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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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FDA warns Mylan about cGMP violations at its Indian facilities


DRUG REGULATORY AFFAIRS INTERNATIONAL

The US FDA has warned Mylan about manufacturing concerns at three of its plants in India.

In a warning letter to the generic drug manufacturer, the FDA said it had found ‘significant violations of current good manufacturing practice’ during inspections at the plants in August and September last year and in February this year.

The inspections relate to Mylan’s Agila Specialty Formulation Facility (SFF), Sterile Product Division (SPD), and Onco Therapies Limited (OTL) sites in Bangalore.

Some of the violations cited were failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products, such as the use of gloves with tears and pinholes, as well as deficiencies in environmental monitoring and poor monitoring of staff……..http://www.manufacturingchemist.com/news/article_page/FDA_warns_Mylan_about_cGMP_violations_at_its_Indian_facilities/111318/cn48579?dm_i=8EU,3MBVR,9ETTTY,D0ENC,1

Recently the Food and Drug Administration (FDA) began ramping up inspections of offshore manufacturing facilities and the results are shocking. Although cGMP violations have been found worldwide, experts are…

View original post 508 more words

Bempedoic Acid


Bempedoic Acid
ETC-1002, ESP-55016
CAS 738606-46-7

  • C19H36O5
  • MW 344.486 Da

8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid

8-Hydroxy-2.2.14,14-tetramethylpentadecanedioic acid
ATP Citrate Lyase Inhibitor and AMP-activated Protein kinase (AMPK) activator
Indication: Hypercholesterolemia
Development Stage: Phase II
Developer: Esperion Therapeutics

Esperion Therapeutics was founded in April 2008 by former executives of, and investors in, the original Esperion Therapeutics which was founded in July 1998 and was bought by Pfizer for $ 1.3 billion in 2004 and then spun out in 2008. ETC-1002 was first discovered at the original Esperion, and Esperion subsequently acquired the rights to it from Pfizer in 2008. Esperion own the exclusive worldwide rights to ETC-1002.

Bempedoic Acid ( ETC-1002) has a UNIQUE Dual mechanism of Action That has the Potential to Regulate Both lipid and Carbohydrate Metabolism. ETC-1002 Appears to Work by inhibitin ATP citrate lyase (ACL), a Key Enzyme in the Cholesterol biosynthetic pathway, and activating a Complementary Enzyme, 5′-adenosine monophosphate-activated Protein kinase (AMPK). Both Enzymes are Known to Play Significant roles in the synthesis of Cholesterol and glucose in the liver. By inhibitin Cholesterol synthesis in the liver, Causes ETC-1002 the liver to take up LDL particles from the blood, which reduces LDL-C levels.

WO 2004067489

Figure imgf000131_0003

 

J1

6.13

7-Bromo-2,2-dimethylheptanoic acid ethyl ester

J27-Bromo-2,2-dimethylheptanoic acid ethyl ester

Under argon atmosphere and cooling with an ice-bath, a solution of lithium diisopropylamide in THF (1.7 L, 2.0 M, 3.4 mol) was slowly dropped into a solution of 1 ,5- dibromopentane (950 g, 4.0 mol) and ethyl isobutyrate (396 g, 3.4 mol) in THF (5 L) while keeping the temperature below +5 DC. The reaction mixture was stiπed at room temperature for 20 h and quenched by slow addition of saturated ammonium chloride solution (3 L). The resulting solution was divided into three 4-L portions. Each portion was diluted with saturated ammonium chloride solution (5 L) and extracted with ethyl acetate (2 ‘ 2 L). Each 4-L portion of ethyl acetate was washed with saturated sodium chloride solution (2 L), 1 N hydrochloric acid (2 L), saturated sodium chloride solution (2 L), saturated sodium bicarbonate solution (2 L), and saturated sodium chloride solution (2 L). The three separate ethyl acetate layers were combined into a single 12-L portion, dried over magnesium sulfate, and concenfrated in vacuo to give the crude material (1.7 L) which was purified by vacuum distillation. Two fractions were obtained: the first boiling at 88 – 104 °C / 0.6 ton (184.2 g), the second at 105 – 120 °C / 1.4 ton (409.6 g) for atotal yield of 60 %. 1H NMR (300 MHz, CDC13/TMS): δ (ppm): 4.11 (q, 2 H, J = 7.2 Hz), 3.39 (t, 2 H, J = 6.8 Hz), 1.85 (m, 2 H), 1.56 – 1.35 (m, 4 H), 1.24 (t, 3 H, J = 7.2 Hz), 1.31 – 1.19 (m, 2 H), 1.16 (s, 6 H). 13C NMR (75 MHz, CDCI3/TMS): δ (ppm): 177.9, 60.2, 42.1, 40.5, 33.8, 32.6, 28.6, 25.2, 24.2, 14.3. HRMS (El, pos): Calcd. for CπH22Brθ2 (MH+): 265.0803, found: 265.0810.

 

6.18

2,2,14.14-Tetramethyl-8-oxo-pentadecanedioic acid diethyl ester

p- toluenesulfonyl methyl isocyanide

J58-isocyano-2,2,14,14-teframethyl-8-(toluene-4-sulfonyl)-pentadecanedioic acid diethyl ester

J32,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester

Under Ar atmosphere, to a solution of 7-bromo-2,2-dimethylheptanoic acid ethyl ester (26.50 g, 100 mmol), tetra-n-butylammonium iodide (3.69 g, 10 mmol) and p- toluenesulfonyl methyl isocyanide (9.80 g, 50 mmol) in anhydrous DMSO (300 mL) was added sodium hydride (4.80 g, 20.5 mmol, 60 % dispersion in mineral oil) at 5 – 10 oC. The reaction mixture was stiπed at room temperature for 20 h and quenched with ice-water (300 mL). The product was extracted with dichloromethane (3 D 100 mL). The combined organic layers were washed with water (200 mL), half-saturated NaCl solution (2 ‘ 200 ■ ■• ■• .. <i„ ‘ir ι., – ib,

mL), and saturated NaCl solution (200 mL), dried over MgS04, and concentrated in vacuo to get the crude 8-isocyano-2,2,14,14-teframethyl-8-(toluene-4-sulfonyl)-pentadecanedioic acid diethyl ester (36.8 g) as an orange oil, which was used in the next step without purification. To a solution of this crude product (36.8 g) in dichloromethane (450 mL) was added concentrated hydrochloric acid (110 mL) and the mixture was stiπed at room temperature for 1 h. The solution was diluted with water (400 mL) and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were washed with saturated NaHC0 solution (2 x 150 mL) and saturated NaCl solution (150 mL). The organic solution was dried over Na2S04 and concenfrated in vacuo. The residue was subjected to column chromatography (silica gel, hexanes : ethyl acetate = 11 : 1) to give 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (12.20 g, 66 % over two steps) as a colorless oil. lH NMR (300 MHz, CDC13/TMS): δ (ppm): 4.11 (q, 4 H, J – 6.9 Hz), 2.37 (t, 4 H, J – 7.5 Hz), 1.58 – 1.47 (m, 8 H), 1.35 – 1.10 (m, 8 H), 1.24 (t, 6 H, J = 7.2 Hz), 1.15 (s, 12 H). 13C NMR (75 MHz, CDC13/TMS): δ (ppm): 211.6, 178.3, 60.5, 43.1, 42.5, 40.9, 30.1, 25.5, 25.1, 24.1, 14.7. HRMS (LSIMS, nba): Calcd. for C23IL3O5 (MH+): 399.3110, found: 399.3129.

6.19

8-Oxo-2,2,14,14-tetramethylpentadecanedioic acid

J4

A solution of KOH (25 g) in water (50 mL) was added to a solution of 2,2,14,14-tetramethyl-8-oxo-pentadecanedioic acid diethyl ester (10.69 g, 155 mmol) in ethanol (400 mL), then heated at reflux for 4 h. After cooling, the solution was evaporated to a volume of ca. 50 mL and diluted with water (800 mL). The organic impurities were removed by extracting with dichloromethane (2 x 200 mL). The aqueous layer was acidified to pH 2 with concentrated hydrochloric acid (50 mL) and extracted with methyl tert.-butyl ether (MTBE, 3 x 200 mL). The combined organic layers were dried over magnesium sulfate and concenfrated in vacuo to give the crude product (9.51 g) as an oil. Crystallization from hexanes / MTBE (50 mL : 25 mL) afforded 8-oxo-2,2,14,14- teframethylpentadecanedioic acid (6.92 g, 79 %) as waxy, white crystals. M.p.: 83 – 84 °C. 1H NMR (300 MHz, CDCI3/TMS): δ (ppm): 12.03 (s, 2 H), 2.37 (t, 4 H, J = 7.3 Hz), 1.52 – 1.34 (m, 8 H), 1.28 – 1.10 (m, 8 H), 1.06 (s, 12 H). 13C NMR (75 MHz, CDCI3/TMS): δ (ppm): 210.5, 178.8, 41.7, 41.2, 29.1, 25.0, 24.4, 23.1. HRMS (LSIMS, gly): Calcd. for C19H3505 (MH+): 343.2484, found: 343.2485.

6.20

8-Hydroxy-2.2.14,14-tetramethylpentadecanedioic acid

Under nitrogen atmosphere, sodium borohydride (0.06 g, 1.6 mmol) was added to a stiπed solution of 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid (1.18 g, 3.4 mmol) in methanol (50 mL) at 0 °C. The reaction progress was momtored by thin layer chromatography (silica; hexanes : ethyl acetate = 50 : 50). Additional sodium borohydride was added after 1 h (0.48 g, 13 mmol). After 8 h, the reaction mixture was hydrolyzed with water (50 mL) and acidified with concenfrated hydrochloric acid (3 mL) to pH 1. The solution was diluted with water (50 mL) and exfracted with dichloromethane (4 x 25 mL). The combined organic layers were washed with saturated sodium chloride solution (2 x 30 mL), dried over magnesium sulfate, concentrated in vacuo, and dried in high vacuo to give 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (0.7 g, 60 %) as a very viscous oil.

!H NMR (300 MHz, CDC13/TMS): δ (ppm): 7.42 (br. s, 3 H), 3.59 (br. s, 1 H), 1.65 – 1.00 (m, 20 H), 1.18 (s, 12 H). 13C NMR (75 MHz, CDC13/TMS): δ (ppm): 184.5, 71.8, 42.1, 40.5, 37.0, 29.8, 25.2, 25.1, 24.9, 24.8.

HRMS (FAB): Calcd. for Cι9H3705 (MH+): 345.2635, found: 345.2646. HPLC: 83.8 % purity.

………………..

PAPER

Journal of Medicinal Chemistry, 47 (24), 6082-6099;. 2004

http://pubs.acs.org/doi/abs/10.1021/jm040006p

Abstract Image

Keto-substituted hydrocarbons with 11−19 methylene and bis-terminal hydroxyl and carboxyl groups have been synthesized and evaluated in both in vivo and in vitro assays for their potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats [Crl:(ZUC)-faBR] following 1 and 2 weeks of oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ketone functionality and the gem dimethyl or methyl/aryl substituents. Furthermore, biological activity was found to be greatest in both in vivo and in vitro assays for the tetramethyl-substituted keto diacids and diols (e.g., 10c, 10g,14c), and the least active were shown to be the bis(arylmethyl) derivatives (e.g., 10e, 10f,14f). Compound 14c dose-dependently elevated HDL-cholesterol, reduced triglycerides, and reduced NEFA, with a minimum effective dose of 30 mg/kg/day. Compound 10g dose-dependently modified non-HDL-cholesterol, triglycerides, and nonesterified fatty acids, with a minimum effective dose of 10 mg/kg/day. At this dose, compound 10g elevated HDL-cholesterol levels 2−3 times higher than pretreatment levels, and a dose-dependent reduction of fasting insulin and glucose levels was observed.

ONLY KETO COMPD DESCRIBED

2,2,14,14-Tetramethyl-8-oxopentadecanedioic Acid (10g). According to the procedure given for 10f, 9g (8.54 g, 21.4 mmol) was saponified with KOH (85%, 4.53 g, 68.6 mmol) in EtOH (13 mL) and water (5 mL) at reflux for 4 h. The solid product obtained after usual workup was recrystallized from Et2O/hexanes (50 mL/50 mL), affording 10g (4.16 g, 57%) as colorless needles.

Mp:  82−83 °C.

1H NMR (CDCl3):  δ 11.53 (br, 2H), 2.39 (t, 4H, J = 7.3), 1.60−1.50 (m, 8 H), 1.30−1.20 (m, 8 H), 1.18 (s, 12 H).

13C NMR (CDCl3):  δ 211.7, 185.0, 42.8, 42.3, 40.4, 29.7, 25.1, 24.8, 23.8.

HRMS (LSIMS, gly):  calcd for C19H35O5 (MH+) 343.2484, found 343.2444.

HPLC:  Alltima C-8 column, 250 × 4.6 mm, 5 μm; 60% acetonitrile/40% 0.05 M KH2PO4, flow rate 1.0 mL/min; RI, tR 6.50 min, 92.6% pure.

Anal. (C19H34O5):  C, H.

J4A PRECURSOR OF Bempedoic Acid

PATENTs/PAPERS

WO2005068412,

WO2004067489,

Journal of Medicinal Chemistry, 47 (24), 6082-6099;. 2004

US20040198814

 

Esperion Therapeutics

Ringing the bell were Roger Newton, Esperion’s founder and chief science officer, and Tim Mayleben, the CEO and president.

Esperion raised about $73 million in its offering on June 26. It hopes to use the funds to conduct two Phase 3 U.S. Food and Drug Administration trials next year on a cholesterol-lowering drug with the working name of ETC-1002.

ETC-1002 has shown good results in preliminary human trials in lowering LDL, the so-called bad cholesterol, in patients who are either intolerant or resistant to such statin drugs as Lipitor and Torvast. More results are expected this summer.

This was the second IPO for a drug company called Esperion. The first Esperion was founded in 1998 to create a drug to raise HDL, the so-called good cholesterol. It went public in 2000 and was sold to Pfizer Inc. for $1.3 billion in 2004.

In 2008, as part of closing its Michigan operations, Pfizer sold the name and rights to some small molecules back to Newton.

Esperion Therapeutics founder and chief scientific officer Roger Newton, left, and CEO and President Tim Mayleben celebrate the company’s initial public …

Esperion cofounder Roger Newton was one of the Key players in the Development of LDL-Cholesterol Lowering Pfizer’s statin atorvastatin (Lipitor), the Biggest Selling Drug of All time with Annual Sales of Almost $ 13 Billion Dollars in 2006 at ITS Peak.

043013_BIZ_Esperion_MRM_01.JPG

Esperion President and CEO Tim Mayleben (left) and Chief Science Officer Roger Newton in the company’s labs at the Michigan Life Science and Innovation Center.Mayleben previously told AnnArbor.com that the drug being developed by the company, which is housed at the Michigan Life Science and Innovation Center in Plymouth Township, is undergoing the second round of “phase two” clinical tests. Most drugs go through three phases of testing before the results are submitted to the Food and Drug Administration. Mayleben said he does not expect the company to submit ETC-1002 to the FDA for approval for at least another three years.,Newton, a co-inventor of Lipitor and founder of the first Esperion, raised more than $22 million to buy the intellectual property from the original company back from Pfizer when the company closed its Ann Arbor offices in 2007…….http://www.annarbor.com/business-review/ann-arbor-pharmaceutical-company-esperion-therapeutics-to-ring-nasdaq-opening-bell-wednesday/

……………………

Michigan Life Science and Innovation Center in Plymouth Township

SRI International’s Helen Parish (from left), David Sahner and Elizabeth Wood in November 2013 at the site of the nonprofit’s new clinical laboratory at the Michigan Life Science and Innovation Center in Plymouth Township.

Michigan Life Science and Innovation Center

Esperion Therapeutics CEO Roger Newton in his laboratory at the Michigan Life Science Innovation Center in Plymouth Township.

Pfizer Inc. announced Jan. 22, 2007 that it would close its Ann Arbor research campus on Plymouth Road and Huron Parkway. In the photo at left, then-Ann Arbor SPARK CEO Michael Finney, then Gov. Jennifer Granholm and Ann Arbor Mayor John Hieftje speak at a press conference addressing Pfizer’s announcement.

///////Bempedoic Acid, PHASE 2, Esperion Therapeutics, Roger Newton, Tim Mayleben, ETC 1002, ESP 55016

ASLAN Pharmaceuticals Gains Orphan Designation for Rare Cancer Drug ASLAN001 (varlitinib)


 

Figure US20050043334A1-20050224-C00061

 

(R)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

 

ASLAN001 , Varlitinib

C22H19ClN6O2S

Molecular Weight: 466.94

Elemental Analysis: C, 56.59; H, 4.10; Cl, 7.59; N, 18.00; O, 6.85; S, 6.87

CAS: 845272-21-1 (Varlitinib); 1146629-86-8 (Varlitinib tosylate).

ASLAN001; ASLAN-001; ASLAN 001; AR 00334543; ARRY-334543; ARRY334543; ARRY-543; ARRY543; ARRY 543.

(R)-N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-N6-(4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

(R)-4-[[3-Chloro-4-[(thiazol-2-yl)methoxy]phenyl]amino]-6-[(4-methyl-4,5-dihydrooxazol-2-yl)amino]quinazoline

4,​6-​Quinazolinediamine, N4-​[3-​chloro-​4-​(2-​thiazolylmethoxy)​phenyl]​-​N6-​[(4R)​-​4,​5-​dihydro-​4-​methyl-​2-​oxazolyl]​-

ASLAN Pharmaceuticals, a Singapore-based drugmaker, announced The Food and Drug Administration (FDA) gave an orphan drug designation on August 13 to its pan-HER inhibitor ASLAN001 (varlitinib), a drug candidate created to treat a destructive form of bile duct cancer called cholangiocarcinoma that has no known cure.  ………http://www.dddmag.com/news/2015/08/aslan-pharmaceuticals-gains-orphan-designation-rare-cancer-drug

Current developer: Array Biopharma Inc,

Varlitinib, also known as ARRY-543 and ASLAN001, is an orally bioavailable inhibitor of the epidermal growth factor receptor family with potential antineoplastic activity.

Varlitinib (ASLAN-001) is an oncolytic drug in phase II clinical trials at ASLAN Pharmaceuticals for the treatment of gastric cancer and for the treatment of metastatic breast cancer in combination with capecitabine. Clinical development is also ongoing for the treatment of solid tumors in combination with cisplatin/FU and cisplatin/capecitabine. The product had been in phase I/II clinical trials at Array BioPharma for the treatment of patients with advanced pancreatic cancer. Phase II clinical trials had also been ongoing for the treatment of solid tumors. No recent development has been reported for this research

Varlitinib selectively and reversibly binds to both EGFR (ErbB-1) and Her-2/neu (ErbB-2) and prevents their phosphorylation and activation, which may result in inhibition of the associated signal transduction pathways, inhibition of cellular proliferation and cell death. EGFR and Her-2 play important roles in cell proliferation and differentiation and are upregulated in various human tumor cell types. Due to the dual inhibition of both EGFR and Her-2, this agent may be therapeutically more effective than agents that inhibit EGFR or Her-2 alone.

The drug is a dual inhibitor of the ErB-2 and EGFR receptor kinases, both of which have been shown to stimulate aberrant growth, prolong survival and promote differentiation of many tumor types. The compound behaves as a reversible ATP-competitive inhibitor with nanomolar potency both in vitro and in cell-based proliferation assays.

In 2011, the compound was licensed to Aslan Pharmaceuticals by Array BioPharma worldwide for the treatment of solid tumors, initially targeting patients with gastric cancer through a development program conducted in Asia.

In 2015, orphan drug designation was assigned to the compound in the U.S. for the treatment of cholangiocarcinoma.

SEE NMR ………….http://www.medkoo.com/Product-Data/Varlitinib/Varlitinib-QC-KB20121128web.pdf

……………..

https://www.google.co.in/patents/US20050043334

Example 52

Figure US20050043334A1-20050224-C00061

 

(R)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

Prepared using (R)-2-aminopropan-1-o1. MS APCI (+) m/z 467, 469 (M+1, Cl pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54 (s, 2H), 4.47 (m, 1H), 3.99 (m, 1H), 3.90 (m, 1H), 1.18 (d, 3H).

Example 53

Figure US20050043334A1-20050224-C00062

 

(S)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

Prepared using (S)-2-amino-propan-1-o1. MS APCI (+) m/z 467, 469 (M+1, Cl pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54 (s, 2H), 4.47 (m, 1H), 3.99 (m, 1H), 3.90 (m, 1H), 1.18 (d, 3H).

………………

 

PATENT

http://www.google.co.in/patents/WO2005016346A1?cl=en

Example 52

 

Figure imgf000056_0002

R VN4-r3-Chloro-4-(thiazol-2-v-metho-xy)-phenyll-N6-(4-methyl-4,5-dihvdro-oxazol- 2-yl)-quinazoUne-4,6-diamine

[00194] Prepared using (R)-2-aminopropan- 1 -ol. MS APCI (+) m/z 467, 469

(M+l, CI pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, IH), 8.47 (s, IH), 8.09 (s, IH), 7.86 (d, IH), 7.81 (d, IH), 7.77 (d, IH), 7.69 (m, 3H), 7.32 (d, IH), 7.02 (s, IH), 5.54 (s, 2H), 4.47 (m, IH), 3.99 (m, IH), 3.90 (m, IH), 1.18 (d, 3H). Example 53

 

Figure imgf000057_0001

(S)-N4-|3-Chloro-4- thiazol-2-ylmethoxy)-phenyll-N6-(4-methyl-4,5-dihvdro-oxazol- 2-yl)-quinazoline-4,6-diamine [00195] Prepared using (S)-2-amino-propan- 1 -ol. MS APCI (+) m z 467, 469

(M+l, CI pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, IH), 8.47 (s, IH), 8.09 (s, IH), 7.86 (d, IH), 7.81 (d, IH), 7.77 (d, IH), 7.69 (m, 3H), 7.32 (d, IH), 7.02 (s, IH), 5.54 (s, 2H), 4.47 (m, IH), 3.99 (m, IH), 3.90 (m, IH), 1.18 (d, 3H).

 

………

CAUTION a very similar molecule but not same 

C2NOTE……..METHYL NEXT TO OXYGEN ATOM

Design, Synthesis and Bioactivities Evaluation of Novel Quinazoline Analogs Containing Oxazole Units

A novel type of quinazoline derivatives, which were designed by the combination of quinazoline as the backbone and oxazole scaffold as the substituent, have been synthesized and their biological activities were evaluated for anti-proliferative activities and EGFR inhibitory potency. Compound 12b demonstrated the most potent inhibitory activity (IC50=0.95 µmol/L for EGFR), which could be optimized as a potential EGFR inhibitor in the further study. The structures of the synthesized quinazoline analogs and all intermediates were comfirmed by 1H and 13C NMR, 2D NMR spectra, IR spectra and MS spectra.

12c: Employing the same method as above, compound 12c was prepared and the amino alcohol was (S)-2-amino-propan-1-ol. Yellow solid, yield 52 %. m.p. 243-244 °C; [α] 20D =﹢22.5 ° (c 1.0, CH3CN); 1 H NMR (DMSO-D6): δ 9.54 (s, 1 H), 8.46 (s, 1 H), 8.06 (s, 2 H), 7.85 (d, 2 H, J=3.3 Hz), 7.79 (d, 2 H, J=3.3 Hz), 7.75 (d, 1 H, J=8.9 Hz), 7.64 (d, 1 H, J=8.3 Hz), 7.30 (d, 1 H, J=9.0 Hz), 5.54 (s, 2 H), 4.76 (m, 1 H), 3.72 (s, 1 H), 3.19 (s, 1 H), 1.34 (d, 3 H, J=6.15 Hz). 13C NMR (DMSO-D6) δ: 165.8, 156.9, 152.0, 148.8, 145.3, 142.6, 134.3, 128.7, 128.0, 123.5, 121.7, 121.3, 121.0, 115.6, 114.6, 72.5, 67.7, 63.0, 29.8, 29.0, 20.0, 13.9. IR (KBr) ν: 3439, 3278, 3101, 2925, 1660, 1631, 1601, 1557, 1500, 1428, 1404, 1384, 1329, 1291, 1257, 1225, 1052 cm-1. Anal. calcd for C22H19N6O2SCl: C 55.59, H 4.10, N 18.00, O 6.85; found C 55.55, H 4.13, N 18.02, O 6.78; MS (ESI) m/z: 467.2 (M+H).

12d: Employing the same method as above, compound 12d was prepared and the amino alcohol was (R)-2-amino-propan-1-ol. Yellow solid, yield 60%. m.p. 242-243 °C; [α] 20D = ﹣22.3 ° (c 1.0, CH3CN); 1 H NMR (DMSO-D6): δ 9.52 (s, 1 H), 8.80 (s, 1 H), 8.52 (dd, 1 H, J=2.7 Hz, J=8.9 Hz), 8.45 (s, 1 H), 8.30 (s, 1 H), 8.07 (s, 1 H), 7.85 (d, 1 H, J=3.2 Hz), 7.79 (d, 1 H, J=3.2 Hz), 7.75 (s, 1 H), 7.63 (d, 1 H, J=8.2 Hz), 7.31 (d, 1 H, J=9.0 Hz), 5.53 (s, 2 H), 4.76 (m, 1 H), 3.81 (s, 1 H), 3.19 (s, 1 H), 1.34 (d, 3 H, J=6.2 Hz). 13C NMR (DMSO-D6) δ: 165.8, 156.9, 152.0, 148.8, 145.3, 142.6, 134.3, 128.7, 128.0, 123.5, 121.7, 121.3, 121.0, 115.6, 114.6, 72.5, 67.7, 63.0, 29.8, 29.0, 20.0, 13.9. IR (KBr) ν: 3439, 3278, 3101, 2925, 1660, 1631, 1601, 1557, 1500, 1428, 1404, 1384, 1329, 1291, 1257, 1225, 1052 cm-1. Anal. calcd for C22H19N6O2SCl: C 55.59, H 4.10, N 18.00, O 6.85; found C 55.55, H 4.13, N 18.02, O 6.78; MS (ESI) m/z: 467.20 (M+H).

The above paper allows you to synthesize the key amino int 11 ………N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)quinazoline-4,6-diamine (11)

this can be applied to varlitinib till int  11

C1

 

6-Nitro-4-hydroxyquinazoline (3)

2-amino-5-nitrobenzoic acid (5.46 g, 30 mmol) was added to a 250 mL flask equipped with a reflux condenser. Then 50 mL formamide was added. The mixture was heated with vigorous stirring at 160 °C for 3 h. After cooling the solution was poured in ice-water to give 3 in almost pure form (Yellow solid 4.70 g, yield 82.0%). m.p. 317-318 °C; 1 H NMR (DMSO-d6): δ 12.74 (1 H, s, OH, exchangeable), 8.78 (1 H, d, J=2.4 Hz), 8.53 (1 H, dd, J=2.6 Hz, 9.0 Hz), 8.30 (s, 1 H), 7.84 (1 H, d, J=9.0 Hz); 13C NMR (DMSO-d6) δ: 160.1, 152.9, 148.9, 145.0, 129.1, 128.3, 122.7, 121.9. IR (KBr) ν: 3172, 3046, 2879, 1674, 1615, 1577, 1514, 1491, 1469, 1343, 1289, 1242, 1167, 1112, 928, 920, 901, 803, 753, 630, 574, 531 cm-1. Anal. calcd for C8H5N3O3: C 50.27, H 2.64, N 21.98; found C 50.30, H 2.65, N 21.96; MS (ESI) m/z: 189.97 (M-H).

nmr1

nmr113C NMR OF 3 IN DMSOD6

IR

 

nmr1

4-chloro-6-Nitroquinazoline (4)

In a 100 mL flask equipped with a reflux condenser, 6-nitroquinazolin-4-one (2.86 g, 15 mmol) and thionyl chloride (SOCl2) 25 mL were added. The mixture was heated under reflux with vigorous stirring for 2 h. After the solution was clear, the reaction mixture was heated for another 2 h. Then, 150 mL of ice MeOH was dropped into it carefully, the mixture was extracted with CH2Cl2. The organic layer was S3 dried under MgSO4, filtered and the solvent removed to give 4-chloro-6-nitroquinazoline (4). Yellow solid 2.45 g, yield 78%. m.p. 134-135 °C; 1 H NMR (DMSO-d6): δ 8.80 (1 H, d, J=3.0 Hz), 8.54(1 H, dd, J=2.7 Hz, 9.0 Hz), 8.35(s, 1 H), 7.87 (1 H, d, J= 9.0 Hz); 13C NMR (DMSO-d6) δ: 160.0, 152.5, 149.1, 145.1, 128.7, 128.4, 122.7, 122.0. IR (KBr) ν: 3431, 3082, 3038, 2664, 2613, 2567, 1724, 1685, 1676, 1646, 1617, 1578, 1526, 1468, 1359, 1346, 1269 cm-1. Anal. calcd for C8H4N3O2Cl: C 45.84, H 1.92, N 20.05, O 15.27; found C 45.81, H 1.97, N 20.02, O 15.21; MS (ESI) m/z: 207.96 (M-H).

 

nmr14 nmr dmsod6

 

 

13C NMR OF4 IN DMSOD6

nmr1

IR

nmr1

Thiazol-2-yl-methano1 (6)

Sodium borohydride (16.0 g, 140 mmol) was added to a stirred solution of thiazole-2-carbaldehyde (24.2 g, 214 mmol) in MeOH (400 mL) at 0 °C . The reaction mixture was warmed to room temperature. After 1 hour, the reaction mixture was quenched by the addition of water and the organics were removed by concentration. The resulting aqueous mixture was extracted with EtOAc. The combined organic extracts were dried under Na2SO4 and concentrated to give thiazol-2-yl-methano1 (23.39 g, 95%). bp:75-76 °C (0.2 mmHg) [lit.[19] bp:70-80 °C (0.2 mmHg)]; m. p. 63-64 °C. 1 H NMR (CDCl3) δ 4.91 (s, 2 H), 5.1(br, l H), 7.28(d, 1 H, J=3.2 Hz), 7.68 (d, 1 H, J=2.9 Hz). IR (KBr) ν: 3135, 3099, 3082, 2814, 1509, 1446, 1351, 1189, 1149, 1073, 1050, 977, 775, 745, 613, 603 cm-1. Anal. calcd for C4H5NOS: C 41.72, H 4.38, N 12.16; found C 41.74, H 4.33, N 12.18; MS (ESI) m/z: 116.11 (M+H).

nmr16 in dmsod6 1H NMR

 

nmr1

2-((2-Chloro-4-nitrophenoxy)methyl)thiazole (8)

2-(2-chloro-4-nitro-phenoxymethy1)-thiazole was prepared by adding thiazol-2-yl-methanol (5.48 g, 47.65 mmol) to a slurry of sodium hydride (2.42 g of a 60% dispersion in oil, 60.5 mmol) in THF (50 ml) at 0 °C After several minutes, 2-chloro-1-fluoro- 4-nitro-benzene (7.58 g, 43.60 mmol) was added and the reaction mixture warmed to room temperature. The reaction mixture was stirred at room temperature for 3 h, and 60 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into 300 mL water. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give 2-(2- chloro-4-nitrophenoxymethy1)-thiazole (11.06 g, 86%) which was used in next step without further purification. m.p. 170-171 °C; 1 H NMR (DMSO-d6): δ 8.35 (1 H, d, J=2.8 Hz), 8.25 (1 H, dd, J=2.8 Hz, 9.15 Hz), 7.87 (1 H, d, J=3.3 Hz), 7.83(1 H, d, J=3.3 Hz), 7.54 (1 H, d, J=9.2 Hz), 5.73(s, 1 H); 13C NMR (DMSO-d6) δ: 164.2, 158.5, 143.2, 141.7, 125.9, 124.9, 122.4, 122.2, 114.6, 68.4; IR (KBr) ν: 3112, 3009, 1587, 1509, 1500, 1354, 1319, 1284, 1255, 1154, 1125, 1054, 1006, 894, 780, 746, 728 cm-1. Anal. calcd for C10H7N2O3SCl: C 44.37, H 2.61, N 10.35, O 17.73; found C 44.31, H 2.67, N 10.29; MS (ESI) m/z: 268.89 (M-H).

nmr11H NMR 8 DMSOD6

13C NMR OF 8 IN DMSOD6

nmr1

nmr1

3-Chloro-4-(thiazol-2-ylmethoxy)aniline (9)

In a flask equipped with a reflux condenser, the compound 8 15.00 g (55.6 mmol), reduced zinc powder 14.44 g (222.0 mmo1, 4 eq), saturated ammonia chloride (5 mL) and methanol (100 mL) were mixed. The mixture was stirred at a temperature of 40 °C for 1.5 h. Then the zinc powder was filtered off, the filtrate was concentrated to obtain yellow solid 13.21 g, yield 99%. m.p. 60-61 °C; 1 H NMR (DMSO-d6): δ 7.80 (1 H, d, J=3.3 Hz), 7.75 (1 H, d, J=3.3 Hz), 6.96 (1 H, d, J=8.8 Hz), 6.64(1 H, d, J=2.7 Hz), 6.46 (1 H, dd, J=2.7 Hz, J=8.7 Hz), 5.30 (s, 2 H), 5.04 (s, 2 H, NH2, exchangeable); 13C NMR (DMSO-d6) δ: 166.8, 145.1, 144.1, 142.80, 123.1, 121.5, 117.7, 115.2, 113.6, 69.1. IR (KBr) ν: 3322, 3192, 3112, 1607, 1499, 1457, 1436, 1291, 1274, 1221, 1191, 1144, 1057, 1027, 857, 797, 767, 733, 584 cm-1. Anal. calcd for C10H9N2OSCl: C 49.90, H 3.77, N 11.64, O 6.65; found C 49.95, H 3.76, N 11.66, O 6.60; MS (ESI) m/z: 239.01 (M-H).

nmr11H NMR DMSOD6 OF 9

 

nmr113C NMR OF 9 IN DMSOD6

 

nmr1

N-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-6-nitro- quinazolin-4-amine(10)

In a flask equipped with a reflux condenser, 6-nitro-4-chloro- quinazoline 8.0 g (38.3 mmol) and 3-Chloro-4-(thiazol-2-ylmethoxy)aniline 8.9 g (37.0 mmol) were dissolved into 150 mL of THF, and the solution was refluxed for 3 h.Then a lot of yellow solid was deposited. Then it was filtered affording to yellow solid 12.8 g, yield 81%. m.p. 183-184 °C (decompose); 1 H NMR (DMSO-d6): δ 11.97(s, 1 H, exchangeable), 9.84 (s, 1 H), 9.00 (s, 1 H), 8.76 (1 H, d, J=9.1 Hz), 8.12-8.14 (m, 1 H), 7.94 (1 H, d, J=2.3 Hz), 7.87 (1 H, d, J=3.2 Hz), 7.81 (1 H, d, J=3.2 Hz), 7.44 (1 H, d, J=9.0 Hz), 7.69 (1 H, dd, J=2.5 Hz, J=8.9 Hz), 5.61 (s, 2 H); 13C NMR (DMSO-d6) δ: 166.8, 145.1, 144.1, 142.8, 123.1, 121.5, 117.7, 115.2, 113.7, 69.1. IR (KBr) ν: 3442, 3100, 1636, 1618, 1570, 1552, 1523, 1492, 1442, 1400, 1377, 1344, 1301, 1267, 1069, 805 cm-1. Anal. calcd for C18H12N5O3SCl: C 52.24, H 2.92, N 16.92, O 11.60; found C 52.26, H 2.93, N 16.96, O 11.58; MS (ESI) m/z: 412.84 (M-H).

nmr11H NMR DMSOD6 OF 10

 

nmr113C NMR OF 10 IN DMSOD6

 

nmr1

N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)quinazoline-4,6-diamine (11)

In a flask equipped with a reflux condenser, the compound 10 5.00 g (12.1 mmol), reduced zinc powder 3.2 g (48.5 mmo1, 4 eq), saturated ammonia chloride (3 mL) and methanol (60 mL) were mixed. The mixture was stirred at room temperature for 30 min. Then the zinc powder was filtered off, the filtrate was concentrated to obtain yellow solid 4.58 g, yield 98%. m.p. 197-198 °C (decompose); 1 H S4 NMR (DMSO-d6): δ 9.33(s, 1 H, exchangeable), 8.31 (s, 1 H), 8.05 (d, 1 H, J=2.6 Hz), 7.85 (d, 1 H, J=3.3 Hz), 7.79 (1 H, d, J=3.3 Hz), 7.73 (1 H, dd, J=2.5 Hz, J=9.0 Hz), 7.51 (1 H, d, J=8.9 Hz), 7.30 (1 H, d, J=2.4 Hz), 7.29 (1 H, d, J=4.7 Hz), 7.23 (1 H, dd, J=2.3 Hz, J=8.9 Hz), 5.57 (s, 2 H, exchangeable), 5.52 (s, 2 H); 13C NMR (DMSO-d6) δ: 165.9, 155.8, 149.7, 148.5, 147.3, 142.6, 142.5, 134.6, 128.7, 123.6, 123.2, 121.4, 121.3, 121.1, 116.5, 114. 7, 100.9, 67.8. IR (KBr) ν: 3443, 3358, 3211, 3100, 1631, 1596, 1577, 1560, 1530, 1494, 1431, 1383, 1217, 910 cm-1. Anal. calcd for C18H14N5OSCl: C 56.32, H 3.68, N 18.24, O 4.17; found C 56.34, H 3.70, N 18.22, O 4.14; MS (ESI) m/z: 382.66 (M-H).

nmr111 1HNMR DMSOD6

 

nmr113C NMR OF 11 IN DMSOD6

nmr1

Construction finally as per patent ……….US20050043334

Treatment of N4-[3-chloro-4-(thiazol-2-ylmethoxy)phenyl]quinazoline-4,6-diamine (11) with 1,1′-thiocarbonyldiimidazole , followed by condensation with 2(R)-amino-1-propanol  in THF/CH2Cl2 affords thiourea derivative , which finally undergoes cyclization in the presence of TsCl and NaOH in THF/H2O to furnish varlitinib .

nmr2

 

  1. ASLAN Pharmaceuticals
  2. Address: 10 Bukit Pasoh Rd, Singapore 089824
    Phone:+65 6222 4235

Map of ASLAN Pharmaceuticals

Image

carl fith

Mr Carl Firth, CEO, Aslan Pharmaceuticals, Singapore (left) and Mr Dan Devine, CEO, Patrys, Australia (right)

///////ASLAN001, varlitinib, ASLAN Pharmaceuticals,  Orphan Designation, ARRY-534, ARRY-334543 , PHASE 2, ORPHAN DRUG DESIGNATION, array

Avatrombopag


 

Figure JPOXMLDOC01-appb-C000003
Avatrombopag
AVATROMBOPAG; UNII-3H8GSZ4SQL; AKR-501; E5501; 570406-98-3; AS 1670542
C29H34Cl2N6O3S2
Molecular Weight: 649.65466 g/mol

Elemental Analysis: C, 53.61; H, 5.28; Cl, 10.91; N, 12.94; O, 7.39; S, 9.87
1-[3-chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid,

1-(3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]pyridin-2-yl)piperidine-4-carboxylic acid,

1-[3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]-2-pyridyl]piperidine-4-carboxylic acid

4-​Piperidinecarboxylic acid, 1-​[3-​chloro-​5-​[[[4-​(4-​chloro-​2-​thienyl)​-​5-​(4-​cyclohexyl-​1-​piperazinyl)​-​2-​thiazolyl]​amino]​carbonyl]​-​2-​pyridinyl]​-

Phase III Clinical Trials

Drugs used in platelet disorders

Idiopathic thrombocytopenic purpura (ITP)

small-molecule thrombopoietin receptor (c-Mpl) agonist that stimulates platelet production

INNOVATOR: YAMANOUCHI PHARMACEUTICAL

DEVELOPER: Eisai

 
Avatrombopag maleate; UNII-GDW7M2P1IS; E5501 MALEATE;  677007-74-8; YM 477, AKR 501
C33H38Cl2N6O7S2
Molecular Weight: 765.72682 g/mol

UNIIGDW7M2P1IS

(Z)-but-2-enedioic acid;1-[3-chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid

INTRODUCTION

Avatrombopag, also known as AKR-501, YM477, AS 1670542 or E5501, is a novel orally-active thrombopoietin (TPO) receptor agonist. AKR-501 specifically targeted the TPO receptor and stimulated megakaryocytopoiesis throughout the development and maturation of megakaryocytes just as rhTPO did. Daily oral administration of AKR-501 dose-dependently increased the number of human platelets in these mice, with significance achieved at doses of 1 mg/kg and above. The peak unbound plasma concentrations of AKR-501 after administration at 1 mg/kg in NOD/SCID mice were similar to those observed following administration of an active oral dose in human subjects.  AKR-501 may be useful in the treatment of patients with thrombocytopenia. (source: Eur J Haematol. 2009 Apr;82(4):247-54).

Avatrombopag is a thrombopoietin receptor (c-Mpl) agonist in phase III clinical evaluation at Eisai for the oral treatment of chronic immune thrombocytopenia (idiopathic thrombocytopenia purpura) and for the treatment of thrombocytopenia associated with liver diseases. Phase II studies are ongoing for the treatment of thrombocytopenia during antiviral therapy (inhibition and maintenance) with Interferon for hepatitis C.

The drug candidate may hold potential in treating thrombocytopenia of diverse etiologies, including idiopathic thrombocytopenic purpura (ITP) and thrombocytopenia of myelodysplastic syndromes (MDS), in combination with or as a substitute for platelet transfusion.

AKR-501, a novel, small-molecule thrombopoietin mimetic being investigated for the treatment of thrombocytopenia. AkaRx is now a wholly-owned subsidiary of Eisai Inc. and Eisai has the exclusive worldwide rights to develop, market and manufacture AKR-501. AKR-501 is an investigational thrombopoietin receptor agonist that, based on preclinical studies, increases platelet production by stimulating megakaryocytic proliferation and differentiation. Eisai is currently conducting Phase II clinical trials of AKR-501 in the United States as a potential treatment for idiopathic thrombocytopenic purpura (ITP) and thrombocytopenia associated with liver diseases (TLD), and has confirmed proof of concept in the clinical studies for ITP. In addition, Eisai will explore the compound’s potential as a treatment for chemotherapy-induced thrombocytopenia (CIT).

E-5501 stimulates the production of thrombopoietin (TPO), a glycoprotein hormone that stimulates the production and differentiation of megakaryocytes, the bone marrow cells that fragment into large numbers of platelets. The drug candidate was originally developed at Yamanouchi, and development responsibilities were passed to AkaRx when it was formed in 2005 as a spin-off following the creation of Astellas Pharma subsequent to the merger of Yamanouchi Pharmaceutical and Fujisawa Healthcare.

In 2007, MGI Pharma was granted a license to E-5501 for the treatment of thrombocytopenia. Eisai eventually gained the rights to the product as results of its acquisition of MGI Pharma. In 2010, Eisai acquired AkaRx. AkaRx is now a wholly-owned subsidiary of Eisai Inc. and Eisai has the exclusive worldwide rights to develop, market and manufacture E-5501. In 2011, orphan drug designation was assigned by the FDA for the treatment of idiopathic thrombocytopenic purpura.

E5501 (or AKR-501 or YM477) is a small molecule agonist c-Mpl, orally available. It is in clinical trials for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). It acts as an agonist of the thrombopoietin receptor active orally, mimicking its biological effect. Thrombocytopenic purpura The is the idiopathic consequence of a low number of platelets (thrombocytopenia) of unknown cause. A very low platelets can even lead to purpura (bruises), or bleeding diathesis.

February 2012: A Phase III, multicenter, randomized, double-blind, controlled against placebo, parallel group, with an open-label extension phase to assess the efficacy and safety of combined oral E5501 to standard treatment for the treatment of thrombocytopenia in adults with chronic immune thrombocytopenia, is underway.

January 2010: Eisai Inc. announced its successful acquisition of the biopharmaceutical company, AkaRx Inc. Following this acquisition, AkaRx became a wholly owned subsidiary of Eisai Inc. Eisai now owns the worldwide exclusive rights to develop , marketing and manufacture AKR-501.

October 2009: Eisai Research Institute of Boston, Inc. (established in 1987) and Eisai Medical Research Inc. (established in 2002) were merged into Eisai Inc. 2005: AkaRx was founded as a spin-out of the merger of Yamanouchi Pharmaceutical Company Ltd. and Fujisawa Pharmaceutical Company Ltd. to form Astellas Pharma Inc. AKR-501 was discovered by Yamanouchi and was licensed to AkaRx as part of the foundation of the company in 2005.

In a Phase I trial in healthy volunteers, 10 mg of AKR-501 for 14 days, increased platelet count by 50%.AKR-501 was well tolerated in both studies, mono- and multi-dose. No adverse effects were reported, even at the highest doses.

……………………

Patent

WO 2004029049

Espacenet

Compound A is a compound of the present invention has the following chemical structure.

That is, compounds useful as a platelet 增多 agent according to the present invention A, as well as medicaments for the Compound A as an active ingredient, in particular increasing platelets agents and Z or thrombocytopenia treating agent.

 

Espacenet 1

………………

PATENT

WO 2003062233

Figure 01010001

Figure 01020001

……………………

JP 2014144916/WO 2013018362

https://www.google.co.in/patents/WO2013018362A1?cl=en

1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid as expressed by the following chemical formula (hereinafter referred to as “Compound X”) and pharmaceutically acceptable salts are known to have excellent thrombocytosis effects (patent literature 1, patent literature 2).

[Formula 1]

Figure JPOXMLDOC01-appb-I000001

Patent literature 1 discloses a hydrochloride of compound X as example 16 (hereinafter referred to as “compound X hydrochloride”).

Furthermore, patent literature 2 discloses a maleic acid salt of compound X that has endothermic peaks near 198 degree C and 271 degree C in thermo gravimetric analysis (hereinafter referred to as “maleic acid salt of compound X”). However, patent literature 2 neither discloses nor suggests that the maleic acid salt of compound X exhibits crystal polymorphism.

On the other hand, compounds exhibiting crystal polymorphism demonstrate entirely different effects regardless of being the same compound, because various physical properties including physicochemical properties differ depending on the crystalline form. In pharmaceutical products in particular, if compounds that have different functional effects are expected to have the same effect, a different functional effect than expected will occur, which is thought to induce unexpected circumstances, and therefore there is demand for supply of a drug substance with constant quality. Therefore, when a compound which has crystal polymorphism is used as a medicine, one type of crystal of that compound must always be constantly provided in order to ensure constant quality and constant effects that are required of the medicine.

Under the aforementioned conditions, from the perspective of supplying a drug substance for medicines, there is a need for compound X or crystals of pharmaceutically acceptable salts thereof, which can ensure constant quality and constant effects and which can be stably supplied in mass production such as industrial production or the like, as well as for establishment of a manufacturing method thereof.

International patent publication WO 03/062233 International patent publication WO 2004/029049

The crystals of compound X maleic acid salt disclosed in patent literature 2 (hereinafter referred to as “compound X maleic acid salt A type crystals”) cannot be isolated as compound X maleic acid salt A type crystals when scaled up for mass production using the method disclosed in example 1 of patent literature 2, and therefore must be isolated in a different crystal form. (This other crystal form is referred to as “compound X maleic acid salt B type crystals”). Therefore, the compound X maleic acid salt A type crystals have a possibility that the crystal form will morph depending on the scale of production, and is clearly inappropriate as a drug substance for medicines which require constant quality and constant effects.

Preparation Example 1: Manufacture of Compound X Maleic Acid Salt B Type Crystal
310 mL of a 1 M aqueous solution of sodium hydroxide at room temperature was added to a mixture of 70.0 g of the ethyl ester of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid and 1.2 L of ethanol, the insoluble matter was filtered out, and then washed with 200 mL of ethanol. The reaction solution was stirred for 90 minutes at 60 degree C. After cooling to room temperature, 1.4 L of an aqueous solution containing 24.11 g of maleic acid was added to the solution obtained, and then the precipitate was collected by filtering.

The same operation was repeated and when combined with the previously obtained precipitate, 136.05 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid was obtained.

18.9 g of maleic acid and 2.1 L of 80% ethanol water were added to 88.90 g of the carboxylic acid obtained, and the solution was stirred for one hour at room temperature and for another hour at 100 degree C. After cooling to room temperature and further cooling with ice, the precipitated solid was filtered out to obtain 87.79 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt as a crude product.

6.84 g of maleic acid was added to 231 g of the crude product containing the crude product obtained above and those manufactured in a similar manner, dissolved in 5.5 L of 80% ethanol water, and then the precipitated solid was collected by filtering to obtain 203 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.

Example 1: Manufacture of Compound X Maleic Acid Salt C Type Crystals (1)
1.52 L of ethanol, 0.38 L of water, and 15.7 g of maleic acid were added to 78.59 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid, and heated while stirring. After cooling to room temperature and further cooling with ice, the precipitated solid was collected by filtering to obtain 71.60 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt as a crude product.

296 mg of maleic acid was added to 10.0 g of the crude product obtained, dissolved in 60 mL of acetone, 60 mL of DMSO, and 30 mL of water, and then the precipitated solids were collected to obtain 8.41 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.

Example 2: Manufacture of Compound X Maleic Acid Salt C Type Crystals (2)
A mixture containing 80.1 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid, 580 mL of DMSO, 580 mL of acetone, 17.2 g of maleic acid, and 290 mL of water was stirred at 69 degree C. The insoluble matter was filtered out, washed with a mixture of 32 mL of DMSO, 32 mL of acetone, and 16 mL of water, and then the filtrate was cooled and the precipitate was collected by filtering. Washing was successively performed using 150 mL of water, 80 mL of acetone, 650 mL of water, and 80 mL of acetone, followed by drying, to obtain 70.66 g of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.

Example 3: Manufacture of Compound X Maleic Acid Salt C Type Crystals (3)
A mixture containing 20 kg of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid, 100 L of DMSO, 100 L of acetone, 4.29 kg of maleic acid, and 50 L of water is stirred at 65 degree C, and then the insoluble matter is filtered out and washed with a mixture of 8 L of DMSO, 8 L of acetone, and 4 L of water, and then the filtrate is cooled, the precipitate is collected by filtering, successively washed using 40 L of acetone, 100 L of water, and 40 L of acetone, and then dried to obtain approximately 20 kg of 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexyl piperazin-1-yl) thiazol-2-yl] carbamoyl} pyridin-2-yl) piperidine-4-carboxylic acid maleic acid salt.

…………………………….

 

REFERENCES

Garabet, L.; Ghanima, W.; Lee, S.; Mowinckel, M.C.; Liebman, H.; Jonassen, C.M.; Bussel, J.; Sandset, P.M.
Thrombopoietin receptor agonists do no not cause coagulation activation: In patients with immune thrombocytopenia
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO311-MON

Terrault, N.; Hassanein, T.; Joshi, S.; Lake, J.R.; Sher, L.S.; Vargas, H.E.; McIntosh, J.W.; Tang, S.; Jenkins, T.
Once-daily oral avatrombopag (E5501) prior to elective surgical or diagnostic procedures in patients with chronic liver disease and thrombocytopenia: Results from a phase 2, randomized, double-blind, placebo-controlled study (study 202)
63rd Annu Meet Am Assoc Study Liver Dis (November 9-13, Boston) 2012, Abst

​​Thiophenyl Triazol-3-one Derivatives As Smooth Muscle relaxers: US6613786 (2003) Priority: US20010336865P, Nov. 2, 2001 (Bristol-Myers Squibb CO, US)

Preparation Of Avatrombopag: 2-Acylaminothiazole derivative or salt thereof: EP1466912 (2004) Priority: JP20020010413, 18 Jan. 2002 (Yamanouchi Pharma Co Ltd, Japan)

Synthesis And Use Of MSE Framework-Type Molecular Sieves: US2009318696 (2009) Priority: US20080214631 20 Jun. 2008 (Exxon Mobil, US).

5,6-Dichloro-Nicotinic Acid Production By Reacting 6-Hydroxy-Nicotinic Acid With Acid Chloride Reacting With Chlorine Products, Then With Acid Chloride And Hydrolysing Products: CH664754 (1988) Priority: CH19850002692, 25 Jun. 1985 (Lonza AG, Switzerland).

David J. Kuter, New Thrombopoietic Growth Factors, Lymphoma and Myeloma Clinical Journal Volume 9, Supplement 3, S347-S356

 

WO2003062233A1 15 Jan 2003 31 Jul 2003 Yamanouchi Pharma Co Ltd 2-acylaminothiazole derivative or salt thereof
WO2004029049A1 29 Sep 2003 8 Apr 2004 Yuuji Awamura Novel salt of 2-acylaminothiazole derivative
Citing Patent Filing date Publication date Applicant Title
EP2764866A1 4 Feb 2014 13 Aug 2014 IP Gesellschaft für Management mbH Inhibitors of nedd8-activating enzyme
Patent Submitted Granted
CANCER TREATMENT METHOD [US2011160130] 2011-06-30
METHOD FOR STIMULATING PLATELET PRODUCTION [US2011166112] 2011-07-07
COMPOSITIONS AND METHODS FOR INCREASING BLOOD PLATELET LEVELS IN HUMANS [US2011224226] 2011-09-15
Method of treating viral diseases with combinations of TPO receptor agonist and anti-viral agents [US2012020923] 2012-01-26

 

Patent Submitted Granted
2-Acylaminothiazole derivative or salt thereof [US7638536] 2005-07-14 2009-12-29
Compositions and methods for treating thrombocytopenia [US2007203153] 2007-08-30
Novel Combinations [US2009304634] 2009-12-10
2-ACYLAMINOTHIAZOLE DERIVATIVE OR SALT THEREOF [US2010222329] 2010-09-02
2-ACYLAMINOTHIAZOLE DERIVATIVE OR SALT THEREOF [US2010222361] 2010-09-02
Compositions and methods for increasing blood platelet levels in humans [US2008039475] 2008-02-14
CANCER TREATMENT METHOD [US2009022814] 2009-01-22
Compositions and methods for treating thrombocytopenia [US2010041668] 2010-02-18
CANCER TREATMENT METHOD [US2010075928] 2010-03-25

 

///////E 5501, AKR 501, Phase III, eisai, Avatrombopag, y 477, orphan drug, ym 477, AS 1670542, Yamanouchi Pharma Co Ltd,  Japan

 

UPDATE MAY 2018

Avatrombopag.png

Avatrombopag

https://newdrugapprovals.org/2015/08/24/avatrombopag/

FDA approves new drug for patients with chronic liver disease who have low blood platelets and are undergoing a medical procedure

The U.S. Food and Drug Administration today approved Doptelet (avatrombopag) tablets to treat low blood platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure. This is the first drug approved by the FDA for this use.Continue reading.

May 21, 2018

Release

The U.S. Food and Drug Administration today approved Doptelet (avatrombopag) tablets to treat low blood platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure. This is the first drug approved by the FDA for this use.

“Patients with chronic liver disease who have low platelet counts and require a procedure are at increased risk of bleeding,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Doptelet was demonstrated to safely increase the platelet count. This drug may decrease or eliminate the need for platelet transfusions, which are associated with risk of infection and other adverse reactions.”

Platelets (thrombocytes) are colorless cells produced in the bone marrow that help form blood clots in the vascular system and prevent bleeding. Thrombocytopenia is a condition in which there is a lower-than-normal number of circulating platelets in the blood. When patients have moderately to severely reduced platelet counts, serious or life-threatening bleeding can occur, especially during invasive procedures. Patients with significant thrombocytopenia typically receive platelet transfusions immediately prior to a procedure to increase the platelet count.

The safety and efficacy of Doptelet was studied in two trials (ADAPT-1 and ADAPT-2) involving 435 patients with chronic liver disease and severe thrombocytopenia who were scheduled to undergo a procedure that would typically require platelet transfusion. The trials investigated two dose levels of Doptelet administered orally over five days as compared to placebo (no treatment). The trial results showed that for both dose levels of Doptelet, a higher proportion of patients had increased platelet counts and did not require platelet transfusion or any rescue therapy on the day of the procedure and up to seven days following the procedure as compared to those treated with placebo.

The most common side effects reported by clinical trial participants who received Doptelet were fever, stomach (abdominal) pain, nausea, headache, fatigue and swelling in the hands or feet (edema). People with chronic liver disease and people with certain blood clotting conditions may have an increased risk of developing blood clots when taking Doptelet.

This product was granted Priority Review, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The FDA granted this approval to AkaRx Inc.

 

//////////////Doptelet, avatrombopag, fda 2018, akarx, priority review,

Lusutrombopag….Oral thrombopoietin (TPO) mimetic


 LUSUTROMBOPAG.pngChemSpider 2D Image | Lusutrombopag | C29H32Cl2N2O5S

Lusutrombopag

Update…..FDA approved july2018

(E)-3-[2,6-dichloro-4-[[4-[3-[(1S)-1-hexoxyethyl]-2-methoxyphenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]-2-methylprop-2-enoic acid

(S)-(-)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid

(2E)-3-{2,6-Dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazol-2-yl)carbamoyl]phenyl}-2-methylacrylic acid

UNII 6LL5JFU42F,  CAS 1110766-97-6,

D10476, MW591.546 , [US2010267783], MF C29H32Cl2N2O5S, S-888711

Shionogi & Co., Ltd.塩野義製薬株式会社 INNOVATOR

Optically active compound (C-3B)  Melting point: 142-145°C………….EP2184279B1

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82-0.87 (m, 3H) Optical rotation -4.5 degrees (DMSO, c = 1.001, 25°C)………….EP2184279B1

Optical rotation: -7.0 ± 0.5 degrees (CHCl3, c = 1.040, 21°C), NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52 – 1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz)), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)………EP2184279B1

 

Thrombopoietin receptor agonist, Oral thrombopoietin (TPO) mimetic

  • 24 Mar 2015 Shionogi plans a phase III trial in Thrombocytopenia (in patients with chronic liver disease) in USA (NCT02389621)
  • 31 Dec 2014 Preregistration for Thrombocytopenia in Japan (PO)
  • 08 Nov 2013 Phase II development is ongoing in the US and the Europe

Process for preparing intermediates of an optically active 1,3-thiazole containing thrombopoietin receptor agonist  Also claims crystalline forms of lusutrombopag intermediates and a process for preparing lusutrombopag. Shionogi is developing lusutrombopag, a small-molecule thrombopoietin mimetic, as an oral tablet formulation for treating thrombocytopenia.

In December 2014, an NDA was submitted in Japan. In May 2015, the drug was listed as being in phase III development for thrombocytopenia in the US and Europe.

  

 

The lusutrombopag, a low molecular-human thrombopoietin receptor agonist, its chemical formula, “(E) -3- [2,6-Dichloro-4- [4- [3 – [(S) -1-hexyloxyethyl] – 2-methoxyphenyl] -thiazol- 2-ylcarbamoyl] -phenyl] is a -2-methylacrylic acid “. lusutrombopag is represented by the following chemical structural formula.

 

Figure JPOXMLDOC01-appb-C000001

 

Eltrombopag is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000002

 

Avatrombopag is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000003

 

 

Totrombopag choline is represented by the following chemical structural formula.

Figure JPOXMLDOC01-appb-C000004
C 3B IS THE COMPD OF ROT (-) AND S, E  FORM
Figure imgb0009
 Example 2
Synthesis of (R)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (C-3A) (not included in the present invention) and (S)-(-)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (C-3B)
According to the same method as in Example 1, an optically active compound (C-3A) and an opticallly active compound (C-3B) were synthesized from (RS)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (B-3) obtained in Reference Example 3.Optically active compound (C-3A)Melting point: 139-141°C   UNDESIRED
NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82 – 0.87 (m, 3H) Optical rotaion +4.5 degrees (DMSO, c = 1.001, 25°C)

Optically active compound (C-3B)Melting point: 142-145°C  DESIRED

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82-0.87 (m, 3H) Optical rotation -4.5 degrees (DMSO, c = 1.001, 25°C)

Example 4: Synthesis of (C-3B)

 

    • Figure imgb0021

First step: Synthesis of (S)-1-(3-bromo-2-methyloxyphenyl)ethane-1-ol (17)

Using the same method as that of the first step of Example 3, the compound (17) was obtained from the compound (16) at a yield 77%.

    • Optical rotation: -23.5 ± 0.6 degrees (CHCl3, c = 1.050, 21°C)
      NMR (CDCl3) θ ppm: 1.49 (3H, d, J = 6.6 Hz), 2.33 (1H, brs), 3.88 (3H, s), 5.19 (1H, q, J = 6.4 Hz), 7.01 (1H, t, J = 7.9 Hz), 7.40 (1H, dd, J = 7.7 Hz, J = 1.1 Hz), 7.46 (1H, dd, J = 8.0 Hz, J = 1.4 Hz)

Second step: Synthesis of (S)-1-bromo-3-(1-hexyloxyethyl)-2-methyloxybenzene (18)

    •  Using the same method as that of the second step of Example 3, the compound (18) was obtained from the compound (17) at a yield of 96%.
      Optical rotation: -29.8 ± 0.6 degrees (CHCl3, c = 1.055, 21°C)
      NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.42 (3H, d, J = 6.5 Hz), 1.54 (2H, m), 3.29 (2H, m), 3.85 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 7.02 (1H, t, J = 7.9 Hz), 7.39 (1H, dd, J = 7.8 Hz, J = 1.7 Hz), 7.45 (1H, dd, J = 7.9 Hz, J = 1.7 Hz)

Third step and fourth step: Synthesis of (S)-4-(3-(1-hexyloxyethyl)-2-methyloxyphenyl)thiazole-2-amine (20)

    • Using the same method as that of the fourth step of Example 3, the compound (19) was obtained from the compound (18), subsequently according to the same method as that of the fourth step, the compound (20) was obtained.

Compound (19)

    •  NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.9 Hz), 1.2-1.4 (6H, m), 1.45 (3H, d, J = 6.6 Hz), 1.55 (2H, m), 3.29 (2H, m), 3.78 (3H, s), 4.73 (2H, m), 4.80 (1H, q, J = 6.4 Hz), 7.24 (1H, t, J = 7.8Hz), 7.52 (1H, dd, J = 7.7 Hz, J = 1.8 Hz), 7.65 (1H, dd, J = 7.7 Hz, J = 1.8 Hz)

Compound (20)

  •  Optical rotation: -4.2 ± 0.4 degrees (DMSO, c = 1.025, 21°C)
    NMR (CDCl3) δ ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2 – 1.3 (6H, m), 1.35 (3H, d, J = 6.5 Hz), 1.48 (2H, m), 3.25 (2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz)
  • Fifth step: Synthesis of ethyl (S)-(E)-3-(2,6-dichloro-4-(4-(3-(1-hexyloxyethyl)-2-metyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate (21)
    •  Using the same method as that of the fifth step of Example 3, the compound (21) was obtained from the compound (20) at a yield of 94%.
      Optical rotation: +4.7 ± 0.4 degrees (CHCl3, c = 1.07, 21°C)
      NMR (CDCl3 ) δ ppm: 0.87 (3H, t, J = 6.9 Hz), 1.2 – 1.35 (6H, m), 1.38 (3H, t, J = 7.1
      Hz), 1.44 (3H, d, J = 6.4 Hz), 1.57 (2H, m), 1.77 (3H, d, J = 1.4 Hz), 3.30 (2H, m), 3.59 (3H, s), 4.31 (2H, q, J = 7.1 Hz), 4.83 (1H, q, J = 6.4 Hz), 7.17 (1H, t, J = 7.7 Hz), 7.42 (1H, d, J = 1.7 Hz), 7.42 (1H, dd, J = 7.7 Hz, J = 1.8 Hz), 7.51 (1H, s), 7.67 (1H, dd, J = 7.6 Hz, J = 1.7 Hz), 7.89 (2H, s), 10.30 (1H, brs)

Sixth step: Synthesis of (S)-(E)-3-(2,6-dichloro-4-(4-(3-(1-hexyloxyethyl)-2-metyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylic acid (C-3B)

  • Using the same method as that of the sixth step of Example 3, the compound (C-3B) was obtained from the compound (21) at a yield of 80%.
    Optical rotation: -7.0 ± 0.5 degrees (CHCl3, c = 1.040, 21°C)
    NMR (CDCl3) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52 – 1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz)), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)
  • Results of powder X-ray deffraction are shown in Fig. 5.
  • Diffraction angle of main peak: 2θ = 17.8, 21.1, 22.5, 23.3, 24.1, and 24.4 degrees

 

 

 

WO2005014561/EP1655291A1

 https://www.google.co.in/patents/EP1655291A1?cl=en

 

 

WO2014003155, claiming a composition comprising lusutrombopag, useful for treating thrombocytopenia.

https://www.google.co.in/patents/US20150148385?cl=en

 

 

 

.

WO  2015093586

Methods respectively for producing optically active compound having agonistic activity on thrombopoietin receptors and intermediate of said compound 

 

(Step 1) Synthesis of compound (VII ‘)  under a nitrogen atmosphere, it was dissolved compound 1 (2.00kg) in 1,2-dimethoxyethane (28.0kg). 25% LDA tetrahydrofuran – heptane – ethyl benzene solution (13.20kg) was added dropwise over 1 hour at -55 ℃, and stirred for 30 minutes. It was added dropwise over 40 minutes to 1,2-dimethoxyethane (3.0kg) solution of N- formyl morpholine (3.74kg) at -55 ℃, and stirred for 1 hour. 1,2-dimethoxyethane (3.0kg) solution of 2-phosphono-propanoic acid triethyl (3.74kg) was added dropwise over 45 minutes at 0 ℃, and stirred for 2 hours. 35% aqueous solution of sulfuric acid (15.8kg) was added dropwise over 40 minutes to the reaction solution. Water (16.0kg) was added and extracted. The resulting organic layer was washed with water (8.0kg), and the solvent was evaporated under reduced pressure. Acetonitrile (16.0kg) was added, and the mixture was stirred for 1 hour at 25 ℃, and the mixture was stirred and cooled to 0 ℃ 5 hours and 30 minutes. The precipitated crystals were collected by filtration, and washed with 5 ℃ acetonitrile (3.2kg). The resulting crystals it was dissolved in acetonitrile (16.0kg) at 75 ℃. It was cooled to 60 ℃, and the mixture was stirred for 30 minutes. Over 1 hour and then cooled to 30 ℃, and the mixture was stirred for 45 minutes. Over 40 minutes and then cooled to 5 ℃, and the mixture was stirred for 3 hours.The precipitated crystals were collected by filtration, and washed with 5 ℃ acetonitrile (3.2kg). The resulting crystals it was dissolved in acetonitrile (13.0kg) at 75 ℃. It was cooled to 60 ℃, and the mixture was stirred for 30 minutes. Furthermore, up to 30 ℃ over 1 hour and then cooled and stirred for 70 minutes. Over 30 minutes and then cooled to 5 ℃, and the mixture was stirred for 4 hours. I precipitated crystals were collected by filtration. Washed with 5 ℃ acetonitrile (3.2kg), and dried to give the compound (VII ‘) (1.63kg, 51.2% yield). NMR (CDCl 3 ) delta ppm: 8.07 (s, 2H), 7.47 (s, 1H), 4.32 (Q, 2H, J = 7.0 Hz), 1.79 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz)  Results of powder X-ray diffraction and I shown in Figure 1 and Table 3. [Table 3]  In the powder X-ray diffraction spectrum, diffraction angle (2θ): 8.1 ± 0.2 °, 16.3 ± 0.2 °, 19.2 ± 0.2 °, 20.0 ± 0. 2 °, the peak was observed at 24.8 ± 0.2 °, and 39.0 ± 0.2 ° degrees.

 

(Synthesis of Compound (XI ‘))

(Step 2) Synthesis of Compound 4  under a nitrogen atmosphere over Compound 3 (3.00kg) and 1mol / L isopropylmagnesium chloride in tetrahydrofuran (11.40kg) 1 hour at 25 ℃ in The dropped, and stirred for 2 hours. 1mol / L isopropylmagnesium chloride in tetrahydrofuran solution (0.56kg) was added at 25 ℃, and stirred for 2 hours. To the reaction mixture N- methoxymethyl -N- methylacetamide the (1.45kg) was added dropwise over at 25 ℃ 40 minutes, and stirred for 80 minutes. 7% hydrochloric acid (9.7kg) was added to the reaction mixture, and the mixture was extracted with toluene (11.0kg). The resulting organic layer twice with water (each 7.5kg) washed, the solvent was evaporated under reduced pressure to give Compound 4 (2.63kg). NMR (CDCl 3 ) delta ppm: 7.69 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.55 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.05 (t, 1H, J = 7.7 Hz), 3.88 (s, 3H), 2.64 (s, 3H) ppm:

(Step 3) Synthesis of Compound 5  Under a nitrogen atmosphere, chloro [(1S Compound 4 (2.63kg), 2S) -N- ( p- toluenesulfonyl) -1,2-diphenyl-ethane diamine] (p- cymene) ruthenium (II) (28.6g), it was added to tetrahydrofuran (1.3kg) and triethylamine (880.0g). Formic acid (570.0g) was added dropwise over 6 hours at 40 ℃, and stirred for 1 hour. In addition 3.5% hydrochloric acid (14.4kg) to the reaction mixture, and the mixture was extracted with toluene (13.0kg).The organic layer was washed with 3.5% hydrochloric acid (14.4kg) and water (7.5kg), the solvent was concentrated under reduced pressure to obtain a toluene solution of Compound 5 (4.44kg).

(Step 4) Synthesis of Compound 6  under a nitrogen atmosphere, it was a potassium hydroxide (6.03kg) was dissolved in water (6.0kg). To the solution, it added tetrabutylammonium bromide (182.0g) and toluene solution of Compound 5 (4.44kg). 1-bromo-hexane (2.79kg) was added dropwise over 1 hour at 60 ℃, and the mixture was stirred for 4 hours. And extracted by adding water (4.4kg) to the reaction solution. The resulting organic layer was filtered through powdered cellulose and extracted with toluene (3.0kg) and water (7.6kg) to the filtrate. The solvent it was evaporated under reduced pressure from the organic layer. Toluene operation of evaporated under reduced pressure and the solvent by the addition of a (7.8kg) was repeated five times to obtain a toluene solution of Compound 6 (10.0kg).

(Step 5) Synthesis of Compound 7  under a nitrogen atmosphere, magnesium powder (301.0g), in tetrahydrofuran (1.3kg), the compound in toluene (6.4kg) and 1mol / L isopropylmagnesium chloride in tetrahydrofuran (432.0g) 6 In addition of the toluene solution (0.50kg) at 30 ℃, and the mixture was stirred for 2 hours. Toluene solution of Compound 6 (9.50kg) was added dropwise over 3 hours at 50 ℃, and stirred for 2 hours. 1-bromo-hexane (746.0g) was added at 50 ℃, and the mixture was stirred for 1 hour. It was added dropwise over 1 hour at 5 ℃ toluene (5.3kg) solution of 2-chloro -N- methoxy -N- methyl-acetamide (1.78kg), and stirred for 1 hour. 3.7% hydrochloric acid (16.7kg) was added to the reaction mixture, and the mixture was extracted. The obtained organic layer was washed with water (15.0kg), and concentrated under reduced pressure to give a toluene solution of Compound 7 (8.25kg).

 

(Step 6) Synthesis of Compound (II ‘)  under a nitrogen atmosphere, thiourea (1.03kg), in ethanol (1.2kg) and 65 ℃ toluene solution of compound 7 (8.25kg) in toluene (6.3kg) over 3 hours was added dropwise and stirred for 2 hours. The reaction solution was extracted by adding 0.7% hydrochloric acid (30.6kg), and washed twice with water (30.0kg). Ethanol in the organic layer (9.5kg), and extracted by addition of heptane (10.0kg) and 3.5% hydrochloric acid (5.9kg). The resulting aqueous layer with 4% hydrochloric acid (1.5kg) and ethanol (3.5kg) merged the aqueous layer was extracted from the organic layer, the ethanol was washed with heptane (10.0kg) (3.1kg) It was added. 8% aqueous sodium hydroxide (6.0kg) was added dropwise over at 5 ℃ 30 minutes, and stirred for 20 minutes. 8% aqueous sodium hydroxide (5.8kg) was added dropwise over a period at 5 ℃ 15 minutes.The precipitated crystals were collected by filtration, washed with 45% aqueous ethanol (10.9kg) and water (15.0kg) (crude crystals of Compound (II ‘)). The resulting crude crystals were dissolved in 50 ℃ in ethanol (8.1kg), over a period of 1 hour and then cooled to 10 ℃, and the mixture was stirred for 30 minutes. Water (10.0kg) over 2 hours was added dropwise and stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with 50% aqueous ethanol (7.5kg) and water (10.0kg) (crystals of the compound after recrystallization from ethanol / water system (II ‘)). The resulting crystals were dissolved at 55 ℃ in toluene (1.6kg) and heptane (1.3kg), over 1 hour and cooled to 20 ℃, and stirred for 30 minutes. Heptane (6.3kg) over a period of 30 minutes was added dropwise and stirred for 15 minutes. The obtained crystals precipitated were collected by filtration, washed with a mixed solvent of toluene (0.3kg) and heptane (2.3kg), and dried to give compound (II ‘) (1.67kg, 44.5% yield) a (crystalline compound after recrystallization from toluene / heptane system (II ‘)).

NMR (CDCl 3 ) delta ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2 – 1.3 (6H, M), 1.35 (3H, D, J = 6.5 Hz), 1.48 (2H, M), 3.25 ( 2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz)  it is shown in Figure 2 and Table 4 the results of powder X-ray diffraction. [Table 4]  In the powder X-ray diffraction spectrum, diffraction angle (2θ): 12.5 ± 0.2 °, 13.0 ± 0.2 °, 13.6 ± 0.2 °, 16.4 ± 0. 2 °, 23.0 ± 0.2 °, a peak was observed at 24.3 ± 0.2 ° degrees.  Above, each of the compounds (II ‘) of the crude crystals, the ethanol / compound after recrystallization from water (II’) crystals and toluene / heptane compound after recrystallization from (II ‘) crystallographic purity of the results of the , Fig. 3, I 4 and 5 as well as Table 5. [Table 5](HPLC was measured by the above method A.)  As shown in the results of the above table, as compared to recrystallization from ethanol / water, recrystallized with toluene / heptane system, compounds having a high optical purity it is possible to manufacture a crystal of (II ‘).  Next, the above-mentioned compound (II ‘) of the crude crystals, the ethanol / compound after recrystallization from water (II’) crystals and toluene / heptane compound after recrystallization from (II ‘) results of crystals of HPLC of the respectively, Fig. 6, I 7 and 8 and Table 6. [Table 6] (units, .N.D shows the peak area of the (%). is, .HPLC to indicate not detected was measured by the above method B.)  As shown in the results of Table, with ethanol / water system Compared to recrystallization, recrystallization from toluene / heptane system is found to be efficiently remove organic impurities A and organic impurities B.

(Step 7) Compound ‘Synthesis of DMSO adduct of (VIII)  Under a nitrogen atmosphere, the compound (II ‘) (1.50kg) and compound (VII’) (1.43kg) in ethyl acetate (17.6kg) and triethylamine (1.09kg) were sequentially added, was dissolved.Diphenyl phosphorochloridate the (1.46kg) was added dropwise over 1 hour at 50 ℃, and the mixture was stirred for 3 hours. The reaction mixture was cooled to 25 ℃, after the addition of 2.6% hydrochloric acid (8.1kg), and extracted. The resulting organic layer to 6.3% aqueous solution of sodium hydroxide (3.2kg) and 14% aqueous sodium carbonate (5.2kg) was added and stirred for 20 minutes. Adjusted to pH7.5 with 8.3% hydrochloric acid and extracted. The organic layer it was washed with 4.8% sodium chloride aqueous solution (11.0kg). DMSO and (16.5kg) was added, and the mixture was concentrated under reduced pressure.DMSO and (5.8kg) was added, over a period at 40 ℃ 30 minutes was added dropwise water (0.9kg), and stirred for 1 hour. Over a period of 30 minutes, cooled to 25 ℃, and the mixture was stirred for 30 minutes. Over at 25 ℃ 30 minutes was added dropwise water (1.4kg), and the precipitated crystals were collected by filtration. After washing with 90% DMSO solution (10.0kg) and water (27.0kg), to obtain crystals of DMSO adduct and dried to Compound (VIII ‘) (2.98kg, 95.2% yield).

1H-NMR (CDCl 3 ) delta: 0.87 (t, J = 6.8 Hz, 3H), 1.20-1.34 (M, 6H), 1.37 (t, J = 7.1 Hz, 3H), 1.44 (D, J = 6.5 Hz , 3H), 1.52-1.59 (m, 2H), 1.77 (d, J = 1.3Hz, 3H), 2.62 (s, 6H), 3.28-3.34 (m, 2H), 3.59 (s, 3H), 4.31 ( q, J = 7.1Hz, 2H), 4.83 (q, J = 6.5Hz, 1H), 7.16 (t, J = 7.7Hz, 1H), 7.40-7.43 (m, 2H), 7.51 (s, 1H), 7.68 (dd, J = 7.7, 1.8Hz, 1H), 7.92 (d, J = 1.3Hz, 2H), 10.58 (s, 1H).  The results of the powder X-ray diffraction and I are shown in Figure 9 and Table 7. [Table 7]

In the powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 7.0 ° ± 0.2 °, 8.7 ° ± 0.2 °, 10.5 ° ± 0.2 °, 12.3 ° ± 0.2 °, 14.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 19.3 ° ± 0.2 °, 22.5 ° peak was observed to ± 0.2 ° and 24.1 ° ± 0.2 °.  TG / DTA analysis result it is shown in Figure 10.  Then, each result of HPLC of concentrated dry solid and the above DMSO adduct crystals described in the following Reference Examples 1, 11 and 12, 13 and 14, and I are shown in Table 8. [Table 8] (unit, .HPLC showing peak areas of (%) was measured by the above methods C.)  As shown in the results of the above Table, when compared with the extract, DMSO adduct of the compound (VIII ‘) The in the crystal, less residual organic impurities D, and it found to be about 56% removal.

(Step 8)  under nitrogen atmosphere, DMSO adduct of the compound (VIII ‘) and (2.50kg) it was dissolved in ethanol (15.8kg). 24% sodium hydroxide aqueous solution (1.97kg) was added dropwise over a period at 45 ℃ 30 minutes to the solution and stirred for 3 hours. The reaction mixture was cooled to 25 ℃, water was added (20.0kg) and ethanol (7.8kg). 18% hydrochloric acid (2.61kg) was added dropwise over at 25 ℃ 30 minutes, followed by addition of seed crystals prepared according to the method described in Patent Document 23. After stirring for 3 hours and allowed to stand overnight. Thereafter, the precipitated crystals were collected by filtration, to give after washing with 50% aqueous ethanol solution (14.2kg), and dried to a compound (XI ‘) (1.99kg, 93.9% yield).

NMR (CDCl 3 ) delta ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, M), 1.48 (3H, D, J = 6.4 Hz), 1.52 – 1.64 (2H, M), 1.86 (3H, d, J = 1.4Hz), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)  I is shown in Figure 15 the results of powder X-ray diffraction.

 

Patent Document 1: JP-A-10-72492 JP
Patent Document 2: WO 96/40750 pamphlet
Patent Document 3: JP-A-11-1477 JP
Patent Document 4: Japanese Unexamined Patent Publication No. 11-152276
Patent Document 5: International Publication No. 00/35446 pamphlet
Patent Document 6: JP-A-10-287634 JP
Patent Document 7: WO 01/07423 pamphlet
Patent Document 8: International Publication WO 01/53267 pamphlet
Patent Document 9: International Publication No. 02 / 059 099 pamphlet
Patent Document 10: International Publication No. 02/059100 pamphlet
Patent Document 11: International Publication No. 02/059100 pamphlet
Patent Document 12: International Publication No. 02/062775 pamphlet
Patent Document 13: International Publication No. 2003/062233 pamphlet
Patent Document 14: International Publication No. 2004/029049 pamphlet
Patent Document 15: International Publication No. 2005/007651 pamphlet
Patent Document 16: International Publication No. 2005/014561 pamphlet
Patent Document 17: JP 2005-47905 Japanese
patent Document 18: Japanese Patent Publication No. 2006-219480
Patent Document 19: Japanese Patent Publication No. 2006-219481
Patent Document 20: International Publication No. 2007/004038 pamphlet
Patent Document 21: International Publication No. 2007/036709 pamphlet
Patent Document 22: International Publication No. 2007/054783 pamphlet
Patent Document 23: International Publication No. 2009/017098 pamphlet

Non-Patent Document 1: Proceedings of the National Akademyi of Science of the United State of America (…. Proc Natl Acad Sci USA) 1992, Vol. 89, p 5640-5644.
Non-Patent Document 2: Journal of Organic (.. J. Org Chem) Chemistry 1984, Vol. 49, p 3856-3857.
Non-Patent Document 3: (.. J. Org Chem). Journal of Organic Chemistry, 1992, Vol. 57, p 6667-6669
Non-Patent Document 4:. Shinretto (Synlett) 2004 year Vol. 6, p 1092-1094

 

POSTER

101 Discovery and biological evaluation of Lusutrombopag (S-888711) as a novel nonpeptide drug candidate for thrombocytopenia
Masami Takayama, Hajime Yamada, Hiroshi Takemoto, Takeshi Shiota, Yoshikazu Tanaka, Noriko Yamane, Kouji Takahashi, Naoki Oyabu, Kenji Kuwabara, Itsuki Oshima, Kenzo Koizumi, Hiroshi Yoshida, Ayumu Nogami, Tomomi Yamada, Yutaka Yoshida, Takami Murashi, Shinichiro Hara.
101 – Discovery and biological evaluation of Lusutrombopag (S-888711) as a novel nonpeptide drug candidate for thrombocytopenia

Masami Takayama1, masami.takayama@shionogi.co.jp, Hajime Yamada3, Hiroshi Takemoto2, Takeshi Shiota2, Yoshikazu Tanaka2, Noriko Yamane2, Kouji Takahashi2, Naoki Oyabu3, Kenji Kuwabara3, Itsuki Oshima2, Kenzo Koizumi3, Hiroshi Yoshida3, Ayumu Nogami3, Tomomi Yamada3, Yutaka Yoshida3, Takami Murashi3, Shinichiro Hara2. (1) Department of Strategic Research Planning Offices, Shionogi & CO., LTD, Toyonaka, Osaka 561-0825, Japan, (2) Department of Innovative Drug Discovery Research Laboratories, Shionogi & CO.,LTD, Toyonaka, Osaka 561-0825, Japan, (3) Department of Medicinal Research Laboratories, Shionogi & CO., LTD, Toyonaka, Osaka 561-0825, Japan

As a drug candidate of thrombocytopenia, Lusutrombopag (S-888711) is in Phase III clinical trial stage right now. It is been proven that Lusutrombopag (S-888711) is excellent property in safety and efficacy by clinical trials. In this meeting, we will present in detail about the history of drug discovery of Lusutrombopag.Because Lusutrombopag (S-888711) acts specifically to human TPO receptor, we prepared TPOR-Ki/Shi mice expressing a mouse-human chimeric TPOR for evaluating the efficacy. This TPOR-Ki/Shi mice worked very well as an evaluation model of drug efficacy, so we were able to select Lusutrombopag from many candidate compounds. In this meeting, we will present the results of the efficacy in TPOR-Ki/Shi mice of Lusutrombopag and the similar drug (Eltrombopag).
Sunday, March 16, 2014 07:00 PM
General Poster Session (07:00 PM – 10:00 PM)
Location: Dallas Convention Center
Room: Hall E
Monday, March 17, 2014 08:00 PM
Sci-Mix (08:00 PM – 10:00 PM)
Location: Dallas Convention Center
Room: Hall F

http://acselb-529643017.us-west-2.elb.amazonaws.com/chem/247nm/program/divisionindex.php?nl=1&act=presentations&val=General+Poster+Session&ses=General+Poster+Session&prog=222964

 

update………..

FDA approves lusutrombopag for thrombocytopenia in adults with chronic liver disease

https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm615348.htm

synthesis………..https://newdrugapprovals.org/2015/08/20/lusutrombopag-oral-thrombopoietin-tpo-mimetic/

On July 31, 2018, the Food and Drug Administration approved lusutrombopag (Mulpleta, Shionogi Inc.) for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure.

Approval was based on two randomized, double-blind, placebo-controlled trials (L-PLUS 1 and L-PLUS 2, NCT02389621) involving 312 patients with chronic liver disease and severe thrombocytopenia who were undergoing an invasive procedure and had a platelet count less than 50 x 109/L. Patients were randomized 1:1 to receive 3 mg of lusutrombopag or placebo once daily for up to 7 days.

In L-PLUS 1, 78% of patients (38/49) receiving lusutrombopag required no platelet transfusion prior to the primary invasive procedure, compared with 13% (6/48) who received placebo (95% CI for treatment difference: 49%, 79%; p<0.0001). In L-PLUS 2, 65% (70/108) of patients who received lusutrombopag required no platelet transfusion prior to the primary invasive procedure or rescue therapy for bleeding from randomization through 7 days after the procedure, compared with 29% (31/107) receiving placebo (95% CI for treatment difference: 25%, 49%; p<0.0001).

The most common adverse reaction in ≥ 3% of patients was headache.

The recommended lusutrombopag dosage is 3 mg orally once daily with or without food for 7 days.

View full prescribing information for Mulpleta.

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

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

Follow the Oncology Center of Excellence on Twitter @FDAOncology.

Check out recent approvals at the OCE’s podcast, Drug Information Soundcast in Clinical Oncology.

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

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09b37-misc2b027LIONEL MY SON

He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy

सुकून उतना ही देना प्रभू, जितने से

जिंदगी चल जाये।

औकात बस इतनी देना,

कि औरों का भला हो जाये।

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL  

 

 

//////

phase 3, shionogi, japan, lusutrombopag, S 888711

CCCCCCOC(C)C1=CC=CC(=C1OC)C2=CSC(=N2)NC(=O)C3=CC(=C(C(=C3)Cl)C=C(C)C(=O)O)Cl

Gamendazole a novel drug candidate for male contraception.


Gamendazole.svg

Gamendazole

(E) 3-(1-(2,4-Dichlorobenzyl)-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic Acid

trans-3-(1-Benzyl-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic acid)

(E)-3-[1-[(2,4-Dichlorophenyl)methyl]-6-(trifluoromethyl)indazol-3-yl]prop-2-enoic acid

  • C18H11Cl2F3N2O2
  • mw415.193
  • RC-MC-110

Heat Shock Protein 90 (HSP90) Inhibitors

University Of Kansas …Innovator

Gamendazole is a novel drug candidate for male contraception. It is an indazole carboxylic acid derived from lonidamine (LND). Gamendazole produced 100% antispermatogenic effects at 25 mg/kg i.p. in rats, whereas 200 mg/kg was fatal for 60% of rats tested. Since gamendazole produced 100% efficacy, it was tested orally. At a dose of 6 mg/kg, 100% of rats were infertile 4 weeks after a single administration. Complete infertility was maintained for 2 weeks, followed by complete recovery in 4 of 7 rats. The other 3 never recovered fertility. Upon dosing 6 mg/kg orally for 7 days, it produced similar infertility results, but only 2 of 7 rats recovered fertility. There were no abnormalities in rates of conception or abnormal conception in rats who recovered fertility.

In August 2004, preclinical data were presented at the 228th ACS meeting in Philadelphia, PA. Gamendazole, an indazole-3-acrylic acid derivative

Pathology reports were conducted on gamendazole treated rats. At 25 mg/kg i.p., 6 mg/kg oral, and in animals that survived 200 mg/kg i.p., there were no remarkable findings, with no evidence of inflammationnecrosistumors, or hemorrhage. There was also a lack of observable behavioral effects at 25 mg/kg i.p., 6 mg/kg oral, and in animals that survived 200 mg/kg i.p. Gamendazole treatment had no effect on testosterone levels, and was reported to affect Sertoli cell function, leading to decreased levels of inhibin B. Low levels of inhibin B were correlated to the infertility of the rat

Female oral contraceptive drugs are widely available in the market by several trade names, including Altravera, Brevicon, Levora, and i-pill, whereas potentially safer, more convenient, and more effective oral male contraceptives are not yet commercially available. However, there are some experimental drugs.AF-2785 1, gamendazole 2, lonidamine 3, and adjudin 4 are most promising among the experimental

Experimental drugs.

 

Gamendazole was recently identified as an orally active antispermatogenic compound with antifertility effects. The cellular mechanism(s) through which these effects occur and the molecular target(s) of gamendazole action are currently unknown. Gamendazole was recently designed as a potent orally active antispermatogenic male contraceptive agent. Here, we report the identification of binding targets and propose a testable mechanism of action for this antispermatogenic agent. Both HSP90AB1 (previously known as HSP90beta [heat shock 90-kDa protein 1, beta]) and EEF1A1 (previously known as eEF1A [eukaryotic translation elongation factor 1 alpha 1]) were identified as binding targets by biotinylated gamendazole (BT-GMZ) affinity purification from testis, Sertoli cells, and ID8 ovarian cancer cells; identification was confirmed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and Western blot analysis. BT-GMZ bound to purified yeast HSP82 (homologue to mammalian HSP90AB1) and EEF1A1, but not to TEF3 or HBS1, and was competed by unlabeled gamendazole. However, gamendazole did not inhibit nucleotide binding by EEF1A1.

Gamendazole binding to purified Saccharomyces cerevisiae HSP82 inhibited luciferase refolding and was not competed by the HSP90 drugs geldanamycin or novobiocin analogue, KU-1. Gamendazole elicited degradation of the HSP90-dependent client proteins AKT1 and ERBB2 and had an antiproliferative effect in MCF-7 cells without inducing HSP90. These data suggest that gamendazole may represent a new class of selective HSP90AB1 and EEF1A1 inhibitors. Testis gene microarray analysis from gamendazole-treated rats showed a marked, rapid increase in three interleukin 1 genes and Nfkbia (NF-kappaB inhibitor alpha) 4 h after oral administration. A spike in II1a transcription was confirmed by RT-PCR in primary Sertoli cells 60 min after exposure to 100 nM gamendazole, demonstrating that Sertoli cells are a target. AKT1, NFKB, and interleukin 1 are known regulators of the Sertoli cell-spermatid junctional complexes. A current model for gamendazole action posits that this pathway links interaction with HSP90AB1 and EEF1A1 to the loss of spermatids and resulting infertility.

 

Synthesis

 

Figure imgf000051_0003

 

Figure imgf000052_0001

Figure imgf000052_0002

Figure imgf000053_0001

Figure imgf000053_0002

Figure imgf000054_0001

 

Figure imgf000054_0002

 

Figure imgf000055_0001

Figure imgf000055_0001

…………………….

2-Halo benzoic acid is converted into aroyl chloride and then to aroyl cyanide in an overall yield of 82%. Aroyl cyanides 5 are converted to 2-halophenyl glyoxylate ester 7 via ketoamide 6 in 85% yields as shown in Scheme below. Direct conversion of aroyl cyanide 5 to ester 7 is also reported[ U.S. Patent 4,596,885, 1986 .] but with lesser yields.

Synthesis of 2-halophenylglyoxalate.

The 2-halophenylglyoxylate 7 esters are reacted with monosubstituted hydrazines 8 to give hydrazones 9. The monosubstituted hydrazones 9 are cyclized to give indazole esters 10. This cyclization is best conducted  in the presence of DPPF · PdCl2 in 94.54% yield as shown in Scheme below.

Synthesis of 1-substituted indazole-3-carboxylate.

The indazole-3-carboxylic esters 10 were reduced with sodium borohydride to alcohol 11 and were oxidized to aldehyde 12with MnO2. The aldehyde is converted to acrylic acids with malonic acid (Knoevenagel condensation) to give 88–95.6% yield of the final compounds, as shown in Schemebelow.

Synthesis of AF-2785 and gamendazole.

Preparation of (E) 3-(1-(2,4-Dichlorobenzyl)-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic Acid (R = CF3) (Gamendazole) (2)

ChemSpider 2D Image | Gamendazole | C18H11Cl2F3N2O2

 desired product 2 as a colorless solid (wt 5.32 g, yield 95.6%, HPLC purity 99.30%
DSC: 203.4 °C).
IR (KBr) (cm−1): 3447, 1697, 1641, 1311, 1122, 872; 
1H NMR (400 MHz, DMSO): δ 5.90 (2H, s), 6.72 (1H, d,J = 16.22 Hz), 6.94 (1H, d, J = 8.34 Hz), 7.36–7.39 (1H, dd, J 1 = 8.24 Hz, J 2 = 1.42 Hz), 7.55 (1H, d, J = 8.56 Hz), 7.69 (1H, d,J = 1.46 Hz), 7.78 (1H, d, J = 16.22 Hz), 8.37 (1H, d, J = 8.63 Hz), 8.40 (1H, s), 12.61 (1H, s); 
19F NMR (400 MHz, CDCl3):δ − 59.97(CF3); 
13C NMR (100 MHz, DMSO): δ 50.05, 109.16, 118.73, 121.61, 122.76, 123.39, 123.98, 127.76, 128.11, 129.42, 131.26, 133.56, 133.65, 133.76, 134.10, 140.64, 140.70, 167.57.
MW for C18H11Cl2F3N2O2 calcd. 415.19; observed: 415.3 and 417.2. HRMS: calcd.: 415.0228, observed: 415.0225.
DOI:
10.1080/00397911.2012.696306

Arava Veerareddya*, Gogireddy Surendrareddya & P. K. Dubeyb

pages 2236-2241

Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry

Volume 43Issue 16, 2013

………………

trans 3-[l- (l^-dichlorobenzy^-ό-trifluoromethyl-lH-indazol-S-ylj-acrylic acid (RC-MC-110) is provided.

 

Figure imgf000011_0002

EXAMPLE 2: Synthesis of a-ll-fl^-dichlorobenzyn-ό-trifluoromethyl-lH-indazol-S-yll-acrylic acid (RC-MC-110)

Step 1 : 2-(2-nitro-4-trifluoromethylphenyl)-malonic acid dimethyl ester.

 

Figure imgf000051_0003

Dimethyl malonate (59.7 g, 0.44 mol) was added dropwise to a stirred solution of potassium tert-butoxide (51 g, 0.44 mol) in dry t-butanol (500 mL). To the resultant suspension, a warm solution of 2-chloro-5-trifluoromethylnitrobenzene (50 g, 0.22 mol) in t-butanol (100 mL) was added and the mixture was refluxed for 6 h (reaction monitored by TLC). After completion of the reaction, most of the t-butanol was distilled off under vacuum, and chilled water was then added to the reaction mixture. The pH was adjusted to neutral with dilute hydrochloric acid, which resulted in the precipitation of the product. The mixture was stirred for 30 minutes and the product was filtered off (68 g, 95%). This material was used without further purification in the next step. A small amount was crystallized (EtOAc/hexane, 4:6) for analysis, to yield a yellow crystalline material, mp 65-67 0C. 1H NMR (CDCl3) 8.30 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 5.37 (s, 1 H), 3.80 (s, 6 H). MS (FAB) m/z: 322.1 (M+ + 1).

Step 2: (2-nitro-4-trifluoromethylphenyl)-acetic acid methyl ester.

 

Figure imgf000052_0001

2-(2-Nitro-4-trifluoromethylphenyl)-malonic acid dimethyl ester (68 g, 0.21 mol) was dissolved in dimethyl sulfoxide (200 mL). Sodium chloride (34 g, 0.58 mol) and water (60 mL) were added and the mixture was stirred for 16-20 h at 120 0C (reaction monitored by TLC). The reaction mixture was then cooled to room temperature and quenched into water, which caused precipitation of the product. After stirring for 30 minutes, the product (45 g, 80%) was isolated by filtration. The product was used without further purification in the next reaction. A small sample was crystallized (EtOAc/hexane, 2:8) for analysis, to yield yellow crystals, mp 104-105 0C. 1H

NMR (CDCl3) 8.3 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 4.12 (s, 2 H), 3.60 (s, 3 H). MS (FAB) m/z: 275.2 (M+ + 1).

Step 3: (2-Acetylamino-4-trifluoromethylphenyl)-acetic acid methyl ester.

 

Figure imgf000052_0002

Hydrogenation and acetylation of (2-nitro-4-trifluoromethylphenyl)-acetic acid methyl ester (25 g, 0.095 mol) in the presence of 5% Pd-C (2.5 g, 50% wet) and acetic anhydride (38 g, 0.37 mol) in toluene (200 mL) was carried out under vigorous stirring at room temperature and atmospheric pressure for about 4-5 h (reaction monitored by TLC). The catalyst was removed by filtration and washed with toluene two times. The combined organics were evaporated in vacuo to yield the product (24.8 g, 95%), which was used without further purification in the next step. A small sample was crystallized from hexane to yield the product as a yellow solid, mp 92-94 0C. H NMR (CDCl3) 8.86 (s, 1 H), 8.21 (s, 1 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.31 (d, J = 8.1 Hz, 1 H), 3.74 (s, 3 H), 3.68 (s, 2 H), 2.23 (s, 3 H). Step 4: ό-Trifluoromethyl-lH-indazole^-carboxylic acid methyl ester.

Figure imgf000053_0001

To a solution of (2-acetylamino-4-trifluoromethylphenyl)-acetic acid methyl ester (16 g, 0.058 mol) in acetic acid (50 mL) was added dropwise t-butyl nitrite (90%) (7.35 g, 0.063 mol) over a period of 20 min. at 90-95 0C. The mixture was then stirred for 0.5 h at 95 0C, poured into cold water and stirred for 1 h. The precipitates were collected by filtration and washed with water. The crude material was dissolved in ethyl acetate and dried over sodium sulfate. The solvent was removed in vacuo. This material (13.4 g, 95%) was used without further purification in the next step. A small sample was crystallized from ethyl acetate to yield a white solid, mp 240-242 0C. H NMR (DMSO-d-6) 8.25 (d, J = 8.5 Hz, 1 H), 8.04 (s, 1 H), 7.58 (d, J = 8.5 Hz, 1 H), 3.95 (s, 3 H). MS (FAB) m/z: 245.1 (M+ + 1).

Step 5: l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carboxylic acid methyl ester.

 

Figure imgf000053_0002

ό-Trifluoromethyl-lH-indazole-S-carboxylic acid methyl ester (2.75 g, 0.0112 mol) was dissolved in acetonitrile (50 mL), and potassium carbonate (1O g, 0.07 mol), 2,4-dichlorobenzyl chloride (2.42 g, 0.01239 mol) and tetrabutylammonium iodide (catalytic) were added. The reaction mixture was heated to reflux and refluxed for 2 h under good stirring. The progress of the reaction was monitored by TLC. After completion of the reaction, potassium carbonate was filtered while hot and then washed with acetone. The combined solvents were distilled off under reduced pressure to afford the crude mixture of Nl and N2 benzylated products. The isomers were separated by column chromatography (silica gel, eluent started with hexane then changed to 8:2 hexane, ethyl acetate). l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carboxylic acid methyl ester. Yield: 3.62 g (80%), white crystals mp 118-120 0C. ‘ H NMR (CDCl3) 8.39 (d, J = 8.4 Hz, 1 H) 7.74 (s, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.45 (d, J = 2.1 Hz, 1 H), 7.12 (dd, J = 8.4 and 2.1 Hz, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 5.82 (s, 2 H), 4.07 (s, 3 H). MS (FAB) m/z: 403 (M+ + 1).Z-^^-DichlorobenzylJ-δ-trifluoromethyl-ZH-indazole-S-carboxylic acid methyl ester. Yield: 680 mg (15%), white crystals mp 132-134 0C. ‘ H NMR (DMSO-d-6) 8.27 (s, 1 H), 8.20 (d, J = 8.7 Hz, 1 H), 7.76 (d, J = 1.8 Hz, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.30 (dd, J = 8.3 and 1.8 Hz, 1 H), 6.78 (d, J = 8.3 Hz, 1 H), 6.17 (s, 2 H), 3.96 (s, 3 H).

Step 6: [l-(2.4-Difluorobenzyl)-6-trifluoromethyl-lH-indazol-3-yl1-methanol.

 

Figure imgf000054_0001

l -(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carboxylic acid methyl ester (3.0 g, 0.0075 mol) dissolved in CH2Cl2(50 mL) was cooled to -78 0C. DIBAL-H (8.18 mL, 0.00818 mol) was added slowly dropwise via a syringe under an argon blanket over a period of 15 minutes. After the complete addition of DIBAL-H, the reaction mixture was stirred at -78°C for another 2 h (reaction monitored by TLC). The reaction was quenched carefully with methanol at -78 0C. The reaction mixture was then carefully poured into water and the layers were separated. The organic layer was washed with water and dried over sodium sulfate. Removal of the solvent yielded the crude alcohol (2.6 g, 93%), which was used without purification in the next step. The alcohol was a white solid, mp 137-139 0C. 1H NMR (CDCl3) 7.97 (d, J = 8.4 Hz, 1 H), 7.66 (s, 1 H), 7.44 (d, J = 2.0 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.12 (dd, J = 8.3 and 2.0 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 5.65 (s, 2 H), 5.09 (s, 2 H). MS (FAB) m/z: 375 (M+ + 1).Step 7: l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carbaldehvde.

 

Figure imgf000054_0002

[l-(2,4-Difluorobenzyl)-6-trifluoromethyl-lH-indazol-3-yl]-methanol (3.75 g, 0.01 mol) was dissolved in CH2Cl2 (100 mL) and manganese(IV)oxide (8.7 g, 0.1 mol) was added and stirred for 2-3 h at room temperature (reaction monitored by TLC). The solids were removed by filtration and the removal of the CH2Cl2 in vacuo yielded the crude aldehyde. The aldehyde was used without further purification in the next step. The aldehyde (3.54 g, 95%) was a white solid, mp 97-98 0C. 1H NMR (CDCl3) 10.25 (s, 1 H), 8.45 (d, J = 8.5 Hz, 1 H), 7.79 (s, 1 H), 7.60 (d, J = 8.5 Hz, 1 H), 7.48 (d, J = 2.0 Hz, 1 H), 7.20 (dd, J = 8.3 Hz and 2.0 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 5.79 (s, 2 H). MS (FAB) m/z: 373 (M+ + 1).

Step 8: 3-ri-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazol-3-yll-acrylic acid ethyl ester.

 

Figure imgf000055_0001

l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carbaldehyde (2.0 g, 0.00536 mol) was dissolved in CH2Cl2 (50 niL) and Wittig reagent (carbethoxymethylene) triphenylphosphorane (1.06 g, 0.0536 mol) was added to the solution. The homogeneous reaction mixture was heated to reflux in an oil bath for 12 h. The reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature and worked up by quenching into water and separating the organic layer. Removal of the CH2Cl2 yielded the crude product, which was purified by column chromatography to yield the pure product (2.25 g, 95%) as a white solid, mp 186-188 0C. 1H NMR (CDCl3) 8.08 (d, J = 8.5 Hz, 1 H), 7.99 (d, J = 16.2 Hz, 1 H), 7.74 (s, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.16 (dd, J = 8.3 and 2.0 Hz, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 6.82 (d, J = 16.2 Hz, 1 H), 5.72 (s, 2 H), 4.32 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H). MS (FAB) m/z: 443 (M+ + 1).It will be appreciated that the acrylic acid ethyl ester can be hydrogenated using 5% Pd-C in the presence of methanol, DCM at RT and 1 atm-pressure to give the propionic acid ester derivative. For example, treatment under such conditions yields 3-[l-(2,4-dichlorobenzyl)-6- trifluoromethyl-lH-indazol-3-yl]-propionic acid ethyl ester (JWS-2-70).

Step 9: l-(2,4-Dichlorobenzyl)-3-r6-trifluoromethyl-lΗ-indazol-3-yll-acrvlic acid.

 

Figure imgf000055_0002

l-(2,4-Dichlorobenzyl)-3-[6-trifluoromethyl-lH-indazol-3-yl]-acrylic acid ethyl ester (2.0 g, 0.0045 mol) was dissolved in a mixture of tetrahydrofuran (50 mL) and methanol (25 mL). A lithium hydroxide solution (0.33 g, 0.013 mol lithium hydroxide in 7.5 mL water) was added slowly at room temperature under good stirring. The reaction mixture was then warmed to 40 0C and held at that temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate in order to remove neutral impurities. The layers were separated and the aqueous layer was cooled to 0 0C and then acidified with 20% sulfuric acid to pH 2. White solids precipitated and were filtered and dried to constant weight. The crude product was recrystallized from ethyl acetate and hexane (1 :1) to afford the pure product (1.68 g, 90%) as a white solid,

mp 186-188 0C.
1H NMR (DMSO-d-6) 8.39 (s, 1 H), 8.36 (d, J = 8.5 Hz, 1 H), 7.79 (d, J = 16.2 Hz, 1 H), 7.66 (d, J = 1.6 Hz, 1 H), 7.55 (d, J = 8.5 Hz, 1 H), 7.35 (dd, J = 8.3 and 1.6 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 6.76 (d, J = 16.2 Hz, 1 H), 5.89 (s, 2 H).
Anal, calcd. for C18HnCl2F3N2O2: C, 52.02; H, 2.65; N, 6.74. Found: C, 50.63; H, 2.63; N, 6.63.
HRMS (FAB +) m/z calcd. for C18HnCl2F3N2O2 415.01, found 415.0233.
MS (FAB) m/z: 415 (M+ + 1).
1H NMR
1h nmr 13c nmr
13C NMR

REFERENCES

  • 1. Corsi , G. ; Palazzo , G. ; Germani , C. ; Barcellona , P. S. ; Silvestrini , B. 1-Halobenzyl-1H-indazole-3-carboxylic acids: A new class of antispermatogenic agents . J. Med. Chem. 1976 , 19 , 778 
  • 2. Palazzo , G. ; Corsi , G. ; Baiocchi , L. ; Silvestrini , B. Synthesis and pharmalogical properties of 1-substituted-3-dimethylaminoalkoxy-1H-indazoles . J. Med. Chem. 1966 , 9 , 38 – 41 . 
  • 3. Silvestrini , B. Basic and applied research in the study of indazole carboxylic acids . Chemotherapy 1981 , 27 ( Suppl.2 ), 9 – 20 . 
  • 4. Silvestrini , B. ; Palazzo , G. ; De Gregorio , M. D. 3-Lonidamine and related compounds . Progr. Med. Chem. 1985 , 21 , 111 – 135 .
  • 5. Cheng , C. Y. ; Silvestrini , B. ; Grima , J. ; Mo , M. Y. ; Zhu , L. J. ; Johnsson , E. ; Saso , L. ; Leone , M. G. ; Palmery , M. ; Mruk , D. Two new male contraceptives exert their effects by depleting germ cells prematurely from the testes . Biol. Reprod. 2001 , 65 , 449 – 461 . 
  • 6. Xia , W. ; Mruk , D. D. ; Lee , W. M. ; Ceng , C. Y. Unraveling the molecular targets pertinent to junction restructuring events during spermatogenesis using the Adjudin-induced germ cell depletion model . J. Endocrinol. 2007 , 192 , 563 – 583 .
  • 7. Cheng , C. Y. ; Mruk , D. D. ; Silvestrini , B. ; Bonanomi , M. ; Wong , C. H. ; Siu , M. K. Y. ; Lee , N. P. Y. ; Mo , M. Y. AF-2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] is a potential male contraceptive: A review of recent data . Contraception2005 , 72 , 251 – 261 . 
  • 8. Tash , J. S. ; Attardi , B. ; Hild , S. A. ; Chakrasali , R. ; Jakkarg , S. R. ; Georg , G. I. A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose . Biol. Reprod. 2008 , 78 , 1127 – 1138 .
  • 9. Sarkar , O. ; Mathur , P. P. Adjudin-mediated germ cell depletion alters the anti-oxidant status of adult rat testes . Mol. Reprod. Dev. 2009 , 76 , 31 – 37 . 
  • 10. Mok , K.-W. ; Mruk , D. D. ; Lie , P. P. Y. ; Lui , W.-Y. ; Cheng , C. Y. Adjudin, a potential male contraceptive, exerts its effects locally in the seminiferous epithelium of mammalian testes. Reproduction. 2011, 141, 571–580. 
  • 11. Wang , H. ; Chen , X. X. ; Wang , L.-R. ; Mao , Y.-D. ; Zhou , Z. M. ; Sha , J.-H. AF-2364 is a prospective spermicide candidate .Asian J. Androl. 2010 , 12 , 322 – 335 . 
    1.  “Gamendazole”NextBio. http://www.nextbio.com. Retrieved 31 July 2011.
    2.  Tash, Joseph (July 2008). “A Novel Potent Indazole Carboxylic Acid Derivative Blocks Spermatogenesis and Is Contraceptive in Rats after a Single Oral Dose”. Biology of Reproduction 78 (6): 1127–1138. doi:10.1095/biolreprod.106.057810PMID 18218612.

Chakrasali, R.; Jakkaraj, S.R.; Tash, J.S.; Hild, S.A.; Attardi, B.; Georg, G.I.
Design, synthesis and in vivo evaluation of Gamendazole(R), a novel orally active male contraceptive agent
228th Am Chem Soc (ACS) Natl Meet (August 22-26, Philadelphia) 2004, Abst MEDI 305

CHENG C.Y. ET AL: “Two New Male Contraceptives Exert Their Effects by Depleting Germ Cells Prematurely from the Testis” BIOLOGY OF REPRODUCTION, SOCIETY FOR THE STUDY OF REPRODUCTION, CHAMPAIGN, IL, US, vol. 65, no. 2, 1 August 2001 (2001-08-01), pages 449-461, XP002547492 ISSN: 0006-3363
2 * GATTA F. ET AL: “Pyrazolo[3,4-d]pyrimidines. Related to Lonidamine” JOURNAL OF HETEROCYCLIC CHEMISTRY, HETEROCORPORATION. PROVO, US, vol. 26, no. 3, 1 March 1989 (1989-03-01), pages 613-618, XP002547493 ISSN: 0022-152X
US3895026 * Feb 9, 1973 Jul 15, 1975 Acraf Substituted 1-benzyl-1h-indazole-3-carboxylic acids and derivatives thereof
WO2003097063A1 * May 5, 2003 Nov 27, 2003 Bayer Ag Derivatives of 2-(1-benzyl-1h-pyrazolo (3, 4-b)pyridine-3yl) -5-(4-pyridinyl)-4-pyrimidine amine and the use thereof as guanylate cyclase stimulators
WO2006015263A2 * Jul 29, 2005 Feb 9, 2006 Duan Jian-Xin Lonidamine analogs
Gamendazole
Gamendazole.svg
Gamendazole ball-and-stick model.png
Names
IUPAC name

(E)-3-[1-[(2,4-Dichlorophenyl)methyl]-6-(trifluoromethyl)indazol-3-yl]prop-2-enoic acid[1]
Other names

trans-3-(1-Benzyl-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic acid)
Identifiers
877773-32-5 Yes
ChemSpider 9387234 
Jmol-3D images Image
PubChem 11212172
Properties
C18H11Cl2F3N2O2
Molar mass 415.19 g·mol−1

 

 

 

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/////////

FDA approves flibanserin first treatment for sexual desire disorder


 

FDA approves first treatment for sexual desire disorder
Addyi approved to treat premenopausal women

SEE FULL SYNTHESIS …CLICK HERE

The U.S. Food and Drug Administration today approved  to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Prior to Addyi’s approval, there were no FDA-approved treatments for sexual desire disorders in men or women.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

 

August 18, 2015

Release

The U.S. Food and Drug Administration today approved Addyi (flibanserin) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Prior to Addyi’s approval, there were no FDA-approved treatments for sexual desire disorders in men or women.

“Today’s approval provides women distressed by their low sexual desire with an approved treatment option,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research (CDER). “The FDA strives to protect and advance the health of women, and we are committed to supporting the development of safe and effective treatments for female sexual dysfunction.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a co-existing medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance. HSDD is acquired when it develops in a patient who previously had no problems with sexual desire. HSDD is generalized when it occurs regardless of the type of sexual activity, the situation or the sexual partner.

“Because of a potentially serious interaction with alcohol, treatment with Addyi will only be available through certified health care professionals and certified pharmacies,” continued Dr. Woodcock. “Patients and prescribers should fully understand the risks associated with the use of Addyi before considering treatment.”

Addyi can cause severely low blood pressure (hypotension) and loss of consciousness (syncope). These risks are increased and more severe when patients drink alcohol or take Addyi with certain medicines (known as moderate or strong CYP3A4 inhibitors) that interfere with the breakdown of Addyi in the body. Because of the alcohol interaction, the use of alcohol is contraindicated while taking Addyi. Health care professionals must assess the likelihood of the patient reliably abstaining from alcohol before prescribing Addyi.

Addyi is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring this REMS because of the increased risk of severe hypotension and syncope due to the interaction between Addyi and alcohol. The REMS requires that prescribers be certified with the REMS program by enrolling and completing training. Certified prescribers must counsel patients using a Patient-Provider Agreement Form about the increased risk of severe hypotension and syncope and about the importance of not drinking alcohol during treatment with Addyi. Additionally, pharmacies must be certified with the REMS program by enrolling and completing training. Certified pharmacies must only dispense Addyi to patients with a prescription from a certified prescriber. Additionally, pharmacists must counsel patients prior to dispensing not to drink alcohol during treatment with Addyi.

Addyi is also being approved with a Boxed Warning to highlight the risks of severe hypotension and syncope in patients who drink alcohol during treatment with Addyi, in those who also use moderate or strong CYP3A4 inhibitors, and in those who have liver impairment. Addyi is contraindicated in these patients. In addition, the FDA is requiring the company that owns Addyi to conduct three well-designed studies in women to better understand the known serious risks of the interaction between Addyi and alcohol.

Addyi is a serotonin 1A receptor agonist and a serotonin 2A receptor antagonist, but the mechanism by which the drug improves sexual desire and related distress is not known. Addyi is taken once daily. It is dosed at bedtime to help decrease the risk of adverse events occurring due to possible hypotension, syncope and central nervous system depression (such as sleepiness and sedation). Patients should discontinue treatment after eight weeks if they do not report an improvement in sexual desire and associated distress.

The effectiveness of the 100 mg bedtime dose of Addyi was evaluated in three 24-week randomized, double-blind, placebo-controlled trials in about 2,400 premenopausal women with acquired, generalized HSDD. The average age of the trial participants was 36 years, with an average duration of HSDD of approximately five years. In these trials, women counted the number of satisfying sexual events, reported sexual desire over the preceding four weeks (scored on a range of 1.2 to 6.0) and reported distress related to low sexual desire (on a range of 0 to 4). On average, treatment with Addyi increased the number of satisfying sexual events by 0.5 to one additional event per month over placebo increased the sexual desire score by 0.3 to 0.4 over placebo, and decreased the distress score related to sexual desire by 0.3 to 0.4 over placebo. Additional analyses explored whether the improvements with Addyi were meaningful to patients, taking into account the effects of treatment seen among those patients who reported feeling much improved or very much improved overall. Across the three trials, about 10 percent more Addyi-treated patients than placebo-treated patients reported meaningful improvements in satisfying sexual events, sexual desire or distress. Addyi has not been shown to enhance sexual performance.

The 100 mg bedtime dose of Addyi has been administered to about 3,000 generally healthy premenopausal women with acquired, generalized HSDD in clinical trials, of whom about 1,700 received treatment for at least six months and 850 received treatment for at least one year.

The most common adverse reactions associated with the use of Addyi are dizziness, somnolence (sleepiness), nausea, fatigue, insomnia and dry mouth.

The FDA has recognized for some time the challenges involved in developing treatments for female sexual dysfunction. The FDA held a public Patient-Focused Drug Development meeting and scientific workshop on female sexual dysfunction on October 27 and October 28, 2014, to solicit perspectives directly from patients about their condition and its impact on daily life, and to discuss the scientific challenges related to developing drugs to treat these disorders. The FDA continues to encourage drug development in this area.

Consumers and health care professionals are encouraged to report adverse reactions from the use of Addyi to the FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch or by calling 1-800-FDA-1088.

Addyi is marketed by Sprout Pharmaceuticals, based in Raleigh, North Carolina.

////////

Addyi, flibanserin, fda 2015, sexual desire disorder

 सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

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09b37-misc2b027LIONEL MY SON

He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy

सुकून उतना ही देना प्रभू, जितने से

जिंदगी चल जाये।

औकात बस इतनी देना,

कि औरों का भला हो जाये।

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL  

Filgotinib


Filgotinib.png

Filgotinib

  • C21H23N5O3S
  • MW425.504
  • Elemental Analysis: C, 59.28; H, 5.45; N, 16.46; O, 11.28; S, 7.54
1206161-97-8
Cyclopropanecarboxamide, N-[5-[4-[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]-
G146034
GLPG0634
N-(5-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide
Galapagos Nv INNOVATOR
PHASE 3,  Crohn’s disease, Rheumatoid arthritis, Ulcerative colitis
Filgotinib is an orally available inhibitor of JAK1/JAK2 and TYK2 in phase III clinical development at Galapagos and Gilead for the treatment of rheumatoid arthritis, moderate or severe Crohn’s disease and ulcerative colitis

IL-6 antagonist; Jak1 tyrosine kinase inhibitor; Tyk2 tyrosine kinase inhibitor; Jak3 tyrosine kinase inhibitor; Jak2 tyrosine kinase inhibitor

Autoimmune disease; Cancer; Colitis; Crohns disease; Inflammatory disease; Neoplasm; Rheumatoid arthritis; Transplant rejection

In 2017, orphan drug designation was assigned to the compound in the U.S. for the treatment of pediatric Crohn’s disease and pediatric ulcerative colitis.

GlaxoSmithKline had been developing filgotinib preclinically for the treatment of rheumatoid arthritis pursuant to a license; however, in 2010, the compound was re-acquired by Galapagos. In 2012, the product was licensed to Abbott for development and marketing. In January 2013, Abbott spun-off its research-based pharmaceutical business into a newly-formed company AbbVie. The license agreement between Galapagos and Abbott was terminated in September 2015, Galapagos regaining all rights to the product. The same year, Galapagos and Gilead entered into a global partnership and Gilead obtained the global rights of codevelopment and commercialization for the treatment of inflammatory diseases

Filgotinib (GLPG0634), by the Belgian biotech company Galápagos NV, is a drug which is currently under investigation for the treatment of rheumatoid arthritis and Crohn’s disease.

Filgotinib (GLPG0634) is an orally-available, selective inhibitor of JAK1 (Janus kinase 1) for the treatment of rheumatoid arthritis and potentially other inflammatory diseases. Filgotinib (GLPG0634) dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. The JAK1 selective inhibitor GLPG0634 (Filgotinib) is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases. Filgotinib (GLPG0634) is currently in a Phase 2 study in Crohn’s disease.

3D

Mechanism of action

Filgotinib is a Janus kinase inhibitor with selectivity for subtype JAK1 of this enzyme. It is considered a promising agent as it inhibits JAK1 selectively. Less selective JAK inhibitors (e.g. tofacitinib) are already being marketed. They show long-term efficacy in the treatment of various inflammatory diseases. However, their lack of selectivity leads to dose-limiting side effects.[1] It is thought that inhibition of all JAK isoenzymes is beneficial in rheumatoid arthritis. However, pan-JAK inhibition might also lead to unwanted side effects that might not outweigh its benefits. This is the rationale for the development of newer and more selective inhibitors like filgotinib.

The signal transmission of large numbers of proinflammatory cytokines is dependent on JAK1. Inhibition of JAK2 may also contribute to the efficacy against RA. Nonetheless it is thought that JAK2 inhibition might lead to anemia and thrombopenia by interference witherythropoietin and thrombopoietin and granulocyte-macrophage colony-stimulating factor. Therefore one might prefer to choose a more selective JAK1 inhibitor as a primary therapeutic option. Filgotinib exerts a 30-fold selectivity for JAK1 compared to JAK2.[2] It is however still to be seen to what extent JAK2 inhibition should be avoided.

Novel crystalline forms of filgotinib salts, particularly hydrochloride salt, useful for treating JAK-mediated diseases eg inflammatory diseases, autoimmune diseases, proliferative diseases, allergy and transplant rejection.  Galapagos and licensee AbbVie are developing filgotinib, a selective JAK-1 inhibitor, for treating rheumatoid arthritis (RA) and Crohn’s disease (CD). In August 2015, the drug was reported to be in phase 2 clinical development for treating RA and CD. The drug is also being investigated for the treatment of colitis and was discovered as part of the company’s arthritis alliance with GSK; however in August 2010 Galapagos reacquired the full rights. See WO2013189771, claiming use of filgotinib analog for treating inflammatory diseases. Also see WO2010010190 (co-assigned with GSK and Abbott) and WO2010149769 (assigned to Galapagos) claiming filgotinib, generically and specifically, respectively.

Clinical trials and approval

The efficacy of filgotinib is currently studied in a phase2b program (DARWIN trial 1, 2) with involvement of 886 rheumatoid arthritis patients and 180 Crohn’s disease patients.

Phase 1 study

It was shown in phase 1 studies that the pharmacokinetics of filgotinib metabolism is independent of hepatic CYP450 enzymatic degradation. The drug metabolism is however mediated by carboxylesterases. There is no interference reported with the metabolism of methotrexate nor with any of the investigated transport proteins.[3]

Phase 2 study: Proof of concept (2011)

In november 2011 Galápagos released the results of their phase 2 study (identification: NCT01384422, Eudract: 2010-022953-40) in which 36 patients were treated who showed a suboptimal clinical response to methotrexate treatment. Three groups of twelve patients were treated either with 200 mg filgotinib in a single dose, 200 mg divided in two doses or placebo. The primary end-point was the ACR20 score, which monitors improvements in the symptomatology of the patient. After the scheduled 4 weeks of treatment, 83% of the respondents showed an improved ACR20-score. Half of the treated patients showed a complete (or near complete) remission of the disease. There were no reports ofanemia nor changes in lipidemia. The company stated in their press release that filgotinib is the first selective JAK1 inhibitor that shows clinical efficacy. As a result of this study, the company stated that “GLPG0634 shows one of the highest initial response rates ever reported for rheumatoid arthritis treatments”.[4]

DARWIN 1 trial

The DARWIN 1 trial is a 24 week double blind placebo-controlled trial with 599 rheumatoid arthritis patients enrolled. All participants have moderate to severe RA and showed an insufficient response to standard methotrexate treatment. The trial compares three dosages of filgotinib as a once or twice per day regimen. During the trial all participants remain on their methotrexate treatment. According to the company, the results of this trial are expected in July 2015.[5]

DARWIN 2 trial

The DARWIN 2 trial is a double blind placebo-controlled trial with 280 rheumatoid arthritis patients enrolled who show an insufficient response to standard methotrexate treatment. This trial, in contrast to the previous DARWIN 1 trial, methotrexate is discontinued. Therefore, this trial investigates filgotinib as a monotherapy.[6] The recruitment of DARWIN trial 2b ended in november 2014.[7] Preliminary results are expected in the second quarter of 2015 and a full completion of the study is expected in the third quarter of 2015.

DARWIN 3 trial

Patients who complete DARWIN 1 and 2 will be eligible for DARWIN 3.

COSY PREDICT

COSY NMR prediction (26)

Time line

  • june 2011: results of first phase 2 trial
  • november 2014: initiation of DARWIN 1 and 2 trials
  • april 2015: expected date of DARWIN 1 trial results
  • june 2015: expected date of DARWIN 2 trial results

ChemSpider 2D Image | Filgotinib | C21H23N5O3S

NMR FROM NET….ABMOLE, DMSOD6

NMR ABMOLE

NMR MEDKOO DMSOD6

NMR MEDKOO

CHEMIETEK

1H NMR PREDICT
1H NMR MOLBASE GRAPH 1H NMR MOLBASE VAL

13C NMR PREDICT

13C NMR MOLBASE GRAPH 13C NMR MOLBASE VAL

……………………

MORE PREDICTS

FIL CHEMDDOODLE

1H NMR PREDICT

1H NMR DB GRAPH

H EXPLODED

1H NMR DB VAL

13C NMR PREDICT

13C NMRDB GRAPH 13C NMRDB VAL

PRODUCT PATENT

http://www.google.com/patents/WO2010149769A1?cl=en

Applicants: GALAPAGOS NV [BE/BE]; Generaal De Wittelaan L11/A3 B-2800 Mechelen (BE) (For All Designated States Except US).
MENET, Christel Jeanne Marie [FR/BE]; (BE) (For US Only).
SMITS, Koen Kurt [BE/BE]; (BE) (For US Only)
Inventors: MENET, Christel Jeanne Marie; (BE).
SMITS, Koen Kurt; (BE)

PRODUCT PATENT SYN 1

WO2010149769

International Filing Date: 25.06.2010

ESTIMATED EXP 2030

Condensation of 2-amino-6-bromopyridine (I) with ethoxycarbonyl isothiocyanate (II) in CH2Cl2 gives 1-(6-bromopyridin-2-yl)-3-carboethoxythiourea (III), which upon cyclization with hydroxylamine hydrochloride (IV) in the presence of DIEA in EtOH/MeOH yields 2-amino-5-bromo[1,2,4]triazolo[1,5-a]pyridine (V). N-Acylation of amine (V) with cyclopropanecarbonyl chloride (VI) using Et3N in acetonitrile, and subsequent treatment with methanolic ammonia furnishes the carboxamide (VII) (1-3), which upon Suzuki coupling with 4-(hydroxymethyl)phenylboronic acid (VIII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C, followed by bromination with PBr3 in CHCl3 affords intermediate (IX). Condensation of benzyl bromide derivative (IX) with thiomorpholine-1,1-dioxide (X) using DIEA in CH2Cl2/MeOH yields filgotinib (1,2). Alternatively, condensation of (4-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (XI) with thiomorpholine 1,1-dioxide (X) in the presence of DIEA in CH2Cl2/MeOH gives intermediate (XII), which undergoes Suzuki coupling with aryl bromide (VII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C to afford the target filgotinib

The present invention is based on the discovery that the compound of the invention is able to act as an inhibitor of JAK and that it is useful for the treatment of inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6. In a specific aspect the compound is an inhibitor of JAKl and JAK2. The present invention also provides methods for the production of this compound, a pharmaceutical composition comprising this compound and methods for treating inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 by administering the compound of the invention.

Accordingly, in a first aspect of the invention, a compound of the invention is provided having a formula (I):

[0017] The compound of the invention is a novel inhibitor of JAK that appears to exhibit a dramatically improved in vivo potency as compared to structurally similar compounds. In a particular embodiment the compound of the invention is an inhibitor of JAKl and JAK2. In particular it appears to exhibit this increase in potency at lower in vivo exposure levels compared to structurally similar compounds. The use of a compound with these improvements is expected to result in a lower dosage requirement (and therefore an improved dosing schedule).

General Synthetic Method Scheme 1

1. RCOCI, Et3N 2. NH3 / MeOH CH3CN, 20 0C 2O 0C


wherein Ar represents phenyl-Ll-heterocycloalkyl, where Ll is a bond, -CH2– or -CO- and the heterocycloalkyl group is optionally substituted.

General

1.1.1 l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2)

(2)

[00117] To a solution of 2-amino-6-bromopyridine (1) (253.8 g, 1.467 mol) in DCM (2.5 L) cooled to 5 0C is added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction mixture is then allowed to warm to room temp. (20 0C) and stirred for 16 h. Evaporation in vacuo gives a solid which may be collected by filtration, thoroughly washed with petrol (3×600 mL) and air-dried to afford (2). The thiourea may be used as such for the next step without any purification. 1H (400 MHz, CDCl3) δ 12.03 (IH, br s, NH), 8.81 (IH, d, J 7.8 Hz, H-3), 8.15 (IH, br s, NH), 7.60 (IH, t, J 8.0 Hz, H-4), 7.32 (IH, dd, J 7.7 and 0.6 Hz, H-5), 4.31 (2H, q, J 7.1 Hz, CH2), 1.35 (3H, t, J 7.1 Hz, CH3).

7.7.2 5-Bromo-[l, 2, 4]triazolo[l, 5-a]pyridin-2-ylamine (3)

[00118] To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH

(1 :1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20 0C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H2S evolved). After 3 h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition Of H2O (250 mL) and filtration. The combined solids are washed successively with H2O (250 mL), EtOH/MeOH (1 : 1, 250 mL) and Et2O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. 1H (400 MHz, DMSO-t/β) δ 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (IH, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1 :1, M+H+, 100%).

7.7.3 General procedure for mono-acylation to afford intermediate (4):


[00119] To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH3CN

(150 mL) at 5 0C is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material (3) is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp, (for 1-16 h) to hydro lyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et2O (50 mL). The solids are collected by filtration, washed with H2O (2x50mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the required bromo intermediate (4).

Method A

Preparation of compounds of the invention via Suzuki coupling (5):

[00120] An appropriate boronic acid (2eq.) is added to a solution of bromo intermediate (4) in

1 ,4-dioxane/water (5:1). K2CO3 (2 eq.) and PdCl2dppf (5%) are added to the solution. The resulting mixture is then heated in a microwave at 140 0C for 30 min (this reaction can also be carried out by traditional heating in an oil bath at 900C for 16h under N2). Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhyd. MgSθ4 and evaporated in vacuo. The final compound is obtained after purification by flash chromatography or preparative HPLC. HPLC: Waters

XBridge Prep Cl 8 5μm ODB 19mm ID x 100mm L (Part No.186002978). All the methods are using

MeCN/H2O gradients. H2O contains either 0.1% TFA or 0.1% NH3.

Method B

Bl. 4 4-[2-(Cyclopropanecarbonyl-amino)-[ 1 , 2, 4]triazolo[l, 5-a] pyridin-5-yl] -benzoyl chloride

[00121] 2 Drops of DMF are added to a solution of 4-[2-(cyclopropanecarbonyl-amino)- [l,2,4]triazolo[l,5-a]pyridin-5-yl]-benzoic acid (1 eq) obtained by Method A using 4-carboxyphenylboronic acid in DCM under N2 atmosphere. Then oxalyl chloride (2 eq) is added dropwise to this resulting solution (gas release). The mixture is stirred at room temperature for 2 hours. After completion of the reaction by LCMS, the solvent is removed. The crude acid chloride is used without further purification in next step.

B2. Amide formation (General Method)

[00122] An appropriate amine (1.1 eq) and Et3N (5 eq) are dissolved in DCM under N2 atmosphere and cooled at 00C. The acid chloride (Bl, 1 eq) dissolved in DCM is added dropwise to this solution. The reaction is stirred at room temperature for 16 h. After this time, reaction is complete. The compound is extracted with EtOAc and water, washed with brine and dried over anhyd. MgSO4. Organic layers are filtered and evaporated. The final compound is isolated by preparative HPLC. Preparative HPLC: Waters XBridge Prep C18 5μm ODB 19mm ID x 100mm L (Part No.186002978). All the methods are using MeCN/H2O gradients. H2O contains either 0.1% TFA or 0.1% NH3.

Method C

Wherein R3a or R3b together with the nitrogen atom to which they are attached, may form a heterocycloalkyl.

Reductive alkylation (general method)

[00123] An appropriate amine (2 eq.), cyclopropanecarboxylic acid (for example cyclopropanecarboxylic acid [5-(4-formyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridine-2-yl]-amide) prepared by method A (1 eq.) and Ti(OPr)4 are mixed and stirred at room temperature for 3 hrs. The mixture is diluted in ethanol and Na(CN)BH3 (leq.) is added. The resulting solution is stirred at room temperature for 16 hrs. The mixture is diluted in water and filtered. The filtrate is washed with ethanol. The combined solvent phases are evaporated under vacuum. The final compound is isolated by preparative HPLC.

Method D 
wherein R1 and R2 together with the Nitrogen atom to which they are attached, may form a heterocycloalkyl.

Reaction ofalkylation

[00124] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (leq) and Et3N (2 eq) (or AgCO3) are dissolved in DCM/MeOH (4:1 v:v) under N2 and an amine (2 eq) is added dropwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is extracted with EtOAc and water, washed with brine and dried over anhyd. MgSθ4. Organic layers are filtered and evaporated. The final compound is isolated by flash chromatography.

Suzuki coupling

[00125] The obtained boronic acid (2eq.) is added to a solution of cyclopropanecarboxylic acid

(5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide (4) in 1 ,4-dioxane/water (5:1). K2CO3 (2 eq.) and PdCl2dppf (5%) are added to the solution. The resulting mixture is then heated in a microwave at 140 0C for 30 min (This reaction can also be carried out by traditional heating in an oil bath at 900C for 16h under N2). Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhyd. MgSθ4 and evaporated in vacuo. The final compound is obtained after purification by flash chromatography or preparative HPLC. HPLC: Waters XBridge Prep C18 5μm ODB 19mm ID x 100mm L (Part No.186002978). All the methods are using MeCN/H2O gradients. H2O contains either 0.1% TFA or 0.1% NH3.

Synthesis of the compound of the invention and comparative examples

Compound l(the compound of the invention)

Step 1:

[00126] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (leq) and DIPEA

(2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1 -dioxide (2 eq) was added portionwise. The resulting solution was stirred at room temperature for 16h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhyd. MgS O4. Organic layers were filtered and evaporated. The final compound was isolated without further purification.

Step 2: Suzuki coupling

[00127] 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide

(l.leq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 900C for 16h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSθ4 and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.

[00128] Alternatively, after completion of the reaction, a palladium scavenger such as 1,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cooled down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HCl is added, and after stirring at RT, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at RT, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H2O, treated with a palladium scavenger (e.g. SMOPEX 234) at 500C, the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the title compound as a free base.

Alternative route to Compound l(the compound of the invention):

Step 1:

[00129] 4-(Hydroxymethyl)phenylboronic acid (l.leq.) was added to a s o luti o n o f cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 900C for 16h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSθ4 and evaporated in vacuo. The resulting mixture was used without further purification.

Step 2:

[00130] To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-yl]-amide (1.0 eq) in chloroform was slowly added phosphorus tribromide (1.0 equiv.). The reaction mixture was stirred at room temperature for 20 hours, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer was dried over anhyd. MgSθ4, filtered and concentrated to dryness. The resulting white residue was triturated in dichloromethane/diethyl ether 2:1 to afford the expected product as a white solid.

Step 3:

[00131] Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin- 2-yl]-amide (leq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1 -dioxide (1.1 eq) was added dropwise. The resulting solution was stirred at room temperature for 16h. After this time, the reaction was complete. The solvent was evaporated. The compound was dissolved in DCM, washed with water and dried over anhyd. MgSO^ Organic layers were filtered and evaporated. The final compound was isolated by column chromatography using EtOAc to afford the desired product.

PATENT

WO 2010010190

WO 2013173506

WO 2013189771

WO 2015117980

WO 2015117981

POLYMORPH

CN 105061420

CN105061420

https://encrypted.google.com/patents/CN105061420A?cl=en

JAK inhibitor N-(5-(4-(1,1-dioxothiomorpholinyl)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide, and methods for preparing the four crystal forms, wherein the four crystal forms respectively are a crystal form H1, a crystal form H2, a crystal form H3 and a crystal form H4,

POLYMORPH

E CRYSTAL

CN 105111206

D CRYSTAL

CN 105111207

H CRYSYAL

CN 105198876

CN 105198877

F CN 105198878

C CN 105198880

POLYMORPH

WO 2016105453

POLYMORPH

POLYMORPH

CN 105669669

The present invention provides a crystal form A, B, D, G and M of N-[5-[4-[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide hydrochloride.

PAPER

Future Medicinal Chemistry (2015), 7(2), 203-235.  |  Language: English, Database: CAPLUSA review.  The discovery of the JAK-STAT pathway was a landmark in cell biol.  The identification of these pathways has changed the landscape of treatment of rheumatoid arthritis and other autoimmune diseases.  The two first (unselective) JAK inhibitors have recently been approved by the US FDA for the treatment of myelofibrosis and rheumatoid arthritis and many other JAK inhibitors are currently in clin. development or at the discovery stage.  Research groups have demonstrated the different roles of JAK member and the therapeutic potential of targeting them selectively. ………..

https://www.future-science.com/doi/10.4155/fmc.14.149

PAPER

Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2018), 107(6), 1624-1632.

PATENT

US2010/331319 A1, ; Page/Page column 13-14

http://www.google.com/patents/US20100331319

Synthetic Preparation of the Compound of the Invention and Comparative Examples

The compound of the invention and the comparative examples can be produced according to the following scheme.

Figure US20100331319A1-20101230-C00003

wherein Ar represents phenyl-L1-heterocycloalkyl, where L1 is a bond, —CH2— or —CO— and the heterocycloalkyl group is optionally substituted.

General 1.1.1 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2)

Figure US20100331319A1-20101230-C00004

To a solution of 2-amino-6-bromopyridine (1) (253.8 g, 1.467 mol) in DCM (2.5 L) cooled to 5° C. is added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction mixture is then allowed to warm to room temp. (20° C.) and stirred for 16 h. Evaporation in vacuo gives a solid which may be collected by filtration, thoroughly washed with petrol (3×600 mL) and air-dried to afford (2). The thiourea may be used as such for the next step without any purification. 1H (400 MHz, CDCl3) δ 12.03 (1H, br s, NH), 8.81 (1H, d, J=7.8 Hz, H-3), 8.15 (1H, br s, NH), 7.60 (1H, t, J=8.0 Hz, H-4), 7.32 (1H, dd, J 7.7 and 0.6 Hz, H-5), 4.31 (2H, q, J 7.1 Hz, CH2), 1.35 (3H, t, J 7.1 Hz, CH3).

1.1.2 5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3)

Figure US20100331319A1-20101230-C00005

To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20° C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H2S evolved). After 3 h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H2O (250 mL) and filtration. The combined solids are washed successively with H2O (250 mL), EtOH/MeOH (1:1, 250 mL) and Et2O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. 1H (400 MHz, DMSO-d6) δ 7.43-7.34 (2H, m, 2×aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1:1, M+H+, 100%).

1.1.3 General Procedure for Mono-Acylation to Afford Intermediate (4)

Figure US20100331319A1-20101230-C00006

To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH3CN (150 mL) at 5° C. is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material (3) is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp. (for 1-16 h) to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et2O (50 mL). The solids are collected by filtration, washed with H2O (2×50 mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the required bromo intermediate (4).

Method A Preparation of Compounds of the Invention Via Suzuki Coupling (5):

An appropriate boronic acid (2 eq.) is added to a solution of bromo intermediate (4) in 1,4-dioxane/water (5:1). K2CO(2 eq.) and PdCl2dppf (5%) are added to the solution. The resulting mixture is then heated in a microwave at 140° C. for 30 min (this reaction can also be carried out by traditional heating in an oil bath at 90° C. for 16 h under N2). Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhyd. MgSOand evaporated in vacuo. The final compound is obtained after purification by flash chromatography or preparative HPLC. HPLC: Waters XBridge Prep C18 5 μm ODB 19 mm ID×100 mm L (Part No. 186002978). All the methods are using MeCN/H2O gradients. H2O contains either 0.1% TFA or 0.1% NH3.

Method B

Figure US20100331319A1-20101230-C00007

B1. 4 4-[2-(Cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoyl chloride

Figure US20100331319A1-20101230-C00008

2 Drops of DMF are added to a solution of 4-[2-(cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoic acid (1 eq) obtained by Method A using 4-carboxyphenylboronic acid in DCM under Natmosphere. Then oxalyl chloride (2 eq) is added dropwise to this resulting solution (gas release). The mixture is stirred at room temperature for 2 hours. After completion of the reaction by LCMS, the solvent is removed. The crude acid chloride is used without further purification in next step.

B2. Amide Formation (General Method)

Figure US20100331319A1-20101230-C00009

An appropriate amine (1.1 eq) and Et3N (5 eq) are dissolved in DCM under Natmosphere and cooled at 0° C. The acid chloride (B1, 1 eq) dissolved in DCM is added dropwise to this solution. The reaction is stirred at room temperature for 16 h. After this time, reaction is complete. The compound is extracted with EtOAc and water, washed with brine and dried over anhyd. MgSO4. Organic layers are filtered and evaporated. The final compound is isolated by preparative HPLC. Preparative HPLC: Waters XBridge Prep C18 5 μm ODB 19 mm ID×100 mm L (Part No. 186002978). All the methods are using MeCN/H2O gradients. H2O contains either 0.1% TFA or 0.1% NH3.

Synthesis of the Compound of the Invention and Comparative Examples Compound 1 (the Compound of the Invention) Step 1:

Figure US20100331319A1-20101230-C00014

2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under Nand thiomorpholine 1,1-dioxide (2 eq) was added portionwise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhyd. MgSO4. Organic layers were filtered and evaporated. The final compound was isolated without further purification.

STEP 2: Suzuki coupling

Figure US20100331319A1-20101230-C00015

4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO(2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSOand evaporated in vacuo. The final compound was obtained after purification by flash chromatography.

Alternatively, after completion of the reaction, a palladium scavenger such as 1,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cooled down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HCl is added, and after stirring at RT, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at RT, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H2O, treated with a palladium scavenger (e.g. SMOPEX 234) at 50° C., the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the title compound as a free base.

Alternative Route to Compound 1 (the Compound of the Invention): Step 1:

Figure US20100331319A1-20101230-C00016

4-(Hydroxymethyl)phenylboronic acid (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K2CO(2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSOand evaporated in vacuo. The resulting mixture was used without further purification.

Step 2:

Figure US20100331319A1-20101230-C00017

To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1.0 eq) in chloroform was slowly added phosphorus tribromide (1.0 equiv.). The reaction mixture was stirred at room temperature for 20 hours, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer was dried over anhyd. MgSO4, filtered and concentrated to dryness. The resulting white residue was triturated in dichloromethane/diethyl ether 2:1 to afford the expected product as a white solid.

Step 3:

Figure US20100331319A1-20101230-C00018

Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under Nand thiomorpholine 1,1-dioxide (1.1 eq) was added dropwise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was dissolved in DCM, washed with water and dried over anhyd. MgSO4. Organic layers were filtered and evaporated. The final compound was isolated by column chromatography using EtOAc to afford the desired product.

…………………….

PATENT

WO 2015117981

Novel salts and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Also claims a method for preparing filgotinib hydrochloride trihydrate. The present filing forms a pair with this week’s filing, WO2015117980, claiming a tablet composition comprising filgotinib hydrochloride.

The compound cyclopropanecarboxylic acid {5-[4-(l,l-dioxo-thiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5-a]pyridin-2-yl -amide (Compound 1), which has the chemical structure:

is disclosed in our earlier application WO 2010/149769 (Menet C. J., 2010) as being an inhibitor of JAK and as being useful in the treatment of inflammatory conditions, autoimmune diseases, proliferative diseases, allergy, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or interferons. Hereafter this compound is named Compound 1. The data presented in WO 2010/149769 demonstrate that despite similar in vitro activities, Compound 1 has unexpectedly high in vivo potency compared with structurally similar compounds.

Example 1. Preparation of Compound 1

1.1. Route 1

1.1.1. 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide

[00205] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1 -dioxide (2 eq) is added portionwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO i. Organic layers are filtered and evaporated. The final compound is isolated without further purification.

1.1.2. Cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide

1.1.2.1. Step i): l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea

[00206] To a solution of 2-amino-6-bromopyridine (1) (253.8 g, 1.467 mol) in DCM (2.5 L) cooled to 5°C is added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction

mixture is then allowed to warm to room temp. (20 °C) and stirred for 16 h. Evaporation in vacuo gives a solid which may be collected by filtration, thoroughly washed with petrol (3 x 600 niL) and air-dried to afford the desired product. The thiourea may be used as such for the next step without any purification. lH (400 MHz, CDC13) δ 12.03 (1H, br s), 8.81 (1H, d), 8.15 (1H, br s), 7.60 (1H, t), 7.32 (1H, dd), 4.31 (2H, q), 1.35 (3H, t).

1.1.2.2. Step ii): 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine

[00207] To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1 : 1, 900 mL) is added NN-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20 °C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H2S evolved). After 3h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H20 (250 mL) and filtration. The combined solids are washed successively with H20 (250 mL), EtOH/MeOH (1 : 1, 250 mL) and Et20 (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. lH (400 MHz, DMSO-i¼) δ 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1 : 1, M+H+, 100%).

1.1.2.3. Step Hi): Cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide

[00208] To a solution of the 2-amino-triazolopyridine obtained in the previous step (7.10 g, 33.3 mmol) in dry MeCN (150 mL) at 5°C is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp, (for 1-16 h) to hydro lyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et20 (50 mL). The solids are collected by filtration, washed with H20 (2x50mL), acetone (50 mL) and Et20 (50 mL), then dried in vacuo to give the desired compound.

1.1.3. Compound 1

[00209] 4-[4-(4,4,5,5-Tetramethyl-[l ,3,2]dioxaborolan-2-yl)-benzyl] hiomoφholine , l -dioxide (l . l eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4: 1). K2CO3 (2 eq.) and PdC^dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90°C for 16h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS04 and evaporated in vacuo.

[00210] The final compound is obtained after purification by flash chromatography.

[00211] Alternatively, after completion of the reaction, a palladium scavenger such as 1 ,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cool down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HC1 is added, and after stirring at room temperature, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at room temperature, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H20, treated with a palladium scavenger (e.g. SMOPEX 234) at 50°C, the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the desired compound as a free base.

1.2. Route 2

1.2.1. Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[l,2, 4]triazolo[l, 5- a] pyridin-2-yl] -amide

[00212] 4-(Hydroxymethyl)phenylboronic acid (l . l eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water

(4:1). K2CO3 (2 eq.) and PdC^dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90°C for 16h under N2. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS04 and evaporated in vacuo. The resulting mixture is used without further purification.

1.2.2. Step 2: Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5- a Jpyridin-2-ylJ -amide

[00213] To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl] -amide (1.0 eq) in chloroform is slowly added phosphorus tribromide (1.0 eq.). The reaction mixture is stirred at room temperature for 20 h, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer is dried over anhydrous MgSO i, filtered and concentrated to dryness. The resulting white residue is triturated in dichloromethane/diethyl ether 2:1 to afford the desired product.

1.2.3. Step 3:

[00214] Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl]-amide (l eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5: 1 v:v) under N2 and thiomorpho line 1,1-dioxide (1.1 eq) is added dropwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is dissolved in DCM, washed with water and dried over anhydrous MgSO i. Organic layers are filtered and evaporated. The final compound is isolated by column chromatography using EtOAc to afford the desired product.

…………………

PATENT

http://www.google.co.in/patents/WO2013189771A1?cl=en

Example 1. Synthesis of the compounds

1.1. Route 1

1.1.1. Synthesis of 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (Intermediate 3)

Figure imgf000030_0001

led to 5 °C was added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction mixture was then allowed to warm to room temp. (20 °C) and stirred for 16 h. Evaporation in vacuo gave a solid which was collected by filtration, thoroughly washed with petrol (3×600 mL) and air-dried to afford (2). The thiourea was used as such in the next step without any purification.

[00157] lH (400 MHz, CDC13) δ 12.03 (IH, br s, NH), 8.81 (IH, d, J 7.8 Hz, H-3), 8.15 (IH, br s, NH), 7.60 (IH, t, J 8.0 Hz, H-4), 7.32 (IH, dd, J 7.7 and 0.6 Hz, H-5), 4.31 (2H, q, J 7.1 Hz, CH2), 1.35 (3H, t, J 7.1 Hz, CH3).

1.1.1.2. 5-Bromo-f 1,2, 4]triazolo[ 1 ,5-a] pyridin-2-ylamine (3)

[00158] To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1 : 1, 900 mL) was added NN-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture was stirred at room temp. (20 °C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber was required to quench H2S evolved). After 3 h at reflux, the mixture was allowed to cool and filtered to collect the precipitated solid. Further product was collected by evaporation in vacuo of the filtrate, addition of H20 (250 mL) and filtration. The combined solids were washed successively with H20 (250 mL), EtOH/MeOH (1 : 1, 250 mL) and Et20 (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound was used as such in the next step without any purification.

[00159] lH (400 MHz, DMSO-i¼) δ 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1 : 1, M+H+, 100%).

1.1.2. Synthesis of 4-[ 4-(4, 4, 5, 5-Tetramethyl-f 1, 3,2] ‘ dioxaborolan-2-yl) -benzyl] ‘- thiomor holine- 1, 1 -dioxide (Intermediate 4)

Figure imgf000031_0001

[00160] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1 -dioxide (2 eq) was added portion wise. The resulting solution was stirred at room temperature for 16h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO i. Organic layers were filtered and evaporated. The final compound was isolated without further purification.

1.1.3. Synthesis of 5-[4-(l, l-Dioxothiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5- a ridin-2-ylamine (Formula I)

Figure imgf000031_0002

[00161] 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide (l .leq.) was added to a solution of 5-bromo-[l,2,4]triazolo[l,5-a]pyrid in-2-ylamine (4: 1). K2CO3 (2 eq.) and PdC^dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90°C for 16h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhydrous MgSC>4 and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.

[00162] lH (400 MHz, CDC13) δ 7.94-7.92 (d, 2H), 7.52-7.48 (m, 3H), 7.37-7.34 (m, 1H), 7.02-7.00 (m, 1H), 6.00 (d, 2H), 3.76 (d, 2H), 3.15-3.13 (m, 4H), 2.93-2.91 (m, 4H).

[00163] m/z 358.2 (M+H+, 100%). 1.2. Route 2

1.2.1. Cyclopropanecarboxylic acid {5-[4-(l, l-dioxo-thiomorpholin-4-ylmethyl)-phenylJ- [l,2,4]triazolo[l,5-a]pyridin-2-yl}-amide (Formula II)

[00164] The compound according to Formula II may be synthesized according to the procedure described in WO 2010/149769.

1.2.2. Synthesis of 5-[4-(l, l-Dioxothiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5- aJpyridin-2-ylamine (Formula I)

[00165] The compound according to Formula I can also be produced by hydrolysis of the compound accor ing to Formula II:

Figure imgf000032_0001

[00166] Hydrochloric acid 30% aq (12.06 kg; 3.9 rel. volumes) was added to a slurry of the compound according to Formula II (3.45 kg; 1.0 equiv.) in demineralized water (10.0 kg; 3.0 rel. volumes). Subsequently, a line rinse was performed with demineralized water (3.4 kg; 1.0 rel. volumes). The reaction mixture was heated to 80±5°C for 14.5 h. After completion of the reaction (conversion > 99%>), the reaction mixture was cooled to 20±5°C. The reaction mixture was diluted with demineralized water (6.8 kg; 2.0 rel. volumes) and sodium hydroxide 33%> aq (9.52 kg; 3.7 rel volumes) was dosed at such a rate that the temperature of the reactor contents remained below 35°C. An additional amount of sodium hydroxide 33%> aq (2.55 kg; 1.0 rel. volumes) was needed to get the pH > 10. The product was filtered off, washed twice with demineralized water (1.5 rel. volumes) and dried under vacuum for 1 h, thus yielding the crude compound according to Formula I.

[00167] The crude compound according to Formula I (5.70 kg) was re-slurried in demineralized water (23.0 kg; 8.5 rel. volumes). Hydrochloric acid 30%> aq (1.65 kg; 0.7 rel. volumes) and demineralized water (4.3 kg; 1.6 rel. volumes) were added and the reaction mixture was stirred at 20±5°C for 45 min. As the compound according to Formula I was not dissolved completely, the reaction mixture was stirred at 45±5°C for 1 h. The reaction mixture was filtered and the residue was washed with demineralized water (2.0 kg 0.75 rel. volumes). Sodium hydroxide 33%> aq (1.12 kg; 0.6 rel volumes) was added to the filtrate. An additional amount of sodium hydroxide 33%> aq (1.01 kg) was needed to get the pH > 10. The resulting reaction mixture was stirred at 20±5°C for about 3 h. The product was filtered off, washed twice with demineralized water (4.1 kg; 1.5 rel. volumes), and twice with methyl tert-butyl ether (MTBE; 3.0 kg; 1.5 rel. volumes) and dried under vacuum for 15.5 h on the filter. The product was further dried in a vacuum oven at 40±5°C for 202 h, thus affording the desired compound according to Formula I.

Update

WO-2016179207

Scheme 1: General S nthesis of Compounds of Formula I or A

Formula A

Scheme 7.

(16) (17) (18)

(18a): R3a=R3b=R2a=R (18b): R3a=R3b=D; R2a 18c): R3a=R3b=H; R2a

References

  1.  Namour, Florence; Diderichsen, Paul Matthias; Cox, Eugène; Vayssière, Béatrice; Van der Aa, Annegret; Tasset, Chantal; Van’t Klooster, Gerben (2015-02-14). “Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection”. Clin Pharmacokinet. Epub ahead of print.doi:10.1007/s40262-015-0240-z.
  2.  Van Rompaey, L; Galien, R; Van der Aar, E; Clement-Lacroix, P; Van der Aar, E; Nelles, L; Smets, B; Lepescheux, L; Cristophe, T; Conrath, K; Vandeghinste, N; Vayssiere, B; De Vos, S; Fletcher, S; Brys, R; Van’t Klooster, G; Feyen, J; Menet, C (2013-10-01). “Preclinical characterization of GLPG0634, a selective inhibitor of JAK1 for the treatment of inflammatory diseases”. J Immunol. 191(7). doi:10.4049/jimmunol.1201348.
  3.  http://acrabstracts.org/abstracts/phase-1-and-phase-2-data-confirm-that-glpg0634-a-selective-jak1-inhibitor-has-a-low-potential-for-drug-drug-interactions/
  4.  “Galapagos’ GLPG0634 shows excellent efficacy and safety in rheumatoid arthritis Phase II study” (PDF) (Press release). Retrieved 2015-02-26.
  5.  “Galapagos reports that the last patient in DARWIN 1 has completed 12 weeks of treatment” (PDF) (Press release). Retrieved 2015-02-26.
  6.  “Galapagos completes recruitment for Darwin 1 study with GLPG0634 (filgotinib) in RA”EuroInvestor. Retrieved 2015-02-26.
  7.  NASDAQ OMX Corporate Solutions. “Galapagos completes recruitment for Darwin 2 monotherapy study with GLPG0634 (filgotinib) in RA”Yahoo Finance. Retrieved 2015-02-26.
US8551980 Nov 17, 2010 Oct 8, 2013 Bayer Intellectual Property Gmbh Substituted triazolopyridines
US8796457 Jun 25, 2010 Aug 5, 2014 Galapagos Nv Compound useful for the treatment of degenerative and inflammatory diseases
Filgotinib
Filgotinib.png
Systematic (IUPAC) name
N-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide
Clinical data
Routes of
administration
Oral
Pharmacokinetic data
Biological half-life 6 hours[1]
Identifiers
CAS Registry Number 1206161-97-8 Yes
ATC code L01XE18
IUPHAR/BPS 7913
ChemSpider 28189566 Yes
UNII 3XVL385Q0M Yes
ChEMBL CHEMBL3301607 
Chemical data
Formula C21H23N5O3S
Molecular mass 425.50402 g/mol
Patent Submitted Granted
Compound useful for the treatment of degenerative and inflammatory diseases [US8088764] 2010-12-30 2012-01-03
NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES [US2011190260] 2011-08-04

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09b37-misc2b027LIONEL MY SON

He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy

सुकून उतना ही देना प्रभू, जितने से

जिंदगी चल जाये।

औकात बस इतनी देना,

कि औरों का भला हो जाये।

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL  

/////////Galapagos,  GLPG0634, Filgotinib, PHASE 2, orphan drug designation, PHASE 3,  Crohn’s disease, Rheumatoid arthritis, Ulceraticolitis

ve SMILES code: O=C(C1CC1)NC2=NN3C(C4=CC=C(CN5CCS(CC5)(=O)=O)C=C4)=CC=CC3=N2

Orilotimod


ChemSpider 2D Image | Orilotimod | C16H19N3O5

Orilotimod

(2R)-2-amino-5-{[(1R)-1-carboxy-2-(1H-indol-3-yl)ethyl]amino}-5-oxopentanoic acid
186087-26-3 
Apo805,UNII-Q66Z43C5XM; Thymodepressin; Orilotimod [USAN]; AC1OIBUF; 
  • C16H19N3O5
  • MW 333.339

Apotex Technologies Inc.  INNOVATOR

2D chemical structure of 960155-19-5

Orilotimod potassium,

  • APO805K1

D-Tryptophan, D-gamma-glutamyl-, potassium salt (1:1), CAS 960155-19-5

The drug, orilotimod, was originally developed and launched by Immunotech Developments; however, ApoPharma (a subsidiary of Apotex) is developing orilotimod, presumably a topical formulation, for the treatment of psoriasis. In August 2015, the ApoPharma’s drug was reported to be in phase 2 clinical development.

Thymodepressin is the free diacid having Chemical Abstracts Service (CAS) Registry Number@ of 186087-26-3. U.S. Pat. No. 5,736,519 discloses H-D-iGlu-D-Trp-OH and a process for its preparation wherein it is purified by ion exchange chromatography. It is an immunosuppressant and selectively inhibits proliferation of hemopoietic precursor cells and stimulates granulocyte and lymphocyte apoptosis (Sapuntsova, S. G., et al. (May 2002), Bulletin of Experimental Biology and Medicine, 133(5), 488-490).

Thymodepressin is currently being sold in Russia as the disodium salt of D-isoglutamyl-D-tryptophan in liquid formulation for injection and intranasal administration for the treatment of psoriasis and atopic dermatitis. The solid form of the disodium salt of D-isoglutamyl-D-tryptophan is an amorphous powder which is hygroscopic and very difficult to handle. The disodium salt of D-isoglutamyl-D-tryptophan has the molecular formula C16H17N3Na2O5 and  is reported in Kashirin, D. M., et al. (2000), Pharmaceutical Chemistry Journal, 34(11), 619-622.

 

Orilotimod.png

PAPENT

BEAWARE EXAMPLE WITH AN ESTER GP

http://www.google.im/patents/WO2012129671A1?cl=en

Preparation of H-D-Glu( -Trp-OH)-0-Et hydrochloride salt (Apo836.HCI)

 

Figure imgf000037_0001

A. Preparation of Boc-D-Glu(D-Trp-0-Bzl)-0-Et

Proceeding in a similar manner as described under Example 3A, Boc-D- Glu(D-Trp-0-Bzl)-0-Et was prepared in 87% yield.1H NMR ( DMSO-D6l 400 MHz) δ ppm: 10.87, (s, 1 H), 8.35 (d, J = 7.2 Hz, 1 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 1 H), 7.29-7.33 (m, 3H), 7.23 (d, J = 7.7 Hz, 1H), 7.09-7.22 (m, 3H), 7.08 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 7,7 Hz, 1 H), 4.98 – 5.06 (m, 2H), 4.55 (apparent q, J = 7.3 Hz, 1 H), 4.04 – 4.11 (m, 2H), 3.90 – 3.95 (m, 1 H), 3.04 – 3.19 (m, 2H), 2.18 – 2.23 (m, 2H), 1.84 – 1.89 (m, 1 H), 1.70 – 1.77 (m, 1 H), 1.38 (s, 9H), 1.16 (t, J = 7.1 Hz, 3H); MS-ESI (m/z): 552 [ +1]+.

B. Preparation of Boc-D-Glu(D-Trp-OH)-0-Et

Proceeding in a similar manner as described under Example 3B, Boc-D-

Glu(D-Trp-OH)-0-Et was prepared in quantitative yield. 1H NMR ( DMSO-D6, 400 MHz) δ ppm: 12.62 (br. 1H), 10.82, (s, 1 H), 8.10 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1 H), 7.12 (s, 1 H), 7.06 (t, J = 7.3 Hz, 1 H), 6.98 (t, J = 7.5 Hz, 1 H)„ 4.45 (apparent q, J = 7.7 Hz, 1 H), 4.03 – 4.11 (m, 2H), 3.87 – 3.92 (m, 1 H), 3.13 – 3.18 (m, 1H), 2.96 – 3.03 (m,

1 H), 2.13 – 2.20 (m, 2H), 1.82 – 1.88 (m, 1H), 1.69-1.75 (m, 1 H), 1.38 (s, 9H>, 1.17 (t, J = 7.1 Hz, 3H); MS-ESI (m/z): 462 [M+1]+.

C. Preparation of H-D-Glu(D-Trp-OH)-0-Et.HCI (Apo836 HCI)

To an ice-cooled solution of Boc-D-Glu(D-Trp-OH)-0-Et (4.55 g, 9.8 mmol) obtained in Section B above in dichloromethane (100 mL) was bubbled HCI gas for 15 min. The reaction mixture was concentrated under vacuum by rotary evaporation to give H-D-Glu(D-Trp-OH)-0-Et hydrochloride (Apo836.HCI, 4.0 g) as a foamy solid. 1 H NMR ( DMSO-D6, 400 MHz) δ ppm: 12.68 (br. s, 1 H), 10.90, (s, 1H), 8.66 (br, s, 3H), 8.33 (d, J = 7.8 Hz, 1 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.12 (d, J = 1.5 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1 H), 6.98 (t, J = 7.2 Hz, 1 H), 4.47 (apparent q, J = 4.8 Hz, 1 H), 4.13 – 4.19 (m, 2H), 3.90 (br, 1 H), 3.16 – 3.20 (m, 1H), 2.98 – 3.04 (m, 1 H), 2.29 – 2.33 (m, 2H), 1.94 – 1.98

(m, 2H), 1.20 (t, J = 7.1 Hz, 3H); MS-ESI (m/z): 362 [M+1]+ (free base).

……………………..

US 20150225341

file:///H:/ORILOTIMODUS20150225341A1.pdf

Novel crystalline and amorphous salts of thymodepressin (orilotimod), particularly potassium salt, useful for treating psoriasis and atopic dermatitis. Also claims salt exchange method for preparing thymodepressin salts.

 

hymodepressin is the free diacid having Chemical Abstracts Service (CAS) Registry Number@ of 186087-26-3. U.S. Pat. No. 5,736,519 discloses H-D-iGlu-D-Trp-OH and a process for its preparation wherein it is purified by ion exchange chromatography. It is an immunosuppressant and selectively inhibits proliferation of hemopoietic precursor cells and stimulates granulocyte and lymphocyte apoptosis (Sapuntsova, S. G., et al. (May 2002), Bulletin of Experimental Biology and Medicine, 133(5), 488-490).

Thymodepressin is currently being sold in Russia as the disodium salt of D-isoglutamyl-D-tryptophan in liquid formulation for injection and intranasal administration for the treatment of psoriasis and atopic dermatitis. The solid form of the disodium salt of D-isoglutamyl-D-tryptophan is an amorphous powder which is hygroscopic and very difficult to handle. The disodium salt of D-isoglutamyl-D-tryptophan has the molecular formula C16H17N3Na2O5 and which is reported in Kashirin, D. M., et al. (2000), Pharmaceutical Chemistry Journal, 34(11), 619-622.

Through investigations in our laboratory, we have determined that the freeze-dried disodium salt of D-isoglutamyl-D-tryptophan is extremely hygroscopic turning into a gel in a matter of minutes in air and cannot easily be handled.

A powdery or amorphous form of a compound, intended for pharmaceutical use may give rise to manufacturing problems due to bulk density issues, hygroscopicity and variable water content that cannot be corrected by vacuum drying. D-isoglutamyl-D-tryptophan is a dipeptide and the drying of an amorphous form at elevated temperature, for example, 80-100° C. under vacuum is not recommended. Thus, there are serious difficulties experienced during the purification of the disodium salt of D-isoglutamyl-D-tryptophan and obtaining the pure disodium salt on a manufacturing scale. Further, there is no published procedure for its preparation.

The monosodium salt of D-isoglutamyl-D-tryptophan is identified by the CAS Registry System and is listed in the CAS REGISTRYSM File with a CAS Registry Number@ of 863988-88-9. However, there are no references citing the substance and thus no publication of its identity, its physical and/or chemical properties, its characterization or a procedure for its preparation. Freeze-dried powders of mono sodium and disodium salts of peptide drugs may not have controllable powder bulk density ranges for formulation. They may require significant investment in freeze-dried dispersion technology.

EXAMPLES

Example 1

Preparation of potassium salt of D-isoglutamyl-D-tryptophan (1:1) from D-isoglutamyl-D-tryptophan and potassium hydroxide

In a 100-mL round bottom flask equipped with a magnetic stir bar was placed 5 mL of potassium hydroxide solution (0.5 N). The solution was cooled to 0° C. in an ice-water bath, and solid H-D-iGlu-D-Trp-OH (1.00 g, 3 mmol) was added. The mixture was stirred while the pH of the solution was adjusted to ca. 6.0 by adding a few drops of potassium hydroxide solution (0.5 N). The solution was filtered to remove any solid particulates. The filtrate was evaporated to dryness at a bath temperature of about 30° C. to afford a solid. After drying under vacuum at room temperature for overnight, the salt was obtained in quantitative yield, with a HPLC purity (peak area percent) of 98.3%. HPLC method; Column: XTerra MS C18; 5 μm, 4.6×250 mm; Mobile phase: A=the aqueous phase: 4 mM Tris, 2 mM EDTA, pH 7.4; B=the organic phase: CH3CN; gradient: B %: 0 min. 5%, 15 min. 55%, 30 min. 55%, 32 min. 5%, 35 min. 5%; Flow rate: 1 mL/min; injection volume: 5 μL; λ: 222, 254, 282, 450 nm; retention time of the product: 6.41 min. The XRPD pattern of this crystalline material is shown in FIG. 1A; the water content by Karl-Fischer test is 0.7%; UV (water, c=23.8 ρM, λmax nm): 221 (ε 33270), 280 (ε 5417); MS (m/z): 372.0 [M]+, 334.2 [C16H20N3O5]+, 187.9 (100%). The FT-IR (KBr) spectrum is shown in FIG. 1B.

Example 2

A. Preparation of mono potassium salt of D-isoglutamyl-D-tryptophan (1:1) from the mono ammonium salt of D-isoglutamyl-D-tryptophan (1:1)

A solution of H-D-iGlu-D-Trp-OH, mono ammonium salt (1:1), (1.66 g, 4.05 mmol) and potassium hydroxide (253 mg, 4.50 mmol) in water (20 mL) was stirred at room temperature for 15 min. The pH of the solution was about 9. The reaction mixture was evaporated under reduced pressure to a volume of about 1 mL. After cooling to room temperature, isopropanol was added until a solid precipitated out. The resulting suspension was stirred at room temperature for 15 min, then filtered. The solid was washed with isopropanol (2×20 mL) and ethyl acetate (20 mL), then dried under vacuum in an oven at 42° C. overnight. An off white solid was obtained (1.49 g, 99% yield). The water content by Karl-Fischer test is 2.5%. Analytical data (XRPD pattern, FT-IR and MS spectra) are similar to those described in Example 1.

B. Preparation of amorphous form of potassium salt of D-isoglutamyl-D-tryptophan (1:1) from the mono ammonium salt of D-isoglutamyl-D-tryptophan (1:1)

A solution of H-D-iGlu-D-Trp-OH, mono ammonium salt (1:1), (517 mg, 1.40 mmol) and potassium hydroxide (82 mg, 1.46 mmol) in water (10 mL) was stirred at room temperature for 30 minutes. The resulting mixture was freeze-dried overnight. An off white solid was obtained in quantitative yield. The XRPD pattern spectrum confirmed that this material is amorphous.

1H NMR (D2O) δ: 7.69 (d, J=7.9 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.22 (s, 1H), 7.16 (t, J=7.4 Hz, 1H), 4.59 (dd, J=8.7, 4.8 Hz, 1H), 3.51 (dd, J=6.8, 5.8 Hz, 1H), 3.38 (dd, J=14.8, 4.8 Hz, 1H), 3.11 (dd, J=14.8, 8.8 Hz, 1H), 2.20-2.49 (m, 2H) and 1.85-1.94 (m, 2H); 

13C NMR (D2O) δ: 181.4, 177.0, 176.6, 138.8, 129.9, 126.9, 124.5, 121.9, 121.4, 114.5, 113.2, 58.6, 57.0, 34.6 (CH2), 30.2 (CH2) and 29.3 (CH2);

the water content by Karl-Fischer test is 5.4%;

the FT-IR (KBr) spectrum is shown in FIG. 1C;

MS (m/z): 371.7 [M]+, 334.2 [C16H20N3O5]+, 187.9 (100%);

HPLC purity (peak area percent): 99.8%, Retention time: 5.04 min; HPLC conditions: Column Waters Symmetry C18, 3.9×150 mm, 5 μm; Mobile phase: 0.035% HClO4, pH 2/CH3CN, 85/15, isocratic, Flow rate: 1 mL/min; λ: 220, 254, 280 nm.

Patent Submitted Granted
GAMMA-GLUTAMYL AND BETA-ASPARTYL CONTAINING IMMUNOMODULATOR COMPOUNDS AND METHODS THEREWITH [EP1042286] 2000-10-11 2010-08-25
CRYSTALLINE D-ISOGLUTAMYL-D-TRYPTOPHAN AND THE MONO AMMONIUM SALT OF D-ISOGLUTAMYL-D-TRYPTOPHAN [US8119606] 2010-01-21 2012-02-21
Pharmaceutically Acceptable Salts of Thymodepressin and Processes for their Manufacture [US8138221] 2010-03-04 2012-03-20
CRYSTALLINE FORMS OF THE MONO-SODIUM SALT OF D-ISOGLUTAMYL-D-TRYPTOPHAN [US8207217] 2010-02-04 2012-06-26
 

////////Orilotimod, PHASE 2, thymodepressin, APO 805K1

C1=CC=C2C(=C1)C(=CN2)CC(C(=O)O)NC(=O)CCC(C(=O)O)N

SD-809, Deutetrabenazine


SD-809,  Deutetrabenazine

  • Tetrabenazine-d6

(3RS,11Brs)-9,10-di((2H3)methoxy)-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-one

2H-​Benzo[a]​quinolizin-​2-​one, 1,​3,​4,​6,​7,​11b-​hexahydro-​9,​10-​di(methoxy-​d3)​-​3-​(2-​methylpropyl)​-​, (3R,​11bR)​-​rel

2H-Benzo(a)quinolizin-2-one, 1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-, (3R,11bR)-rel-

2H-Benzo(a)quinolizin-2-one, 1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-, (3R,11bR)-rel-

(RR,SS)-1,3,4,6,7,11b-Hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one

(3RS,11Brs)-9,10-di((2H3)methoxy)-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-one
Treatment of Chorea Associated with Huntington Disease

MF C19-H21-D6-N-O3

  • C19-H27-N-O3
Molecular Weight, 323.4629
CAS 1392826-25-3
UNII P341G6W9NB
Chemistry Review(s) (PDF) fda approved 2017

Deutetrabenazine

TEVA

Deutetrabenazine.svg

Image result for deutetrabenazineImage result for deutetrabenazineImage result for deutetrabenazine

LINK……………https://newdrugapprovals.org/2015/08/15/sd-809-deutetrabenazine-nda-submitted-by-teva/

Austedo FDA 4/3/2017 For the treatment of chorea associated with Huntington’s disease
Drug Trials Snapshot   Chemistry Review(s) (PDF)

STR1STR2str3


SD-809 was granted Orphan Drug Designation for the treatment of HD by the FDA in November 2014 and became part of Teva’s CNS portfolio with the acquisition of Auspex Pharmaceuticals in May 2015.

Teva announced that the New Drug Application (NDA) for SD-809 (deutetrabenazine) has been accepted by the U.S. Food and Drug Administration (FDA) for the treatment of chorea associated with Huntington disease (HD), a rare and fatal neurodegenerative disorder caused by the progressive breakdown of nerve cells in the brain that affects about five to seven people per 100,000 in western countries, according to the World Health Organization.

(3RS,11Brs)-9,10-di((2H3)methoxy)-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-one.png

…………………….

Patent for preparing tetrabenazine

http://www.google.com/patents/WO2012081031A1?cl=en

Chemically tetrabenazine is cis rac -1, 3, 4, 6, 7, 1 lb-hexahydro-9, 10-dimethoxy-3-(2- methylpropyl)-2Hbenzo[a]quinolizin-2-one and it is represented by compound of structural formula I.

Formula 1

The proprietary name of tetrabenazine is Xenazine and is marketed by Biovail Americas. Xenazine is indicated for the treatment of chorea associated with Huntington’s disease. U.S. patent no. 2,830,993 discloses a process for the preparation of tetrabenazine compound of structural formula I wherein 1 -carbethoxymethyl-6, 7-dimethoxy-l , 2, 3, 4- tetrahydroisoquinoline compound of structural formula IV is being reacted with mono- isobutylmalonic acid dimethyl ester compound of structural formula V and paraformaldehyde in methanol solvent to get l-carbethoxymethyl-2 (2, 2-dicarbomethoxy-4-methyl-n-pentyl)-6, 7- dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline compound of structural formula VI. The 1- carbethoxymethyl-2(2,2-dicarbomethoxy-4-methyl-n-pentyl)-6,7-dimethoxy-l ,2,3,4- tetrahydroisoquinoline compound of structural formula VI is subjected to Dieckmann cyclization , hydrolysis and decarboxylation to get tetrabenazine compound of structural formula I, which is recrystallized from di-isopropyl ether solvent.

Formula I

Scheme I

U. S. patent no. 4,678,792 discloses a process for the preparation of 6, 7-dimethoxy-3, 4- dihydroisoquinoline compound of structural formula VII wherein 2-(3, 4-dimethoxyphenyl)- ethylamine compound of structural formula II is being reacted with chloral hydrate at 120°C to get N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III. The N- formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III is further reacted with polyphosphoric acid to get 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII. The 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is being used as an intermediate for the preparation of tetrabenazine compound of structural formula I.

Formula III

Formula II

Polyphosphoric acid

Formula VII

Scheme II

Bull. Korean Chem. Soc. 2002 Volume (23). No. l , page no. 149 discloses N-formylation of various amines and alcohols with formic acid in toluene.

U.S. patent publication no. 2010/0130480 discloses a process for the preparation of 6, 7- dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII by reacting 2-(3, 4- dimethoxyphenyl)-ethylamine compound of structural formula II with hexamethylenetetramine in presence of acetic acid or trifluoroacetic acid.

Hexamethylenetetramine

Formula II Formula VII

U.S. patent publication no. 2008/0167337 discloses a process for the preparation of tetrabenazine compound of structural formula I wherein 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is reacted with 3-dimethylaminomethyl-5-methyl-hexan-2-one methiodide compound of structural formula VIII to get crude tetrabenazine compound. The crude tetrabenazine compound was purified by employing flash column chromatography technique and

Formula VIII Formula I

The prior-art processes for preparing N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III produces below mentioned compound of structural formula XVII, XVIII, XIX, XX, XXI and XXII as a by-product of the reaction due to the demethylation and formylation of resulting hydroxy compounds.

Formula XX Formula XXI Formula XXII

The compounds of structural formula XVII, XVIII, XIX, XX, XXI and XXII are being carry- forwarded into the further steps of reactions of preparing tetrabenazine compound of structural formula I and therefore there is a need in the art to develop an improved process of preparing 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII, which obviates the prior-art problems. Accordingly there is provided a process of preparing tetrabenazine compound of structural formula I wherein 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is being formed without the formation of above mentioned compounds of structural formula XVII, XVIII, XIX, XX, XXI and XXII.

EXAMPLE: PROCESS FOR THE PREPARATION OF SUBSTANTIAL PURE CRYSTALLINE FORM A OF TETRABENAZINE

Stage A: Process for the preparation of 6, 7-dimethoxy-3, 4-dihydroisoquinoIine

Step 1 : Process for the preparation of N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine

A solution of 2-(3, 4-dimethoxyphenyl)-ethylamine (500gm) in toluene (2000ml) was added formic acid (150gm) at 25°C, the resulting reaction mixture was diluted with toluene (500ml) and heated up to 45°C. The reaction mixture was maintained at 40-45°C for 5 hours and then the resulting reaction mixture was concentrated under reduced pressure at 50°C to get the title compound

Yield: 570gm

Purity: 99.98% (By HPLC)

Step 2: Process for the preparation of 6, 7-dimethoxy-3, 4-dihydroisoquinoline

A solution of N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine (250gm) obtained from step 1 in toluene (500ml) and polyphosphoric acid (50gm) was heated at 110°C for 5 hours. The resulting reaction mixture was cooled to 50°C, quenched with water (500ml) and pH of the resulting solution was adjusted to about 8.3 with aqueous solution of sodium hydroxide [sodium hydroxide (690gm) + water (690ml)]. The resulting reaction mass was extracted by ethyl acetate (2 1250ml), dried over anhydrous sodium sulfate (50gm) and concentrated under reduced pressure to get 6, 7-dimethoxy-3, 4-dihydroisoquinoline (190gm).

Yield: 215gm

Purity: 99.67% (By HPLC)

Stage B: Process for the preparation of 3-((dimethylamino) methyi)-5-methylhexan-2-one methiodide

Step 1 : Process for the preparation of 3-((dimethylamino) methyl)-5-methylhexan-2-one Dimethylamine hydrochloride (180gm) and paraformaldehyde (lOOgm) were added to a solution of 5-methylhexan-2-one (900ml) in methanol (1600ml). The resulting reaction mass was heated at reflux for 12 hours, and then the pH was adjusted to about 8.75 with aqueous solution of sodium hydroxide [sodium hydroxide(90gm) + water (900ml)] at 25 °C. The resulting reaction solution was extracted by toluene (2x1234ml). The organic layer was dried over anhydrous sodium sulfate (50gm) and concentrated under reduced pressure to get title compound.

Yield: 900gm

Purity: 99.80% (By HPLC)

Step 2: Process for the preparation of 3-((dimethylamino) methyl)-5-methylhexan-2-one methiodide

Methyl iodide (323gm) was added dropwise to a solution of 3-((dimethylamino) methyl)-5- methylhexan-2-one (195gm) obtained from step 1 , in ethyl acetate (1650ml) at 25-30°C in 30 minutes. The resulting reaction mixture was stirred at 25 °C for 12 hours and then the resulting solids were filtered, washed with water (200ml) and suck-dried to get wet compound (400gm). The wet compound was slurried with water (1000ml) at 25°C for 1 hour and then it was again filtered, washed with water (200ml) and dried at 45-50°C to get title compound

Yield: 300gm

Purity: 99.86% (By HPLC)

Stage C: Preparation of substantial pure crystalline form A of Tetrabenazine

3-((Dimethylamino) methyl)-5-methylhexan-2-one methiodide (80gm) was added to the solution of 6, 7-dimethoxy-3, 4-dihydroisoquinoline (40gm) in isopropanol (288ml) at 25°C and the resulting reaction mass was heated at 40-45°C for 15 hours. The resulting insoluble material was filtered, washed with isopropanol (80ml) and filtrate was concentrated under reduced pressure up to the 150ml reaction volume. The reaction solution was diluted with methylene dichloride (1200ml) and water (1000ml) and pH was adjusted to 8.5 with sodium hydroxide solution [10%, 100ml]. The organic layer was separated, washed with water (3 x 1000ml) and concentrated under reduced pressure to obtain residue. The residue was dissolved in methanol (300ml) at 50°C, and resulting solution was treated with an activated carbon (20gm) at 50-60°C for 30minutes and then it was filtered and filtrate was further stirred at 20-25°C for 2 hours. The resulting solids were filtered, washed with methanol (150ml), dried at 50-55°C for 8 hours. The resulting solids were milled, sifted through 40 mesh sieve and micronized.

Yield: 65gm

Purity: 99.96% (By HPLC)

………………………

PAPER

Org. Lett., 2011, 13 (24), pp 6500–6503
DOI: 10.1021/ol202792q
Abstract Image

A concise synthesis of tetrabenazine and dihydrotetrabenazine is described. The key feature of this synthesis is the intramolecular aza-Prins-type cyclization of an amino allylsilane via oxidative C–H activation.

T1 T2 T3 T4

http://www.hgxb.com.cn/EN/abstract/abstract12047.shtml

……………
PAPER

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126153/

An external file that holds a picture, illustration, etc. Object name is nihms279693f2.jpg

The TBZ (4) for these reactions was prepared by reacting 3,4-dihydro-6,7-dimethoxyisoquinoline (3) and the Mannich base (2) as shown in Scheme 1.14 The α,β-unsaturated TBZ (5), which was the original substrate, was obtained by further treatment with chloranil in refluxing benzene.

Tetrabenazine (4a)

To a solution of 3,4-dihydro-6,7-dimethoxyisoquinoline hydrochloride (3, 3.5 g, 15.4 mmol) in cold H2O (20 mL) in an ice water bath, was added 3-(dimethylaminomethyl)-5-methyl-2-hexanone (2, 3.15 g, 18.3 mmol) as the free base with stirring. Precipitate formed within 3 h, and stirring was continued until the solid-gummy precipitate prevented stirring. The mixture was allowed to stand at RT (room temperature) for 3 days. The solid–gum mixture was filtered, and the yellow solid–gum mixture was dissolved in hot MeOH. The solution was chilled at −10°C for 18 h. The pale yellow solid was filtered to give 2.1 g (43%) of TBZ (4a).
TLC: Rf = 0.62; silica gel; 4% MeOH/96% CH2Cl2.
MS: (DCl-NH3) m/z 318 (M+H).
UV: (EtOH) λmax 282.0 nm (ε4431).
1H NMR: (300 MHz, CDCl3) δ 6.61 (s, 1H), 6.55 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.51 (br dd, 1H), 3.29 (dd, 1H), 3.13 (m, 2H), 2.90 (dd, 1H), 2.75 (m, 2H), 2.57 (m, 2H), 2.35 (t, 1H), 1.81 (ddd, 1H), 1.65 (m, 1H), 1.04 (ddd, 1H), 0.92 (d, 3H), 0.89 (d, 3H) ppm.
13C NMR: (75 MHz, CDCl3) δ 210.00, 147.86, 147.54, 128.60, 126.11, 111.53, 107.94, 62.48, 61.52, 56.01, 55.92, 50.58, 47.62, 47.57, 36.09, 29.38, 25.44, 23.21, 22.11 ppm.
EA: Anal. Calc for C19H17NO3: C, 71.89; H, 8.57; N, 4.41. Found C, 72.15; H, 8.69; N, 4.47.
HPLC: Brownlee 25 cm × 4.6 mm silica gel column; 30% isopropanol/70% hexane; 1 mL/min; ret. time 5.94 min; purity >99.5%.

…………….

http://www.google.ga/patents/WO2008154243A1?cl=en

Example 10 Removal The Boc Protecting Group From First Intermediate 12 And Amino Cyclization Provide (+)-Tetrabenazine XVII

[0063] First intermediate 12 (1.0 eq) was dissolved in 10% Me2S- dichloromethane to provide an 82 mM solution. The solution was cooled to 0 0C and triisopropylsilane (1.1 eq.) followed by TFA (precooled to 0 0C) was added to the reaction mixture to provide a final concentration of 41 mM. The reaction mixture was permitted to stir at 0 0C for 1 h. Following the allotted time the reaction mixture was quenched at 0 0C by the addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove the majority of the dimethylsulfide. The mixture was extracted with five portions of dichloromethane, and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to provide the crude product as a yellow solid. The crude product was recrystallized from 3.5% dimethoxyethane in hexanes. The resulting colorless crystals were washed with hexanes to provide pure (+)- tetrabenazine (XVII) 46%: mp 126.0 0C (3.5% DME-hexanes) (a crystal polymorph was observed at 116 0C); [α]26 D +37.2 (c 0.41, CH2Cl2); 1H NMR (CD2Cl2) δ 0.89 (apparent t, J = 7.2 Hz, 6H), 0.98 (ddd, J = 12, 6.0, 4.0 Hz, IH), 1.59-1.68 (m, IH), 1.74 (ddd, J = 12, 5.9, 5.7 Hz, IH), 2.32 (apparent t, J = 11.7 Hz, IH), 2.46 (apparent t, J = 12.3 Hz, IH), 2.55 (ddd, J = 12, 10.0, 3.8 Hz, IH), 2.65-2.73 (m, 2H), 2.83 (dd, J = 5.5, 2.8Hz, IH), 2.97-3.07 (m, IH), 3.07-3.14 (m, IH), 3.25 (dd, J =9.7, 6.3 Hz, IH), 3.47 (apparent d, J = 12Hz, IH), 3.75 (s, 3H), 3.77 (s, 3H), 6.55 (s, IH), 6.60 (s, IH) 13C NMR (CD2Cl2) δ 21.98, 23.02, 25.51, 29.46, 35.16, 47.47, 47.63, 50.47, 55.87, 56.01, 61.47, 62.46, 108.46, 111.72, 126.37, 128.96, 147.65, 147.98, 209.72; HRMS-(ESI+) calcd for (C19H27NO3 + H) ([M+H]+ 318.2069, found 318.2082.

…………….

US 20150152099

d1 d2 d3

………….

WO 2015077520

NBI-98854 (CAS # 1025504-59-9), (S)-(2R,3R,l lbR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,1 lb-hexahydro-lH-pyrido[2,l-a]isoquinolin-2-yl 2-amino-3-methylbutanoate, is a VMAT2 inhibitor. NBI-98854 is currently under investigation for the treatment of movement disorders including tardive dyskinesia. WO 2008058261; WO 2011153157; and US 8,039,627. NBI-98854, a valine ester of (+)-a-dihydrotetrabenazine, in humans is slowly hydrolyzed to (+)-a-dihydrotetrabenazine which is an active metabolite of tetrabenazine.

NBI-98854

 

EXAMPLE 1

D6-(±)-3-Isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-lH-pyrido[2,l-a]isoquinolin-2(l lbH)-one ((±)-Tetrabenazine-<d6)

Step 1

[0193] Jgrt-butyl 3,4-dihydroxyphenethylcarbamate : A solution of dopamine

hydrochloride (209 g, 1.11 mol, 1.00 equiv), sodium carbonate (231 g, 2.75 mol, 2.50 equiv) and di-tert-butyl dicarbonate (263 g, 1.21 mol, 1.10) in 2.4 L tetrahydrofuran / water (5: 1) was stirred at 20°C for 2.5 h. After the starting material was consumed completedly, the reaction was diluted with ethyl acetate (2 L) and washed with water (2×600 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure until two volumes of solvent was left. The precipitated solid was isolated by filtration and dried under vacuum to give 254 g (91%) of ieri-butyl 3,4-dihydroxyphenethylcarbamate as white solid. Ή-ΝΜΪ (300 MHz, CDC13) 8.72 (s, 1H), 8.62 (s, 1H), 6.79 (m, 1H), 6.62 (m, 1H), 6.51 (m, 1H), 6.40 (m, 1H), 3.03 (m, 2H), 2.50 (m, 2H), 1.37 (s, 1H). LC-MS: m /z = 254 (MH) +.

Step 2

[0194] D6-fert-butyl 3,4-dimethoxyphenethylcarbamate: A solution of ieri-butyl 3,4-dihydroxyphenethylcarbamate (127 g, 397 mmol, 1.00 equiv), potassium carbonate (359.3 g, 2.604 mmol, 3.00 equiv) and 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane ) (68.64 g, 0.26 mmol, 0.03 equiv) in acetone (800 mL) was stirred at 38°C. After 30 min., CD3I (362 g, 2.604 mmol, 3.00 equiv) was added to the reaction, and the mixture was stirred at 38°C for 12 h. Then an additional CD3I (120 g, 0.868 mmol, 1.00 equiv) was added to the solution and the solution was stirred for 5 h. Then the mixture was cooled to room temperature and the solid was filtered. The filtrate was concentrated under vacuum. The resultant solid was dissolved in H2O (300 mL) and extracted with EA (3×300 mL), the organic layers was combined and concentrated under vacuum to give 114 g (79%) of de-tert-butyl 3,4-dimethoxyphenethylcarbamate as white

solid. ^-NMR (300 MHz, CDC13) <Π.39 (m, 5H), 6.82 (m, 1H), 6.73 (m, 2H), 5.12 (s, 1H), 3.45 (m, 2H), 2.77 (m, 2H). LC-MS: m /z = 288 (MH) +.

Step 3

[0195] D6-2-(3,4-dimethoxyphenyl)ethanamine: A solution of de-tert-butyl 3,4-dimethoxyphenethylcarbamate (128 g, 455.26 mmol, 1.00 equiv) in ethyl acetate (1.5 L) was stirred at room temperature. Then HC1 gas was introduced into the reaction mixture for 2h. The precipitated solid was isolated by filtration. The solid was dissolved in 300 mL of water. The pH value of the solution was adjusted to 12 with sodium hydroxide (solid). The resulting solution was stirred for 1 h at 5-10°C. The resulting solution was extracted with 6×800 mL of ethyl acetate and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum to give 64 g (78%) of d6-2-(3,4-dimethoxyphenyl)ethanamine as yellow oil.

^-NMR (300 MHz, CDC ) 6.77 (m, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 2.96 (m, 2H), 2.71 (m, 2H), 1.29 (s, 2H). LC-MS: m /z = 182 (MH) +.

Step 4

[0196] D6-N-r2-(3,4-dimethoxy-phenyl)ethyllformamide: A solution of d6-2-(3,4-dimethoxyphenyl)ethanamine (69 g, 368 mmol, 1.00 equiv) in ethyl formate(250 mL) was heated under reflux overnight. The solution was concentrated under vacuum to give 71 g (91%) of d6-N-[2-(3,4-dimethoxy-phenyl)ethyl]formamide as yellow solid. The crude solid was used in next step without purification. ^-NMR (300 MHz, CDCb) £8.17 (s, 1H), 6.81 (m, 3H), 5.53 (br, 1H).3.59 (m, 2H), 2.81 (t, 2H, / = 6.9 Hz). LC-MS: m /z = 216 (MH) +.

Step 5

[0197] D6-6,7-dimethoxy-3,4-dihvdroisoguinoline: A solution of d6-N-[2-(3,4-dimethoxy-phenyl)ethyl]formamide (71 g, 329 mmol, 1.00 equiv) in phosphorus oxychloride (100 mL) was stirred at 105°C for 1 h. Then the solution was concentrated under vacuum to remove

phosphorus oxychloride. The residual oil was dissolved in ice / water. The solution was made basic with potassium carbonate with cooling. The basic aqueous solution was extracted with dichloromethane. The collected organic phase was dried using sodium sulfate and then filtered. The dichloromethane was removed by concentration under vacuum to give an orange oil.

Purification by silica gel (ethyl acetate:petroleum ether = 1: 1 ~ ethyl acetate) to give 43 g (66%) of d6-6,7-dimethoxy-3,4-dihydroisoquinoline as orange solid (yield 66%). Ή-ΝΜΡ (300 MHz, CDC13) 8.24 (s, 1H), 6.82 (s, 1H), 6.68 (s, 1H), 3.74 (m, 2H), 2.69 (t, 2H, J = 12 Hz). LC-MS: m /z = 198 (MH) +.

Step 6

[0198] Trimethyl(5-methylhex-2-en-2-yloxy)silane: To a cold (-78°C), stirred solution of j-PrMgBr (500 mL of 2 M solution in tetrahydrofuran, 1 mol, 1.00 equiv) in anhydrous tetrahydrofuran (1 L) was added Cul (19.02 g, 0.1 mol, 0.10 equiv) and the resultant mixture was stirred for 15 min at -78°C. Anhydrous hexamethylphosphorous triamide (358.4 g, 2 mmol, 2 equiv) was added and after 20 min, a solution of methyl vinyl ketone (70 g, 0.1 mol, 1.00 equiv), trimethylsilyl chloride (217 g, 0.2 mol, 2.00 equiv), in tetrahydrofuran (200 mL) was added dropwise over 30 min. After the reaction mixture was stirred at -78 °C for lh, triethylamine (20.2g, 200 mmol, 2.00 equiv) was added and the resulting mixture stirred for 10 min at 0 °C. To this was added ie/ -butyl methyl ether (2 L), and the solution was washed with 5% ammonia solution (6×300 mL). Then the organic phase was dried over sodium sulfate and concentrated under vacuum at 25°C to give 155 g crude product as yellow liquid. The liquid was purified by distilling (64-68°C/40 mmHg) to provide 118 g (63.3%) of trimethyl(5-methylhex-2-en-2-

yloxy)silane (E:Z = 56 : 44) as a colorless oil. XH-NMR (300 MHz, J6-DMSO) 4.58 (m, 0.56H), 4.43 (m, 0.44H), 1.73 (s, 1.69H), 1.66 (s, 1.32H), 1.53 (m, 1H), 0.84 (m, 6 H), 0.15(m, 9H).

Step 7

[0199] 3-r(Dimethylamino)methyl1-5-methylhexan-2-one: To a stirred solution of trimethyl(5-methylhex-2-en-2-yloxy)silane (118 g, 633 mmol, 1.00 equiv) in anhydrous acetonitrile (800 mL) was added N-methyl-N-methylenemethanaminium iodide (128.8 g, 696.3 mmol, 1.10 equiv) in several batches and the resultant mixture was stirred at 20°C overnight. Then the solution was concentrated under vacuum to remove the solvent. The residue was dissolved in 400 mL 1 N HC1 (aq.) and extracted with ieri-butyl methyl ether. Then the water phase was basiced with 2 N aq. NaOH and extracted with ie/ -butyl methyl ether. The organic phase was dried and concentrated under vacuum. The liquid was purified by distilling (80°C/0.5 mmHg) to provide 50 g (46%) of 3-[(dimethylamino)methyl]-5-methylhexan-2-one as a colorless oil. XH-NMR (300 MHz, J6-DMSO) £0.92 (d, 3H), 0.98 (d, 3H), 1.11-1.23 (m, 1H), 1.23-1.38 (m, 1H), 1.54-1.70 (m, 1H), 2.30 (s, 3H), 3.01 (s, 9H), 3.10-3.32 (m, 2H), 3.81-3.88 (m, 1H).

Step 8

[0200] 2-Acetyl-N,N V,4-tetramethylpentan-l-aminium iodide: A solution of 3-[(dimethylamino)methyl]-5-methylhexan-2-one (50 g, 15.00 mmol, 1.00 equiv) and methyl iodide (4.26 g, 30.00 mmol, 2.00 equiv) in 50 mL diethyl ether was stirred overnight at room temperature. The precipitated solid was isolated by filtration and dried under vacuum to give 79 g (86%) of 2-acetyl-N,N,N,4-tetramethylpentan-l-aminium iodide as white solid. XH-NMR (300 MHz, Je-DMSO) 0.89-0.98 (m, 6H), 1.11-1.20 (m, 1H), 1.40 (m, 1H), 1.66 (m, 1H), 2.30 (s, 3H), 3.01(s, 9H), 3.21 (m, 2H), 3.85 (m, 1H).

Step 9

[0201] Ρό- (±) -tetrabenazine : A solution of d6-6,7-dimethoxy-3,4-dihydroisoquinoline (33.4 g, 169 mmol, 1.10 equiv) and 2-acetyl-N,N,N,4-tetramethylpentan-l-aminium iodide (48 g, 153 mmol, 1.00 equiv) in 300ml of methanol was heated under reflux for 48 h. Then 150 mL water was added. The solution was cooled to room temperature. The precipitated solid was isolated by filtration and dried under vacuum to give 38 g of crude d6-tetrabenazine as yellow solid. The crude tetrabenazine was dissolved in ieri-butyl methyl ether (15 volumes), the mixture was heated until the solid was almost dissolved. The yellow solid which was unsolvable was filtered. The filtrate was concentrated under vacuum until 2 volumes ieri-butyl methyl ether was left. The solid was filtered and collected. The above solid was dissolved in ethanol (4 volumes), then the mixture was heated until the solid was dissolved. The solution was stirred and cooled to room temperature at the rate of 20°C/h. Then the mixture was stirred at 0°C for lh. The precipitated solid was isolated by filtration and dried under vacuum to give 25 g (50.4%) of tetrabenazine-<d6 as white solid.

^-NMR (300 MHz, CD2C12) £6.61 (s, 1H), 6.55 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.50 (d, 1H, / = 12 Hz), 3.27 (dd, 1H, / = 11.4Hz, / = 6.3 Hz), 3.11 (m, 2H), 2.84 (dd, 1H, / = 10.5 Hz, / = 3 Hz), 2.74 (m, 2H), 2.56 (m, 2H), 2.31 (t, 1H, J = 12 Hz), 1.76 (m, 1H), 1.63 (m, 1H), 0.98 (m, 1H), 0.89 (m, 6H).

LC-MS: m /z = 324 (MH) +.

………………

NMR PREDICT

C1

D2

D3

Watch out will be updated……………….

Rob Koremans, MD, President and CEO of Global Specialty Medicines at Teva.

Michael Hayden, M.D., Ph.D., President of Global R&D and Chief Scientific Officer at Teva

 

 

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update on 2018

Novel Process for Preparation of Tetrabenazine and Deutetrabenazine

Lupin Research ParkLupin Limited46 & 47A, Village Nande, Taluka Mulshi, Pune-412115, Maharashtra, India
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00011

Abstract

Abstract Image

A novel process for the synthesis of tetrabenazine (1) and deutetrabenazine (2), two well-known drugs used for the treatment of chorea associated with Huntington’s disease, has been developed. All of the reaction parameters were optimized through a series of reactions and by using Design of Experiment techniques. The newly developed methods are industrially scalable and employ cheap, commercially available raw materials and hence are highly efficient. The added advantage is that the developed processes evade the use of genotoxic alkylating agents and therefore could be considered as safe and viable alternatives to the existing methods.

Tetrabenazine (1) was invented by Hoffmann-La-Roche (Nutley, NJ, USA). It was also known as Ro 1-9569, Nitoman, and Xenazine. It is a benzoquinolizine derivative with the chemical name 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[α]quinolizin-2-one . Initially it was developed as an antipsychotic agent.Despite 50 years of medicinal background, the U.S. Food and Drug Administration (FDA) approved 1 on August 15, 2008, for the treatment of chorea associated with Huntington’s disease.

Figure

 Chemical structures of 1 and 2.

Deutetrabenazine (2) (trade name Austedo) is a stable, nonradioactive deuterium analogue of the approved drug tetrabenazine in which the six hydrogen atoms of the 9- and 10-methoxy (−OCH3) substituents have been replaced by deuterium atoms . Deutetrabenazine was found to be more effective for the treatment of chorea associated with Huntington’s disease because of improved pharmacokinetic properties compared with the nondeuterated drug tetrabenazine. Deutetrabenazine was originally developed by Auspex Pharmaceuticals (La Jolla, CA, USA). In 2015, Teva acquired Auspex Pharmaceuticals and submitted a new drug application (NDA) in the United States for the treatment of Huntington’s disease. On April 3, 2017, Teva Pharmaceutical received approval from the FDA to market deutetrabenazine as the first deuterated drug for the treatment of chorea associated with Huntington’s disease.(4) Both 1 and 2 are racemic mixtures .
  1. (a) Brossi, A.Lindlar, H.Walter, M.Schnider, O. Helv. Chim. Acta 195841119– 139DOI: 10.1002/hlca.660410117

    .

    (b) Brossi, A.Schnider, O.Walter, M. Quinolizine derivatives.U.S. Patent 2,830,9931958.

  2. Pletscher, A.Brossi, A.Gey, K. F. Int. Rev. Neurobiol. 19624275– 306DOI: 10.1016/S0074-7742(08)60024-0
  3. Mestre, T.Ferreira, J.Coelho, M. M.Rosa, M.Sampaio, C. Cochrane Database Syst. Rev. 20093,CD006456DOI: 10.1002/14651858.CD006456.pub2

  4. U.S. Food and Drug Administration. Novel Drug Approvals for 2017.https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm537040 (accessed Jan 15, 2018).
  5. Brossi, A. Preparation of substituted 2-oxobenzoquinolizinesU.S. Patent 3,045,0211962.

  6. Gant, T. G.Shahbaz, M. M. Benzoquinoline inhibitors of vesicular monoamine transporter-2U.S. Patent 8,524,7332013.

Large-Scale Preparation of Tetrabenazine (1)

1 (262.3 g, 96%). FTIR (in KBr): 2942, 2919, 1701, 1516, 1465, 1370, 1263, 1159, 1010, 860, 749 cm–11H NMR (500 MHz, CDCl3): δ 6.63 (s, 1H), 6.57 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.52 (d, 1H, J = 11.2 Hz), 3.32 (dd, 1H, J = 11.6, 6.4 Hz), 3.13–3.10 (m, 2H), 2.93–2.90 (m, 1H), 2.77–2.73 (m, 2H), 2.64–2.53 (m, 2H), 2.37 (t, 1H, J = 11.6 Hz), 1.83–1.80 (m, 1H), 1.69–1.66 (m, 1H), 1.08–1.04 (m, 1H), 0.94–0.91 (m, 6H). ESI-MS: m/z 318.3 [M + H]+.

Purification of 1

1 (9.6 g, 96%). HPLC purity: 99.75%.

FTIR (in KBr): 2942, 2919, 1701, 1516, 1465, 1370, 1263, 1159, 1010, 860, 749 cm–1

1H NMR (500 MHz, DMSO-d6): δ 6.70 (s, 1H), 6.69 (s, 1H), 3.72 (s, 6H), 3.46 (d, 1H, J = 10.0 Hz), 3.24 (dd, 1H, J = 11.5, 6.0 Hz), 3.15–3.11 (m, 1H), 2.95–2.89 (m, 1H), 2.85 (dd, 1H, J = 13.0, 3.0 Hz), 2.69–2.65 (m, 2H), 2.52–2.46 (m, 2H), 2.28 (t, 1H, J= 12.0 Hz), 1.66–1.63 (m, 2H), 0.94–0.85 (m, 7H).

ESI-MS: m/z 318.3 [M + H]+.

Large-Scale Preparation of Deutetrabenazine (2)FTIR (in KBr): 2942, 2920, 2246, 2067, 1700, 1513, 1269, 1113, 990, 747 cm–11H NMR (500 MHz, CDCl3): δ 6.63 (s, 1H), 6.56 (s, 1H), 3.53 (d, 1H, J = 10.5 Hz), 3.32–3.30 (m, 1H), 3.17–3.13 (m, 2H), 2.92 (dd, 1H, J = 13.5,3.0 Hz), 2.77–2.73 (m, 2H), 2.64–2.53 (m, 2H), 2.37 (t, 1H, J = 11.5 Hz), 1.84–1.79 (m, 1H), 1.69–1.67 (m, 1H), 1.08–1.04 (m, 1H), 0.94–0.91 (m, 6H). ESI-MS: m/z 324.4 [M + H]+

Large-Scale Purification of 2

Mp: 128.75–129.42 °C.

FTIR (in KBr): 2942, 2920, 2246, 2067, 1700, 1513, 1269, 1113, 990, 747 cm–1

1H NMR (500 MHz, DMSO-d6): δ 6.69 (s, 2H), 3.46 (d, 1H, J = 10.0 Hz), 3.25 (dd, 1H, J = 11.5, 6.0 Hz), 3.15–3.11 (m, 1H), 2.95–2.89 (m, 1H), 2.85 (dd, 1H, J = 13.5, 3.0 Hz), 2.70–2.64 (m, 2H), 2.52–2.44 (m, 2H), 2.28 (t, 1H, J = 11.5 Hz), 1.66–1.63 (m, 2H), 0.93–0.85 (m, 7H).

ESI-MS: m/z 324.4 [M + H]+.

[α]D −0.3 [c 0.3, DCM at 25 °C].

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
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09b37-misc2b027LIONEL MY SON
He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy
सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

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