability and eventually leads to apoptosis. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and is activated by single-strand DNA breaks. BMN-673 has been proven to be highly active in mouse models of human cancer and also appears to be more selectively cytotoxic with a longer half-life and better bioavailability as compared to other compounds in development. Check for active clinical trials or closed clinical trials using this agent.

Talazoparib is C19H14F2N6O.

Talazoparib tosylate is C26H22F2N6O4S.[1]

Approvals and indications

None yet.

Mechanism of action

Main article: PARP inhibitor

Clinical trials

After trials for advanced hematological malignancies and for advanced or recurrent solid tumors.[2] it is now in phase 3 for metastatic germline BRCA mutated breast cancer.[3] Trial estimated to complete in June 2016.[4]

As of January 2016 it in 14 active clinical trials.[5]

WO2010017055,  WO2015069851, WO 2012054698, WO 2011130661, WO 2013028495, US 2014323725, WO 2011097602

PAPER

Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent

BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, California 94949, United States
J. Med. Chem.201659 (1), pp 335–357
DOI: 10.1021/acs.jmedchem.5b01498
Publication Date (Web): December 10, 2015
Copyright © 2015 American Chemical Society
*Phone: 1-415-506-3319. E-mail: bwang@bmrn.com.

Abstract

Abstract Image

We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC50 of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC50 = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations.

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01498

http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01498/suppl_file/jm5b01498_si_001.pdf

Preparation of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one Tosylate Salt ((8S,9R)-47 Tosylate Salt)

A suspension of (8S,9R)-47 (BMN 673) (400 mg, 1.05 mmol) in a mixture of acetone (27 mL) and THF (13 mL) was heated to reflux until the suspension became clear. TsOH (220 mg, 1.16 mmol) was then added to the solution. White solids started to precipitate out from the solution shortly after the addition of TsOH. After stirring at 25 °C for 30 min, the mixture was filtered to collect the white crystal solids, which were washed with a mixture of acetone (10 mL) and 1,4-dioxane (4 mL) and then dried under vacuum at 45 °C for 3 days. This afforded the product as a white crystalline solid (540 mg, yield 93%). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 2.29 (s, 3H), 3.67 (s, 3H), 4.97–5.06 (m, 2H), 6.91–6.94 (dd, J1 = 2.0 Hz, J2 = 10.8 Hz, 1H), 7.06–7.19 (m, 5H), 7.19–7.51 (m, 4H), 7.74 (s, 1H), 7.87 (s, 1H), 10.32 (brs, 1H), 12.36 (s, 1H). LC-MS (ESI)m/z: 381 (M + H)+. Anal. Calcd for C19H14F2N6O·toluene sulfonic acid: C, 56.52; H, 4.01; N, 15.21. Found: C, 56.49; H, 3.94; N, 15.39.

(8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (8S,9R)-47 or BMN 673 and (8R,9S)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (8R,9S)-47

Compound 47 was dissolved in DMF, and chiral resolution was performed using supercritical-fluid chromatography (SFC) with a CHIRALPAK IA chiral column and methanol (20% with 0.1% DEA) and CO2 (80%) as the eluents. Yield 90%. For (8S,9R)-47 (BMN 673): retention time 8.8 min and ee 99.3%. For (8R,9S)-47: retention time 10.2 min and ee 99.2%.
Alternatively, compound (8S,9R)-47 could also be made using (2S,3R)-60a as a starting material and employing the same procedure described for the conversion of 60a to 47.
The optical rotation for both (8S,9R)-47 and (8R,9S)-47 was measured using a RUDOLPH (AUTOPOL V) automatic polarimeter at a concentration of 6.67 mg/mL in MeOH/MeCN/DMF = 0.5:0.5:1 at 20 °C. The specific rotation for (8S,9R)-47 was +92.2°, whereas it was −93.4° for (8R,9S)-47.

PATENT

WO-2016019125

WO2016019125

The compound (85,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one toluenesulfonate salt (Compound (A))

Compound (A)

is an inhibitor of poly(ADP-ribose)polymerase (PARP). Methods of making it are described in WO2010017055, WO2011097602, and WO2012054698. However, the disclosed synthetic routes require chiral chromatography of one of the synthetic intermediates in the route to make Compound (A), methyl 7-fluoro-2-(4-fluorophenyl)-3-(l -methyl- lH-1, 2,4-triazol-5-yl)-4-oxo- 1 ,2,3,4-tetrahydroquinoline-5-carboxylate (Intermediate (A)),

Intermediate (A)

to yield the chirally pure (2S,35)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH- 1,2,4-triazol-5-yl)-4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (Compound (1))

Compound (1).

Using conventional chiral chromatography is often solvent and time intensive.

Use of more efficient chromatography methods, such as simulated moving bed (SMB) chromatography still requires the use of expensive chiral chromatography resins, and is not practical on a large scale to purify pharmaceutical compounds. Also, maintaining

Compound (1) in solution for an extended time period during chromatography can lead to epimerization at the 9-position and cleavage of the methyl ester group in Compound (1). Replacing the chromatography step with crystallization step(s) to purify Compound (1) is desirable and overcomes these issues. Therefore, it is desirable to find an alternative to the use of chiral chromatography separations to obtain enantiomeric Compound (1).

Scheme 1 below describes use of Ac49 as a coformer acid for the preparation of Compound (la) and for the chiral resolution of Compound (1).

Scheme 1

Compound (1 )

Example 2 – Preparation of Compound (1) Using Scheme 1

Step la

Intermediate (A) (5 g, 12.5 mmol) was dissolved in 9: 1 v/v MIBK/ethanol (70 mL, 14 vol.) at 50 °C with stirring and dissolution was observed in less than about 5 minutes. [(lS)-en<io]-(+)-3-bromo-10-camphor sulfonic acid monohydrate (4.1 g, 12.5 mmol) was added and dissolution was observed in about 10-20 minutes. Seeding was then performed with Compound (la) (95% e.e., 5 mg, 0.1% w.) and the system was allowed to equilibrate for about 1 hour at 50 °C, was cooled to about 20 °C at 0.15 °C/min, and then equilibrated at 20 °C for 2 hours. The solid phase was isolated by filtration, washed with ethanol, and dried at about 50 °C and 3 mbar for about 2 to 3 hours to yield Compound (la) as a 0.6 molar equiv. EtOH solvate and 0.6 molar equiv. hydrate (93.4% e.e.).

Step lb

Compound (la) was then suspended in MIBK/ethanol 95/5% by volume (38 mL, 10 vol.) at 50 °C with stirring. After about 2 hours at 50 °C, the suspension was cooled to about 5 °C for 10 to 15 hours. The solid phase was recovered by filtration and dried at about 50 °C and 3 mbar for about 3 hours. Compound (la) (97.4% e.e.) was recovered. Step 2

000138] Compound (1) was released by suspending Compound (la) (3.9 g, 5.5 mmoi), without performing the optional reslurrying in Step 1, in 20 mL of water at room temperature and treating with 5M sodium hydroxide in water (1.3 mL, 1.2 mol). The mixture was kept at room temperature for about 15 hours and the solid was isolated by filtration and dried at 50 °C and 3 mbar for about 3 hours. Compound (1) was recovered (94.4% e.e.).

Example 3 – Large Scale Preparation of Compound (1) Using Scheme 1

The procedure of Example 1 was followed using 3.3 kg of Intermediate (A) and the respective solvent ratios to provide 95.7% e.e. in Step la; 99.2% e.e. in Step lb; and 99.2% e.e. in Step 2.

Example 4 – Alternative Preparation of Compound (1) Using Scheme 1

Step la

Intermediate (A) (751 mg, 1.86 mmol)) was dissolved in 9: 1 v/v

MIBK/ethanol (7.5 mL, 10 vol.) at 50 °C with stirring. [(15)-eni o]-(+)-3-bromo-10-camphor sulfonic acid monohydrate (620 mg, 1.88 mmol, 1 equiv.) was added. Formation of a precipitate was observed at about 1 hour at 50 °C. The system was then cooled to about 5 °C at 0.1 °C/min, and then equilibrated at 5 °C for about 60 hours. The solid phase was isolated by filtration and dried at about 50 °C and 3 mbar for about 2 hours to yield

Compound (la)(92% e.e.). See Figures 1-4 for XRPD (Figure 1), chiral HPLC (Figure 2), Ή NMR (Figure 3), and TGA/DSC analyses (Figure 4). The XRPD pattern from the material in Example 3 is similar to that in Example 1 with some slight shifts in the positions of specific diffraction peaks (highlighted by black arrows in Figure l). The ‘H NIVIR was consistent with a mono-salt of Compound (la) containing 0.5 molar equivalent of EtOH and 0.6% by weight residual MIBK. The TGA analysis showed a stepwise mass loss of 3.5% between 25 and 90 °C (potentially representing loss of the 0.5 molar equivalent of EtOH) and a gradual mass loss of 1.2% between 90 and 160 °C (potentially representing the loss of adsorbed water). The DSC analysis had a broad endotherm between 25 and 90 °C

representing desolvation and an endotherm at 135 °C representing melt/degradation.

Step lb

Compound (la) (100.3 mg, 0.141 mmol) was re-suspended in 95:5 v/v MIBK EtOH (1 mL, 10 vol.) at 50 °C and stirred for 1 hour before cooling to 5 °C at

0.1 °C/min. The solid (99.4% e.e.) was recovered by filtration after 1 night at 5 °C. Shifts in the XRPD diffraction peaks were no longer detected (Figure 5; compare Figure 1). Figure 6 shows the chiral HPLC for Compound (la).

Step 2

Compound (la) (100.2 mg, 0.141 mmol) from Step la was suspended in water (2 mL, 20 vol.) at 50 °C and 5 M NaOH in water (34 μL·, 1.2 molar equiv) was added. The resulting suspension was kept at 50 °C for one night, cooled to room temperature

(uncontrolled cooling) and filtered to yield Compound (1) (92% e.e.). The chiral purity was not impacted by this step and no [(15)-enJo]-(+)-3-bromo-10-camphor sulfonic acid was detected by NMR. Figure 7 compares the XRPD of Compound (1) in Step 2 with

Intermediate (A), the starting material of Step 1. Figure 8 shows the NMR of Compound (1) in Step 2 with Intermediate (A), the starting material of Step 1.

Example 5 – Alternative Preparation of Compound (1) Using Scheme 1 Step la

000144] Intermediate (A) (1 equiv.) was added with stirring to a solution of MIBK (12-13 vol), ethanol (1-1.5 vol), and water (0.05-0.10 vol) and the reaction was heated within 15 minutes to an internal temperature of about 48 °C to about 52 °C . [(lS)-endo]-(+)-3-bromo- 10-camphor sulfonic acid (1 equiv) was added and the reaction was stirred for about 5-10 mins at an internal temperature of about 48 °C to about 52 °C until dissolution occurred. Seed crystals of Compound (la) were added and the reaction was allowed to proceed for 1 hour at an internal temperature of about 48 °C to about 52 °C. The reaction was cooled at a rate of 0.15 °C /min to about 19-21 °C. The suspension was stirred for 2 hours at an internal temperature of about 19 °C to 21 °C and then was collected by filtration and washed twice with ethanol. The product was characterized by 1H NMR and 13C NMR (Figures 13a and 13b), IR Spectrum (Figure 14), DSC (Figure 15), and chiral HPLC (Figure 16).

Step 2a

To Compound (la) (1 equiv.) was added acetone (1.1 vol), IPA (0.55 vol), and methanol (0.55 vol) and the reaction was heated to an internal temperature of about 38 °C to 42 °C. Aqueous ammonia (25%) (1.3 equiv) was added and the reaction was stirred for about 10 minutes. The pH of the reaction was confirmed and the next step performed if > 7. Water was added (0.55 vol), the reaction was cooled to an internal temperature of about 35 °C, seed crystals of Compound (1) were added, and the reaction was stirred for about 10 mins. Water was added (3.3 vol) dropwise within about 30 minutes, the suspension was cooled within 30 minutes to an internal temperature of about 0 °C to 5 °C, and the reaction was stirred for 15 minutes. The solid was collected by filtration and washed three times with water.

Step 2b

To the product of Step 2a) was added acetone (4 vol), ΓΡΑ (1 vol), and methanol (1 vol) and the reaction was heated to an internal temperature of about 38 °C to 42 °C resulting in a clear solution. Water (2 vol) and seed crystals of Compound (1) were added and the system was stirred for about 15 minutes at an internal temperature of about 35 °C. Water (342 mL) was added dropwise in about 30 minutes. The suspension was then cooled in 30 min to an internal temperature of about 0 °C to 5 °C and was stirred for an additional 15 minutes. The solid was collected by filtration, washed twice with water, and chiral purity was determined. If > 99% e.e., then the solid was dried at an internal temperature of about 60 °C under reduced pressure to yield Compound (1). The product was characterized by Ή NMR (Figure 19), 13C NMR (Figure 20), IR (Figure 21), DSC (Figure 22), chiral HPLC (Figure 23).

Scheme 2 below describes use of Acl 10 as a coformer acid for the preparation of Compound (lb) and the chiral resolution of Compound (1).

Intermediate (A)

Compound (1 b)

Intermediate (A)

Compound (1 b)

Compound (1 )

Example 6 – Preparation of Compound (1) Using Scheme 2

Step la

Intermediate (A) (102 mg, 0.256 mmol) was dissolved in MIBK (1 mL, 10 vol.) at 65 °C with stirring. (lS)-phenylethanesulfonic acid, prepared using procedures known to one of skill in the art, in MIBK (3.8 M, 80 μί, 1 molar equiv.) was added and a suspension was observed after 30 minutes at 65 °C. The system was kept at 65 °C for another 30 minutes before cooling to 5 °C at 0.1 C/min. After one night at 5 °C, the solid was filtered, dried at 50 °C, 3 mbar pressure for about 2 hours to yield Compound (lb). See Figures 9-12 for XRPD (Figure 9), chiral HPLC (Figure 10), Ή NMR (Figure 11), and TGA/DSC analyses (Figures 12a and 12b). The XRPD diffraction pattern of the solid obtained in Example 5 differed from the XRPD pattern obtained with the solid from in the salt screen of Example 1 and was consistent with the production of different solids in Examples 1 and 5. The Ή NMR was consistent with the mono-salt with a 0.3% by weight residue of dioxane. In Figure 12a, the thermal behavior was consistent with a non-solvated form exhibiting a melt/degradation at 201 °C. Figure 12b compares the melt pattern of Compound (lb) in Example 5 with Compound (lb) in Example 1.

Steps lb and 2 can be carried out using procedures similar to those used in Examples 2-5.

Example 7 – Polymorphism of Compound (la)

Compound (1) (92% e.e., 10 mg, mmol) was placed in 1.5 mL vials and the solvents (1 mL or less) of Table 3 were added at 50 °C until dissolution was achieved. [(1S)-eni o]-(+)-3-bromo-10-camphorsulfonic acid was added as a solid at 50 °C. The samples were kept at 50 °C for about 1 hour prior to being cooled to room temperature overnight

(uncontrolled cooling rate). Clear solutions were successively cooled to 4 °C, -20 °C and evaporated at room temperature. Any gum obtained after evaporation was re-suspended in diethyl ether. The solid phases generated were characterized by XRPD and if relevant, by Ή NMR and TGA/DSC.

Table 3. Compound (la) Polymorphism Conditions

C.S. means clear solution and Susp. means suspension. “A” means the XRPD diffraction pattern was new but similar to that for Ac49 in

Example 1. “B” means the XRPD diffraction pattern was the same as that for Ac49 in Example 1. “M.E.” means molar equiv.

Page 38 of 64

NAI- 1500460480V I

Each of the seven solvents in which solvates were observed (heterosolvates not included) were mixed with MIBK (90% vol). Solutions of Intermediate (A) were prepared in the solvent mixtures (10 vol) at 50 C and [(15)-en<io]-(+)-3-bromo-10-camphor sulfonic acid (1 molar equivalent) was added. The resulting clear solutions were cooled to 5 °C at 0.2 C/min. Surprisingly, no crystallization was reported in any sample. Seeding was performed with a few crystals of each solvate at about 25 °C. The solid phases were analyzed by XRPD and the liquid phases were analyzed by chiral HPLC. See Table 4 for a summary of the results (where “Dias 2” is the (2R, 3R) diastereomer of Compound (la)) .

Table 4. Compound (la) Solvate Analysis

As seen in Table 4 above, the ethanol/MIBK system yielded 93% pure Compound (la) which demonstrates that Compound (la) does crystallize in a very pure form as an ethanolate solvate.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following description. It should be understood, however, that the description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present description will become apparent from this detailed description.

All publications including patents, patent applications and published patent applications cited herein are hereby incorporated by reference for all purposes.

PATENT

US 2011196153

http://www.google.co.ve/patents/US20110237581

STR1.jpg

Patent

US 2011237581

PATENTSTR1.jpg

PATENT

http://www.google.com/patents/WO2015069851A1?cl=en

SYNTHETIC EXAMPLES

Example 1

\ , 

(1 a) (2) (3) (la) (5)

To a flask was added N-methyl-l,2,4-triazole (la)(249.3 g, 3.0 mol, 1 equiv.),

2-methyl-THF (1020 mL, about 1 :4 m/v), and DMF (2)(230.2 g, 3.15 mol, 1.05 equiv.), in any order. The solution was cooled to an internal temperature of about -5 to 0 °C. To the flask was added LiHMDS (3) as a 20% solution in 2-methyl-THF (3012 g, 3.6 mol, 1.2 equiv.) dropwise within about 60 minutes. During the addition of the LiHMDS (3), the desired Compound (la) was precipitated as the 2-methyl-THF solvate, and the flask was cooled to about -30 °C. The reaction was stirred for about 30 minutes at an internal temperature of about -5 to 0 °C.

The precipitated crystals were removed from the reaction mixture by filtration and washed with 2-methyl-THF. The product, Compound (la) as the 2-methyl-THF solvate, was dried under vacuum at an internal temperature of about 60 °C (about 72.5% as measured by NMR) to yield Compound (la).

Example 2

As shown in Example 2, the Compounds of Formula I are useful in the synthesis of more complex compounds. See General Scheme 1 for a description of how the first step can be accomplished. Compounds of Formula I can be reacted with compound (6) to yield Compounds of Formula II. In Example 2, Compound (la) can be reacted with

Compound (6) to yield Compound (7). The remaining steps are accomplished using procedures known to one of ordinary skill in the art, for example, as disclosed in

WO2010017055 and WO2011097602 to yield Compound (12).

PATENT

US 2014323725/http://www.google.com/patents/WO2011097602A1

5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9- dihydro-2H-pyrido[4,3,2-Je]phthalazin-3(7H)-one, as shown in formula (1), and its enantiomer compounds, as shown in formulas (la) and (lb):

Figure imgf000003_0001

Example 1

(Z)-6-Fluoro-3-(( 1 -methyl- IH- 1 ,2,4-triazol-5 -yl)methylene)-4-nitroisobenzofuran- 1 (3H)-one (3)

Figure imgf000013_0001

[0053] To a 80 L jacketed glass reactor equipped with a chiller, mechanical stirrer, thermocouple, and nitrogen inlet/outlet, at 15 – 25 °C, anhydrous 2-methyl-tetrahydrofuran (22.7 kg), 6-fluoro-4- nitroisobenzofuran-l(3H)-one (2) (2.4 kg, 12.2 mol, 1.00 eq.), and 2-methyl-2H-l,2,4-triazole-3- carbaldehyde (49.6 – 52.6 % concentration in dichloromethane by GC, 3.59 – 3.38 kg, 16.0 mol, 1.31 eq.) were charged consecutively. Triethylamine (1.50 kg, 14.8 mol, 1.21 eq.) was then charged into the above reaction mixture. The reaction mixture was stirred for another 10 minutes. Acetic anhydride (9.09 – 9.10 kg, 89.0 – 89.1 mol, 7.30 eq.) was charged into the above reaction mixture at room temperature for 20 – 30 minutes. The reaction mixture was heated from ambient to reflux temperatures (85 – 95 °C) for 80 – 90 minutes, and the mixture was refluxed for another 70 – 90 minutes. The reaction mixture was monitored by HPLC, indicating compound (2) was reduced to < 5 %. The resulting slurry was cooled down to 5 – 15 °C for 150 – 250 minutes. The slurry was aged at 5 – 15 °C for another 80 – 90 minutes. The slurry was filtered, and the wet cake was washed with ethyl acetate (2L x 3). The wet cake was dried under vacuum at 40 – 50 °C for 8 hours to give 2.65 – 2.76 kg of (Z)-6-fluoro-3-((l -methyl-lH-l ,2,4-triazol-3- yl)methylene)-4-nitroisobenzofuran-l(3H)-one (3) as a yellow solid (2.66 kg, yield: 75.3 %, purity: 98.6 – 98.8 % by HPLC). LC-MS (ESI) m/z: 291 (M+l)+. Ή-ΝΜΡ (400 MHz, DMSO-d6) δ (ppm): 3.94 (s, 3H), 7.15 (s, 1H), 8.10 (s, 1H), 8.40-8.42 (dd, Jx = 6.4 Hz, J2 = 2.4 Hz, 1H), 8.58-8.61 (dd, Jx = 8.8 Hz, J2 = 2.4 Hz, 1H).

Example 2

Methyl 5- enzoate (4)

Figure imgf000014_0001

Example 2A

[0054] (¾-6-Fluoro-3-((l-methyl-lH-l,2,4-taazol-3-yl)m (3) (177 g, 0.6 mol, 1.0 eq.), and HC1 (2 N in methanol, 3 L, 6 mol, 10 eq.) were charged into a 5 L 3-neck flask equipped with mechanical stirrer, thermometer, and nitrogen inlet/outlet. The reaction mixture was stirred at room temperature for 25 hours. The reaction mixture was monitored by HPLC, indicating 0.8 % compound (3) remained. The reaction mixture was concentrated under vacuum at 40 °C to dryness, and methyl 5-fluoro-2-(2-(l -methyl- lH-l,2,4-triazole-3-yl)acetyl)-3-nitrobenzoate hydrochloride (4) was obtained as a yellow solid (201 g, yield: 93.4 %). It was used for the next step without further purification. LC-MS (ESI) m/z: 323 (M+l)+ ¾-NMR (400 MHz, DMSO-J6) δ (ppm): 3.89 (s, 3H), 3.92 (s, 3H), 4.60 (s, 2H), 7.85 (s, 1H), 8.25-8.28 (dd, Jx = 8.4 Hz, J2 = 2.8 Hz, 2H), 8.52-8.54 (dd, Jx = 8.4 Hz, J2 = 2.8 Hz, 2H).

Example 2B

An alternative workup procedure to that illustrated in Example 2A follows. Instead of evaporating the reaction mixture to dryness, it was condensed to 2 volumes, followed by solvent exchange with 12 volumes of THF, and then 12 volumes of heptane. The slurry mixture was concentrated to 2 volumes and filtered to give the product. As such, 1.8 kilograms of (Z)-6-fluoro-3-((l-methyl-lH-l,2,4-triazol-3- yl)methylene)-4-nitroisobenzofuran-l(3H)-one (3) gave 2.15 kilograms (yield 96.4 %) of the product methyl 5-fluoro-2-(2-(l -methyl- lH-l,2,4-triazole-3-yl)acetyl)-3-nitrobenzoate hydrochloride (4).

Example 3

Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4- tetrahydroquinoline-5 -carboxylate (5)

Figure imgf000015_0001

Example 3A

To a suspension of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3-nitrobenzoate (4) (5 g, 15.5 mmol, leq.) and 4-fluorobenzaldehyde (3.6 g, 29 mmol, 1.87 eq.) in a mixture of solvents tetrahydrofuran (30 mL) and MeOH (5 mL) was added titanium(III) chloride (20 % w/w solution in 2N Hydrochloric acid) (80 mL, 6 eq.) dropwise with stirring at room temperature. The reaction mixture was allowed to stir at 30~50°C for 2 hours. The mixture was then diluted with water (160 mL), and the resulting solution was extracted with ethyl acetate (100 mL x 4). The combined organic layers were washed with saturated NaHC03 (50 mL x 3) and aqueous NaHS03 (100 mL x 3), dried by Na2S04, and concentrated to dryness. This afforded a crude solid, which was washed with petroleum ether (120 mL) to obtain the title compound as a yellow solid (5.9 g, yield: 95 %, purity: 97 %). LC-MS (ESI) m/z: 399 (M+l)+. ^-NMR (400 MHz, CDCla) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.16-4.19 (d, J2=13.2 Hz, 1H), 4.88 (s, 1H), 5.37-5.40 (d, J2=13.2 Hz, 1H), 6.47-6.53 (m, 2H) , 6.97-7.01 (m, 2H), 7.37-7.41 (m, 2H), 7.80 (s, 1H).

Example 3B

An alternative workup procedure to that illustrated in Example 3A follows. After the completion of the reaction, the mixture was extracted with isopropyl acetate (20 volumes x 4) without water dilution. The product was isolated by solvent exchange of isopropyl acetate with heptanes followed by re-slurry with MTBE and filtration. As such, 3 kilograms of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5- yl)acetyl)-3-nitrobenzoate (4) afforded 2.822 kilograms of the title compound (5) (yield 81 %).

Example 3C

To a stirred solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3- nitrobenzoate (4) (580 mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in methanol (0.75 mL) and tetrahydrofuran (4.5 mL) was added concentrated HC1 solution (w/w 37 %, 6 mL), then reductive powdered Fe (672 mg, 12 mmol) was added slowly to the reaction system. After the addition was complete, the resulting mixture was heated to 60 °C and kept at this temperature for 3 hours. After the disappearance of the starting material (4) as monitored by LC-MS, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with Na2S04, concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) as a pale yellow solid (300 mg, yield 40 %). LC-MS (ESI) m/z: 399 (M+l)+LH-NMR (400 MHz, CDC13) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.17 (d, 1H), 4.87 (s, 1H), 5.38 (d, 1H), 6.50 (dd, 2H), 6.99 (dd, 2H), 7.38 (dd, 2H), 7.80 (s, 1H).

Example 3D

To a stirred solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3- nitrobenzoate (4) (580 mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in methanol (0.75 mL) and tetrahydrofuran (4.5 mL) was added SnCl2 (2.28 g, 12 mmol) and concentrated HC1 (w/w 37 %, 6 mL), the resulting mixture was reacted at 45 °C for 3 hours, until LC-MS indicating the disappearance of the starting material (4) and about 50 % formation of the product. The mixture was then partitioned between ethyl acetate (30 mL) and water (30 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with Na2S04, concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) as a pale yellow solid (10 mg, yield 1.3 %). LC-MS (ESI) m/z: 399 (M+l)+LH-NMR (400 MHz, CDC13) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.17 (d, 1H), 4.87 (s, 1H), 5.38 (d, 1H), 6.50 (dd, 2H), 6.99 (dd, 2H), 7.38 (dd, 2H), 7.80 (s, 1H).

Example 3E

A solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3-nitrobenzoate (4) (580 mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in methanol (20 mL) and acetic acid (1 mL) was stirred at room temperature for 24 hours under hydrogen (1 barr) in the presence of a catalytic amount of 10 % Pd/C (212 mg, 0.2 mmol). After the reaction was complete, the catalyst was removed by filtration through a pad of Celite, the solvent was removed in vacuo, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) as a pale yellow solid (63 mg, yield 8 %). LC-MS (ESI) m/z: 399 (M+l)+ . 1HNMR (400 MHz, DMSO-d6) δ (ppm): 3.56 (s, 3H), 3.86 (s, 3H), 7.02 (dd, 2H), 7.21 (dd, 2H), 7.90 (s, 1H), 8.08 (s, 1H), 8.26 (dd, 1H), 8.56 (dd, 1H).

Example 4

5-Fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-

Figure imgf000016_0001

 Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l -methyl-lH-l ,2,4-triazol-5-yl)-4-oxo-l,2,3,4- tetrahydroquinoline-5-carboxylate (5) (150 g, 0.38 mol, 1.0 eq.) and methanol (1.7 L) were charged into a 3 L 3-neck flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet/outlet. The resulted suspension was stirred at room temperature for 15 minutes. Hydrazine hydrate (85 % of purity, 78.1 g, 1.33 mol, 3.5 eq.) was charged dropwise into the above reaction mixture within 30 minutes at ambient temperature. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by HPLC, showing about 2 % of compound (5) left. The obtained slurry was filtered. The wet cake was suspended in methanol (2 L) and stirred at room temperature for 3 hours. The above slurry was filtered, and the wet cake was washed with methanol (0.5 L). The wet cake was then dried in vacuum at 45 – 55 °C for 12 hours. This afforded the title compound as a pale yellow solid (112 g, yield: 78.1 %, purity: 95.98 % by HPLC). LC-MS (ESI) m/z: 381 (M+l)+. ^-NMR (400 MHz, DMSO-J6) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, Jx = 2.4, J2 = 11.2 Hz, 1H), 7.06-7.09 (dd, Jx = 2.4, J2 = 8.8 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H).

Example 5

5 -Amino-7-flu in- 1 (2H)-one

Figure imgf000017_0001

To a solution of 6-fluoro-3-((l-methyl-lH-l,2,4-triazol-3-yl)methylene)-4-nitroiso-benzofuran- l(3H)-one (3) (4.0 g, 135 mmol) in THF (100 mL) was added hydrazine monohydrate (85 %) (6 mL) at room temperature under nitrogen atmosphere. The mixture was stirred for 2 hours, then acetic acid (6 mL) was added and the mixture was heated to and kept at 60 °C for 18 hours. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was dried over anhydrous Na2S04 and evaporated to dryness to afford the title compound as a yellow solid (1.6 g, yield 42 %). LC-MS (ESI) m/z: 275(M+1)+.

Example 6

(£’)-7-fluoro-5-(4-fluorobenzylideneamino)-4-((l -methyl- IH- 1 ,2,4-triazol-5-yl)methyl)phthalazin- 1 (2H)- one

Figure imgf000018_0001

(7)

To a suspended of 5-amino-7-fluoro-4-((l-methyl-lH-l,2,4-triazol-3-yl)methyl) phthalazin- l(2H)-one (7) (1.6 g, 5.8 mmol) in acetonitrile (50 mL) was added 4-fluorobenzaldehyde (2.2 g, 17.5 mmol). The mixture was stirred under reflux under nitrogen for 48 hours. The precipitate was filtered and washed with a mixture of solvents (ethyl acetate/hexane, 1 :1, 10 mL). After drying in vacuum, it afforded the title compound as a yellow solid (1.2 g, yield 52 %). LC-MS (ESI) m/z: 381(M+1)+.

Example 7

5-Fluoro-8 4-fluorophenyl)-9 l-methyl H-l,2,4-triazol-5-yl)-8,9-dihydro-2H^yrido[4,3,2-

Figure imgf000018_0002

(8) (1 )

To a suspension of (£’)-7-fluoro-5-(4-fluorobenzylideneamino)-4-((l-methyl-lH-l,2,4-triazol-5- yl)methyl)phthalazin-l(2H)-one (8) (2.0 g, 5.3 mmol) in THF (80 mL) was added cesium carbonate (3.4 g, 10.6 mmol). The reaction mixture was stirred at 55 °C for 4 hours and cooled down to room temperature. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and evaporated to dryness to afford the title compound as a white solid (1.6 g, yield 80 %). LC-MS (ESI) m/z: 381(M+1)+. ^-NMR (400 MHz, DMSO- ) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, Jx = 2.4, J2 = 11.2 Hz, 1H), 7.06-7.09 (dd, Ji = 2.4, J2 = 8.8 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H).

Example 8

(£)-Methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(l-methyl-lH-l,2,4-triazol-5-yl)acryloyl)-3-nitrobenzoate

(9)

Figure imgf000019_0001

To a stirred solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3- nitrobenzoate (4) (580mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in dimethylsulfoxide (2 mL) was added L-proline (230 mg, 2 mmol). The resulting mixture was kept with stirring at 45 °C for 48 hours. The reaction system was then partitioned between ethyl acetate (50 mL) and water (30 mL), and the organic phase was washed with water (20 mL x 3), dried with Na2S04, concentrated in vacuo, and purified by column chromatography (ethyl acetate: petroleum ether = 1 :3) to give the title compound (9) as a pale yellow foam (340 mg, yield 40 %). LC-MS (ESI) m/z: 429 (M+l)+. ^-NMR (400 MHz, DMSO-dg); δ (ppm): 3.56 (s, 3H), 3.86 (s, 3H), 7.02 (dd, 2H), 7.21 (dd, 2H), 7.90 (s, IH), 8.08 (s, IH), 8.26 (dd, IH), 8.56 (dd, IH).

Example 9

Methyl 7-fluoro-2-(4-fluorophenyl)- 1 -hydroxy-3-( 1 -methyl- IH- 1 ,2,4-triazol-5-yl)-4-oxo- 1 ,2,3,4- tetrahydroquinoline-5 -carboxylate (10)

Figure imgf000019_0002

To a solution of (£)-Methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(l-methyl-lH-l,2,4-triazol-5- yl)acryloyl)-3-nitrobenzoate (9) (200 mg, 0.467 mmol) in methanol (20 mL) was added 10 % Pd/C (24 mg). After the addition, the mixture was stirred under H2 (1 atm) at room temperature for 0.5 h. The reaction system was then filtered and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate: petroleum ether = 1 :1) to give the title compound (10) (110 mg, yield 57 %) as an off-white foam. LC-MS (ESI) m/z: 415 (M+H)+. ¾-NMR (400 MHz, DMSO-d6) δ (ppm): 3.53 (s, 3H), 3.73 (s, 3H), 5.08 (d, 2H), 5.27 (d, 2H), 6.95 (dd, IH), 7.08 (dd, 2H), 7.15 (dd, IH), 7.42 (dd, 2H), 7.77 (s, IH), 9.92 (s, IH). Example 10

Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-

Figure imgf000020_0001

(10) (5)

To a stirred solution of methyl 7-fluoro-2-(4-fluorophenyl)-l-hydroxy-3-(l-methyl-lH-l,2,4- triazol-5-yl)-4-oxo-l, 2,3, 4-tetrahydroquinoline-5 -carboxylate (10) (41.4 mg, 0.1 mmol) in methanol (5 mL) was added concentrated HCl solution (w/w 37 %, 1 mL) and reductive powdered Fe (56 mg, 1 mmol). The reaction mixture was refluxed for 3 hours. After the disappearance of compound (10) as monitored by LC-MS, the reaction system was partitioned between ethyl acetate (20 mL) and water (20 mL) and then the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried with Na2S04, concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether = 1 :1) to give the title compound (5) as a pale yellow solid (12 mg, yield 30 %). LC-MS (ESI) m/z: 399 (M+l)+. ¾-NMR (400 MHz, CDC13) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.17 (d, 1H), 4.87 (s, 1H), 5.38 (d, 1H), 6.50 (dd, 2H), 6.99 (dd, 2H), 7.38 (dd, 2H), 7.80 (s, 1H).

Example 11

Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-

Figure imgf000020_0002

To a solution of (£)-Methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(l-methyl-lH-l,2,4-triazol-5- yl)acryloyl)-3-nitrobenzoate (9) (214 mg, 0.5 mmol) in methanol (5 mL) was added concentrated HCl solution (w/w 37 %, 1 mL), then reductive Fe powder (140 mg, 2.5 mmol) was added slowly to the reaction system. After the addition was complete the resulting mixture was refluxed for 24 hours. The reaction mixture was then filtered, concentrated, neutralized with saturated NaHC03 (20 mL), and extracted with ethyl acetate (10 mL x 3). The residue was purified by chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) (30 mg, yield 15 %) as an off-white foam. LC-MS (ESI) m/z: 399 (M+H)+. ^-NMR (400 MHz, DMSO-d6) δ (ppm): 3.56 (s, 3H), 3.86 (s, 3H), 7.02 (dd, 2H), 7.21 (dd, 2H), 7.90 (s, 1H), 8.08 (s, 1H), 8.26 (dd, 1H), 8.56 (dd, 1H).

Example 12

(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(l-me

Je]phthalazin-3(7H)-one (la) and (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-

Figure imgf000021_0001

(1) (la) (lb)

A chiral resolution of 5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9- dihydro-2H-pyrido[4,3,2-Je]phthalazin-3(7H)-one (1) (52.5 g) was carried out on a super-fluid chromatography (SFC) unit using a CHIRALPAK IA column and C02/methanol/diethylamine

(80/30/0.1) as a mobile phase. This afforded two enantiomers with retention times of 7.9 minute (23.6 g, recovery 90 %, > 98 % ee) and 9.5 minute (20.4 g, recovery 78 %, > 98 % ee) as analyzed with a CHIRALPAK IA 0.46 cm x 15 cm column and C02/methanol/diethylamine (80/30/0.1) as a mobile phase at a flow rate of 2 g/minute.

Example 13

(2R,3R)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4- tetrahydroquinoline-5-carboxylate (6a) and (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-

Figure imgf000021_0002

(5) (6a) (6b)

Example 13A

The chiral resolution of compound (5) was carried out on a SFC unit with a CHIRALPAK®IC 3 cm (I.D.) x 25 cm, 5 μηι column, using C02/MeOH (80/20) as a mobile phase at a flow rate of 65 g/ minute while maintaining the column temperature at 35 °C and with a detection UV wavelength of 254 nm. As such, a racemate of compound (5) (5 g) in methanol solution was resolved, which resulted in two enantiomers with a retention times of 2.35 minute (2.2 g, 88 % recovery, >98 % ee) and 4.25 minute (2.3 g, 92 % recovery, >98 % ee), respectively when analyzed using CHIRALPAK®IC 0.46 cm x 15 cm column and CO2/MeOH(80/20) as a mobile phase at a flow rate of 2 mL/ minute.

Example 13B

The chiral resolution of compound (5) was carried out on a SFC unit with a CHIRALPAK®IC 5cm (I.D.) x 25 cm, 5 μηι column, using C02/MeOH (75/25) as a mobile phase at a flow rate of 200 mL/ minute while maintaining the column temperature at 40 °C and with a detection UV wavelength of 255 nm. As such, a racemate of compound (5) (1.25 kg) in methanol solution was resolved, which resulted in two enantiomers in about 83 % yield and 97.4 % purity.

Example 13C

Alternatively, the separation can also be achieved on a Simulated Moving Bed (SMB) unit with a CHIRALPAK®IC column and acetonitrile as a mobile phase. The retention times for the two enantiomers are 3.3 and 4.1 minutes, respectively. In certain embodiments, the productivity can be greater than 6 kg Feed/day/kg CSP.

Example 14

(8R,9S)-5-fluoro-8 4-fluorophenyl)-9<l-me

Je]phthalazin-3(7H)-one (la) and (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5- (lb)

Figure imgf000022_0001

Example 14A

To a solution of (2R,3R)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)- 4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6a) or (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l- methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6b) (400 mg, 1.0 mmol) in ethanol (8.0 mL) was added hydrazine monohydrate (85 %, 2.0 mL), and the solution stirred at room temperature for 2 hours. The resulting solution was then concentrated to a volume of 2 mL and filtered, and the resultant cake washed with ethanol (1 mL). After drying in vacuum at 50°C, this afforded the title compound as a white solid (209 mg, yield 55 %). LC-MS (ESI) m/z: 381(M+1)+. ^-NMR (400 MHz, DMSO-dg): δ (ppm): 3.681 (s, 3H), 4.99-5.06 (m, 2H), 6.92-6.96 (m, 1H), 7.08-7.11 (m, 1H), 7.16-7.21 (t, J= 8.8 Hz, 2H), 7.49-7.53 (m, 2H), 7.75 (s, 1H), 7.83 (s, 1H), 12.35 (s, 1H).

Example 14B

To a solution of (2R,3R)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)- 4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6a) or (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l- methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6b) (446 g) in acetonitrile (10 volume) was added hydrazine monohydrate (2.9 eq.), and the solution stirred at room temperature for 2 hours. The resulting solution was then concentrated to a volume of 2 mL and filtered. The crude product was re-slurried with water (3~5 volumes) at 15-16 °C. After drying in vacuum at 50 °C, this affords the title compound as a white solid (329 g, yield 77%, 99.93% purity). LC-MS (ESI) m/z:

381(M+1)+; ¾-NMR (400 MHz, DMSO-d6) δ (ppm): 3.681 (s, 3H), 4.99-5.06 (m, 2H), 6.92-6.96 (m, 1H), 7.08-7.11 (m, 1H), 7.16-7.21 (t, J= 8.8 Hz, 2H), 7.49-7.53 (m, 2H), 7.75 (s, 1H), 7.83 (s, 1H), 12.35 (s, 1H).

Talazoparib (BMN-673) is an orally available poly ADP ribose polymerase (PARP) inhibitor currently in development by Pfizer for the treatment of advanced breast cancer patients with germline BRCA mutations.[1] Talazoparib is similar to the first in class PARP inhibitor, olaparib.[2][3] However, talazoparib is thought to be more potent than olaparib.[3]

Mechanism of action

Talazoparib acts as an inhibitor of poly ADP ribose polymerase(PARP) which aids in single strand DNA repair. Cells that have BRCA1/2mutations are susceptible to the cytotoxic effects of PARP inhibitors because of an accumulation of DNA damage.[1] Talazoparib is theorized to have a higher potency than olaparib due to the additional mechanism of action called PARP trapping. PARP trapping is the mechanism of action where the PARP molecule is trapped on the DNA, which interferes with the cells ability to replicate. Talazoparib is found to be ~100 fold more efficient in PARP trapping than olaparib.[4] However, this increased potency may not translate directly to clinical effectiveness as many other factors must be considered.[3][4]

Commercialization

Talazoparib was originally developed by BioMarin Pharmaceutical Inc. However, Medivation Inc. acquired all worldwide rights to talazoparib in August 2015 to expand their global oncology franchise.[5] Medivation acquired talazoparib for $410 million with additional payments of up to $160 million in royalties and milestones. Under this agreement, Medivation assumed all financial responsibilities for the continued development, regulatory, and commercialization of talazoparib.[5][6]

Clinical trials

As of January 2016, talazoparib is in 14 active clinical trials [7] including a new arm of I-SPY 2.[8] These trials cover a variety of cancers types and combination therapies. The most notable clinical trials are the ABRAZO and EMBRACA studies.

ABRAZO

ABRAZO is a phase II study for the safety and efficacy of treatment of BRCA breast cancer patients with Talazoparib monotherapy. This study is for patients who have failed at least two prior chemotherapy treatments for metastatic breast cancer or been previously treated with a platinum regimen.[6][9][10] The original target enrollment for the study was 70 patients but Biomarin expanded the trial to 140 patients.[9][10] The estimated completion date is December 2016.[10]

EMBRACA

EMBRACA is a phase III study for the treatment of BRCA breast cancer patients with Talazoparib.[11][12][13] This trial is an open-label, randomized, parallel, 2-arm, multi-center comparison of talazaporib against physician’s preference for the treatment of patients with locally advanced or metastatic breast cancer. Patients must also have received prior chemotherapy regimens for metastatic breast cancer.[12][13] Patients participating in this study are randomly selected for either talazoparib or physician’s choice of chemotherapy at a 2:1 ratio to talazoparib.[6] The target enrollment for the study was 430 patients [12][13] and the estimated completion date is June 2017.[13]

References

  1. Jump up to:a b Medivation Inc. “Talazoparib”.
  2. Jump up^ FDA (19 December 2014). “FDA approves Lynparza to treat advanced ovarian cancer”FDA News Release.
  3. Jump up to:a b c Jessica Brown, Stan Kaye, Timothy Yap (29 March 2016). “PARP inhibitors: the race is on”British Journal of Cancer114: 713–5. doi:10.1038/bjc.2016.67PMC 4984871Freely accessiblePMID 27022824.
  4. Jump up to:a b Yuqiao Shen, Mika Aoyagi-Scharber, Bing Wang (June 2015). “Trapping Poly(ADP-Ribose) Polymerase”Journal of Pharmacology and Experimental Therapeutics.
  5. Jump up to:a b Biomarin (24 August 2015). “Medivation to Expand Global Oncology Franchise With the Acquisition of All Worldwide Rights to Talazoparib (BMN 673), a Potent PARP Inhibitor, From BioMarin”.
  6. Jump up to:a b c Silus Inman (25 August 2015). “Medivation Acquires BioMarin’s PARP Inhibitor Talazoparib”.
  7. Jump up^ BMN 673 trials registered
  8. Jump up^ I-SPY 2 TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2)
  9. Jump up to:a b “BioMarin Provides Program Update for Talazoparib in Metastatic Breast Cancer”. 20 July 2015.
  10. Jump up to:a b c “A Phase 2, 2-Stage, 2-Cohort Study of Talazoparib (BMN 673), in Locally Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (ABRAZO Study)”ClinicalTrials.gov.
  11. Jump up^ “EMBRACA CLINICAL STUDY IS NOW ENROLLING”.
  12. Jump up to:a b c “A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study)”ClinicalTrials.gov.
  13. Jump up to:a b c d “BioMarin Initiates Phase 3 BMN 673 Trial for Metastatic gBRCA Breast Cancer”Benzinga.

External links

nmr……http://www.medkoo.com/uploads/product/Talazoparib__BMN-673_/qc/BMN673-QC-BBC20130523-Web.pdf

Patent                       Submitted                        Granted

PROCESSES OF SYNTHESIZING DIHYDROPYRIDOPHTHALAZINONE DERIVATIVES [US2014323725]2014-06-022014-10-30

CRYSTALLINE (8S,9R)-5-FLUORO-8-(4-FLUOROPHENYL)-9-(1-METHYL-1H-1,2,4-TRIAZOL-5-YL)-8,9-DIHYDRO-2H-PYRIDO[4,3,2-DE]PHTHALAZIN-3(7H)-ONE TOSYLATE SALT [US2014228369]2014-04-142014-08-14

Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt [US8735392]2011-10-202014-05-27

DIHYDROPYRIDOPHTHALAZINONE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP) [US8012976]2010-02-112011-09-06

DIHYDROPYRIDOPHTHALAZINONE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP) FOR USE IN TREATMENT OF DISEASES ASSOCIATED WITH A PTEN DEFICIENCY [US2014066429]2013-08-212014-03-06

METHODS AND COMPOSITIONS FOR TREATMENT OF CANCER AND AUTOIMMUNE DISEASE [US2013184342]2013-03-132013-07-18

WO2012054698A1 Oct 20, 2011 Apr 26, 2012 Biomarin Pharmaceutical Inc. Crystalline (8s,9r)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1h-1,2,4-triazol-5-yl)-8,9-dihydro-2h-pyrido[4,3,2-de]phthalazin-3(7h)-one tosylate salt
WO2015069851A1 Nov 6, 2014 May 14, 2015 Biomarin Pharmaceutical Inc. Triazole intermediates useful in the synthesis of protected n-alkyltriazolecarbaldehydes
US8420650 Mar 31, 2011 Apr 16, 2013 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US8541403 Feb 3, 2011 Sep 24, 2013 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) for use in treatment of diseases associated with a PTEN deficiency
US8735392 Oct 20, 2011 May 27, 2014 Biomarin Pharmaceutical Inc. Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt
US8765945 Feb 8, 2011 Jul 1, 2014 Biomarin Pharmaceutical Inc. Processes of synthesizing dihydropyridophthalazinone derivatives
US8999987 Mar 6, 2013 Apr 7, 2015 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US9018201 Aug 21, 2013 Apr 28, 2015 Biomarin Pharmaceuticial Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) for use in treatment of diseases associated with a PTEN deficiency

SEE………..http://orgspectroscopyint.blogspot.in/2016/02/talazoparib.html

http://apisynthesisint.blogspot.in/2016/02/talazoparib.html

Talazoparib
Talazoparib.svg
Systematic (IUPAC) name
(8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one
Clinical data
Legal status
  • Investigational
Chemical data
Formula C19H14F2N6O
Molar mass 380.35 g/mol
Talazoparib
Talazoparib.svg
Legal status
Legal status
  • Investigational
Identifiers
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C19H14F2N6O
Molar mass 380.35 g/mol
3D model (JSmol)

/////////////BMN 673, talazoparib, phase 3, BMN673, BMN673, BMN-673, LT673, LT 673, LT-673, Poly ADP ribose polymerase 2 inhibitor, Poly ADP ribose polymerase 1 inhibitor, cancer, MDV-3800 , MDV 3800

Cn1c(ncn1)[C@H]2c3c4c(cc(cc4N[C@@H]2c5ccc(cc5)F)F)c(=O)[nH]n3

O=C1NN=C2C3=C1C=C(F)C=C3N[C@H](C4=CC=C(F)C=C4)[C@H]2C5=NC=NN5C

Talazoparib tosylate タラゾパリブトシル酸塩;

str1

1373431-65-2.png

Talzenna

fda 2018/10/16

CAS: 1373431-65-2

Biocon Launches KRABEVA® in India, A Biosimilar Bevacizumab for Treating Several Types of Cancer


Image result for KRABEVA®

Biocon Launches KRABEVA® in India,  A Biosimilar Bevacizumab for Treating Several Types of Cancer

On November 23, 2017, Biocon India’s premier Biopharmaceuticals Company announced that it has launched KRABEVA®, a biosimilar Bevacizumab for the treatment of patients with metastatic colorectal cancer and other types of lung, kidney, cervical, ovarian and brain cancers, in India 1.
KRABEVA®, a monoclonal antibody (mAb) developed by Biocon, will help expand access to a world-class, high quality biosimilar Bevacizumab for cancer patients in India. It is the world´s first and only Bevacizumab with a unique ´QualCheck ´ mechanism, which ensures that patients get a quality-ascertained product right up to infusion.
Bevacizumab is indicated as a first-line treatment of patients with metastatic colorectal cancer (mCRC), and is accepted as a standard treatment option in combination with chemotherapy for patients with non-small-cell lung cancer (NSLC), metastatic renal cell carcinoma or recurrent ovarian cancer.
KRABEVA® is the second key oncologic biosimilar product, from Biocon´s global biosimilars portfolio to be launched in India. It is being offered to patients at an MRP of Rs 24,000 for 100 mg / 4 ml vials and Rs 39,990 for 400 mg / 16 ml vials, making it a high quality affordable alternative to the innovator brand. In comparison, the Innovator brand for Bevacizumab marketed as Avastin® by Roche India Private Limited costs over Rs 10, 7065 for 400mg / 16ml vial.
Bevacizumab is a monoclonal antibody (mAb) targeting Vascular Endothelial Growth Factor- A (VEGF-A), a cell protein that induces growth of blood vessels that feed tumors. By blocking this protein, Bevacizumab cuts the  supply of food and oxygen to the tumor, thus starving it.

Bevacizumab is prescribed in the treatment of several cancers including metastatic colorectal cancer, ovarian cancer, advanced non-small-cell lung cancer, recurrent glioblastoma, cervical cancer and renal cancer. Bevacizumab was first approved by the United States Food and
Drug Administration (USFDA), in February 2004 2.

It also features in the World Health Organization’s (WHO) list of essential medicines 3. The WHO list of essential medicines contains the medications considered to be most effective and safe to meet the most important needs in a health system. The list is frequently used by countries to help develop their own local lists of essential medicine.

1 https://www.biocon.com/biocon_press_releases_231117.asp
2 https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125085
http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1
Approval and launch of a Bevacizumab biosimilar in India would provide an affordable therapy option for patients of various types of cancer.

//////////Biocon, KRABEVA®, India,  Biosimilar,  Bevacizumab, Cancer

FDA approves first biosimilar Herceptin (trastuzumab) for the treatment of certain breast and stomach cancers


FDA approves first biosimilar for the treatment of certain breast and stomach cancers

Ogivri, a biosimilar to the cancer drug Herceptin, is approved for HER2+ breast cancer and metastatic stomach cancers

The U.S. Food and Drug Administration today approved Ogivri (trastuzumab-dkst) as a biosimilar to Herceptin (trastuzumab) for the treatment of patients with breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma) whose tumors overexpress the HER2 gene (HER2+). Ogivri is the first biosimilar approved in the U.S. for the treatment of breast cancer or stomach cancer and the second biosimilar approved in the U.S. for the treatment of cancer. Continue reading.

December 1, 2017

Release

The U.S. Food and Drug Administration today approved Ogivri (trastuzumab-dkst) as a biosimilar to Herceptin (trastuzumab) for the treatment of patients with breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma) whose tumors overexpress the HER2 gene (HER2+). Ogivri is the first biosimilar approved in the U.S. for the treatment of breast cancer or stomach cancer and the second biosimilar approved in the U.S. for the treatment of cancer.

As with any treatment, health care professionals should review the prescribing information in the labeling for detailed information about the approved uses.

“The FDA continues to grow the number of biosimilar approvals, helping to promote competition that can lower health care costs. This is especially important when it comes to diseases like cancer, that have a high cost burden for patients,” said FDA Commissioner Scott Gottlieb, M.D. “We’re committed to taking new policy steps to advance our biosimilar pathway and promote more competition for biological drugs.”

Biological products are generally derived from a living organism and can come from many sources, such as humans, animals, microorganisms or yeast. A biosimilar is a biological product that is approved based on data showing that it is highly similar to a biological product already approved by the FDA (reference product) and has no clinically meaningful differences in terms of safety, purity and potency (i.e., safety and effectiveness) from the reference product, in addition to meeting other criteria specified by law.

The FDA’s approval of Ogivri is based on review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Ogivri is biosimilar to Herceptin. Ogivri has been approved as a biosimilar, not as an interchangeable product.

Common expected side effects of Ogivri for the treatment of HER2+ breast cancer include headache, diarrhea, nausea, chills, fever, infection, congestive heart failure, difficulty sleeping (insomnia), cough and rash. Common expected side effects of Ogivri for the treatment of HER2+ metastatic stomach cancer include low levels of certain white blood cells (neutropenia), diarrhea, fatigue, low levels of red blood cells (anemia), inflammation of the mouth (stomatitis), weight loss, upper respiratory tract infections, fever, low levels of blood platelets (thrombocytopenia), swelling of the mucous membranes (mucosal inflammation), common cold (nasopharyngitis) and unusual taste sensation (dysgeusia). Serious expected side effects of Ogivri include worsening of chemotherapy-induced neutropenia.

Like Herceptin, the labeling for Ogivri contains a Boxed Warning to alert health care professionals and patients about increased risks of heart disease (cardiomyopathy), infusions reactions, lung damage (pulmonary toxicity) and harm to a developing fetus (embryo-fetal toxicity). Patients should stop taking Ogivri if cardiomyopathy, life-threatening allergic reactions (anaphylaxis), swelling below the skin (angioedema), inflammation of the lungs (interstitial pneumonitis) or fluid in the lungs (acute respiratory distress syndrome) occur. Patients should be advised of the potential risk to a developing fetus and to use effective contraception.

The FDA granted approval of Ogivri to Mylan GmbH. Herceptin was approved in September 1998 and is manufactured by Genentech, Inc.

/////////////Ogivri, biosimilar , cancer, Herceptin, Trastuzumab, FDA 2017

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