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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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CC-90009


str1

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

CC-90009

CC-90009-AML-001

CAS 1860875-51-9

461.8 g/mol, C22H18ClF2N3O4

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

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

Phase 1 Clinical, Acute myelogenous leukemia, Protein cereblon modulator

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

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

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

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

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

Development Overview

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

WO 2017120446,

PATENT

WO2016007848

US 20170348298

WO 2017120415

WO 2017120446

WO 2017120437

PATENT

WO2017214014

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

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

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

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

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

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

PATENT

WO-2019136016

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

str2

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

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

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

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SHR-0532


SHR-0532

CAS 2166329-09-3

C24 H26 N4 O5 . C4 H6 O6

2-Pyridinecarboxamide, 5-cyano-N-[1-[(2R)-2-(1,3-dihydro-4-methyl-1-oxo-5-isobenzofuranyl)-2-hydroxyethyl]-4-piperidinyl]-4-methoxy-, (2R,3R)-2,3-dihydroxybutanedioate (1:1)

str1

FREE FORM

1945997-37-4

C24 H26 N4 O5
450.49
2-Pyridinecarboxamide, 5-cyano-N-[1-[(2R)-2-(1,3-dihydro-4-methyl-1-oxo-5-isobenzofuranyl)-2-hydroxyethyl]-4-piperidinyl]-4-methoxy-

5-Cyano-N-[1-[(2R)-2-(1,3-dihydro-4-methyl-1-oxo-5-isobenzofuranyl)-2-hydroxyethyl]-4-piperidinyl]-4-methoxy-2-pyridinecarboxamide

KCNJ potassium channel-1 inhibitor, Hypertension; Renal insufficiency

  • Originator Jiangsu Hengrui Medicine Co.
  • Class Antihypertensives
  • Mechanism of Action Undefined mechanism
  • Preclinical Hypertension
  • 03 Jun 2019 Jiangsu Hengrui Medicine Co. plans a phase I trial for Hypertension (PO) in June 2019 (NCT03971929)
  • 26 Aug 2018 Jiangsu HengRui Medicine plans a phase I trial for Hypertension (In volunteers) (PO) in August 2018 (NCT03645278)

Jiangsu Hengrui Medicine is developing an oral tablet formulation of SHR-0532, a small molecule specific inhibitor of ROMK (renal outer medullary potassium channel), for use as a diuretic to treat hypertension and renal insufficiency inducing water and sodium retention. In January 2019 a phase trial was completed, and in June 2019, another phase I trial for mild hypertension was planned.

PATENT

WO2016091042

WO 2017211271

CN 108113988

PATENT

WO2019011200

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019011200&redirectedID=true

Diuretics are widely recommended as first-line antihypertensive drugs in national hypertension guidelines for mild to moderate hypertension, especially in elderly hypertension or complicated heart failure.

Clinically, traditional diuretics have a risk of causing hypokalemia. ROMK antihypertensive diuretic development of new targets, as ROMK of inward rectifier K + channel (inwardly rectifying K channels, Kir) a family, belong Kir1 type, the maintenance of renal potassium ions play a crucial balance effect. In the rat kidney, there are at least three subtypes of ROMK channels: ROMK1, ROMK2, and ROMK3. Most of ROMK2 is distributed in the ascending limb of Henle (TALH); ROMK1 and ROMK3 are mainly expressed on the cortical collecting duct (CCD). Expressed in the TALH and ROMK of Na + / K + / 2Cl  transporter with regulating the secretion of potassium ions and sodium reabsorption, and expressed in the CCD ROMK of Na + / K + secretion was adjusted with potassium transporter. Therefore, blocking the ROMK site can be a good diuretic research direction by inhibiting the reabsorption of Na + by diuretic and reducing blood potassium and causing hypokalemia.

WO2016091042A1 (publication date 2016-06-16) discloses a class of extrarenal medulla secretory potassium channel (ROMK) inhibitors, chemical name (R)-5-cyano-N-(1-(2-hydroxy-2) a compound of (4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide, relative In other ROMK inhibitors, the compound increases the polar group, lowers the ClogP, enhances the hERG selectivity and increases the safety based on the activity of the ROMK inhibitor, and its structure is as shown in the formula (A).
Example 1 of WO2016091042A1 discloses a preparation method of Compound A, which has a total of five steps of reaction, and the specific reaction is as follows:
The method has the problems of more reaction steps, small batch size, post-treatment method using thin layer chromatography purification, low yield, etc., wherein the yield of the second step reaction is 22.4%, and the yield of the product prepared in the last step is only 11.3. % is not conducive to industrial expansion of production, it is necessary to improve its preparation method.
Example 1. Preparation of (R)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one
First step, preparation of compound of formula (h)
Sodium borohydride (57.8 g) was dissolved in tetrahydrofuran (2000 mL), argon-protected, cooled to 0 ° C, material i (130.0 g) was added portionwise, and stirred at 5-10 ° C for 1 hour, 5-10 ° C Add boron trifluoride diethyl ether (237 mL) dropwise, stir at room temperature for 4 hours, stop the reaction, add methanol (800 mL) to quench the reaction, stir, add 1N hydrochloric acid (1000 mL) solution, stir at 0-20 ° C for 1 hour, decompress The organic solvent was evaporated, and the residue was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Concentration gave the title product (95 g).
The second step, the preparation of the compound of formula (g)
The raw material h (120.0 g) and trifluoroacetic acid (64 mL) were dissolved in acetonitrile (1 L), stirred, and cooled to 0-5 ° C under ice bath, and solid N-bromosuccinimide (147.0 g) was added portionwise. The reaction temperature was controlled at 0-8 ° C. After the reaction was completed, the reaction was quenched by adding 200 mL of potassium carbonate aqueous solution (containing 66.0 g of potassium carbonate) under ice-cooling, and concentrated under reduced pressure, water (200 mL) and ethyl acetate (800 mL) ×1,400 mL×2), and the organic phase was combined with EtOAc EtOAc (EtOAc m. Drying gave 150.0 g of product.
The third step, the preparation of the compound of formula (f)
The cuprous cyanide (123.0 g) was added to N,N-dimethylformamide (500 mL), and the material g (150.0 g) was dissolved in N,N-dimethylformamide (250 mL), and added to the dropping funnel. Under an argon atmosphere, after heating to 140-150 ° C, the N,N-dimethylformamide solution of the raw material g was added dropwise, and the reaction was stirred at 145 ° C for 2 hours. After the reaction was completed, the temperature was lowered to 90-95 ° C, and the mixture was added dropwise. Ionized water (62 mL), reacted for 18 hours, stopped the reaction, and cooled to room temperature. The reaction solution was added to a mixed solvent of isopropyl acetate/methanol (V/V = 4:1, 1500 mL), stirred for 30 minutes, and padded with silica gel and silicon. The mixture was filtered with celite, and the filter cake was washed with isopropyl acetate/methanol (V/V = 4:1, 100 mL×3), and the filtrate was concentrated under reduced pressure. The residue was slowly added to deionized water (3 L) and stirred for 1 hour. Filtration, the filter cake was washed with ethanol (50 mL×3), and the filter cake was dried to give 133.0 g of crude product. The crude product was added to ethyl acetate/methanol (V/V=4:1, 2.0L) and heated to reflux. After filtration, the cake was washed with ethyl acetate /methanol (EtOAc/EtOAc (EtOAc)
The fourth step, the preparation of the compound of formula (e)
The starting material f (26.0 g) was dissolved in dichloromethane (520 mL), triethylamine (33 mL) was added, and the mixture was cooled to -5-0 ° C and added trifluoromethanesulfonic anhydride (29.2 mL), 0-10 After reacting at ° C for 2 hours, the reaction was stopped. Under ice-cooling conditions, water (250 mL) was added dropwise to the reaction mixture to quench the reaction, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (100 mL×2). The sodium solution (300 mL) was washed with EtOAc EtOAc (mjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH After dissolving at 70 ° C, the supernatant liquid was separated, and the lower layer of the oil was dissolved in a mixed solution of petroleum ether and ethyl acetate (V/V = 5:1) (300 mL × 2), and the organic phases were combined and concentrated under reduced pressure. (41.0 g), EtOAc (EtOAc m.
The fifth step, the preparation of the compound of formula (d)
The starting material e (50.1 g) was dissolved in isopropanol (500 mL), and ethylene trifluoroborate (29.5 g) and 1,1′-bisdiphenylphosphinoferrocene palladium dichloride (1.25 g) were added. Further, triethylamine (71 mL) was added, and the reaction was refluxed for 1.5 hours under an argon atmosphere. The reaction was stopped, cooled to room temperature, filtered, and the filtrate was washed with ethyl acetate (20 mL×3), and the filtrate was concentrated and concentrated through silica gel column. The title product (29.0 g) was obtained (yield: ethyl acetate: petroleum ether = 1:5-1:3).
The sixth step, the preparation of the compound of formula (c)
Potassium ferricyanide (279.0 g) was added to the reaction flask, followed by potassium carbonate (116.0 g) and hydrogenated quinidine 1,4-(2,3-naphthyridinyl)diether ((DHQD) 2 PHAL , 1.1g) and potassium citrate dihydrate (103mg), add 2L of deionized water, stir for 30 minutes, add tert-butanol (1.5L) under argon atmosphere, stir for 15 minutes, 0-5 ° C raw material d ( 49.0g) was added in portions, stirred at 0-5 ° C for 4 hours, warmed to room temperature and stirred for 18 hours, the reaction was stopped, saturated sodium sulfite solution (800 mL) and ethyl acetate (1000 mL) were added, stirred until fully dissolved, layered, The aqueous layer was extracted with EtOAc (EtOAc (EtOAc) (EtOAc (EtOAc) The mixture was cooled to rt.
The seventh step, the preparation of the compound of formula (a)
The raw material c (54.0 g) was added to dichloromethane (600 mL), and the mixture was white turbid. Under argon atmosphere, b (46.9 g) was added, stirred at room temperature for 10 minutes, cooled to 0 ° C, and trimethylchlorosilane was added dropwise. (54.0g), stirring at 0 ° C for 30 minutes, the solution became clear, warmed to room temperature for 1 hour, then cooled to 0 ° C, added b (23.0g), raised to room temperature for 30 minutes, stop the reaction, the reaction solution Concentration under reduced pressure gave the crude title product which was used in the next step without purification.
The eighth step, the preparation of the compound of formula (VI)
The raw material a (69.6 g) was added to methanol (1000 mL), and potassium carbonate (90.0 g) was added, and the mixture was stirred at room temperature for 2 hours, the reaction was stopped, and the mixture was evaporated under reduced pressure. ethyl acetate (500 mL) and water (200 mL) The aqueous phase was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) The title compound (35.0 g) was obtained in vacuo.
Example 2 Preparation of 5-cyano-4-methoxypyridinecarboxylic acid hydrochloride
First step, preparation of the compound of formula (p)
Raw material n (110.0g), o (150.0g), acetic anhydride (151.5g) was added to the reaction flask and refluxed for 4 hours, the reaction was stopped, concentrated under reduced pressure, and the obtained residue was controlled at a temperature of 0-10 ° C to add ammonia water and Water (V / V = 1:1, 600mL) mixed solution, when a large amount of solids were formed, add ice water (400mL), drip, stir for 30 minutes, adjust to pH 2-3 with concentrated hydrochloric acid, stir 30 After a minute, the mixture was filtered, and the filter cake was dried, and then filtered with anhydrous ethanol (500 mL) for 1 hour, filtered, filtered, washed with cold anhydrous ethanol (100 mL×3), and the filter cake was dried to give the title product (80.0 g) The yield was 59%.
The second step, the preparation of the compound of formula (q)
Sodium hydroxide (43.6 g) was added to water (800 mL) under ice bath, and the starting material p (79.8 g) was added portionwise to the above aqueous sodium hydroxide solution, the ice bath was removed, and the mixture was heated to reflux for 2 hours to terminate the reaction. The reaction solution was cooled to room temperature with ice water, 2M hydrochloric acid solution was added dropwise to adjust the pH to 2-3, stirred for 30 minutes, filtered, and the filter cake was washed with ice water (100 mL) and cold ethanol (100 mL), and the obtained solid was dried. The title product (71.2 g), yield 100%.
The third step, the preparation of the compound of formula (r)
The raw material q (70.3 g) was dissolved in phosphorus oxychloride (210 mL), stirred at 110 ° C for 2 hours under reflux, concentrated under reduced pressure to remove phosphorus oxychloride, and the residue was added to acetonitrile (350 mL). Add diisopropylethylamine (117.0 g), dilute the solution to a black suspension, add the suspension to the ammonia water (350 mL) under ice bath, drop the reaction for 30 minutes, ethyl acetate (500 mL × 3) Extraction, the organic phase was combined, washed with saturated sodium chloride (500 mL), dried over anhydrous sodium sulfate, filtered and evaporated. (44.7 g), yield 51%.
The fourth step, the preparation of the compound of formula (s)
The raw material r (44.3 g) was added to dichloromethane (440 mL) under an argon atmosphere, and the temperature was controlled to 0-5 ° C under ice-cooling, triethylamine (58.6 g) was added dropwise, and the mixture was stirred for 10 minutes. Trifluoroacetic anhydride (58.5g) was added dropwise, the addition was completed, and the reaction was carried out for 1 hour in an ice bath. The reaction was stopped, the pH of the reaction mixture was 7-8, and the reaction was quenched by adding water (400 mL), and the mixture was separated. The organic phase was extracted with EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH g), yield 91%.
The fifth step, the preparation of the compound of formula (t)
The raw material s (25.6 g) and cesium carbonate (49.2 g) were dissolved in N,N-dimethylformamide (260 mL), cooled to 0 ° C in an ice bath, and methanol (9.5 g) was added dropwise in an ice bath, 0 ° C After reacting for 6 hours, the mixture was stirred at 20-25 ° C for 12 hours, and the reaction was stopped. The reaction mixture was quenched with water (650 mL), and extracted with ethyl acetate (200 mL×3). The title compound (16.8 g) was obtained. The title compound (16.8 g) was obtained from EtOAc (EtOAc). The rate is 67%.
The sixth step, the preparation of the compound of formula (II-1)
Add t (22.0g), palladium acetate (1.46g), 1,3-bis(diphenylphosphino)propane (2.68g), triethylamine (36mL) to the mixed solution, pressurize with carbon monoxide to 10bar, heat up The reaction was stopped at 70 ° C for 18 hours, the reaction was stopped, the organic solvent was removed by concentration, the aqueous phase was added with saturated sodium chloride solution and dichloromethane (300 mL×3), and the organic phase was combined, decolorized by activated carbon, filtered, and the organic phase was adjusted to pH with concentrated hydrochloric acid. =1, a solid precipitated, and after adding 50 mL of isopropanol, the dichloromethane was concentrated to remove the product, which was filtered and dried to give a product (23.6 g).
Example 3, (R)-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl) Preparation of ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide (formula (I))
First step, synthesis of intermediate (IV)
Into the reaction flask, 4.0 L of absolute ethanol was added, and (R)-4-methyl-5-(oxiran-2-yl)-benzoisofuran-1(3H)-one (274.8) was added under stirring. g), 4-Boc-aminopiperidine (341.2 g), heated to 65-70 ° C, stirred for 18-20 h, and the heating was stopped. Naturally cooled to 50-55 ° C, 8.0 L of n-hexane was added under stirring, stirred until the temperature naturally dropped to 20-25 ° C, a large amount of solids were precipitated, the temperature of the ice bath was lowered to 0-5 ° C, stirred, suction filtered, filter cake It was washed twice with n-hexane (250 ml × 2) and dried to give a solid (354.3 g).

The second step, the synthesis of intermediate (III-1)

5.2 L of ethyl acetate was placed in a glass bottle, and the temperature was lowered to 0 to 5 ° C under stirring. The stirring was stopped, hydrogen chloride gas (0.48 kg) was introduced, and the temperature of the reaction liquid was controlled to be lower than 5 ° C during the passage of hydrogen chloride. The above product (349.3 g) was added to the reaction mixture with slow stirring. After the addition, the reaction was stirred for 3-4 hours, and the reaction temperature was naturally raised to 20-25 ° C, and the stirring was stopped. After suction filtration, the filter cake was washed three times with ethyl acetate (1.0 L×3), and the filter cake was dried under vacuum at 40-45 ° C for 6-8 h to give a solid (322.8 g) in a yield of 99.3%; The ratio of hydrochloric acid was determined by silver nitrate titration to be 20.5%.

The third step, the synthesis of the compound of formula (I)

Into the reaction flask, 4.0 L of N, dimethylformamide was added, and the product of the above step (317.8 g), 5-cyano-4-methoxypyridinecarboxylate II-1 (205.9 g) was sequentially added with stirring. Triethylamine (528.2 g), 1-hydroxybenzotriazole (152.7 g), N,N-diisopropylcarbodiimide (142.6 g). After the addition, the argon gas was replaced three times, and the mixture was heated to 40-45 ° C to stir the reaction for 16-18 h. The heating was stopped, and the reaction liquid was poured into ice water (30 L), and stirred for 1 hour. After suction filtration, the filter cake was washed three times with purified water, dried, and then pulverized with anhydrous ethanol (3.0 L) at 20-25 ° C for 1 h. Filtering, drying 10-12h to obtain crude (290.4g), yield 73.7%, purity: 97.76%;
N,N-dimethylformamide (2.0 L) was added to the crude product (290.4 g) with stirring. The reaction solution was heated to 70-75 ° C, 20.3 g of activated carbon (7% w/w) was added, and the mixture was stirred for 1 h. Heat filtration, wash the filter residue with hot N,N-dimethylformamide (70-75 ° C, 200 mL), combine the filtrate, heat the filtrate to 70-75 ° C, add hot (65-70 ° C, 5 L) with stirring Anhydrous ethanol to the reaction liquid in the previous step, stirring and crystallization, until the temperature naturally drops to 20-25 ° C, the reaction bottle is transferred to an ice water bath and stirring for 1 h, suction filtration, the filter cake is washed with absolute ethanol, dried to obtain a solid 219.5 g, total yield 55.7%, purity: 99.69%.
1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.88 (s, 1H), 8.75 (d, 1H), 7.77 (s, 1H), 7.71-7.69 (m, 2H), 5.43-5.40 (m, 2H), 5.35 (s, 1H), 5.08 (s, 1H), 4.09 (s, 3H), 3.78 (s, 1H), 2.95 (s, 3H), 2.38 (s, 1H), 2.27 (s, 3H) ), 2.25 (s, 2H), 1.72 (s, 4H).

PATENT

WO-2019109935

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019109935&tab=FULLTEXT&maxRec=1000

Novel crystalline forms of a renal outer medullary potassium channel inhibitor and their salts, preferably Form III, for treating hypertension or heart failure.

Strengthening the salt reabsorption of the kidneys can trigger a risk of high blood pressure. On the contrary, inhibiting the reabsorption function of the kidney can promote the excretion of urine and play a diuretic and antihypertensive effect. Common diuretics are thiazide diuretics, as the first-line antihypertensive drugs in the United States, mainly acting on Na + -Cl transport carriers; Loop diuretics are more effective in patients with impaired renal function, mainly through Na + -K + -2Cl  Transport proteins play a role. But both diuretics cause hypokalemia (symptoms: weakness, fatigue, muscle cramps, constipation and heart rhythm problems such as arrhythmia), increasing the risk of cardiovascular disease morbidity and mortality.
The renal outer medullary potassium channel (ROMK) is also called inward-rectifying potassium channel 1.1 (Kir1.1). Ion channels may ROMK thick ascending limb segment (the TAL) conductance through apical membrane of renal medullary loop, and of Na + -K + -2Cl  cotransporter NKCC2 (responsible for transport of NaCl) synergy regulation of Na + reabsorption. The study found that ROMK is directly associated with the secretory pathway of the kidney, knocking out the ROMK gene, missing the 35-pS ion channel and other TAL K + ion channels of mouse TAL and CCD . Batter syndrome is an autosomal recessive hereditary disease characterized by massive loss of salt in the kidneys, hypokalemia, and low blood pressure. Paramyelocytic hyperplasia is mainly caused by mutation of ROMK or Na + -K + -2Cl  cotransporter, except that hypokalemia caused by rotaside cell hyperplasia caused by ROMK mutation is better than Na + -K + – Parathyroid cell hyperplasia induced by 2Cl  cotransporter mutations is greatly alleviated. In summary, suppressing the function of ROMK can effectively inhibit Na without causing hypokalemia. + -K + -2Cl  The salt reabsorption function of transporters promotes the excretion of urine and acts as a diuretic and antihypertensive agent .
WO2016091042A1 (Publication Date 2016.06.16) discloses an extrarenal medullary secretory potassium channel (ROMK) inhibitor having the chemical name (R)-5-cyano-N-(1-(2-hydroxy-2-() 4-methyl-1-carbonyl-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methoxypyridinecarboxamide relative to other ROMK inhibitors The compound increases the polar group, reduces the ClogP on the basis of maintaining the activity of the ROMK inhibitor, improves the selectivity of hERG, and increases the safety, and the structure is as shown in formula (II):
The crystal structure of the pharmaceutically active ingredient often affects the chemical and physical stability of the drug, and the difference in crystallization conditions and storage conditions may cause changes in the crystal structure of the compound, sometimes accompanied by the formation of other forms of crystal form. In general, amorphous pharmaceutical products have no regular crystal structure and often have other defects, such as poor product stability, difficulty in filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve various aspects of the compound of the formula (II).

/////////////SHR-0532, SHR0532, SHR 0532, Jiangsu Hengrui Medicine Co, phase I, Antihypertensives

COc1cc(ncc1C#N)C(=O)NC2CCN(CC2)C[C@H](O)c4ccc3C(=O)OCc3c4C

TAK-981


LXRZVMYMQHNYJB-UNXOBOICSA-N.png

TAK-981

C25 H28 Cl N5 O5 S2, 578.103

[(1R,2S,4R)-4-[(5-[4-[(1R)-7-Chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl)amino]-2-hydroxycyclopentyl]methyl sulfamate

[(1R,2S,4R)-4-[[5-[4-[(1R)-7-Chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-thiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxy-cyclopentyl]methyl sulfamate

Sulfamic acid, [(1R,2S,4R)-4-[[5-[[4-[(1R)-7-chloro-1,2,3,4-tetrahydro-1-isoquinolinyl]-5-methyl-2-thienyl]carbonyl]-4-pyrimidinyl]amino]-2-hydroxycyclopentyl]methyl ester

CAS 1858276-04-6 FREE

CAS 1858279-63-6 HYDRATE

 MW 578.103
  • Originator Takeda Oncology
  • Class Antineoplastics
  • Mechanism of Action Small ubiquitin-related modifier protein inhibitors
  • Phase I Lymphoma; Solid tumours
  • 01 Oct 2018 Phase-I clinical trials in Solid tumours (Late-stage disease, Metastatic disease) and and Lymphoma (Refractory metastatic disease, Second-line therapy or greater) in USA (IV) (NCT03648372)
  • 03 Sep 2018 Takeda Oncology plans a phase I trial for Solid tumours (Late-stage disease, Metastatic disease) and Lymphoma (Refractory metastatic disease, Second-line therapy or greater) in September 2018 (IV) (NCT03648372)
  • 03 Sep 2018 Preclinical trials in Lymphoma in USA (IV) prior to September 2018 (NCT03648372)

Takeda is evaluating TAK-981, a SUMO-Activating Enzyme (SAE) inhibitor, in early clinical trials for the treatment of adult patients with advanced or metastatic solid tumors or with relapsed or refractory lymphomas.

str1

Small ubiquitin-like modifier (SUMO) is a member of the ubiquitin-like protein (Ubl) family that is covalently conjugated to cellular proteins in a manner similar to Ub-conjugation (Kerscher, O., Felberbaum, R., and Hochstrasser, M. 2006. Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol. 22: 159-80). Mammalian cells express three major isoforms: SUMO l , SUM02 and SUM03. SUM02 and SUM03 share -95% amino acid sequence homology but have -45% sequence homology with SUMO l (Kamitani, T., Kito, K., Nguyen, H. P., Fukuda-Kamitani, T., and Yeh, E. T. 1998. Characterization of a second member of the sentrin family of ubiquitin-like proteins. J Biol Chem. 273( 18): 1 1349-53). SUMO proteins can be conjugated to a single lysine residue of a protein (monosumoylation) or to a second SUMO protein that is already conjugated to a protein forming a SUMO chain (polysumoylation). Only SUM02/3 can form such chains because they possess internal consensus SUMO modification sites (Tatham, M. H., Jaffray, E., Vaughan, O. A., Desterro, J. M., Botting, C. H., Naismith, J. H., Hay, R. T. 2001. Polymeric chains of SUMO-2 and SUM 0-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem. 276(38):35368-74). An additional isoform, SUM04, is found in kidney, lymph node and spleen cells, but it is not known whether SUM04 can be conjugated to cellular proteins.

[0003] SUMO l , SUM02 and SUM03 are activated in an ATP-dependent manner by the SUMO-activating enzyme (SAE). SAE is a heterodimer that consists of SAE 1 (SUMO-activating enzyme subunit 1) and SAE2 (UBA2). SAE, like other El activating enzymes, uses ATP to adenylate the C-terminal glycine residue of SUMO. In a second step, a thioester intermediate is then formed between the C-terminal glycine of SUMO and a cysteine residue in SAE2. Next, SUMO is transferred from the El to the cysteine residue of the SUMO conjugating enzyme (E2), UBC9. Unlike the Ub pathway that contains many E2 enzymes, Ubc9 is currently the only known conjugating enzyme for SUMO and functions with SUMOl , SUM02 and SUM03 proteins. SUMO proteins are then conjugated to the target protein, either directly or in conjunction with an E3 ligase, through isopeptide bond formation with the epsilon amino group of a lysine side chain on a target protein. Several SUMO E3 ligases, including PIAS (protein inhibitor of activated signal transducer and activator of transcription protein) proteins and Ran-binding protein 2 (RanBP2), and polycomb 2 (Pc2), have been identified (Johnson, E. S., and Gupta, A. A. 2001. An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell. 106(6):735-44; Pichler, A., Gast, A., Seeler, J. S., Dejean, A.; Melchior, F. 2002. The nucleoporin RanBP2 has SUMOl E3 ligase activity. Cell. 108(1): 109-20; Kagey, M. H., Melhuish, T. A., and Wotton, D. 2003. The polycomb protein Pc2 is a SUMO E3. Cell. 1 13(1): 127- 37). Once attached to cellular targets, SUMO modulates the function, subcellular localization, complex formation and/or stability of substrate proteins (Miiller, S., Hoege, C, Pyrowolakis, G., and Jentsch, S. 2001. SUMO, ubiquitin’s mysterious cousin. Nat Rev Mol Cell Biol. 2(3):202-10). SUMO- conjugation is reversible through the action of de-sumoylating enzymes called SENPs (Hay, R. T. 2007. SUMO-specific proteases: a twist in the tail. Trends Cell Biol. 17(8):370-6) and the SUMO proteins can then participate in additional conjugation cycles.

[0004] SAE-initiated SUMO-conjugation plays a major role in regulating diverse cellular processes, including cell cycle regulation, transcriptional regulation, cellular protein targeting, maintenance of genome integrity, chromosome segregation, and protein stability (Hay, R. T. 2005. SUMO: a history of modification. Mol Cell. 18( 1): 1 -12; Gill, G. 2004. SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev. 18(17):2046-59). For example, SUMO- conjugation causes changes in the subcellular localization of RanGAPl by targeting it to the nuclear pore complex (Mahajan, R., Delphin, C., Guan, T., Gerace, L., and Melchior, F. 1997. A small ubiquitin-related polypeptide involved in targeting RanGAPl to nuclear pore complex protein RanBP2. Cell. 88(1):97- 1070). Sumoylation counteracts ubiquitination and subsequently blocks the degradation of Ι Β, thereby negatively regulating NF-κΒ activation (Desterro, J. M., Rodriguez, M. S., Hay, R. T. 1998. SUMO- 1 modification of IkappaB alpha inhibits NF-kappaB activation. Mol Cell. 2(2):233-9). Sumoylation has been reported to play an important role in transcription exhibiting both repressive and stimulatory effects. Many of the transcriptional nodes that are modulated play important roles in cancer. For example, sumoylation stimulates the transcriptional activities of transcription factors such as p53 and HSF2 (Rodriguez, M. S., Desterro, J. M., Lain, S., Midgley, C. A., Lane, D. P., and Hay, R. T. 1999. SUMO- 1 modification activates the transcriptional response of p53. EMBO J. 18(22):6455-61 ; Goodson, M. L., Hong, Y., Rogers, R., Matunis, M. J., Park-Sarge, O. K., Sarge, K. D. 2001. Sumo- 1 modification regulates the DNA binding activity of heat shock transcription factor 2, a promyelocytic leukemia nuclear body associated transcription factor. J Biol Chem. 276(21 ): 18513-8). In contrast, SUMO-conjugation represses the transcriptional activities of transcription factors such as LEF (Sachdev, S., Bruhn, L., Sieber, H., Pichler, A., Melchior, F., Grosschedl, R. 2001. PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev. 15(23):3088- 103) and c-Myb (Bies, J., Markus, J., and Wolff, L. 2002. Covalent attachment of the SUMO- 1 protein to the negative regulatory domain of the c-Myb transcription factor modifies its stability and transactivation capacity. / Biol Chem. 277( 1 1):8999-9009). Thus, SUMO-conjugation controls gene expression and growth control pathways that are important for cancer cell survival.

[0005] Altered expression of SAE pathway components have been noted in a variety of cancer types: (Moschos, S. J., Jukic, D. M., Athanassiou, C., Bhargava, R., Dacic, S., Wang, X., Kuan, S. F., Fayewicz, S. L., Galambos, C., Acquafondata, M., Dhir, R., and Becker, D. 2010. Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues. Hum Pathol. 41(9): 1286-980); including multiple myeloma (Driscoll, J. J., Pelluru, D., Lefkimmiatis, K., Fulciniti, M., Prabhala, R. H., Greipp, P. R., Barlogie, B., Tai, Y. T., Anderson, K. C, Shaughnessy, J. D. Jr., Annunziata, C. M., and Munshi, N. C. 2010. The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome. Blood. 1 15(14):2827-34); and breast cancer (Chen, S. F., Gong, C, Luo, M., Yao, H. R., Zeng, Y. J., and Su, F. X. 201 1. Ubc9 expression predicts chemoresistance in breast cancer. Chin J Cancer. 30(9):638-44), In addition, preclinical studies indicate that Myc-driven cancers may be especially sensitive to SAE inhibition (Kessler, J. D., Kahle, K. T., Sun, T., Meerbrey, K. L., Schlabach, M. R., Schmitt, E. M., Skinner, S. O., Xu, Q., Li, M. Z., Hartman, Z. C, Rao, M., Yu, P., Dominguez-Vidana, R., Liang, A. C, Solimini, N. L., Bernardi, R. J., Yu, B., Hsu, T., Golding, I., Luo, J., Osborne, C. K., Creighton, C. J., Hilsenbeck, S. G., Schiff, R., Shaw, C. A., Elledge, S. J., and Westbrook, T. F. 2012. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science. 335(6066):348-53; Hoellein, A., Fallahi, M., Schoeffmann, S., Steidle, S., Schaub, F. X., Rudelius, M., Laitinen, I., Nilsson, L., Goga, A., Peschel, C, Nilsson, J. A., Cleveland, J. L., and Keller, U. 2014. Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma. Blood. 124( 13):2081 -90). Since SUMO-conjugation regulates essential cellular functions that contribute to the growth and survival of tumor cells, targeting SAE could represent an approach to treat proliferative disorders such as cancer.

[0006] SAE inhibitors may also be applicable for the treatment of other diseases and conditions outside of oncology. For example, SUMO modifies proteins that play important roles in neurodegenerative diseases (Steffan, J. S., Agrawal, N., Pallos, J., Rockabrand, E., Trotman, L. C, Slepko, N., Hies, K., Lukacsovich, T., Zhu, Y. Z., Cattaneo, E., Pandolfi, P. P., Thompson, L. M., Marsh, J. L. 2004. SUMO modification of Huntington and Huntington’s disease pathology. Science. 304(5667): 100-4); Dorval, V., and Fraser, P. E. 2006. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein. J Biol Chem. 281 ( 15):9919-24; Ballatore, C, Lee, V. M., and Trojanowski, J. Q. 2007. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 8(9):663-72). Sumoylation also has been reported to play important role in pathogenic viral infection, inflammation and cardiac function (Lee, H. R., Kim, D. J., Lee, J. M., Choi, C. Y., Ahn, B. Y., Hayward, G. S., and Ahn, J. H. 2004. Ability of the human cytomegalovirus ΓΕ1 protein to modulate sumoylation of PML correlates with its functional activities in transcriptional regulation and infectivity in cultured fibroblast cells. / Virol. 78(12):6527-42; Liu, B., and Shuai, K. 2009. Summon SUMO to wrestle with inflammation. Mol Cell. 35(6):731-2; Wang, J., and Schwartz, R. J. 2010. Sumoylation and regulation of cardiac gene expression. Circ Rei. l07( l): 19-29). [0007] It would be beneficial therefore to provide new SAE inhibitors that possess good therapeutic properties, especially for the treatment of proliferative, inflammatory, cardiovascular and neurodegenerative disorders.

PATENT

WO 2016004136

https://patents.google.com/patent/WO2016004136A1/en

Example 133: [(lR,2S,4R)-4-[[5-[4-[(lR)-7-Chloro-l,2,3,4-tetrahydroisoquinolin-l-yl]-5-methyl- thiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxy-cyclopentyl]methyl sulfamate I-263a

Figure imgf000367_0001

Step 1: 7-Chloro-l-[5-(l,3-dioxolan-2-yl)-2-methyl-3-thienyl]-l,2,3,4-tetrahydroisoquinoline

[00714] An oven-dried 2-neck 250 mL round bottom flask under nitrogen was charged with THF (40 mL) and cooled to -74 °C . Added 2.50 M ra-BuLi in hexane (6.92 mL, 17.3 mmol). Added a solution of Int-1 (4.00 g, 16.0 mmol) in THF (60 mL) slowly keeping the internal temperature less than -70 °C . Stirred with cooling 5 min. A second oven-dried 250 mL round bottom flask under nitrogen was charged with THF (60 mL) and Int-50 (2.04 g, 12.4 mmol) and the resulting solution was cooled to 0 °C . Added boron trifluoride diethyl ether complex ( 1.71 mL, 13.6 mmol) slowly and cooled to -30 °C . The contents of the first flask were transferred via cannula to the second flask. Reaction was quenched with saturated aqueous NaHC03 and warmed to rt. Water was added, and the mixture was extracted three times with EtOAc. Combined organic portions were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. Residue was purified via flash column chromatography eluting with a hexane / EtOAc gradient (0 to 100% EtOAc) to afford the title compound as a white solid ( 1.88g, 45%). Ή NMR (400 MHz, Chloroform-d) δ 7.17 – 7.01 (m, 2H), 6.83 – 6.61 (m, 2H), 5.92 (s, 1H), 5.09 (s, 1H), 4.17 – 4.04 (m, 2H), 4.03 – 3.92 (m, 2H), 3.37 – 3.25 (m, 1H), 3.13 – 2.91 (m, 2H), 2.82 – 2.69 (m, 1H), 2.46 (s, 3H). LCMS: (AA) M+l 336.1

Step 2: ieri-Butyl 7-chIoro-l-[5-(l,3-dioxolan-2-yl)-2-methyl-3-thienyl]-3,4-dihydroisoquinoIine -2(lH)-carboxyIate [00715] A 50 mL round bottom flask under nitrogen was charged with 7-chloro-l -[5-(l ,3-dioxolan-2- yl)-2-methyl-3-thienyl]- l ,2,3,4-tetrahydroisoquinoline (5.67 g, 16.9 mmol) and DCM ( 100 mL), to which was added triethylamine (4.71 mL, 33.8 mmol), di-ieri-butyldicarbonate (4.61 g, 21.1 mmol), and N,N-dimethylaminopyridine (23 mg, 0.18 mmol). Reaction was stirred for 1 h at rt and then poured into saturated NaHC03 solution. Mixture was extracted three times with DCM, and the combined organic portions were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a hexane / EtOAc gradient to afford 6.96g (95%) of the title compound. LCMS: (AA) M+ l 436.1

Step 3: tert-Butyl 7-chloro-l-(5-formyl-2-methyl-3-thienyl)-3,4-dihydroisoquinoline -2(1H)- carboxylate

[00716] A 1 L round bottom flask was charged with ferf-butyl 7-chloro-

1 -[5-( 1 ,3-dioxolan-2-yl)-2-methyl-3-thienyl]-3 ,4-dihydroisoquinoline-2( 1 H)-carboxylate (7.30 g, 16.7 mmol), methanol (200 mL), and water (20 mL), to which was added a solution of 12M HC1 (4.00 mL, 130 mmol) in methanol (200 mL), and the reaction was stirred at rt for 1 h. Reaction was quenched via addition of 50mL of saturated NaHC03 and stirred for 5 min. Methanol was removed in vacuo, and the resulting aqueous mixture was extracted three times with EtOAc, and then the combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a hexane / EtOAc gradient to afford the title compound (4.55g, 70%). Ή NMR (400 MHz, Chloroform-d) δ 9.67 (s, 1 H), 7.27 – 7.15 (m, 2H), 7.12 (s, 1 H), 6.98 – 6.94 (m, 1 H), 6.34 (m, l H), 4.15 (s, 1 H), 3.18 – 3.06 (m, 1 H), 3.05 – 2.93 (m, 1H), 2.82 – 2.73 (m, 1 H), 2.69 (s, 3H), 1.50 (s, 9H). LCMS: (AA) M+Na 414.2

Step 4: tert-Butyl 7-chIoro-l-{5-[(4-chloropyrimidin-5-yl)(hydroxy)methyI]-2-methyl-3-thienyl}- 3,4-dihydroisoquinoline-2(lH)-carboxylate

[00717] An oven-dried 500 mL 3-neck round bottom flask under nitrogen was charged with 4-chloro- 5-iodopyrimidine (4.08 g, 17.0 mmol) and 2-methyltetrahydrofuran ( 150 mL). An addition funnel containing a solution of rert-butyl 7-chloro- l -(5-formyl-2-methyl-3-thienyl)-3,4- dihydroisoquinoline-2(l H)-carboxylate (4.75 g, 12.1 mmol) in 2-methyltetrahydrofuran (50 mL) was attached, and the contents of the reaction flask were cooled to -75 °C . 2.50 M n-BuLi in hexane ( 14.1 mL, 35.2 mmol) was added in small portions keeping the internal temperature less than -70 °C , at which point the contents of addtion funnel were added in a single portion. Upon completion of addition, the reaction was quenched by adding 20 mL of saturated NaHC03 in small portions and warmed to rt. The aqueous mixture was extracted three times with EtOAc, and then the combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a hexane / EtOAc gradient to afford the title compound (4.85g, 79%). LCMS: (AA) M+Na 528.1

Step 5: tert-Butyl 7-chloro-l-{5-[(4-chloropyrimidin-5-yl)(hydroxy)methyl]-2-methyl-3-thienyl}- 3,4- dihydroisoquinoline-2(lH)-carboxylate

[00718] A 1 L round bottom flask was charged with fe/Y-butyl 7-chloro- l – { 5-[(4-chloropyrimidin-5- yl)(hydroxy)methyl]-2-methyl-3-thienyl}-3,4-dihydroisoquinoline-2(l H)-carboxylate (4.85 g, 9.58 mmol) and DCM (300 mL). Manganese (IV) oxide (14.2 g, 163 mmol) was added and the reaction was stirred at rt for 18 h. Mixture was filtered through Celite, and the filter cake was rinsed with hot EtOAc. Filtrate was concentrated in vacuo to afford the title compound (4.47g , 93%). Ή NMR (400 MHz, Chloroform-d) δ 9.09 (s, 1 H), 8.70 (s, 1 H), 7.24 – 7.16 (m, 1 H), 7.16

– 7.07 (m, 1 H), 7.00 – 6.90 (m, 2H), 6.32 (s, 1 H), 4.28 – 3.97 (m, 1H), 3.14 – 2.89 (m, 2H), 2.78

– 2.65 (m, 4H), 1 .53 – 1.43 (m, 9H).

Step 6: tert-Butyl (lR)-7-chloro-l-[5-[4-[[(lR,3R,4S)-3-(hydroxymethyl)-4-triisopropylsiIyloxy- cyclopentyl]amino]pyrimidine-5-carbonyl]-2-methyl-3-thienyl]-3,4-dihydro-lH-isoquinoline-2- carboxylate

[00719] A 1 L round bottom flask under nitrogen was charged with iert-butyl 7-chloro- l – { 5-[(4- chloropyrimidin-5-yl)carbonyI]-2-methyl-3-thienyl }-3,4-dihydroisoquinoline-2( l H)-carboxylate (4.47 g, 8.86 mmol), DMF (20.0 mL, 258 mmol), Int-259 (3.06 g, 10.6 mmol), and triethylamine (3.09 mL, 22.2 mmol) and the mixture was stirred at rt for 18 h. Reaction mixture was poured into water and saturated NaHC03, and then extracted three times with EtOAc, and then the combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a 70/30 to 60/40 hexane/EtOAc gradient to afford 0.56g of first-eluting diastereomer 1 (not pictured), 4.3 l g of a mixture of diastereomers, and 1.1 lg ( 17%) of second-eluting diastereomer 2 (the title compound). The mixture of diastereomers thus obtained was resubjected to the described chromatography conditions two additional times to afford a total of 2.62 g of the desired diastereomer. Ή NMR (400 MHz, Methanol-d4) δ 8.54 – 8.46 (m, 2H), 7.27 – 7.19 (m, 2H), 7.09 – 6.99 (m, 2H), 6.37 (s, 1H), 4.87 – 4.75 (m, 1H), 4.38 – 4.29 (m, 1H), 4.20 – 4.09 (m, 1H), 3.66 – 3.52 (m, 2H), 3.28- 3.14 (m, 2H), 3.02 – 2.89 (m, 1 H), 2.89 – 2.78 (m, 1 H), 2.68 (s, 3H), 2.54 – 2.41 (m, 1 H), 2.22 – 2.09 (m, 2H), 1.86 – 1.73 (m, 1H), 1.50 (s, 8H), 1.39 – 1.23 (m, 2H), 1.15 – 1.04 (m, 20H).

LCMS: (AA) M+ 1 755.3

Step 7: tert-Butyl (lR)-7-chloro-l-[2-methyl-5-[4-[[(lR,3R,4S)-3-(sulfamoyloxymethyl)-4- triisopropylsilyloxy-cyclopentyl]amino]pyrimidine-5-carbonyl]-3-thienyl]-3,4-dihydro-lH- isoquinoline-2-carboxylate [00720] A solution of ie/t-butyl (lR)-7-chloro-l-[5-[4-[[( lR,3R,4S)-3-(hydroxymethyl)-4- triisopropylsilyloxy-cyclopentyl]amino]pyrimidine-5-carbonyl]-2-methyl-3-thienyl]-3,4-dih lH-isoquinoline-2-carboxylate (2.46 g, 3.26 mmol) in 2-methyltetrahydrofuran (25 mL), and DMF (25 mL) was cooled to 0 °C. Triethylamine ( 1.82 mL, 13.0 mmol) and chlorosulfonamide (1.50 g, 13.0 mmol) were added and the reaction was stirred for 10 min. Added methanol (0.53 mL, 13.0 mmol) and stirred for 15 min. Reaction mixture was poured into saturated NaHC03, extracted three times with EtOAc, and then the combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a hexane / EtOAc gradient to afford the title compound (2.41g, 89%). Ή NMR (400 MHz, Methanol-d4) δ 8.58 – 8.45 (m, 2H), 7.29 – 7.17 (m, 2H), 7.1 1 – 6.98 (m, 2H), 6.36 (s, 1 H), 4.84 – 4.73 (m, 1H), 4.44 – 4.33 (m, 1H), 4.21 – 4.08 (m, 4H), 3.27- 3.17 (m, 1 H),3.02 – 2.89 (m, 1 H), 2.88 – 2.78 (m, 1 H), 2.67 (s, 3H), 2.57 – 2.47 (m, 1 H), 2.41 – 2.30 (m, 1 H), 2.23 – 2.13 (m, 1 H), 1.87- 1.78 (m, 1 H), 1.50 (s, 9H), 1.43 – 1 .33 (m, 1 H), 1 .17 – 1.04 (m, 20H). LCMS: (AA) M+l 834.3

Step 8: [(lR,2S,4R)-4-[[5-[4-[(lR)-7-Chloro-l,2,3,4-tetrahydroisoquinolin-l-yl]-5-methyl- thiophene-2-carbonyl]pyrimidin-4-yI]aniino]-2-hydroxy-cyclopentyl]methyl sulfamate

[00721] A solution of f«?r/-butyl ( l R)-7-chloro- l -[2-methyl-5-[4-[[( l R,3R,4S)-3-

(sulfamoyloxymethyl)-4-triisopropylsilyloxy-cyclopentyl]amino]pyrimidine-5-carbonyl]-3- thienyl]-3,4-dihydro- l H-isoquinoline-2-carboxylate (2.41 g, 2.89 mmol) in CH3CN ( 10 mL) was cooled in an ice bath to + 1 °C . Phosphoric acid ( 10 mL, 200 mmol) was added dropwise and the reaction was stirred with ice bath cooling for 60 min. The mixture was warmed to rt and stirred for an additional 3 h. Reaction was poured into a stirring mixture of 50 mL water and 50 mL EtOAc, and the the pH was adjusted to ~9 by slowly adding 200 mL of saturated NaHC03 with stirring. Resulting aqueous mixture was extracted three times with EtOAc, and then the combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was subjected to flash column chromatography eluting with a gradient that began with 100% DCM and increased in polarity to 80% DCM / 20% methanol / 2% ammonium hydroxide gradient to afford the title compound (1.50 g, 90%). Ή NMR (400 MHz, Methanol-d4) δ 8.61 (s, 1H), 8.52 (s, 1 H), 7.27 (s, 1 H), 7.18 – 7.13 (m, 2H), 6.73 – 6.68 (m, 1 H), 5.23 (s, 1H), 4.81 – 4.70 (m, 1 H), 4.26 – 4.10 (m, 3H), 3.29 – 3.23 (m, 2H), 3.1 1 – 2.96 (m, 2H), 2.87 – 2.76 (m, 1H), 2.60 (s, 3H), 2.55 – 2.42 (m, 1 H), 2.33 – 2.19 (m, 1H), 2.18 – 2.07 (m, 1H), 1.95 – 1.81 (m, 1H), 1.47 – 1.35 (m, 1 H). LCMS: (AA) M+l 580.0

CLIP

Candidate: TAK-981

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20190404lnp1-tak981.jpg

Credit: Tien Nguyen/C&EN

Presenter: Steven Paul Langston, associate director at Takeda Pharmaceuticals International

Target: Sumo activating enzyme

Disease: Solid tumors

Reporter’s notes: Langston gave the last talk of the morning session, placing him in the “precarious position of being between you and lunch,” he said. Takeda acquired this drug development program, falling under the umbrella of immuno-oncology, along with Millenium Pharmaceuticals in 2008. The team targeted a pathway known as SUMOylation, a protein post translation modification that is implicated in a number of cellular processes including immune response. In SUMOylation, enzymes attach a small protein to another protein. They found that inhibiting this pathway activates a type I interferon response in immune cells. How the molecule, TAK-981, inhibits this pathway is quite complicated, Langston said. TAK-981 forms an adduct with a small ubiquitin like modifier (SUMO) to inhibit a SUMO activating enzyme that catalyzes SUMOylation. While the synthesis of TAK-981 is fairly short, it requires a nonideal chiral chromatography separation after the first step. TAK-981 is in Phase I clinical trials as an intravenous infusion for patients with metastatic solid tumors or lymphomas.

Patent ID Title Submitted Date Granted Date
US2018311239 HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF SUMO ACTIVATING ENZYME 2018-03-16
US9962386 HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF SUMO ACTIVATING ENZYME 2017-04-17
US9683003 HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF SUMO ACTIVATING ENZYME 2015-06-30 2016-01-14

//////////TAK-981, TAK 981, Phase I,  Lymphoma, Solid tumours, TAKEDA, 

Cc3sc(cc3[C@@H]1NCCc2ccc(Cl)cc12)C(=O)c5cncnc5N[C@@H]4C[C@H](COS(N)(=O)=O)[C@@H](O)C4

https://cen.acs.org/pharmaceuticals/drug-discovery/Drug-structures-displayed-first-time-in-Orlando/97/web/2019/04?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN

VNRX-7145


str1

str1

CAS 1842399-68-1

MF C19 H26 B N O7

MW 391.22

2H-1,2-Benzoxaborin-8-carboxylic acid, 3,4-dihydro-2-hydroxy-3-[(1-oxopropyl)amino]-, (2-ethyl-1-oxobutoxy)methyl ester, (3R)-

The VNRX-7145 combination is now in Phase I studies to treat resistant urinary tract infections.

str1

VNRX-7145

PATENT

WO 2015191907

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015191907

ntibiotics are the most effective drugs for curing bacteria-infectious diseases clinically. They have a wide market due to their advantages of good antibacterial effect with limited side effects. Among them, the beta-lactam class of antibiotics (for example, penicillins, cephalosporins, and carbapenems) is widely used because they have a strong bactericidal effect and low toxicity.

[0005] To counter the efficacy of the various beta-lactams, bacteria have evolved to produce variants of beta-lactam deactivating enzymes called beta-lactamases, and in the ability to share this tool inter- and intra-species. These beta-lactamases are categorized as“serine” or“metallo” based, respectively, on presence of a key serine or zinc in the enzyme active site. The rapid spread of this mechanism of bacterial resistance can severely limit beta-lactam treatment options in the hospital and in the community.

SCHEME 1

SCHEME 2

SCHEME 3

[00390] Alternatively, (II) can be obtained by treatment of (I) with hydrochloric acid (around 3-5 Molar in dioxane) in an alcohol solvent such as methanol, ethanol, or n-butanol at a temperature between room temperature and 120 ºC (SCHEME 4).

SCHEME 4

SCHEME 5

EXAMPLE 62: (R)-2-Hydroxy-3-propionylamino-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid

Step 1. Synthesis of 2-Methoxy-3-[2-propionylamino-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester.

[00540] Prepared from [(1S)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-chloro-ethyl]boronic acid (+) pinanediol ester and propionic acid following the procedure in Step 2 of Example 1. The crude product was purified by flash chromatography on silica gel (25-100% EtOAc/Hexane). ESI-MS m/z 486 (MH)+.

Step 2. Synthesis of (R)-2-Hydroxy-3-propionylamino-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid.

[00541] Prepared from 2-Methoxy-3-[2-propionylamino-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester following the procedure described in Step 3 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 264 (MH)+

CLIP

https://cen.acs.org/pharmaceuticals/drug-discovery/Drug-structures-displayed-first-time-in-Orlando/97/web/2019/04?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN

Candidate: VNRX-7145

20190404lnp1-vnrx7145.jpg

Credit: Tien Nguyen/C&EN

Presenter: Christopher John Burns, president and chief executive officer of VenatoRx Pharmaceuticals

Target: β-lactamases

Disease: Resistant urinary tract infections

Reporter’s notes: Having unveiled an antibacterial candidate at last spring’s first time disclosures session, Burns was back with another, this time the molecule can be taken orally. Both VenatoRx (pronounced Ven-a-tor-ix) compounds resuscitate the activity of β-lactam drugs, which make up more than 60% of all antibiotics prescribed. Unfortunately, many bacteria have grown resistant to these antibiotics. The new compounds rescue the old antibacterials by inhibiting β-lactamases, enzymes that chew up the antibiotics. To test the activity of new β-lactamase-targeting compounds, the researchers settled on several “sentinel” bacteria strains. Then to find a candidate with oral bioavailability, the team focused on molecules with low polarity and low molecular weight. They found VNRX-7145, developed as a prodrug in which esterases in the liver clip off the tips of the molecule to reveal the active drug. VNRX-5133, disclosed at last year’s meeting, had to be delivered intravenously along with another IV-antibiotic Cefepime, and targeted serine and metallo β-lactamases. The new oral candidate VNRX-7145 inhibits serine β-lactamases with Ceftibuten as its partner. The VNRX-7145 combination is now in Phase I studies to treat resistant urinary tract infections.

////////////VNRX-7145, VNRX7145, VNRX 7145, Phase I, VenatoRx

CCC(CC)C(=O)OCOC(=O)c1cccc2C[C@H](NC(=O)CC)B(O)Oc12

CCC(CC)C(=O)OCOC(=O)c1cccc2C[C@H](NC(=O)CC)B(O)Oc12

LHC 165


SDLWKRZBLTZSEL-UHFFFAOYSA-N.png

str1

LHC165

3-[5-amino-2-[2-[4-[2-(3,3-difluoro-3-phosphonopropoxy)ethoxy]-2-methylphenyl]ethyl]benzo[f][1,7]naphthyridin-8-yl]propanoic acid

C29H32F2N3O7P, 603.56 g/mol

CAS  1258595-14-0

5-Amino-2-[2-[4-[2-(3,3-difluoro-3-phosphonopropoxy)ethoxy]-2-methylphenyl]ethyl]benzo[f][1,7]naphthyridine-8-propanoic acid

Benzo[f][1,7]naphthyridine-8-propanoic acid, 5-amino-2-[2-[4-[2-(3,3-difluoro-3-phosphonopropoxy)ethoxy]-2-methylphenyl]ethyl]-

  • Originator Novartis
  • Class Antineoplastics
  • Mechanism of Action
  • Undefined mechanism
  • Phase I Solid tumours
  • 31 Jan 2018 Phase-I clinical trials in Solid tumours (Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater) in USA, Belgium, Italy, Japan (Intratumoural) (NCT03301896)
  • 31 Jan 2018 Phase-I clinical trials in Solid tumours (Inoperable/Unresectable, Late-stage disease, Metastatic disease, Monotherapy, Second-line therapy or greater) in USA, Japan, Italy, Belgium (Intratumoural) (NCT03301896)
  • 10 Oct 2017 Novartis plans a phase I trial for Solid tumours (Monotherapy, Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater) in USA, Belgium, Canada, France, Germany, Italy, South Korea and Spain in November 2017 (Intratumoural) (NCT03301896)

PATENT

WO 2010144734

PATENT

US 20110053893

PATENT

WO 2011130379

PATENT

WO 2011027222

 

Scheme (III)

Scheme (IV)

Scheme (V)

Example 19 (Table 1: Compound 19): Synthesis of 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][ 1, 7]naphthyridin-8-yl)propanoic acid (19)

Scheme 6

Step 1: (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3)

[517] To a solution of tert-butyl 5-bromo-2-chlorophenylcarbamate (6-1) (1.0 equiv.) in acetonitrile (0.3 M) and EtOH (0.5 M) was added K2C03 (2.0 equiv.). The reaction was degassed and flushed with N , then added (E)-ethyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (6-2) (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.). The reaction was flushed again with N2 and stirred at 100 °C overnight. After cooling to room temperature, hexane was added, and the mixture was filtered through a pad of silica, eluting with EA/Hex (1 : 1) until the product was completely eluted. The filtrate was concentrated and purified on Combiflash, eluting with 0-15% EA in Hex to give (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3) as a white solid.

Step 2: ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)propanoate (6-4)

[518] To a solution of (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3) (1.0 equiv.) in ethyl acetate/ethanol (1 : 1 , 0.3 M) was added Wilkinson’s catalyst (0.10 equiv.).

Hydrogen gas was introduced via a ballon, and the reaction was stirred at room temperature for 24 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated in vacuo and purified by Combiflash using 0-10% ethyl acetate in hexane to give ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)propanoate (6-4) as a solid.

Step 3: ethyl 3-(3-(tert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (6-5)

[519] A solution of ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)propanoate (6-4) (1 .0 equiv.), 4,4,4,,4′,5,5,5′,5′-octamethyl-2,2′-bi(l ,3,2-dioxaborolane) (2.0 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.05 equiv.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.20 equiv.), and potassium acetate (2.0 equiv.) in 1 ,4-dioxane (0.2 M) was degassed and stirred at 100 °C overnight. After cooling to ambient temperature, the reaction content was concentrated in vacuo. The crude material was purified by Combiflash using 0-50% ethyl acetate in hexane to afford ethyl 3-(3-(tert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)propanoate (6-5) as a brown oil. The product was stored at -20°C and used within a month of synthesis.

Step 4: l-bromo-4-(methoxymethoxy)-2-methylbenzene (6-7)

[520] To a solution of 4-bromo-3-methylphenol (6-6) (1.0 equiv.) in DMF (0.5 M) at 0 °C was added portionwise 60% wt NaH (1.5 equiv.). The addition was controlled such that internal reaction temperature never went above 10 °C. The reaction was stirred at room temperature for 45 minutes, then a solution of chloro(methoxy)methane (1.2 equiv.) in DMF (3 M) was added dropwise via additional funnel. The reaction was stirred at room temperature for 3.5 hours, and then quenched by pouring into ice. The resulting mixture was stirred at room temperature for 1 hour. Ether was added, and the two layers were separated. The aqueous layer was extracted (lx) with ether. The combined organic layers were washed with water (2x), brine, dried over MgS04, and concentrated to give 1 -bromo-4-(methoxymethoxy)-2-methylbenzene (6-7) as a colorless oil. The crude material was used in the next step without further purification.

Step 5: triethylf (4-(methoxymethoxy)-2-methylphenyl)ethynyl)silane

[521] A solution of l -bromo-4-(methoxymethoxy)-2-methylbenzene (1.0 equiv.), triethylamine (5.0 equiv.) in DMF (0.5 M) was degassed and flushed with nitrogen. To the reaction was added TES-acetylene (1.05 equiv.), Cul (0.098 equiv.), and Pd(PPh3)2Cl2 (0.098 equiv.). The reaction was heated to 60 °C and stirred overnight. After cooling to room temperature, water and ether were added. The layers were separated, and the organic layer was washed with water (2x). The organic layer was separated and passed through a pad of silica (packed with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated to give triethyl((4-(methoxymethoxy)-2-methylphenyl)ethynyl)silane as a black oil. The crude material was used in the next step without further purification.

Step 6: l-ethynyl-4-(methoxymethoxy)-2-methylbenzene (6-8)

[522] To a solution of triethyl((4-(methoxymethoxy)-2-methylphenyl)ethynyl)silane (1.0 equiv.) at

0 °C was slowly added tetrabutylammonium fluoride (1M solution in THF, 0.20 equiv.). At this

point, the ice-bath was removed and the reaction mixture was allowed to stir at room temperature for 45 minutes. The reaction mixture was then passed through a pad of silica (packed with hexane) and eluted with 20% EtOAc in Hexanes to remove insoluble salts. The crude product was then purified by Combiflash using 0-10% EtOAc in Hexanes to give 1 -ethynyl-4-(methoxymethoxy)-2-methylbenzene (6-8) as a slightly brown liquid.

Step 7: 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (6-10)

[523] A solution of l -ethynyl-4-(methoxymethoxy)-2-methylbenzene (6-8) (1 .0 equiv.), 3,5-dichloropicolinonitrile (6-9) (0.90 equiv.), Cul (0.10 equiv.), and Pd(PPh3)2CI2 (0.10 equiv.), and triethylamine (5.0 equiv.) in DMF (0.25 M) was degassed and flushed with nitrogen. The reaction mixture was then heated to 60 °C and stirred overnight. After cooling to room temperature, water was added. The mixture was extracted with EA (2x). The combined organic layers were washed with 10% aq NH4OH (2x), brine, and concentrated. The crude material was filtered through a pad of silica (wetted with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated. The resulting solids were washed in hot ether and filtered to give a yellow solid, which was used in the next step without further purification. The filtrate was concentrated and purified by Combiflash using 0- 10% EtOAc in Hexanes to give 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (6-10) as a yellow solid.

Step 8: ethyl 3-(5-amino-2-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)-ben∑o fJfl, 7J

naphthyridin-8-yl)propanoate (6-11)

[524] A solution of 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (6-10) (1 .0 equiv.), ethyl 3-(3-(tert-butoxycarbonylamino)-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)propanoate (6-5) (1.25 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.10 equiv.), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.20 equiv.), and sodium bicarbonate (3.0 equiv.) in «-butanol /H20 (5: 1 , 0.2 M) was degassed and stirred at 100 °C overnight. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgS04, and concentrated in vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (1SCO) using 0-40% ethyl acetate in DCM first to remove the impurity, then 0-4% MeOH in DCM to give ethyl 3-(5-amino-2-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)-benzo[f][l ,7]naphthyridin-8-yl) propanoate (6-11). Further purification was accomplished by precipitating and washing in hot ether.

Step 9: ethyl 3-(5-amino-2-(4-(methoxymethoxy)-2-methylphenethyl)benzo[fl[l ]naphthyridin-8-yl)propanoate (6-12)

[525] A solution of ethyl 3-(5-amino-2-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)-benzo[f][l ,7]naphthyridin-8-yl)propanoate (6-11) (1.0 equiv.) in EtOH/THF (3: 1 , 0.16 M) was flushed with nitrogen. Then, 10% wt Pd/C (0.20 equiv. by weight) was added. The reaction was flushed with hydrogen (2x) and stirred under a hydrogen balloon. After 24 hours, the reaction was filtered through a pad of celite, washing with 5%MeOH in DCM. The filtrate was checked for the presence of starting material using LCMS. The hydrogenation reaction was repeated until no more

of the alkyne starting material or alkene intermediate was detected. The crude product was purified by Combiflash using 0-4% eOH in DCM to give ethyl 3-(5-amino-2-(4-(methoxymethoxy)-2-methylphenethyl)benzo[f][l ,7]naphthyridin-8-yl)propanoate (6-12) as a white solid.

Step 10: ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[fl[l ]naphthyridin-8-yl)propanoate (6-13)

[526] Ethyl 3-(5-amino-2-(4-(methoxymethoxy)-2-methylphenethyl)benzo[fJ[l ,7]naphthyridin-8-yl)propanoate (6-12) (1 .0 equiv.) was dissolved in EtOH (0.2 M), then added a solution of 4M HC1 in dioxane (0.2 M). The product precipitated out as a yellow salt. After stirring for 3 hours, the reaction was poured into a stirring solution of ether. The mixture was stirred for 10 minutes, then filtered and washed with ether. Ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[fJ[l ,7]naphthyridin-8-yl)propanoate (6-13) was obtained as a yellow solid which was dried on vacuum overnight (bis-HCl salt). Alternatively, the crude product was purified by Combiflash using 0-5% MeOH in DCM to give the free base.

Step 11: ethyl 3-(5-amino-2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methylphenethyl)benzo[f] [1 , 7]naphthyridin-8-yl)propanoate ( 6-15)

[527] To a solution of ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[fJ [ l ,7]naphthyridin-8-yl)propanoate (6-13) (1.0 equiv.) dissolved in DMF (0.14 M) was added a solution of diethyl 3-(2-bromoethoxy)-l ,l -difluoropropylphosphonate (6-14: described in Example 7 – Step 1) (1 .3 equiv.) in DMF (0.7 M) and cesium carbonate (4 equiv.). The reaction was stirred at 60 °C. After 1.5 hours (or until reaction is complete by LCMS), DCM (2 volume equivalent) was added to the reaction. The solids (inorganic) were filtered, and the filtrate was concentration. The crude product was purified by Combiflash using 0-5%MeOH in DCM to give ethyl 3-(5-amino-2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methylphenethyl)benzo[fJ

[1 ,7]naphthyridin-8-yl)propanoate (6-15) as an oil which upon standing became a white solid.

Step 12: 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphompropoxy)ethoxy)-2-methylphenethyl)be o[f]

[1, 7]naphthyridin-8-yl)propanoic acid (19)

[528] To a solution of ethyl 3-(5-amino-2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methylphenethyl)benzo[f][l ,7]naphthyridin-8-yl)propanoate (6-15) (1.0 equiv.) in DCM (0.16 M) at 0 °C was added slowly TMSBr (10 equiv.). The reaction was stirred at room temperature overnight. Additional TMSBr (5.0 equiv.) was added at 0 °C, and the reaction was again stirred at room temperature overnight. The solvent was removed by evaporation and the crude orange solids dried on hi-vac briefly. The solids were suspended in EtOH (0.5 M) and added 2.5 N

NaOH (10.0 equiv.). The reaction was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was adjusted to pH 9 to 10 and directly purified on RP-HPLC using a CI 8 column, eluting with 10-40% 95:5 (MeCN/5mM NH4OAc) in l OmM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo. The resulting white gel was dissolved in refluxing 1 :1 EtOH/water (0.04 M) with the addition of a few drops of ammonium hydroxide. While hot, the mixture was slowly poured into a stirring hot solution of acetone (0.009

M) preheated at 50 °C. The acetone suspension was slowly cooled to room temperature for 15 minutes with continued stirring, and then sat in an ice bath for 10 minutes. The solids were filtered and washed successively with acetone (2x) and ether (2x). The solids were dried on hi-vac overnight to give the 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo [fj[l ,7]naphthyridin-8-yl)propanoic acid (19) as a solid. Ή NMR (Dimethylsulfoxide-d6): δ 9.02 (s, 1 H), 8.82 (s, 1H), 8.55 (d, 1H, J = 8.4 Hz), 7.58 (s, 1H), 7.48 (d, 1 H, J = 8.4 Hz), 7.07 (d, 1H, J = 8.4 Hz), 6.75 (s, 1 H), 6.68 (d, 1H, J = 8.4 Hz), 4.03-4.00 (m, 2H), 3.72-3.68 (m, 4H), 3.16-3.12 (m, 2H), 3.03-2.96 (m, 4H), 2.67-2.64 (m, 2H), 2.33-2.32 (m, 2H), 2.26 (s, 3H). LRMS [M+H] = 604.2

PATENT

US 20120237546

PATENT

WO 2012031140

PATENT

WO 2018211453

Toll-like receptors (TLRs) are pattern recognition receptors which play an essential role in the innate immunity, by recognizing invasion of microbial pathogens and initiating intracellular signal transduction pathways to trigger expression of genes, the products of which can control innate immune responses. Specifically, Toll like receptor (TLR) agonists activate innate immune cells through the TLR-MyD88-NFk and IRF3/7 pathways. TLR7, TLR8, and TLR9 belong to a subfamily of TLRs based on their genomic structure, sequence similarities, and homology. TLR7, TLR8, and TLR9 are located in intracellular endolysosomal compartments and show a unique pattern of cell type-specific expression that is thought to be responsible for different pathogen response profiles.

Small molecule agonists of TLR7 and/or TLR8 have been reported and shown to activate innate immune responses by inducing selected cytokine biosynthesis, the induction of co-stimulatory molecules, and by increased antigen-presenting capacity. Such compounds include imidazoquinoline amine derivatives (U.S. Patent No. 4689338), imidazopyridine amine derivative (U.S. Patent No. 5446153), imidazonaphthyridine derivative (U.S. Patent No.

6194425), oxazoloquinoline amine derivatives (U.S. Patent No. 61 10929); thiazoloquinoline amine derivatives (U.S. Patent No. 61 10929), selenazoloquinoline amine derivatives (U.S. Patent No. 61 10929), pyrazolopyridine derivatives (U.S. Patent No. 9145410), and

benzonaphthyridine amine derivatives (U.S. Patent Nos. 8466167 and 9045470).

The synthetic TLR7 agonist, Imiquimod (1 -(2-methylpropyl)-1 H-imidazo[ 4,5-c]quinolin-4-amine) is FDA-approved in a cream formulation for the topical treatment of cutaneous basal cell carcinoma, actinic keratosis and genital warts, and has limited activity against cutaneous melanoma and breast tumors (J. Immunol. 2014, 193(9) : 4722^1-731 ). Systemic administration of Imiquimod, and structurally similar Resiquimod, is limited by cytokine- mediated adverse effects including severe flu-like symptoms (Expert Opin. Emerging Drugs (2010), 15:544-555). Consequently, Imiquimod is used exclusively in topical applications and is not used to treat deep, non-cutaneous tumors such as melanoma or solid tumors.

An injectable lipid modified imidazoquinoline (TLR7/8 dual agonist) that forms a tissue depot with gradual, sustained release which allows for local TLR triggering activity without systemic cytokine release has been reported (J. Immunol. 2014, 193(9): 4722^731 ). However, this compound was shown to be ineffective for large tumors and in addition the serum concentration of this compound 24 hours post subcutaneous administration decreased by approximately 50% (Journal for ImmunoTherapy of Cancer, 2014, 2:12). Therefore, there remains a need for intratumor administration of a TLR7 agonist with prolonged sustained release, which may benefit the treatment of large tumors.

clip

https://cen.acs.org/pharmaceuticals/drug-discovery/Drug-structures-displayed-first-time-in-Orlando/97/web/2019/04?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN

Candidate: LHC165

20190404lnp1-lhc165.jpg

Credit: Tien Nguyen/C&EN

Presenter: Alex Cortez, senior Investigator I at the Genomics Institute of the Novartis Research Foundation

Target: Toll-like receptor 7 (TLR7)

Disease: Solid tumors

Reporter’s notes: Cortez shared another story in the realm of immuno-oncology, although the program that yielded this compound actually started in the world of vaccines. Cortez’s team had been focusing on vaccine adjuvants, small molecules that turn on the immune system to enhance a vaccine’s effect. They developed one such class of compound that activates toll-like receptor 7 (TLR7), a protein in the immune system that recognizes dangerous-looking molecules and can trigger the release of infection-clearing proteins. After observing TLR7 agonists’ ability to induce an immune response with vaccines, the researchers wondered whether the molecules could also be effective in immuno-oncology.

They found that LHC165 adsorbed to aluminum hydroxide reduced tumor growth in mice and, intriguingly, showed signs of an abscopal effect, in which untreated tumors shrink concurrently with treated tumors. The implication is that if the immune system recognizes one tumor site, it can recognize others. As with several of the candidates presented throughout the day, LHC165 bears a phosphate group and is injected into the tumor. It’s currently in Phase I trials in patients with advanced malignancies, which means they’ve already tried second and third line therapies, as a single agent and in combination with the checkpoint inhibitor PDR001.

US9618508FLOW CYTOMETRY ANALYSIS OF MATERIALS ADSORBED TO METAL SALTS2011-12-142013-12-12
US2014112950COMBINATION VACCINES WITH LOWER DOSES OF ANTIGEN AND/OR ADJUVANT2012-03-022014-04-24
Patent ID Title Submitted Date Granted Date
US9597326 BENZONAPTHYRIDINE COMPOSITIONS AND USES THEREOF 2011-04-13 2013-05-16
US9950062 COMPOUNDS AND COMPOSITIONS AS TLR ACTIVITY MODULATORS 2010-09-01 2012-09-20
US9517263 BENZONAPHTHYRIDINE-CONTAINING VACCINES 2010-06-10 2012-10-18
US2015225432 COMPOUNDS AND COMPOSITIONS AS TLR ACTIVITY MODULATORS 2015-04-24 2015-08-13
US9315530 ADSORPTION OF IMMUNOPOTENTIATORS TO INSOLUBLE METAL SALTS 2011-09-01
Patent ID Title Submitted Date Granted Date
US2016213776 ADSORPTION OF IMMUNOPOTENTIATORS TO INSOLUBLE METAL SALTS 2016-04-07 2016-07-28
US2012177681 Formulation of immunopotentiators 2011-09-01 2012-07-12
US9045470 COMPOUNDS AND COMPOSITIONS AS TLR ACTIVITY MODULATORS 2011-03-03
US2018169204 COMBINATION VACCINES WITH LOWER DOSES OF ANTIGEN AND/OR ADJUVANT 2018-02-02
US9375471 ADJUVANTED FORMULATIONS OF BOOSTER VACCINES 2013-03-08 2013-09-12

//////LHC165, LHC 165, LHC -165, Phase I,  Solid tumours, novartis

O=P(O)(O)C(F)(F)CCOCCOc4ccc(CCc1cc2c3ccc(CCC(=O)O)cc3nc(N)c2nc1)c(C)c4

CC1=C(C=CC(=C1)OCCOCCC(F)(F)P(=O)(O)O)CCC2=CN=C3C(=C2)C4=C(C=C(C=C4)CCC(=O)O)N=C3N

https://cen.acs.org/pharmaceuticals/drug-discovery/Drug-structures-displayed-first-time-in-Orlando/97/web/2019/04?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN

THELIATINIB


img str1

THELIATINIB

CAS: 1353644-70-8
Chemical Formula: C25H26N6O2

Molecular Weight: 442.523

HMPL-309; HMPL 309; HMPL309; Theliatinib.

  • Originator Hutchison MediPharma
  • Class Antineoplastics; Small molecules
  • Mechanism of Action Epidermal growth factor receptor antagonists

Highest Development Phases

  • Phase I Oesophageal cancer; Solid tumours

Most Recent Events

  • 29 Sep 2017 Efficacy and adverse events data from a phase I trial in Oesophageal cancer released by Hutchison Pharma
  • 13 Mar 2017 Phase-I clinical trials in Oesophageal cancer (First-line therapy) in China (PO) before March 2017 (Hutchison MediPharma pipeline, July 2017)
  • 02 Aug 2016 Hutchison MediPharma plans a phase Ib proof-of-concept trial for Oesophageal cancer, and Head and Neck cancer in China

Theliatinib, also known as HMPL-309, is a novel small molecule, epidermal growth factor receptor tyrosine kinase inhibitor with potential antineoplastic and anti-angiogenesis activities. In vitro studies suggest that Theliatinib is a potent EGFR kinase inhibitor with good kinase selectivity and in vivo data demonstrated broad spectrum anti-tumor activity via oral dosing in multiple xerographs such as A-431, Bcap-37 and Fadu.

PRODUCT PATENT

  • By Zhang, Weihan; Su, Wei-Guo; Yang, Haibin; Cui, Yumin; Ren, Yongxin; Yan, Xiaoqiang

WO2012000356 , covering quinazoline compounds as EGFR inhibitors

https://encrypted.google.com/patents/WO2012000356A1?cl=pt-PT&hl=en&output=html_text

Example 3:

(3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-l-methyl-hexahydropyrrolo [3,4-b]pyrrole-5(lH)-carboxamide

[060] To a solution of Compound 3-a (40 g, 0.138 mol, prepared according to procedures disclosed in WO2010002845), pyridine (40 mL, 0.495 mol) and DMF (anhydrous, 22 mL) in anhydrous THF (500 mL), was added phenyl carbonochloridate 3-b (22 mL, 0.175 mol) dropwise at -10°C. The mixture was stirred at room temperature for 12 hours. The precipitates were filtered and then suspended in saturated NaHC03 solution (500 mL). The solid was filtered, washed with H20 and EtOAc, and dried in vacuum to give compound 3-c (46 g).

A mixture of compound 3-c (1 g, 2.44 mmol) and compound 3-d (369 mg, 2.92 mmol) in dioxane (30mL) was stirred at 70°C for 5 hours, and then cooled to the ambient temperature. The precipitates were filtered, washed with EtOAc, and dried in vacuum to give compound 3 (0.8 g). MS (m/e): 443.4 (M+l)+.

PATENT

https://patents.google.com/patent/WO2010002845A2/en

PATENT

US 9168253

https://patents.google.com/patent/US9168253

Example 3 (3aR,6aR)—N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide

Figure US09168253-20151027-C00004

To a solution of Compound 3-a (40 g, 0.138 mol, prepared according to procedures disclosed in WO2010002845), pyridine (40 mL, 0.495 mol) and DMF (anhydrous, 22 mL) in anhydrous THF (500 mL), was added phenyl carbonochloridate 3-b (22 mL, 0.175 mol) dropwise at −10° C. The mixture was stirred at room temperature for 12 hours. The precipitates were filtered and then suspended in saturated NaHCO3solution (500 mL). The solid was filtered, washed with H2O and EtOAc, and dried in vacuum to give compound 3-c (46 g). A mixture of compound 3-c (1 g, 2.44 mmol) and compound 3-d (369 mg, 2.92 mmol) in dioxane (30 mL) was stirred at 70° C. for 5 hours, and then cooled to the ambient temperature. The precipitates were filtered, washed with EtOAc, and dried in vacuum to give compound 3 (0.8 g). MS (m/e): 443.4 (M+1)+.

PATENT

THELIATINIB BY HUTCHISON

WO-2018099451

The present invention belongs to the field of pharmacy and provides a crystal form of a compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, a pharmaceutical composition thereof, and a preparation method therefor and the use thereof.
(FR)La présente invention concerne le domaine de la pharmacie et fournit une forme cristalline d’un composé (3aR,6aR)-N-(4-(3-éthynylphénylamino)-7-méthoxyquinazolin-6-yl)-1-méthyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, une composition pharmaceutique de celui-ci, et son procédé de préparation et son utilisation.

Novel crystalline forms of the compound presumed to be theliatinib , processes for their preparation and compositions comprising them are claimed. Also claimed is their use for treating lung cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, brain cancer, esophageal cancer, bone cancer and leukemia.

Hutchison Medipharma is developing theliatinib, a small molecule EGFR tyrosine kinase and AKT cell proliferation pathway inhibitor, for treating cancer, including brain tumor, esophageal tumor and NSCLC; in September 2017, positive preliminary data were presented. Hutchison is also developing epitinib succinate , for treating cancer including glioblastoma.

Binding of epidermal growth factor (EGF) to epidermal growth factor receptor (EGFR) activates tyrosine kinase activity and triggers a response that leads to cell proliferation. Overexpression and/or overactivation of EGFR can lead to uncontrolled cell division, and uncontrolled cell division can be a cause of cancer. Therefore, compounds that inhibit the over-expression and/or over-activation of EGFR are candidates for treating tumors.
Relevant compounds of the present invention (3aR, 6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo [3, 4-b]pyrrole-5(1H)-carboxamide, whose chemical structure is shown in Formula A, has the effect of effectively inhibiting overexpression and/or overactivation of EGFR. Therefore, it can be used for the treatment of diseases associated with overexpression and/or overactivation of EGFR, such as the treatment of cancer.
Before discovering the crystal form of a compound, it is difficult to predict (1) whether a particular compound exists in crystalline form; (2) how an unknown crystal form is made; (3) what the properties of the crystal form would be, such as stability , bioavailability and so on.
Since the properties of the solid depend on the structure and the nature of the compound itself, different solid forms of the compound often exhibit different physical and chemical properties. Differences in chemical properties can be measured, analyzed, and compared using a variety of analytical techniques that ultimately can be used to distinguish these different solid forms. Differences in physical properties, such as solubility and bioavailability, are also important in describing the solid form of the drug compound. Likewise, in the development of pharmaceutical compounds, such as compounds of Formula A, the new crystalline and amorphous forms of the pharmaceutical compounds are also important.

Patent CN102906086A discloses compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 4-b]pyrrole-5(1H)-carboxamide and its preparation method.

Experimental part
 
The starting material of the compound of formula A used in the examples was prepared according to CN102906086A
PATENT

Example 3: (3aR, 6aR) -N- (4- (3- ethynyl-phenylamino) -7-methoxy-quinazolin-6-yl) -1-methyl-hexahydro-pyrrolo [3,4-b] pyrrol -5 (IH) – carboxamide

[0102]

Figure CN102906086AD00131

[0103] at -10 ° C, to (40g, 0. 138mol, was prepared in accordance with the operation disclosed in W02010002845) Compound 3-a, pyridine (40mL, O. 495mol) and DMF (anhydrous, 22mL) in dry solution (500 mL) in THF dropwise phenyl chloroformate 3-b (22mL, O. 175mol). The mixture was stirred at room temperature for 12h. The precipitate was filtered off, and then it was suspended in saturated NaHCO3 solution (500mL). The solid was filtered off, washed with H2O and EtOAc, and dried in vacuo to give compound 3_c (46g). Compound 3-c (lg, 2. 44mmol) and the compound 3_d (369mg, 2. 92mmol) in a mixture of two anger dioxane (30mL) was stirred at 70 ° C 5 h, then cooled to ambient temperature. The precipitate was filtered off, washed with EtOAc, and dried in vacuo to give compound 3 (O. 8g). MS (m / e): 443. 4 (M + 1) +.

Theliatinib (HMPL-309)

Theliatinib (HMPL-309) is a novel small molecule, epidermal growth factor receptor tyrosine kinase inhibitor with potential antineoplastic and anti-angiogenesis activities. Theliatinib is being developed as an oral formulation for the treatment of solid tumors like non-small cell lung cancer.

Theliatinib pre-clinical studies were conducted in China. In vitro studies suggest that Theliatinib is a potent EGFR kinase inhibitor with good kinase selectivity and in vivo data demonstrated broad spectrum anti-tumor activity via oral dosing in multiple xerographs such as A-431, Bcap-37 and Fadu. Non-clinical safety studies have indicated that Theliatinib is generally well tolerated in animals.

In November 2012, HMP initiated the first-in-human clinical trials of theliatinib.

Patent Citations (4)

Publication number Priority date Publication date  AssigneeTitle
CN101094840A *2004-12-292007-12-26韩美药品株式会社Quinazoline derivatives for inhibiting cancer cell growth and method for the preparation thereof
CN101619043A *2008-06-302010-01-06和记黄埔医药(上海)有限公司Quinazoline derivant and medical application thereof
WO2010002845A2 *2008-06-302010-01-07Hutchison Medipharma Enterprises LimitedQuinazoline derivatives
CN102311438A *2010-06-302012-01-11和记黄埔医药(上海)有限公司Quinazoline compound
CN106117182A *2016-06-202016-11-16中国药科大学Quinazoline-N-phenethyl tetrahydroisoquinoline compound and preparation method and application thereof

REFERENCES

1: Ren Y, Zheng J, Fan S, Wang L, Cheng M, Shi D, Zhang W, Tang R, Yu Y, Jiao L,
Ni J, Yang H, Cai H, Yin F, Chen Y, Zhou F, Zhang W, Qing W, Su W. Anti-tumor
efficacy of theliatinib in esophageal cancer patient-derived xenografts models
with epidermal growth factor receptor (EGFR) overexpression and gene
amplification. Oncotarget. 2017 Apr 19. doi: 10.18632/oncotarget.17243. [Epub
ahead of print] PubMed PMID: 28472779.

//////THELIATINIB, HMPL-309, HMPL 309, HMPL309, Phase I,  Oesophageal cancer,  Solid tumours

 O=C(N1C[C@]2([H])N(C)CC[C@]2([H])C1)NC3=CC4=C(NC5=CC=CC(C#C)=C5)N=CN=C4C=C3OC

BMS-986195


img
BMS-986195
  • Molecular FormulaC20H23FN4O2
  • Average mass370.421 Da
  • CAS: 1912445-55-6
1H-Indole-7-carboxamide, 5-fluoro-2,3-dimethyl-4-[(3S)-3-[(1-oxo-2-butyn-1-yl)amino]-1-piperidinyl]-
4-[(3S)-3-(2-Butynoylamino)-1-piperidinyl]-5-fluor-2,3-dimethyl-1H-indol-7-carboxamid
(S)-4-(3-(2-Butynoylamino)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide
(S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimeth -lH-indole-7-carboxamide
  • Originator Bristol-Myers Squibb
  • Class Anti-inflammatories; Antirheumatics
  • Mechanism of Action Agammaglobulinaemia tyrosine kinase inhibitors

Highest Development Phases

  • Phase I Rheumatoid arthritis

Most Recent Events

  • 30 Jan 2018 Bristol-Myers Squibb completes a phase I trial in Rheumatoid arthritis (In volunteers, In adults, Combination therapy) in USA (PO) (NCT03262740)
  • 10 Nov 2017 Bristol-Myers Squibb completes a phase I drug-drug interaction trial in Healthy volunteers (NCT03131973)
  • 03 Nov 2017 Safety, pharmacokinetic, and pharmacodynamic data from a pharmacokinetic trial in healthy volunteers presented at the 81st American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2017)
  • Image result for BMS-986195

BMS-986195 is a potent, covalent, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases essential in antigen-dependent B-cell signaling and function. BMS-986195 is more than 5000-fold selective for BTK over all kinases outside of the Tec family, and selectivity ranges from 9- to 1010-fold within the Tec family. BMS-986195 inactivated BTK in human whole blood with a rapid rate of inactivation (3.5×10-4 nM-1·min-1) and potently inhibited antigen-dependent interleukin-6 production, CD86 expression and proliferation in B cells (IC50 <1 nM) without effect on antigen-independent measures in the same cells.

Bristol-Myers Squibb is developing BMS-986195, an oral candidate for the treatment of rheumatoid arthritis. A phase I clinical trial in healthy adult volunteers is ongoing.

Image result

Structure of BMS986195.
Credit: Tien Nguyen/C&EN

Presented by: Scott H. Watterson, principal scientist at Bristol-Myers Squibb

Target: Bruton’s tyrosine kinase (BTK)

Disease: Autoimmune diseases such as rheumatoid arthritis

Reporter’s notes: Completing another set of back-to-back presentations on the same target, Watterson revealed another BTK inhibitor also in Phase II clinical trials. Chemists made BMS-986195 in seven steps, and the molecule showed high levels of BTK inactivation in mice. The team aimed to develop an effective compound that required low doses and that had low metabolic degradation.

Patent

WO 2016065226

Inventor Saleem AhmadJoseph A. TinoJohn E. MacorAndrew J. TebbenHua GongQingjie LiuDouglas G. BattKhehyong NguScott Hunter WattersonWeiwei GuoBertrand Myra Beaudoin

Original Assignee Bristol-Myers Squibb Company

https://patents.google.com/patent/WO2016065226A1/en

PATENT

WO 2018045157

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E81EF2BDB127473D100AAA55455FC42B.wapp1nA?docId=WO2018045157&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

otein kinases, the largest family of human enzymes, encompass well over 500 proteins. Btk is a member of the Tec family of tyrosine kinases, and is a regulator of early B-cell development, as well as mature B-cell activation, signaling, and survival.

B-cell signaling through the B-cell receptor (BCR) leads to a wide range of biological outputs, which in turn depend on the developmental stage of the B-cell. The magnitude and duration of BCR signals must be precisely regulated. Aberrant BCR-mediated signaling can cause dysregulated B-cell activation and/or the formation of pathogenic auto-antibodies leading to multiple autoimmune and/or inflammatory diseases. Mutation of Btk in humans results in X-linked agammaglobulinaemia (XLA). This disease is associated with the impaired maturation of B-cells, diminished immunoglobulin production, compromised T-cell-independent immune responses and marked attenuation of the sustained calcium signal upon BCR stimulation.

Evidence for the role of Btk in allergic disorders and/or autoimmune disease and/or inflammatory disease has been established in Btk-deficient mouse models. For example, in standard murine preclinical models of systemic lupus erythematosus (SLE), Btk deficiency has been shown to result in a marked amelioration of disease progression. Moreover, Btk deficient mice are also resistant to developing collagen-induced arthritis and are less susceptible to Staphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoral immune system in the pathogenesis of autoimmune and/or inflammatory diseases. Protein-based therapeutics (such as Rituxan) developed to deplete B-cells, represent an important approach to the treatment of a number of autoimmune and/or inflammatory diseases.

Because of Btk’s role in B-cell activation, inhibitors of Btk can be useful as inhibitors of B-cell mediated pathogenic activity (such as autoantibody production).

Btk is also expressed in mast cells and monocytes and has been shown to be important for the function of these cells. For example, Btk deficiency in mice is associated with impaired IgE -mediated mast cell activation (marked diminution of T F-alpha and other inflammatory cytokine release), and Btk deficiency in humans is associated with greatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment of allergic disorders and/or autoimmune and/or inflammatory diseases including, but not limited to: SLE, rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin diseases, Evan’s syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjogren’s syndrome, peripheral neuropathies (e.g., Guillain-Barre syndrome), pemphigus vulgaris, and asthma.

In addition, Btk has been reported to play a role in controlling B-cell survival in certain B-cell cancers. For example, Btk has been shown to be important for the survival of BCR-Abl-positive B-cell acute lymphoblastic leukemia cells. Thus inhibition of Btk activity can be useful for the treatment of B-cell lymphoma and leukemia.

In view of the numerous conditions that are contemplated to benefit by treatment involving modulation of protein kinases, it is immediately apparent that new compounds capable of modulating protein kinases such as Btk and methods of using these compounds should provide substantial therapeutic benefits to a wide variety of patients.

WO 2016/065226 discloses indole carboxamide compounds useful as Btk inhibitors, including (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (Example 223), which has the structure:

Also disclosed is multistep synthesis process for preparing (S)-4-(3-(but-2-ynamido) piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide.

There are difficulties associated with the adaptation of the multistep synthesis disclosed in WO 2016/065226 to larger scale synthesis, such as production in a pilot plant or a manufacturing plant for commercial production. Further, there is a continuing need to find a process that has few synthesis steps, provides higher yields, and/or generates less waste.

Applicants have discovered a new synthesis process for the preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide that has fewer synthesis steps and/or provides higher yields than the process disclosed in WO 2016/065226. Furthermore, this process contains no metal-catalyzed steps, no genotoxic intermediates, and is adaptable to large scale manufacturing.

EXAMPLE 1

(S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

Step 1 : Preparation of Methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-fluorobenz

To a 250 mL ChemGlass reactor were charged methyl 2-amino-4,5-difluoro-benzoate (11.21 g, 59.90 mmol), tert-butyl N-[(3S)-3-piperidyl]carbamate (10 g, 49.930 mmol), potassium phosphate, dibasic (10.44 g, 59.94 mmol), and dimethyl sulfoxide (100 mL, 1400 mmol). The resulting thin slurry was heated to 95 to 100 °C and agitated at this temperature for 25 hours. The mixture was cooled to 50 °C. Methanol (100 mL) was added and followed by slow addition of water (50 mL). The mixture was aged at 50 °C for 30 minutes to result in a thick white slurry. Additional water (150 mL) was slowly charged to the above mixture and agitated at 50 °C for 1 hour. The slurry was cooled to 20 °C in 1 hour and aged at this temperature for 4 hours. The slurry was filtrated. The wet cake washed with 25% MeOH in water (30 mL), water (100 mL) and dried under vacuum at 60 °C for 24 h. Methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate was obtained as a white solid (7 g, yield: 72.5%). ¾ MR (400MHz, METHANOLS) δ 7.34 (d, J=14.6 Hz, 1H), 6.27 (d, J=7.3 Hz, 1H), 3.83-3.71 (s, 3H), 3.68-3.57 (m., 1H), 3.50 -3.40 (m 1H), 3.39 -3.31 (m, 1H), 3.31-3.26 (m, 1H), 2.86-2.70 (m, 1H), 2.64 (t, J=10.0 Hz, 1H), 1.97-1.84 (m, 1H), 1.84-1.74 (m, 1H), 1.73-1.61 (m, 1H), 1.44 (s, 9H), 1.38 (m, 1H). LC-MS [M+H] 368.

Step 2: Preparation of Methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate

To a reactor were charged methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate (5.0 g), DPPOH (diphenyl phosphate, 6.81 g, 2 eq) and 3-hydroxybutanone (1.2 eq, 1.44 g), followed by addition of isopropyl acetate (100 mL, 20 mL/g). The mixture was allowed to warm up to 70 to 75 °C, resulting in a yellow solution. The solution was stirred at 70 to 75 °C for 30 h to complete the cyclization.

Water (2 mL) was added and the mixture was aged at 70 °C over 24 h to remove the Boc group. The mixture was cooled to room temperature. Next, aqueous 20% K3PO4 solution (50 mL) was added and the mixture was stirred for 15 min. The organic layer was separated and washed with water (50 mL). The organic layer was then concentrated under vacuum (200 Torr) to -50 mL. The resulting slurry was stirred at 50 °C for 2 h and then heptane (100 mL) was added over 1 h. The mixture was cooled to room

temperature, stirred for 20 h, and then filtered. The cake was washed with heptane (50 mL). Methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate, DPPOH salt was obtained as a light yellow solid. The wet-cake was added to a reactor. Isopropyl acetate (100 mL) was added, followed by addition of aqueous K3PO4 solution (4 g in water 50 mL). The mixture was stirred at room temperature for -half-hour, resulting in a two phase clear solution (pH >10 for aqueous). The organic layer was separated and washed with water (50 mL), and then concentrated under vacuum to a volume of 15 mL. The resulting slurry was stirred at room temperature for 4 h, then heptane (75 mL) was added over 1 h. The mixture was aged at room temperature for 24 h, then concentrated to a volume to -50 mL. The slurry was filtered. The cake was washed with heptane 20 mL and dried under vacuum at 50 °C for 24 h. Methyl (S)-4-(3- aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate was obtained as a light yellow solid (2.76 g, yield: 69%). ¾ NMR (400MHz, DMSO-d6) δ 10.64 (s, 1H), 7.33 (d, J=13.7 Hz, 1H), 3.89 (s, 3H), 3.14 (br. m., 1H), 3.07-2.90 (m, 2H), 2.84 (br. m., 1H), 2.70 (br. m., 1H), 2.35 (s, 3H), 2.33 (s, 3H), 1.87 (br. m., 1H), 1.67 (br. m., 3H). LC-MS: M+H= 320.

Alternative Preparation

Step 2: Preparation of ethyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt

To a reactor were charged ethyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate (1.0 g, limiting reagent), DPPOH (diphenyl phosphate, 1.97 g, 3.0 eq) and 3-hydroxybutanone (1.4 eq, 0.32 g), followed by addition of toluene (20 mL, 20 mL/g). The mixture was allowed to warm up to 80-90 °C, resulting in a yellow solution. The solution was stirred at 80-90 °C for 10 h to complete the

cyclization. Water (0.4 mL, 0.4 ml/g) was added and the mixture was aged at 80-90 °C for 8 hours. The mixture was cooled to room temperature. Next, aqueous 20% K3PO4 solution (15 mL, 15 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated and the aqueous layer was washed with toluene (7.5 mL, 7.5 mL/g). To combined organic layers water (10 mL, 10 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated. To the organic layer water (10 mL, 10 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated. The organic layer was concentrated under vacuum (100 Torr) to 8 mL (8 ml/g). Following concentration the reaction mixture was cooled to 20-25 °C and MTBE (20 mL, 20 mL/g) was added. Trifluoroacetic acid (1.2 eq., 0.36 g) was slowly added to make the salt maintaining temperature at 20-25 °C. The resulting slurry was aged for 4 hours and then filtered. The filtered solids are washed with MTBE (8 mL, 8 mL/g) and the cake

was dried under vacuum at 50 °C. (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt was obtained as a white to tan crystalline material (85% yield, 1.0 g). ¾ NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.16-7.88 (m, 2H), 7.37 (d, 7=13.6 Hz, 1H), 4.38 (q, 7=7.1 Hz, 2H), 3.18-3.01 (m, 3H), 2.96 (br s, 1H), 2.35 (s, 6H), 2.30 (s, 1H), 2.12 (br d, 7=9.3 Hz, 1H), 1.78 (br s, 2H), 1.45-1.31 (m, 4H), 1.10 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 165.1, 165.1, 158.4, 158.1, 135.4, 134.7, 134.6, 132.2, 128.8, 128.2, 126.9, 126.8, 118.7, 115.7, 110.6, 110.3,108.7, 108.6, 106.6, 106.5, 83.5, 79.8, 60.5, 54.9, 51.7, 48.7, 47.2, 28.4, 26.8, 23.6, 14.2, 11.1, 10.2

Step 3A: Preparation of (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

A 40 mL vial was charged with methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate (1.5 g, 4.70 mmol), followed by the addition of N,N-dimethylformamide (12.0 mL, 8.0 mL/g). The vial was purged with N2. Formamide (1.49 mL, 37.6 mmol) was added followed by sodium methoxide solution in methanol (35 wt%, 1.29 mL, 3.76 mmol). The resulting solution was heated at 50 °C over 8 hours. The reaction mixture was cooled down to room temperature and the reaction was quenched with water (12.0 mL, 8.0 mL/g). 2-methyltetrahydrofuran (30 mL, 20 mL/g) was added to the mixture. The mixture was shaken vigorously. The layers were separated and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL, 10 mL/g) two more times. Organic extracts were then washed with brine and water (15 mL each, 10 mL/g). The organic layer was evaporated. Solids were dried in vacuo at 60 °C to afford (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide as a yellow solid (1.04 g, 69% yield). ¾ NMR (500MHz, DMSO-d6) δ 10.60 (br. s.,

1H), 7.91 (br. s., 1H), 7.40 (d, 7=14.0 Hz, 1H), 7.32 (br. s., 1H), 3.10 (br. s., 1H), 2.98 (br. s., 2H), 2.82 (br. s., 1H), 2.68 (br. s., 1H), 2.34 (br. s., 3H), 2.30 (br. s., 3H), 1.88 (br. s., 1H), 1.67 (br. s., 2H), 1.45 (br. s., 2H), 1.05 (br. s., 1H). LCMS [M+H] 305.24.

Step 3B: Alternative Preparation of (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

A 100 mL Hastelloy high pressure EasyMax reactor was charged with methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate (1.5 g, 4.70 mmol), followed by addition of 7 N ammonia solution in methanol (45.0 mL, 30.0 mL/g) followed by addition of l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (1.33 g, 9.39 mmol). The reactor was sealed and purged with N2 three times. The reactor was then heated to 80 °C for 24 hrs. The reaction mixture was cooled to room temperature and the vessel contents were purged with N2 three times. Volatiles were concentrated to ~6 mL (4 mL/g) and water (24 mL, 16 mL/g) was added. The yellow precipitate was collected and filtered. The precipitate was washed with methanol/water mixture (20:80 v/v, 6 mL, 4 mL/g), and then water (18 mL, 12 mL/g). The solids were dried in vacuo at 60 °C to afford (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide as a yellow crystalline material (0.93 g, 62% yield). ¾ MR (500MHz, DMSO-de) δ 10.60 (br. s., 1H), 7.91 (br. s., 1H), 7.40 (d, J=14.0 Hz, 1H), 7.32 (br. s., 1H), 3.10 (br. s., 1H), 2.98 (br. s., 2H), 2.82 (br. s., 1H), 2.68 (br. s., 1H), 2.34 (br. s., 3H), 2.30 (br. s., 3H), 1.88 (br. s., 1H), 1.67 (br. s., 2H), 1.45 (br. s., 2H), 1.05 (br. s., 1H). LCMS [M+H] 305.24.

Alternative Preparation:

Step 3C: Preparation of (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt

Ethyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt (1.0 g, limiting reagent) and formamide (5 mL, 5 mL/g) were added to a nitrogen inerted reactor. The temperature was maintained at 20-25 °C. To the reactor was added a solution of 20 wt% potassium t-butoxide in THF. The reaction mixture was allowed to sit for 6 hours. To reaction mixture was added Me-THF (15 mL, 15 mL/g) and 12.5 wt % aqueous NaCl (5 mL, 5 mL/g). The reaction mixture was stirred for 0.5 hour. The organic layer was separated, 5 wt% aqueous NaCl (1 mL, 1 mL/g) and 0.25 N aqueous NaOH (4 mL, 4 mL/g) were added, and then stirred for 0.5 hour. The organic layer was separated and 5 wt% aqueous NaCl (5 mL, 5 mL/g) was added, the mixture was stirred for 0.5 hour, and organic phase was separated. The rich organic phase was dried distillation at a pressure of 100 mtorr with Me-THF to obtain KF in 1.5-4wt% range at 5 mL Me-THF volume. The volume was adjusted to 15 mL Me-THF by adding Me-THF (10 mL, 10 mL/g) and EtOH (4 mL, 4 mL/g). Next, 2-butynoic acid (1.0 eq., 0.19 g) was added and the mixture was agitated for 10 hrs. The resulting slurry was filtered. The cake was washed with Me-THF (10 mL, 10 mL/g) and dried under vacuum at 75 °C to afford (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt (0.7 g, 80% yield) as white crystalline powder. ¾ NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.98 (br s, 1H), 7.50-7.32 (m, 2H), 3.32 (br d, J=8.6 Hz, 2H), 3.21 (br t, J=10.5 Hz, 1H), 3.13-2.89 (m, 3H), 2.32 (d, J=5.1 Hz, 5H), 2.11 (br d, J=10.9 Hz, 1H), 1.81-1.67 (m, 4H), 1.55-1.28 (m, 1H).

Step 4A: Preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

To Reactor-1 was charged N,N-dimethylformamide (DMF, 12.77 kg, 13.5 L). Reactor-1 was purged with N2 to inert. (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (3.0 kg, 1.0 equiv) was charged followed by 2-butynoic acid (0.854 kg, 1.04 equiv). Reactor-1 was rinsed with DMF (1.42 kg, 1.5 L). The mixture was sparged with N2 for 20 min. Triethylamine (2.99 kg, 3.0 equiv) was charged followed by a DMF rinse (1.42 kg, 1.5 L). TBTU (O-(Benzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium tetrafluorob orate, 3.256 kg, 1.04 equiv) was charged followed by a DMF rinse (1.42 kg, 1.5 L). The reaction mixture was agitated for 1.5 h at 20 °C. MeTHF (46.44 kg, 60 L) was charged to the batch. The reaction was quenched with LiCl (20 wt%, 26.76 kg, 24 L) at 20 °C. The bottom aqueous layer was discharged as waste. The organic layer was washed with 2N HCl solution (24.48 kg, 24 L), 10 wt% sodium bicarbonate solution (25.44 kg, 24 L) and deionized water (24.0 kg, 24 L). THF (26.61 kg, 30 L) was charged into Reactor-1. The rich organic stream in MeTHF/TFIF was polish filtered. The stream was distilled down to 15 L at 75-100 Torn Constant volume distillation was carried out at 15 L with THF feed (39.92 kg, 45 L). The stream was heated to 60 °C for 1 hr and cooled to 50 °C. MTBE (33.30 kg, 45 L) was charged slowly over 2 h. The slurry was aged at 50 °C for 4 h and cooled to 20 °C over 2 h, and aged at 20 °C for >2 h. The 1st drop slurry was filtered and was rinsed with MTBE (8.88 kg, 12 L) twice. Wet cake was dried under vacuum 60 to 70 °C at 25 mbar overnight (>15 h). Reactor-1 was thoroughly cleaned with IPA. The dry cake was charged into Reactor-1 followed by the charge of IPA (47.10 kg, 60 L). The batch was heated to 60 °C to achieve full dissolution and cooled to 40 °C. Rich organic (24 L) was transferred to Reactor-2 for crystallization. The stream was distilled at 24 L constant volume and 100 mbar using remaining rich organic from reactor-1 as distillation feed. Following distillation completion, the batch was heated to 60 °C, aged at 60 °C for 2 h, cooled to 20 °C over 2 h, and aged at 20 °C over 2 h. The slurry was filtered. IPA (1.18 kg) was used to rinse the reactor and washed the cake. The wet cake was dried under vacuum at 70 °C and 25 mbar for >15 h. The dry cake (2.196 kg, 63.2% yield) was discharged as an off-white crystalline solid. ¾ NMR (400MHz, DMSO-d6): δ 10.62 (s, 1H), 8.48 (d, J= 7.1 Hz, 1H), 7.91 (s, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.33 (s, 1H), 3.88 (m, 1H), 3.11 (t, J= 8.0 Hz, 1H), 3.0 (m, 1H), 2.96 (m, 1H), 2.78 (t, J= 10.0 Hz, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.92 (s, 3H), 1.86 (m, 1H), 1.31 (m, 1H), 1.70 (m, 2H); 13C NMR (400 MHz, DMSO-d6): δ 168.2, 153.2, 151.9, 134.4, 133.2, 132.1, 126.5, 112.3, 108.4, 106.0, 82.3, 75.7, 56.9, 51.9, 46.3, 29.7, 24.4, 11.1, 10.2, 3.0; LC-MS: M+H= 371.2.

Step 4B: Alternative preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimeth -lH-indole-7-carboxamide

To Reactor-1 was charged N,N-dimethylformamide (DMF 4.5 mL, 4.5 mL/g). Reactor-1 was purged with N2 to inert. (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt (1.0 g, limiting reagent) was charged followed by 2-butynoic acid (0.065g, 0.3 equiv.). The mixture was inerted with N2 for 20 min. N-methylmorpholine (0.78 g, 3.0 equiv) was charged. Next,

diphenylphosphinic chloride (0.79 g, 1.3 equiv) was charged over 0.5 h while maintaining the reaction temperature at 20-25 °C. The reaction mixture was agitated for 1.5 hour at 20 °C. Me-THF (14 mL, 14 mL/g) was charged to the reaction mixture. The reaction was quenched with the addition of aqueous NaCl (12.5 wt%, 6 mL, 6 mL/g) at 20 °C. The bottom aqueous layer was discharged as waste. Aqueous NaCl (12.5 wt%, 6 mL, 6 mL/g) at 20 °C was added to the organic layer, stirred for 0.5 hour and the bottom aqueous layer was discharged to waste. Deionized water (6 mL, 6 mL/g) was charged to the organic layer, stirred for 0.5 hour and the bottom aqueous layer was discharged to waste. THF (8 mL, 8 mL/g) was charged into Reactor-1 and the mixture was

concentrated under vacuum to remove Me-THF and water, and reconstituted in 4 L/kg of THF. The mixture was heated to 60 °C and stirred for 1 hour; the temperature was reduced to 50 °C and MTBE (12 mL, 12 mL/g) was added. The mixture was aged for 4 hours while maintaining the temperature of 50 °C and then cooled to room temperature. The solids were filtered and washed with MTBE (6.5 mL, 6.5 mL/g). The solids of crude were dried at 70 °C under vacuum for 12 hours.

Crude (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide was charged to Reactor-2, followed by THF (12 mL, 12 mL/g). The mixture was stirred for 0.5 hour. The solution was polish filtered. The solution was concentrated under vaccuum to remove THF and reconstituted in EtOH (7 mL, 7 mL/g). (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide seeds (0.01 g, 0.01 g/g) were added, the mixture was heated to 60 °C and aged for 2 hours, n-heptane (21 mL, 21 mL/g) was added slowly over 4 hours. The mixture was aged for additional 2 hours at 60 °C, followed by cooldown to room temperature. The slurry was filtered, washed with n-heptane (6 mL, 6 mL/g), and dried under vacuum at 70 °C for 12 hours. The dry cake (0.68 g, 71% yield) was discharged as an off-white crystalline solid. ¾ NMR (400MHz, DMSO-d6): δ 10.62 (s, 1H), 8.48 (d, J= 7.1 Hz, 1H), 7.91 (s, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.33 (s, 1H), 3.88 (m, 1H), 3.11 (t, J= 8.0 Hz, 1H), 3.0 (m, 1H), 2.96 (m, 1H), 2.78 (t, J= 10.0 Hz, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.92 (s, 3H), 1.86 (m, 1H), 1.31 (m, 1H), 1.70 (m, 2H); 13C MR (400 MHz, DMSO-d6): δ 168.2, 153.2, 151.9, 134.4, 133.2, 132.1, 126.5, 112.3, 108.4, 106.0, 82.3, 75.7, 56.9, 51.9, 46.3, 29.7, 24.4, 11.1, 10.2, 3.0; LC-MS: M+H= 371.2.

Applicants have discovered a new synthesis process for the preparation of (S)-4- (3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide which offers significant advantages.

The new synthesis process utilizes fewer synthesis steps (4 vs 8) than the process disclosed in WO 2016/065226.

Additionally, the process of the present invention provided (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide at an overall

yield of 22% (step 1 : 73.%, step 2: 69%, step 3 : 69%, step 4: 63%). In comparison, (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide was prepared according to the process of WO 2016/065226, which provided (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide at an overall yield of 2.9% yield (step 1 : 91%, step 2: 71%, step 3 : 35%, step 4: 88%, step 5: 80%, step 6: 29%, step 7: 99%, step 8: 63%).

Furthermore, the process of the present invention does not include any transition metal-catalyzed steps, no genotoxic intermediates, and is adaptable to large scale manufacturing. In comparison, the process disclosed in WO 2016/065226 employed lead (Pb) in process step (8) and included a potentially genotoxic hydrazine intermediate in process step 8.

The process of the present invention has an estimated manufacturing cycle time of approximately 6 months versus a estimated manufacturing cycle time of approximately 12 months for the process disclosed in WO 2016/065226.

REFERENCE

http://acrabstracts.org/abstract/bms-986195-is-a-highly-selective-and-rapidly-acting-covalent-inhibitor-of-brutons-tyrosine-kinase-with-robust-efficacy-at-low-doses-in-preclinical-models-of-ra-and-lupus-nephritis/

/////////////////BMS-986195, Phase I,  Rheumatoid arthritis, BMS

NC(=O)c2cc(F)c(c1c(C)c(C)nc12)N3CCC[C@@H](C3)NC(=O)C#CC

PRN 1371


ChemSpider 2D Image | PRN 1371 | C26H30Cl2N6O4

str1SCHEMBL16993012.png

PRN 1371

  • Molecular Formula C26H30Cl2N6O4
  • Average mass 561.460

cas 1802929-43-6

8-[3-(4-Acryloyl-1-piperazinyl)propyl]-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-[3-[4-(1-oxo-2-propen-1-yl)-1-piperazinyl]propyl]pyrido[2,3-d]pyrimidin-7(8H)-one

Phase I Solid tumours

  • Originator Principia Biopharma
  • Class Small molecules
  • Mechanism of Action Fibroblast growth factor receptor antagonists
  • 06 Jun 2016 Adverse events data from a phase I trial in Solid tumours presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO- 2016)
  • 01 Nov 2015 Phase-I clinical trials in Solid tumours in USA (PO) (NCT02608125)
  • 12 Jan 2015 Preclinical trials in Cancer in USA (PO)
Inventors Erik Verner, Kenneth Albert Brameld
Applicant Principia Biopharma, Inc.

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Erik Verner

Erik Verner

Ken Brameld

Kenneth Albert Brameld

CONTD………………..

Fibroblast growth factors (FGFs) and their receptors (FGFRs) play important roles in physiological processes relating to tissue repair, hematopoiesis, bone growth, angiogenesis and other aspects of embryonic development. Alterations in the FGF signaling pathway have also emerged as important drivers in human disease. FGF signaling can be deregulated through multiple mechanisms, including gene amplification, activating mutations and translocations, overexpression, altered FGFR gene splicing, and autocrine or paracrine overproduction of the ligands of FGFR. Deregulated FGF signaling has been documented in human tumors, including breast (see Ray, M. E., et. al., 2004. Genomic and expression analysis of the 8pl 1-12 amplicon in human breast cancer cell lines. Cancer Res 64:40-47), multiple myeloma (see Keats, J.J., et. al., 2006. Ten years and counting: so what do we know about t(4;14)(pl6;q32) multiple myeloma. Leuk Lymphoma 47:2289-2300), non-invasive bladder (see Billerey, C, et al. 2001. Frequent

FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol 158: 1955-1959), endometrial (see Pollock, P.M., et al. 2007. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene 26:7158-7162), gastric (see Jang, J.H., et. al, 2001. Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Res 61 :3541-3543), prostate cancers (see Sahadevan, K., D et. al., 2007. Selective over-expression of fibroblast growth factor receptors 1 and 4 in clinical prostate cancer. J Pathol 213:82-90), lung (see Hammerman P, et al. Genomic characterization and targeted therapeutics in squamous cell lung cancer [abstract]; Proceedings of the 14th World Conference on Lung Cancer; 2011 3-7 July; Aurora (CO); and International Association for the Study of Lung Cancer; 2011), esophageal (see Hanada K, et al, Identification of fibroblast growth factor-5 as an overexpressed anti-gen in multiple human adenocarcinomas. Cancer Res 2001; 61 : 5511-6), cholangiocarcinoma (see Arai, Y., et al. 2014. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 59, 1427-1434 and Borad, M. J., et al. 2014). Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS genetics 10, el004135), glioblastoma (see Rand V., et. al. Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas. Proc Natl Acad Sci U S A 2005; 102: 14344 – 9 and Parker, et. al. 2014. Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours. The Journal of pathology 232, 4-15). FGFR1 translocations and FGFR1 fusions are frequently observed in 8pl 1 myeloproliferative syndromes (Jackson, C. C, Medeiros, L. J., and Miranda, R. N. (2010). 8pl 1 myeloproliferative syndrome: a review. Human pathology 41, 461-476). Activating mutations in FGFR3 have been shown to cause a number of dwarf syndromes (see Harada, D., et. al, 2009. FGFR3-related dwarfism and cell signaling. J Bone Miner Metab 27:9-15) including achondroplasia (see Bellus, G.A., et. al., 1995. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet 56:368-373; Bellus, G.A., et. al., 1995. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet 10:357-359; and Rousseau, F., et. al, 1994. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371 :252-254), Crouzon dermoskeletal syndromes (see Robin, N.H., et. al, 1993. FGFR-Related Craniosynostosis Syndromes), hyopochondroplasia (see Prinos, P., et. al., 1995. A common FGFR3 gene mutation in hypochondroplasia. Hum Mol Genet 4:2097-2101), Muenke syndrome (see Muenke, M., et al. 1997. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am J Hum Genet 60:555-564), SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) (see Bellus, G.A., et al. 1999. Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3. Am J Med Genet 85:53-65;

Tavormina, P.L., et al. 1999. A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am J Hum Genet 64:722-731), thanatophoric dysplasia ( see dAvis, P.Y., et. al, 1998. Constitutive activation of fibroblast growth factor receptor 3 by mutations responsible for the lethal skeletal dysplasia thanatophoric dysplasia type I. Cell Growth Differ 9:71-78; Kitoh, H., et. al, 1998. Lys650Met substitution in the tyrosine kinase domain of the fibroblast growth factor receptor gene causes thanatophoric dysplasia Type I. Mutations in brief no. 199. Online. Hum Mutat 12:362- 363; and Tavormina, P.L., et. al, 1995. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 9:321-328), platyspondylic lethal skeletal dysplasia (see Brodie, S.G., et. al, 1999. Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations. Am J Med Genet 84:476-480), and cervical cancer (see Cappellen, D., et. al., 1999. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet 23: 18-20). Activating mutations in FGFR4 have been identified in rhabdomyosarcoma (see Shukla, N., et. al, Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways. Clin Cancer Res 18:748-757 and Marshall, A.D., et. al, PAX3-FOX01 and FGFR4 in alveolar rhabdomyosarcoma. Mol Carcinog 51 :807-815). For these reasons, FGFRs are attractive therapeutic target for the treatment of diseases.

Patent

WO 2015120049

Example 6

Synthesis of 8-(3-(4-acryloylpiperazin-l-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2- (methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

Step 1

To a solution of 3-(piperazin-l-yl)propan-l-ol (1 g, 6.93 mmol, 1.00 equiv) in THF (50 mL) and TEA (2 g) was added di-tert-butyl dicarbonate (2.26 g, 10.36 mmol, 1.49 equiv). The resulting solution was stirred for 2 h at room temperature and then concentrated. The residue was purified by chromatography (DCM/MeOH (15: 1)) to provide 1.48 g (87%) of tert-butyl 4-(3-hydroxypropyl)piperazine-l-carboxylate as a light yellow liquid.

Step 2

To a solution of tert-butyl 4-(3-hydroxypropyl)piperazine-l-carboxylate (1.48 g, 6.06 mmol, 1.00 equiv) in DCM (60 mL), imidazole (620 mg) and TPP (2.38 g, 9.07 mmol, 1.50 equiv) was added I2 (2.31 g, 9.10 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature and then concentrated. The residue was purified by chromatography

(DCM/MeOH (50: 1)) to provide 1.65 g (77%) of tert-butyl 4-(3-iodopropyl)piperazine-l-carboxylate as yellow oil.

Step 3

To a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfanyl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one (600 mg, 1.51 mmol, 1.00 equiv) in acetone (50 mL) and K2C03 (630 mg) was added tert-butyl 4-(3-iodopropyl)piperazine-l-carboxylate (640 mg, 1.81 mmol, 1.20 equiv). The resulting solution was heated to reflux for 3 h and then the solids were filtered out. The residue was purified by chromatography (DCM/EtOAc (2:1)) to provide 720 mg (77%) of tert-butyl 4-[3-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfanyl)-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl]propyl]piperazine-l-carboxylate as a yellow solid.

Step 4

To a solution of tert-butyl 4-[3-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methyl-sulfanyl)-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl]propyl]piperazine-l-carboxylate (720 mg, 1.15 mmol, 1.00 equiv) in CHC13 (50 mL) was added mCPBA (600 mg). The resulting solution was stirred overnight at room temperature and then quenched with sat. Na2C03. The resulting solution was extracted DCM/MeOH(10: l) and the organic layer was concentrated. This provided 750 mg (97%)) of 4-[(tert-butoxy)carbonyl]-l-[3-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-

methanesulfonyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl]propyl]piperazin- 1 -ium- 1 -olate as a yellow solid.

Step 5

To a solution of 4-[(tert-butoxy)carbonyl]-l-[3-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methanesulfonyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl]propyl]piperazin- 1 -ium- 1 -olate (750 mg, 1.12 mmol, 1.00 equiv) in tert-BuOH (50 mL), was added MeNH2/THF(2N) (1 mL). The resulting solution was stirred for 2 h at 60° C and then concentrated. This provided 680 mg (98%) of 4-[(tert-butoxy)carbonyl]-l-[3-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl]propyl]piperazin-l-ium-l-olate as a yellow solid.

Step 6

To a solution of 4-[(tert-butoxy)carbonyl]-l-[3-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl]propyl]piperazin-l-ium-l-olate (680 mg, 1.09 mmol, 1.00 equiv) in MeOH (100 mL) was added Zn (1 g) and sat. NH4C1 (4 mL). The resulting reaction mixture was stirred overnight at room temperature and then solids were filtered out. The residue was purified by chromatography (DCM/MeOH (35: 1)) to provide 650 mg (98%) of tert-butyl 4-[3-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl]propyl]piperazine-l-carboxylate as a yellow solid.

Step 7

To a solution of tert-butyl 4-[3-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-8-yl]propyl]piperazine-l-carboxylate (650 mg, 1.07 mmol, 1.00 equiv) in dioxane (12 mL), was added cone. HC1 (3 mL). The resulting solution was stirred for 3 h at room temperature and then concentrated. This provided 550 mg (95%) of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(3-(piperazin-l-yl)propyl)pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride as an off-white solid.

Step 8

To a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-[3-(piperazin-l-yl)propyl]-7H,8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride (250 mg, 0.49 mmol, 1.00 equiv) in DCM (20 mL) was added TEA (120 mg, 1.19 mmol, 2.41 equiv) and prop-2-enoyl chloride (54 mg, 0.60 mmol, 1.21 equiv). The resulting solution was stirred for 2 h at room temperature and then quenched with H20 (30 mL). The resulting solution was extracted with DCM/MeOH(10:l) and the organic layers combined and concentrated. The crude product was purified by Prep-HPLC (Column, SunFire Prep CI 8 OBD Column, 150mm 5um lOnm; mobile phase, Water with lOmmol NH4HC03and MeCN (30.0% MeCN up to 80.0% in 10 min);

Detector, nm). This provided 112.1 mg (41%>) of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-

(methylamino)-8-[3-[4-(prop-2-enoyl)piperazm^

one as a white solid. MS (ESI, pos. ion) m/z: 561.1 (M+l).

PATENT

Example 1

Synthesis of Compound (I)

Step 1

2-(3,5-Dimethoxyphenyl)acetic acid (1000 g) was charged into appropriately sized three-neck RBF equipped with a condenser and dissolved with methanol (10 L). Concentrated sulfuric acid (20 g) was added and a solution was brought to gentle boiling. Reaction progress was monitored by HPLC. The reaction mixture was transferred to appropriately sized RBF and

concentrated to ca. 3 L. and then co-evaporated with DMSO (3 L) to about 4 L and the residue containing methyl 2-(3,5-dimethoxyphenyl)acetate (1071 g) was telescoped to Step 2.

Step 2

To an appropriate reactor equipped with mechanical stirrer methyl 2-(3,5-dimethoxyphenyl)acetate (1071 g) in DMSO (3.2 L), 4-amino-2-(methylthio)-pyrimidine-5-carbaldehyde (819 g, 0.95 eq.), potassium carbonate (1057 g, 1.5 eq.) and cesium carbonate (249 g, 0.15 eq.) was charged and the mixture was stirred at 50 °C. After 15 h, the mixture containing 6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one was cooled to RT. Potassium carbonate (854g, 1.2 eq.) and tert-butyl 4-(3 -((methyl sulfonyl)oxy )propyl)piperazine-1-carboxylate HC1 (2112 g, 1.1 eq.) was charged. Upon completion of ther eaction, ethyl acetate and water were added.

Organic layer was separated and aqueous layer was extracted with ethyl acetate.

Combined organic layers were washed with 25% aqueous solution of sodium chloride. Organic phase was dried over anhydrous magnesium sulfate. Drying agent was filtered off and washed with ethyl acetate. The filtrate was concentrated to ca. 9.6 L. and cooled to 0-5°C. A solution of ^-toluenesulfonic acid (970 g, 1.0 eq.) in ethyl acetate (4.28 L) was added dropwise. The resulted suspension was slowly warmed to RT and stirred for 5 h. Solids were filtered off, washed with ethyl acetate and dried give tert-butyl-4-(3-(6-(3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)piperazine- 1-carboxylate 4-methylbenzenesulfonate. Step 3

To an appropriate reactor equipped with mechanical stirrer was charged acetic acid (12 L), 6-(3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2000 g) and triethylamine (639 g, 2.3 eq.). Internal temperature was adjusted to approximately 20°C and N-chlorosuccinimide (1651 g, 4.5 eq.) was added at 20-30°C. Reaction was stirred for 2 hours. Ethyl acetate (30 L) was added. 5% aqueous NaCl solution (20 L) was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with 30 % aqueous potassium carbonate solution (14 L). The organic layer was concentrated to ~ 12 L and used for next step directly.

Step 4

To tert-butyl-4-(3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)piperazine- 1-carboxylate (1804 g) in ethyl acetate extract (12 L)from Step 3, was added 2M methylamine solution in THF (3435 mL) was slowly added maintaining temperature below 30°C. After reaction was complete, the suspension concentrated to 3.3 L and ethyl acetate (6 L) was added. The mixture was heated at 50°C for 2h, and then cooled to RT. Solids were filtered off and washed with ethyl acetate, water and dried to give tert-butyl-4-(3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)piperazine-l-carboxylate (1845 g).

Step 5

tert-Butyl-4-(3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxo-pyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)piperazine-l-carboxylate (125 g) was charged into appropriately sized three-neck RBF equipped with a condenser and suspended in acetone (1000 mL). Concentrated (36%) aqueous hydrochloric acid (100 mL) was slowly added and the mixture was heated to 45°C for 1 h. the reaction mixture was gradually cooled to RT over 4 h and filtered, washed with acetone and dried to give tert-butyl-4-(3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)piperazine-l-carboxylate»3HCl (125 g) in 98% yield.

Step 6

To an appropriate reactor tert-butyl-4-(3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)propyl)piperazine-l-carboxylate (50 g) and DMF (500 mL) was charged while stirring at RT. The suspension was cooled to 0-5°C and saturated aqueous sodium bicarbonate solution (375 mL) was slowly added maintaining temperature below 15°C with emission of C02. The mixture was cooled again to 0-5°C and acryloyl chloride (8.6 mL, 1.3 eq.) was slowly added at temperature below 10°C. Once acryloyl chloride addition was finished the reaction mixture was gradually warmed to RT over 1 h.

Saturated aqueous sodium bicarbonate solution (75 mL) was slowly added and the resulted mixture was heated at 45-55°C for 0.5-1.5 h. It was then gradually cooled to RT and stirred for another 0.5-1.5 h. Solids were filtered off, washed with water and dried.

Crude product was dissolved in dichloromethane (750 mL) at reflux and the solution was cooled to ambient temperature. Silica gel (7.5 g) was added while stirring. After 30 min. the mixture was filtered through Celite and the filtering bed was washed with dichloromethane.

Ethyl acetate (250 mL) was added and the solution was concentrated under reduced to about 250 mL at 40 – 50 °C. Ethyl acetate (450 mL) was slowly added at 50°C. After 30 min. the suspension was slowly cooled to 40°C and solids were filtered off, washed with ethyl acetate and dried to give 36 g of 8-(3-(4-acryloylpiperazin-l-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one in 82%. XRPD analysis of the product showed an XRPD pattern for a highly crystalline compound, which was assigned as Form 1 (discussed in further detail below).

Patent ID Patent Title Submitted Date Granted Date
US2016229849 QUINOLONE DERIVATIVES AS FIBROBLAST GROWTH FACTOR RECEPTOR INHIBITORS 2015-02-04 2016-08-11
US2016200725 QUINOLONE DERIVATIVES AS FIBROBLAST GROWTH FACTOR RECEPTOR INHIBITORS 2016-03-22 2016-07-14

///////////PRN 1371, Phase I,  Solid tumours,  Principia Biopharma

Clc1c(OC)cc(OC)c(Cl)c1C4=Cc2cnc(NC)nc2N(CCCN3CCN(CC3)C(=O)C=C)C4=O

str0

Now in 1st time disclosures Principia Biopharma’s Kenneth Brameld on another FGFR inhibitor for solid tumors

RG 6080, Nacubactam


STR1

RG-6080

Sulfuric acid, mono[(1R,2S,5R)-2-[[(2-aminoethoxy)amino]carbonyl]-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester

Phase I

A β-lactamase inhibitor potentially for the treatment of bacterial infections.

RG-6080; FPI-1459; OP-0595

CAS No. 1452458-86-4

Molecular Formula C9 H16 N4 O7 S
Formula Weight 324.31
  • Originator Fedora Pharmaceuticals
  • Developer Meiji Seika Pharma
  • Class Antibacterials; Azabicyclo compounds
  • Mechanism of Action Beta lactamase inhibitors
  • Phase IBacterial infections

Most Recent Events

  • 13 Jan 2015 OP 0595 licensed to Roche worldwide, except Japan ,
  • 30 Nov 2014 Meiji Seika Pharma completes a phase I trial in Healthy volunteers in Australia (NCT02134834)
  • 01 May 2014 Phase-I clinical trials in Bacterial infections (in volunteers) in Australia (IV)

SYNTHESIS

WO 2015046207,

STR1

CONTD…………………..

STR1

CONTD………………………………..

STR1

Patent

WO 2015053297

The novel heterocyclic compound in Japanese Patent 4515704 (Patent Document 1), preparation and shown for their pharmaceutical use, sodium trans-7-oxo-6- (sulfooxy) as a representative compound 1,6-diazabicyclo [3 .2.1] discloses an octane-2-carboxamide (NXL104). Preparation in regard to certain piperidine derivatives which are intermediates Patent 2010-138206 (Patent Document 2) and JP-T 2010-539147 (Patent Document 3) are shown at further WO2011 / 042560 (Patent Document 4) NXL104 to disclose a method for producing the crystals.
 In Patent 5038509 (Patent Document 5) (2S, 5R) -7- oxo -N- (piperidin-4-yl) -6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane – 2- carboxamide (MK7655) is shown, discloses the preparation of certain piperidine derivatives with MK7655 at Patent 2011-207900 (Patent Document 6) and WO2010 / 126820 (Patent Document 7).
 The present inventors also disclose the novel diazabicyclooctane derivative represented by the following formula (VII) in Japanese Patent Application 2012-122603 (Patent Document 8).
Patent Document 1: Japanese Patent No. 4515704 Pat
Patent Document 2: Japanese Patent Publication 2010-138206 Pat
Patent Document 3: Japanese patent publication 2010-539147 Pat
Patent Document 4: International Publication No. WO2011 / 042560 Patent
Patent Document 5: Japanese Patent No. 5038509 Pat
Patent Document 6: Japanese Patent Publication 2011-207900 Pat
Patent Document 7: International Publication No. WO2010 / 126820 Patent
Patent Document 8: Japanese Patent application 2012-122603 Pat.
[Chemical formula 1] (In the formula, R 3 are the same as those described below)

Reference Example
5 of 5 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)
Formula 43]
step 1 tert-butyl {2 – [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate  (IV-1)(2S, 5R)-6-(benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxylic acid (4 .30g, dehydrated ethyl acetate (47mL) solution of 15.56mmol) was cooled to -30 ℃, isobutyl chloroformate (2.17g, washing included dehydration ethyl acetate 1mL), triethylamine (1.61g, washing included dehydration ethyl acetate 1 mL), successively added dropwise, and the mixture was stirred 1 hour at -30 ° C.. To the reaction solution tert- butyl 2-dehydration of ethyl acetate (amino-oxy) ethyl carbamate (3.21g) (4mL) was added (washing included dehydration ethyl acetate 1mL), raising the temperature over a period of 1.5 hours to 0 ℃, It was further stirred overnight. The mixture of 8% aqueous citric acid (56 mL), saturated aqueous sodium bicarbonate solution (40 mL), sequentially washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, filtered, concentrated to 5 mL, up to 6mL further with ethanol (10 mL) It was replaced concentrated. Ethanol to the resulting solution (3mL), hexane the (8mL) in addition to ice-cooling, and the mixture was stirred inoculated for 15 minutes. The mixture was stirred overnight dropwise over 2 hours hexane (75 mL) to. Collected by filtration the precipitated crystals, washing with hexane to give the title compound 5.49g and dried in vacuo (net 4.98 g, 74% yield). HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 50/50, 1.0 mL / min, UV 210 nm, Retweeted 4.4 min; 1 H NMR (400 MHz, CDCl 3 ) [delta] 1.44 (s, 9H), 1.56-1.70 (m, 1H), 1.90-2.09 (m, 2H), 2.25-2.38 (m, 1H), 2.76 (d, J = 11.6 Hz, 1H), 3.03 (br.d., J = 11.6 Hz , 1H), 3.24-3.47 (m, 3H), 3.84-4.01 (m, 3H), 4.90 (d, J = 11.6 Hz, 1H), 5.05 (d, J = 11.6 Hz, 1H), 5.44 (br. . s, 1H), 7.34-7.48 (yd, 5H), 9.37 (Br.S., 1H); MS yd / z 435 [M + H] + .
Step 2
tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate
(V-1) tert-butyl {2 – [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl ] carbonyl} amino) oxy] ethyl} carbamate (3.91 g, to a methanol solution (80 mL) of 9.01mmol), 10% palladium on carbon catalyst (50% water, 803 mg) was added, under hydrogen atmosphere and stirred for 45 minutes . The reaction mixture was filtered through Celite, after concentrated under reduced pressure to give 3.11g of the title compound (quantitative).
HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 75/25, 1.0 mL / min, UV 210 nm, Retweeted 3.9 from min; 1 H NMR (400 MHz, CD 3 OD) [delta] 1.44 (s, 9H) , 1.73-1.83 (m, 1H), 1.86-1.99 (m, 1H), 2.01-2.12 (m, 1H), 2.22 (br.dd., J = 15.0, 7.0 Hz, 1H), 3.03 (d, J= 12.0 Hz, 1H), 3.12 (br.d., J = 12.0 Hz, 1H), 3.25-3.35 (m, 2H), 3.68-3.71 (m, 1H), 3.82-3.91 (m, 3H); MS M / Z 345 [M Tasu H] Tasu .
Step 3
Tetrabutylammonium tert- butyl {2 – [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate
(VI-1) tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct 2-yl] carbonyl} amino) oxy] ethyl} carbamate (3.09g, in dichloromethane (80mL) solution of 8.97mmol), 2,6- lutidine (3.20mL), sulfur trioxide – pyridine complex (3 .58g) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into half-saturated aqueous sodium bicarbonate solution, washed the aqueous layer with chloroform, tetrabutylammonium hydrogen sulfate to the aqueous layer and (3.47 g) chloroform (30 mL) was added and stirred for 10 minutes. The aqueous layer was extracted with chloroform, drying the obtained organic layer with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound 5.46g (91% yield).
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 80/20, 1.0ML / Min, UV210nm, RT 2.0 Min; 1 H NMR (400 MHz, CDCl 3 ) Deruta 1.01 (T, J = 7.4 Hz, 12H), 1.37-1.54 (m , 8H), 1.45 (s, 9H), 1.57-1.80 (m, 9H), 1.85-1.98 (m, 1H), 2.14-2.24 (m, 1H), 2.30- 2.39 (m, 1H), 2.83 (d, J = 11.6 Hz, 1H), 3.20-3.50 (m, 11H), 3.85-3.99 (m, 3H), 4.33-4.38 (m, 1H), 5.51 (br s , 1H), 9.44 (Br.S., 1H); MS yd / z 425 [M-Bu 4 N + 2H] + .
Step 4 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)
tetra butylammonium tert- butyl {2 – [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (5.20g, 7.82mmol) in dichloromethane (25mL) solution of ice-cold under trifluoroacetic acid (25mL), and the mixture was stirred for 1 hour at 0 ℃. The reaction mixture was concentrated under reduced pressure, washed the resulting residue with diethyl ether, adjusted to pH7 with aqueous sodium bicarbonate, subjected to an octadecyl silica gel column chromatography (water), after freeze drying, 1.44 g of the title compound obtained (57% yield).
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 99/1, 1.0ML / Min, UV210nm, RT 3.1 Min; 1 H NMR (400 MHz, D 2O) Deruta 1.66-1.76 (M, 1H), 1.76-1.88 (m, 1H ), 1.91-2.00 (m, 1H), 2.00-2.08 (m, 1H), 3.02 (d, J = 12.0 Hz, 1H), 3.15 (t, J = 5.0 Hz , 2H), 3.18 (br d , J = 12.0 Hz, 1H), 3.95 (dd, J = 7.8, 2.2 Hz, 1H), 4.04 (t, J = 5.0 Hz, 2H), 4.07 (dd, J = 6.4 3.2 Hz &, 1H); MS yd / z 325 [M + H] + .

PATENT

WO 2015046207

Example
64 tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy ] ethyl} carbamate (V-1)
[of 124]

tert- butyl {2 – [({[(2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl } carbamate (example 63q, net 156.42g, 360mmol) in methanol solution (2.4L) of 10% palladium carbon catalyst (50% water, 15.64g) was added, under an atmosphere of hydrogen, stirred for 1.5 hours did. The catalyst was filtered through celite, filtrate was concentrated under reduced pressure until 450mL, concentrated to 450mL by adding acetonitrile (1.5 L), the mixture was stirred ice-cooled for 30 minutes, collected by filtration the precipitated crystals, washing with acetonitrile, and vacuum dried to obtain 118.26g of the title compound (net 117.90g, 95% yield). Equipment data of the crystals were the same as those of the step 2 of Reference Example 3.

Example
65 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VI-1)
[of 125]
 tert- butyl {2 – [({[(2S, 5R) -1,6- -6- hydroxy-7-oxo-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (example 64,537.61g, 1.561mol) in acetonitrile (7.8L) solution of 2,6-lutidine (512.08g), sulfur trioxide – pyridine complex (810.3g) was added, at room temperature in the mixture was stirred overnight. Remove insolubles and the mixture was filtered, the filtrate concentrated to 2.5 L, diluted with ethyl acetate (15.1L). The mixture was extracted with 20% phosphoric acid 2 hydrogencarbonate aqueous solution (7.8L), the resulting aqueous layer into ethyl acetate (15.1L), added tetrabutylammonium hydrogen sulfate (567.87g), was stirred for 20 min. The organic layer was separated layers, dried over anhydrous magnesium sulfate (425 g), after filtration, concentration under reduced pressure, substituted concentrated tetrabutylammonium tert- butyl with dichloromethane (3.1L) {2 – [({[(2S, 5R ) -7-oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate was obtained 758g (net 586.27g, Osamu rate 84%).
 The tetra-butyl ammonium salt 719g (net 437.1g, 0.656mol) in dichloromethane (874mL) solution was cooled to -20 ℃, dropping trifluoroacetic acid (874mL) at 15 minutes, 1 the temperature was raised to 0 ℃ It was stirred time. The reaction was cooled to -20 ° C. was added dropwise diisopropyl ether (3.25L), and the mixture was stirred for 1 hour the temperature was raised to 0 ° C.. The precipitate is filtered, washed with diisopropyl ether to give the title compound 335.36g of crude and vacuum dried (net 222.35g, 99% yield).
 The title compound of crude were obtained (212.99g, net 133.33g) and ice-cold 0.2M phosphate buffer solution of pH5.3 mix a little at a time, alternating between the (pH6.5,4.8L). The solution was concentrated under reduced pressure to 3.6L, it was adjusted to pH5.5 at again 0.2M phosphate buffer (pH6.5,910mL). The solution resin purification (Mitsubishi Kasei, SP207, water ~ 10% IPA solution) is subjected to, and concentrated to collect active fractions, after lyophilization, to give the title compound 128.3 g (96% yield). Equipment data of the crystals were the same as those of step 3 of Reference Example 3.

PATENT

US 20140288051

WO 2014091268

WO 2013180197

US 20130225554

///////////RG-6080, 1452458-86-4, FPI-1459,  OP-0595, Phase I ,  β-lactamase inhibitor, bacterial infections, Fedora parmaceuticals, Meiji Seika Pharma

MK 8876


STR1

MK 8876
CAS 1426960-33-9

2-(4-Fluorophenyl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethanesulfonamido)-1-benzofuran-3-carboxamide

2-(4-Fluorophenyl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-[methyl(methylsulfonyl)amino]-3-benzofurancarboxamide
Molecular Formula C32H24F2N4O5S
Molecular Weight 614.62
  • Originator Merck & Co
  • Class Antivirals
  • Phase I Hepatitis C

Most Recent Events

  • 11 Oct 2013 Phase-I clinical trials in Hepatitis C in Germany (PO)
  • 11 Oct 2013 Phase-I clinical trials in Hepatitis C in Moldova (PO)
  • 23 Aug 2013 Preclinical trials in Hepatitis C in USA (PO)

DATA

2-(4-Fluorophenyl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethanesulfonamido)-1-benzofuran-3-carboxamide

MK-8876 off-white solid

1H NMR (500 MHz, DMSO-d6) δ 8.56 (q, J = 4.7 Hz, 1H), 8.06–8.01 (m, 2H), 8.05 (s, 1H), 7.86 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.46–7.40 (m, 2H), 7.29–7.22 (m, 1H), 7.11 (s, 1H), 6.94 (dd, J = 10.6, 7.9 Hz, 1H), 6.27 (s, 2H), 3.31 (s, 3H), 2.96 (s, 3H), 2.85 (d, J = 4.7 Hz, 3H);

13C NMR (125.7 MHz, DMSO-d6) δ 162.86, 162.82 (d, JC–F = 248.5 Hz), 155.74 (d, JC–F = 246.1 Hz), 153.80, 152.43, 152.28, 147.20, 137.08, 137.00 (d, JC–F = 10.8 Hz), 136.36, 136.20, 132.37, 129.50 (d, JC–F = 8.6 Hz), 127.17, 125.45 (d, JC–F = 3.1 Hz), 125.08, 125.02, 123.70 (d, JC–F = 7.7 Hz), 122.28, 117.23 (d, JC–F = 22.4 Hz), 116.01 (d, JC–F = 21.9 Hz), 113.65, 111.76, 106.90 (d,JC–F = 3.5 Hz), 105.32 (d, JC–F = 18.5 Hz), 94.16, 73.57, 39.39, 37.24, 26.16;

HR-ESI-MS m/zcalcd for C32H25N4O5SF2+ [M + H]+ 615.1514, found 615.1500.

. HPLC Method and Retention Time Data
HPLC Method
column Ascentis Express C18 2.7 μm (fused core), 100 mm × 4.6 mm
detection UV at 210 nm
column temperature 40 °C
flow rate 1.8 mL/min
injection volume 5.0 μL
gradient 90% A to 5% A over 11 min, hold at 5% A for 2 min, 5% A back to 90% A over the next 0.1 min, and then hold at 90% A for 2.9 min
run time 16 min
data collection acquisition for the first 13 min
mobile phases solvent A: water with 0.1% H3PO4
solvent B: acetonitrile
Retention Time Data
identity tR (min)
boronic acid 27 4.24
desbromoarene 28 5.33
MK-8876 (1) 7.89
chloropyridine starting material 2 8.03
BHT 10.22

SYNTHESIS 

Figure imgf000211_0002

Figure imgf000212_0002

Figure imgf000213_0001

STR1

CONTD……………

STR1

STR1

MK 8876

Figure imgf000207_0002

Figure imgf000211_0001

Figure imgf000211_0002

Figure imgf000212_0002

Figure imgf000213_0001

Figure imgf000213_0002

Figure imgf000214_0001

Figure imgf000207_0001

MK 8876

Patent

WO 2013033900

Scheme 1

Figure imgf000024_0001

Scheme 2

Figure imgf000025_0001

Scheme 3

Figure imgf000026_0001

Q

Scheme 4

Figure imgf000027_0001

EXAMPLES

Example 1

Preparation of Compound 1

Figure imgf000028_0001THIS COMPD HAS ONE FLUORO MISSING, APPLY TO YOUR MK  8876

Step 1 – Synthesis of 2,6-dichloropyridin-3-ol

Figure imgf000028_0002

Η202 (1.60 g, 47.12 mmol) was added slowly to the solution of compound 2,6- dichloropyridin-3-ylboronic acid (3 g, 15.71 mmol) in CH2CI2 (30 mL) at 0 °C. After stirred at room temperature for about 15 hours, the mixture was quenched with sat. Na2S203 aqueous (50 mL) and adjusted to pH < 7 with IN HC1. The mixture was extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (100 mL), dried over Na2S04, filtered and the solvent was evaporated to provide2,6-dichloropyridin-3-ol (2.34 g, yield: 91.4%). 1H-NMR (CDC13, 400 MHz) δ 7.30 (d, / = 8.4 Hz, 1H), 7.19 (d, / = 8.4 Hz, 1H), 5.70 (br, 1H).

– Synthesis of 2,6-dichloro- -methoxypyridine

Figure imgf000028_0003

To a solution of 2,6-dichloropyridin-3-ol (16.3 g, 0.1 mol) and K2C03 (41.4 g, 0.3 mol) in DMF (200 mL) were added Mel (21.3 g, 0.15 mol). The mixture was allowed to stir at 80 °C for 2 hours. The mixture was then diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layer was washed with brine (200 mL x 3), dried over Na2S04, filtered and the solvent was evaporated to provide 2,6-dichloro-3-methoxypyridine (17.0 g, yield: 96.0%). 1H-NMR (CDC13, 400 MHz) δ 7.12-7.18 (m, 2H), 3.86 (s, 3H). Step 3 – Synthesis of2-(6-chloro-3-methoxypyridin-2-yl)-lH-indole

Figure imgf000029_0001

To a degassed solution of compound 2,6-dichloro-3-methoxypyridine (8.9 g, 0.05 mol), (l-(tert-butoxycarbonyl)-lH-indol-2-yl)boronic acid (13 g, 0.05 mol) and K3PO4 (31.8 g, 3.0 mol) in DMF (100 mL) was added Pd(dppf)Cl2 (3.65 g, 0.005 mol) under N2. The mixture was heated at 60 °C for about 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After being concentrated in vacuo, the resulting residue was purified using prep-HPLC to provide the desired product of 2-(6-chloro-3-methoxypyridin-2-yl)-lH-indole (9.0 g, yield:

69.8%). 1H-NMR (CDC13, 400 MHz) δ 9.52 (s, 1H), 7.65 (d, / = 7.6 Hz, 1H), 7.38-7.43 (m, 2H), 7.07-7.26 (m, 4H), 4.03 (s, 3H).

Step 4 – Synthesis of6-chlor -2-(lH-indol-2-yl)pyridin-3-ol

Figure imgf000029_0002

BBr3 (0.4 mL, 0.39 mmol) was added to the solution of 2-(6-chloro-3- methoxypyridin-2-yl)-lH-indole (50 mg, 0.194 mmol) in CH2C12 (0.5 mL) at -78 °C under N2. The mixture was allowed to stir at room temperature for 3 hours. The mixture was then quenched with CH3OH (10 mL) at -78 °C. After being concentrated in vacuo, the resulting residue was purified using prep-TLC (PE : EtOAc = 2.5 : 1) to afford the desired product of 6- chloro-2-(lH-indol-2-yl)pyridin-3-ol (40 mg, yield: 85.1%). 1H-NMR (CDC13, 400 MHz) δ 10.09 (s, 1H), 9.72 (s, 1H), 7.50 (d, / = 7.9 Hz, 1H), 7.17-7.32 (m, 3H), 7.08-7.14 (m, 1H), 6.87-6.96 (m, 2H).

Step 5 – Synthesis of 2-chlo -6H-pyrido[2′ ,3′ : 5 ,6] [ 1 ,3]oxazino[3 ,4-a]indole

Figure imgf000029_0003

To a solution of chloroiodomethane (3.51 g, 20.0 mmol) and K2CO3 (1.38 g, 10.0 mmol) in DMF (50 mL) was allowed to stir at 100 °C, 6-chloro-2-(lH-indol-2-yl)pyridin-3-ol (480 mg, 2.0 mmol) in DMF (50 mL) was added dropwise. After addition, the mixture was allowed to stir for another 0.5 hours. The mixture was then diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine (100 mL x 3), dried over Na2S04 and concentrated. The residue was purified using prep-TLC (PE : EtOAc = 3 1) to afford the desired product of 2-chloro-6H-pyrido[2′,3′:5,6][l,3]oxazino[3,4-a]indole (260 mg, yield: 50.7%). 1H-NMR (CDC13, 400 MHz) δ 7.63 (d, / = 8.0 Hz, 1H), 7.22-7.27 (m, 3H), 7.19 (d, / = 2.4 Hz, 1H), 7.08-7.12 (m, 2H), 5.86 (s, 2H).

Step 6 – Synthesis of2-(4-fluowphenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6H- pyridol 2 ‘,3’:5,6][ l, mpound 1 )

To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (502 mg, 1.0 mmol), 2-chloro-6H-pyrido[2′,3′:5,6][l,3]oxazino[3,4-a]indole (256 mg, 1.0 mmol) and K3PO4 (636 mg, 3.0 mmol) in dioxane : H20 (1.5 mL : 0.4 mL) was added Pd2(dba)3 (91 mg, 0.1 mmol) and X-phos (91 mg, 0.2 mmol) under N2. The mixture was heated to 110 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After being concentrated in vacuo, the resulting residue was purified using prep-HPLC to provide the desired product of Compound 1 (275 mg, yield: 46.1%). 1H-NMR (CDC13, 400 MHz) δ 7.88-7.94 (m, 3H), 7.61-7.63 (m, 2H), 7.40 (s, 2H), 7.09-7.28 (m, 6H), 5.94 (s, 2H), 5.86 (d, / = 4.4 Hz, 1H), 3.29 (s, 3H), 2.92 (d, / = 5.2 Hz, 3H), 2.65 (s, 3H). MS (M+H)+: 596.

Compounds 2-15, depicted in the table below, were prepared using the method described above.

COMPD 2 IS MK 8876

Figure imgf000031_0001

PATENT

WO 2013033971

Example 81

Preparation of Compound 2

Figure imgf000207_0001

Synthesis of ethyl 3- 4-fluorophenyl)-3-oxopropanoate

Figure imgf000207_0002

Diethyl carbonate (130 g, 1.1 mol) was dissolved in a suspension ofNaH (60% in oil, 50.2 g, 1.3 mol) in anhydrous tetrahydrofuran (1.5 L), and then l-(4-fluorophenyl)ethanone (150 g, 1.09 mol) was added dropwise at 70 °C. The resulting mixture was stirred at 70 °C for 3 hours. After the reaction mixture was cooled to room temperature and poured into HCl (1 N). The mixture was extracted with EtOAc, the organic phase was dried with anhydrous NaS04 and concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with petroleum ether / EtOAc = 50 / 1) to provide ethyl 3-(4-fluorophenyl)-3-oxopropanoate (217 g, yield: 95%). 1H-NMR (CDC13, 400 MHz) δ 7.92-7.97 (m, 2H), 7.07-7.13 (m, 2H), 4.14-4.20 (m, 2H), 3.93 (s, 2H), 1.22 (d, J= 7.2 Hz, 3H). MS (M+H)+: 211. Step 2 – Synthesis of ethyl 5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate

Figure imgf000207_0003

A solution of ethyl 3-(4-fluorophenyl)-3-oxopropanoate (130 g, 0.6 mol), 4- bromophenol (311 g, 1.8 mol) and FeCl3-6H20 (19.5 g, 0.09 mol) in DCE (700 mL) was heated to reflux, and then 2-(tert-butylperoxy)-2-methylpropane (193 g, 1.32 mol) was added dropwise under nitrogen. After 6 hours of refluxing, the mixture was cooled to RT, quenched with saturated NaHS03 and extracted with dichloromethane. The organic phases were washed with water, brine and dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether / dichloromethane = 15 / 1) to provide the crude product, which was crystallized from cold MeOH to provde ethyl 5-bromo-2- (4-fluorophenyl)benzofuran-3-carboxylate (37 g, yield: 14.3%) as solid. 1H- MR (CDC13, 400 MHz) δ 8.12 (s, 1H), 7.97-8.01 (m, 2H), 7.37 (d, J= 4.0 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.11 (t, J= 8.0 Hz, 2H), 4.32-4.38 (m, 2H), 1.36 (t, J= 8.0 Hz, 3H). MS (M+H)+: 363 / 365.

Step 3 – Synthesis of eth l 5-bromo-2-(4-fluorophen -6-nitrobenzofuran-3-carboxylate

Figure imgf000208_0001

To a solution of ethyl 5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (50 g,

137.6 mmol) in CHC13 (500 mL), fuming HN03 (50 mL) was added dropwise at -15 °C and the mixture was stirred for 0.5 hour. The reaction mixture was poured into ice water and extracted with CH2C12. The organic layer was washed with a.q. sat. NaHC03 and brine, after removed the most of solvent, the resulting residue was crystallized with petroleum ether / dichloromethane = 20 / 1 to provide product of ethyl 5-bromo-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (35 g, yield: 66%). 1H- MR (CDC13, 400 MHz) δ 8.36 (s, 1H), 8.02-8.04 (m, 3H), 7.13-7.18 (m, 2H), 4.36-4.41 (m, 2H), 1.37 (t, J= 4.0 Hz, 3H). MS (M+H)+: 408 / 410.

Step 4 – Synthesis of ethyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate

Figure imgf000208_0002

A mixture of ethyl 5-bromo-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (52 g, 127 mmol), iron filings (21.3 g, 382.2 mmol) and H4C1 (41 g, 764.4 mmol) in MeOH / THF / H20 (2 / 2 / 1, 500 mL) was stirred at reflux for 3 hour. After filtered and concentrated, the resulting residue was purified using column chromatography (petroleum ether / EtOAc / dichloromethane = 20 : 1 : 20) to provide ethyl 6-amino-5-bromo-2-(4-fluorophenyl) benzofuran-3-carboxylate (40 g, yield: 82%). 1H- MR (CDC13, 400 MHz) δ 8.01 (s, 1H), 7.94-7.98 (m, 2H), 7.08 (t, J= 8.0 Hz, 2H), 6.83 (s, 1H), 4.32-4.36 (m, 2H), 4.18 (s, 2H), 1.35 (t, J= 8.0 Hz, 3H). MS (M+H)+: 378 / 380.

Step 5 – Synthesis of 5-Bromo-2-(4-fluoro-phenyl)-6-methanesulfonylamino-benzofuran-3- carboxylic acid eth l ester

Figure imgf000209_0001

MsCI (31.7 g, 277.5 mmol) was added to a solution of ethyl 6-amino-5-bromo-2- (4-fluorophenyl)benzofuran-3-carboxylate (35 g, 92.5 mmol) and pyridine (60 mL) in

dichloromethane (300 mL) at 0 °C. After stirred overnight at room temperature, the mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo, the resulting residue was purified using crystallized with EtOAc to provde the pure product of ethyl 5-bromo-2-(4-fluorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxylate (35 g, yield: 82%). 1H- MR (CDC13, 400 MHz) δ 8.27 (s, 1H), 8.01-8.05 (m, 2H), 7.87 (s, 1H), 7.15-7.19 (m, 2H), 6.87 (s, 1H), 4.38-4.43 (m, 2H), 3.00 (s, 3H), 1.40 (t, J= 40 Hz, 3H). MS (M+H)+: 456 / 458.

Step 6 – Synthesis of 5-Bromo-2-(4-fluoro-phenyl)-6-methanesulfonylamino-benzofuran-3- carboxylic acid

Figure imgf000209_0002

To a solution of ethyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido) benzofuran-3-carboxylate (53 g, 0.23 mol) in dioxane / H20 (5 / 1, 600 mL) was added

LiOH-H20 (25 g, 1.17 mol), and the mixture was stirred at 100 °C for 3 hours. After

concentrated, the resulting residue was dissolved in H20, 1 N HCl was added until pH reached 3, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and filtered. The solvent was removed to provide the product of 5-bromo-2-(4- fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (48 g, yield: 96%).1H- MR (DMSO- e, 400 MHz) δ 13.49 (s, 1H), 9.67 (s, 1H), 8.30 (s, 1H), 8.12-8.17 (m, 2H), 7.87 (s, 1H), 7.45-7.50 (m, 2H), 3.16 (s, 3H). MS (M+H)+: 428 / 430. Step 7 – Synthesis of 5-Bromo-2-(4-fluoro-phenyl)-6-methanesulfonylamino-benzofuran-3- carboxylic acid methylamide

Figure imgf000210_0001

A solution of 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido) benzofuran-3- carboxylic acid (33 g, 77 mmol), HOBT (15.6 g, 115.5 mmol) and EDCI (22.2 g, 115.5 mmol) in DMF (250 mL) was stirred at room temperature. After 2 hours, Et3N (50 mL) and CH3 H2 (HC1 salt, 17.7 g, 231 mmol) was added to the mixture, and the mixture was stirred overnight. After the solvent was removed, H20 was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with H20, brine and concentrated in vacuo. The resulting residue was washed with EtOAc to provide the product of 5-bromo-2-(4-fluorophenyl)-N- methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (32 g, yield: 94%). 1H- MR (DMSO- ck, 400 MHz) δ 9.55 (br s, 1H), 8.46-8.48 (m, 1H), 8.12-8.17 (m, 2H), 7.96 (s, 1H), 7.87 (s, 1H), 7.45-7.50 (m, 2H), 3.16 (s, 3H), 2.93 (d, J= 8.4 Hz, 3H). MS (M+H)+: 441 / 443.

Step 8 – Synthesis of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido benzofuran-3-carboxamide

Figure imgf000210_0002

CH3I (31.6 g, 223 mmol) was added to a mixture of 5-bromo-2-(4-fluorophenyl)- N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (32 g, 74 mmol), K2C03 (25.6 g, 186 mmol) and KI (246 mg, 1.5 mmol) in DMF (150 mL) under N2 protection. The mixture was stirred at 80-90 °C overnight. After concentrated in vacuo, the resulting residue was washed with water (200 mL) and EtOAc (200 mL) to provide the product of 5-bromo-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (31.5 g, 94%). 1H- MR (CDCI3, 400 MHz) δ 8.16 (s, 1H), 7.88-7.92 (m, 2H), 7.70 (s, 1H), 7.18-7.23 (m, 2H), 5.78 (br s, 1H), 3.34 (s, 3H), 3.09 (s, 3H), 3.00 (d, J= 4.8 Hz, 3H). MS (M+H)+: 455 / 457. Step 9 – Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4, 4, 5, 5- tetramethyl-1 -dioxaborolan-2-yl)benzofuran-3-carboxamide

Figure imgf000211_0001

a degassed solution of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (1.0 g, 2.2 mmol) and pinacol diborane (2.79 g, 11.0 mmol) in 1,4-Dioxane (25 mL) was added KOAc (647 mg, 6.6 mmol) under N2 and stirred for 4 hours at room temperature. Then Pd(dppf)Cl2 (60 mg) was added, and the mixture was stirred for another 30 minutes. Then the mixture was put into a pre-heated oil-bath at 130 °C and stirred for another 1 hour under N2. The reaction mixture was cooled to room

temperatureand concentrated and extracted with EtOAc. The organic layers were washed with brine, dried over Na2S04. After concentrated, the crude product of the boronic ester was purified using column chromatography (petroleum ether / EtOAc = 5 / 1 to 2 / 1) to obtain 2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzofuran-3-carboxamide as white solid (700 mg, yield: 64%). 1H- MR (CDCI3, 400 ΜΗζ) δ 8.17 (s, 1H), 7.87-7.91 (m, 2H), 7.52 (s, 1H), 7.11 (t, 7= 7.6 Hz, 2H), 5.81 (d, 7= 2.8 Hz, 1H), 3.30 (s, 3H), 2.97 (d, 7= 5.2 Hz, 3H), 2.90 (s, 3H), 1.31 (s, 12H). MS (M+H)+: 503.

Step 10 – Synthesis of tert-butyl 4-fluoro-lH-indole-l -car boxy late

Figure imgf000211_0002

To a solution of 4-fluoro-lH-indole (5 g, 0.11 mol) and DMAP (150 mg, 3%Wt) in THF (50 mL) was added (Boc)20 (8.5 g, 0.04 mol) dropwise. The mixture was stirred at room temperature for 2 hours. The organic solvent was removed in vacuo, and the resulting residue was purified using column chromatography (pure petroleum ether) to provide tert-butyl 4-fluoro- lH-indole-l-carboxylate (8.3 g, yield: 96%). 1H- MR (CDC13, 400 MHz) δ 7.92 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 3.6 Hz, 1H), 7.23 (m, 1H), 6.90 (m, 1H), 6.66 (d, J= 3.6 Hz, 1H), 1.67 (s, 9H). MS (M+H)+: 236.

Step 11 – Synthesis of (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid

Figure imgf000212_0001

To a solution of diisopropylamine (7.5 mL, 0.11 mol) in THF (35 mL) at 0 °C was added «-BuLi (21 mL, 0.055 mol) dropwise. The mixture was stirred at 0 °C for 40 minutes. Then the mixture was cooled to -78 °C. Tert-butyl 4-fluoro-lH-indole-l-carboxylate (5 g, 0.02 mol) in THF (13 mL) was added dropwise slowly. After addition, the mixture was stirred at -78 °C for 2 hours. Then triisopropyl borate (3.29 g, 0.03 mol) was added. The mixture was stirred at -78 °C for another 40 minutes. The reaction was monitored using TLC. When the reaction was completed, the mixture was adjusted to pH = 6 with 1 N HC1. After extracted with EtOAc (25 mL x 3), the combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo. The obtained solid was recrystallized with EtOAc and petroleum ether to provide (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid (4.5 g, yield: 76.7%, which might be unstable at high temp, work up, store in fridge). 1H- MR (CDC13, 400 MHz) δ 7.77 (d, J= 8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.

Step 12 – Synthesis of 6-chloro-2-iodopyridin-3-ol

Figure imgf000212_0002

6-chloropyridin-3-ol (5.0 g, 38.6 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2C03 (8.2 g, 77.4 mmol) was added followed by iodine (9.8 g, 38.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M Na2S203 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04 and concentrated to provide the product of 6-chloro-2- iodopyridin-3-ol (7.0 g, yield: 70.9%). 1H- MR (CDC13, 400 MHz) δ 7.17 (d, J= 8.4 Hz, 1H), 7.06 (d, J= 8.4 Hz, 1H). MS (M+H)+: 256 / 258.

Step 13 – Synthesis of 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol

Figure imgf000213_0001

A mixture of (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid (5 g, 18.0 mmol), 6-chloro-2-iodopyridin-3-ol (3.82 g, 15.0 mol) and NaHC03 (3.78 g, 45.0 mol) in 1, 4-dioxane (76 mL) and water (7 mL) was stirred at room temperature for 15 minutes. Then Pd(PPh3)2Cl2 (527 mg, 0.75 mmol) was added under nitrogen atmosphere, and the mixture was heated at 100 °C under N2 for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), filtered and concentrated in vacuo. The resulting residue was diluted with H20 (60 mL) and EtOAc (30 mL), and the layer was separated, the aqueous layer was extracted with EtOAc (3*30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether / EtOAc = 20 / 1 ~ 3 / 1) to provide 6-chloro-2- (4-fluoro-lH-indol-2-yl)pyridin-3-ol (3 g, yield: 76.5%). 1H- MR (MeOD, 400 MHz) δ 7.36 (s, 1H), 7.23-7.27 (m, 2H), 7.03-7.11 (m, 2H), 6.63-6.68 (m, 1H). MS (M+H)+: 263 / 265.

Ste 14 – Synthesis of 2-chloro-ll-fluoro-6H-pyrido[2′,3′:5, 6][l,3]oxazino[3,4-a]indole

Figure imgf000213_0002

A solution of 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol (2 g, 7.6 mmol) and Cs2C03 (7.46 g, 22.89 mmol) in DMF (100 mL) was stirred at 100 °C (internal temperature) for 15 min, and then chloroiodomethane (2.85 g, 15.3 mmol) in DMF (2 mL) was added dropwise. After the reaction was completed, the mixture was filtered and concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EA=10: l) to provde 2-chloro-l l-fluoro-6H-pyrido[2′,3′:5,6][l,3]oxazino[3,4-a]indole (1.8 g, yield: 86.1%). 1H- MR (DMSO-i¾, 400 MHz) δ 7.64 (d, J= 8.8 Hz, 1H), 7.39-7.46 (m, 2H), 7.21-7.25 (m, 1H), 7.06 (s, 1H), 6.88-6.92 (m, 1H), 6.18 (s, 2H). MS (M+H)+: 275 / 277. Step 15 – Synthesis of5-(ll-fluoro-6H-pyrido[2 3′:5, 6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxam

Figure imgf000214_0001

To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (100 mg, 0.199 mmol), 2-chloro-l l-fluoro-6H-pyrido[2′,3′:5,6][l,3]oxazino[3,4- a]indole (56 mg, 0.199 mmol) and Κ3Ρ04·3Η20 (159 mg, 0.597 mmol) in dioxane / H20 (0.8 mL / 0.2 mL) was added Pd2(dba)3 (9 mg, 0.01 mmol) and X-Phos (9 mg, 0.02 mmol) under N2. The mixture was heated at 80 °C for 1 hour. The mixture was then diluted with water (30 mL) and extracted with EtOAc (15 mL x 3). The organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether / EtOAc = 1 : 1.5) to provde the pure product of 5-(l l-fluoro-6H- pyrido [2′, 3 ‘ : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, 48.8%). 1H- MR (CDC13, 400 MHz) δ: 7.99 (s, 1H), 7.93-7.96 (m, 2H), 7.65 (s, 1H), 7.45-7.50 (m, 2H), 7.17-7.21 (m, 4H), 7.10 (d, J= 8.0 Hz, 1H), 6.81-6.85 (m, 1H), 5.98 (s, 3H), 3.35 (s, 3H), 2.98 (d, J= 4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 615.

Paper

Abstract Image

We describe the route development and multikilogram-scale synthesis of an HCV NS5B site D inhibitor, MK-8876. The key topics covered are (1) process improvement of the two main fragments; (2) optimization of the initially troublesome penultimate step, a key bis(boronic acid) (BBA)-based borylation; (3) process development of the final Suzuki–Miyaura coupling; and (4) control of the drug substance form. These efforts culminated in a 28 kg delivery of the desired active pharmaceutical ingredient.

Process Development of the HCV NS5B Site D Inhibitor MK-8876

Department of Process Research and Development, Merck Research Laboratories, Rahway, New Jersey 07065, United States
Department of Process Chemistry, Merck Sharp & Dohme Ltd., Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, United Kingdom
§ Werthenstein BioPharma GmbH (MSD Switzerland), Industrie Nord 1, CH-6105 Schachen, Switzerland
WuXi AppTec Co., Ltd., No. 1 Building, #288 FuTe ZhongLu, WaiGaoQiao Free Trade Zone, Shanghai 200131, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00405

*E-mail: qinghao.chen@merck.com

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00405

PAPER

Abstract Image

Using the Teasdale method, purge factor estimates for six impurities identified as mutagenic alerts in the synthesis of MK-8876 are compared to actual measured amounts of these impurities determined via appropriate analytical methods. The results from this comparison illustrate the conservative nature of purge factor estimates, meaning that overprediction of mutagenic impurity purging is unlikely when using this method. Industry and regulatory acceptance of the purge factor estimation method may help minimize analytical burden in pharmaceutical development projects.

Evaluation and Control of Mutagenic Impurities in a Development Compound: Purge Factor Estimates vs Measured Amounts

Merck and Co., Rahway, New Jersey 07065, United States
Advanced Polymer Technology, The Dow Chemical Company, 400 Arcola Road, Collegeville, Pennsylvania 19426, United States
Org. Process Res. Dev., 2015, 19 (11), pp 1531–1535
DOI: 10.1021/acs.oprd.5b00263

*E-mail: mark_mclaughlin@merck.com.

This article is part of the Genotoxic Impurities 2015 special issue.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00263?journalCode=oprdfk

WO2004041201A2 * Oct 31, 2003 May 21, 2004 Viropharma Incorporated Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases
WO2011106992A1 * Mar 2, 2011 Sep 9, 2011 Merck Sharp & Dohme Corp. Inhibitors of hepatitis c virus ns5b polymerase
WO2004041201A2 * Oct 31, 2003 May 21, 2004 Viropharma Incorporated Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases
WO2010030592A1 * Sep 8, 2009 Mar 18, 2010 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis c
WO2011106992A1 * Mar 2, 2011 Sep 9, 2011 Merck Sharp & Dohme Corp. Inhibitors of hepatitis c virus ns5b polymerase
Citing Patent Filing date Publication date Applicant Title
WO2014123794A1 * Feb 3, 2014 Aug 14, 2014 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
WO2014123795A2 * Feb 3, 2014 Aug 14, 2014 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
WO2014123795A3 * Feb 3, 2014 Oct 30, 2014 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
US9242998 Feb 3, 2014 Jan 26, 2016 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis C

//////MK-8876, 1426960-33-9, Merck & Co, Antivirals, Phase I,  Hepatitis C

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