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PRI-724, ICG 001, What is correct structure?

March 27, 2015 4:00 am / 1 Comment on PRI-724, ICG 001, What is correct structure?

PRI 724 AND ICG001 do confuse us, my efforts to unlock this confusion

STRUCTURE 4

4-(((6S,9S,9aS)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate……………seems most likely PRI 724

STRUCTURE 5

Cas 1422253-37-9

(6S,9S,9aS)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-yImethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazine- 1 -carboxamide.

compd 2 and 1

COMPD 3

http://www.medkoo.com/Anticancer-trials/PRI-724.htm and similar/Same

http://www.nature.com/nrc/journal/v14/n4/fig_tab/nrc3690_T1.html

compd 3.both above str are same

One of compd 1,2, 3, 4, 5 see at the end as an update , CAN BE ICG001, PRI-724,

Prism Biolab Corporation

Beta-catenin (CTNNB1) inhibitor

ICG001, also known as PRI-724, is a potent, specific inhibitor of the canonical Wnt signaling pathway in cancer stem cells with potential antineoplastic activity. Wnt signaling pathway inhibitor PRI-724 specifically inhibits the recruiting of beta-catenin with its coactivator CBP (the binding protein of the cAMP response element-binding protein CREB); together with other transcription factors beta-catenin/CBP binds to WRE (Wnt-responsive element) and activates transcription of a wide range of target genes of Wnt/beta-catenin signaling. Blocking the interaction of CBP and beta-catenin by this agent prevents gene expression of many proteins necessary for growth, thereby potentially suppressing cancer cell growth. The Wnt/beta-catenin signaling pathway regulates cell morphology, motility, and proliferation; aberrant regulation of this pathway leads to neoplastic proliferation.

JAPAN

4-(((6S,9S)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahy- dro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl) phenyl dihydrogen phosphate

(6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahydro-1H-pyrazino[2,1-c] [I,z,4]triazine-1-carboxamide,

4-(((6S,9S,9aS)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate

(6S,9S,9aS)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-yImethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazine- 1 -carboxamide.

Compound A as in wo 2014061827……..4-(((6S,9S,9aS)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazin-6-yl)methyl)phenyI dihydrogen phosphate in WO2014061827

4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate (presumed to be PRI-724; first disclosed in WO2009148192), useful for treating cancer, neurodegenerative diseases, glaucoma and idiopathic pulmonary fibrosis.

Eisai, under license from PRISM Pharma, is developing PRI-724, an inhibitor of CREB binding protein or beta-catenin complex formation, for treating cancer (phase 1, as of March 2015) and HCV-induced cirrhosis (preclinical trial).

Follows on from WO2014061827, claiming the use of PRI-724 for treating pulmonary fibrosis.

IS IT

PRI-724 structure

cas 847591-62-2…………http://www.medkoo.com/Anticancer-trials/PRI-724.htm

(6S,9aS)-N-Benzyl-6-(4-hydroxybenzyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxoperhydropyrazino[1,2-a]pyrimidine-1-carboxamide

COMPD 3

COMPD 2

PRI724

1198780-43-6, 578.66, C₃₃ H₃₄ N₆ O₄

(6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahydro-1H-pyrazino[2,1-c] [I,z,4]triazine-1-carboxamide,

COMPD1

PRI 724

4-(((6S,9S)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahy- dro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl) phenyl dihydrogen phosphate

COMPD 1

SEE

http://www.google.co.in/patents/WO2009148192A1?cl=en

About PRI-724
PRI-724 is an antiproliferative small molecule that selectively inhibits the CBP/beta-catenin complex, which modulates the beta-catenin dependent pathway of Wnt signaling. Activation of the Wnt/beta-catenin signaling pathway is observed in various tumor cells and results in proliferation and metastasis. PRI-724 exhibits a selective antiproliferative effect, inhibiting various cancer cell lines in vitroand substantially inhibiting tumor growth in animal studies. PRI-724 is currently in clinical trials in oncology indications, partnered with Eisai Co., Ltd. PRI-724 also has potential to provide therapeutic benefit in non-oncology areas such as fibrosis and clinical trials in that indication are targeted to start in the second half of 2013.

About PRISM Pharma Co., Ltd.
PRISM Pharma Co., Ltd. has developed its platform technology to modulate inter-cellular protein-protein interactions using peptide mimetic small molecules and found various hit compounds including PRI-724.

SEE

WO 2015037587

Eisai Research Institute; PRISM Pharma Co Ltd

出願人：エ_ ザイ■ ア_ ル■ アンド■ ディ_ ■
マネジメン卜株式会社(EISAI R&D MANAGEMENT
CO., LTD.) [JP /JP ];亍1128088 東京都文京区
小石川四丁目6 番1 O 号Tokyo (JP).株式会社P
R I S M P h a r m a (PRISM PHARMA CO.,
LTD.) [JP /JP ];亍2268510神奈川県横浜市緑区長津
田町 4 2 5 9 — 3 Kanagawa (JP)

(IO) 国際公開番号
2 0 1 5 ^ ® S 3 .2 0 1 5 )

WO 2015/037587 Al

This method of producing 4-(((6S,9S)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahy- dro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl) phenyl dihydrogen phosphate involves a step for adding a reaction solution (I) comprising (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl) octahydro-1H-pyrazino[2,1-c] [I,z,4]triazine-1-carboxamide, triethylamine and a solvent to a reaction solution (2) comprising a phosphorylating agent and a solvent.

1H-NMR (600MHz, METHAN0L-d4) δ (ppm):1.15 (d, J=6 Hz, 3H), 2.65 (s, 3H), 3.12 (d, J=18 Hz, 1H), 3.35 (d, J=7 Hz, 2H), 3.48 (d, J=18 Hz,1H), 4.15 (m,1H), 4.32 (d, J=15 Hz, 1H), 4.40 (d, J=15 Hz, 1H), 5.33(d, J=16 Hz, 1H), 5.41(d, J=16 Hz, 1H), 5.44 (d, J=7 Hz, 1H), 5.64 (d, J=10 Hz, 1H), 7.07 (dd, J=9,1 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 7.24 (t, J=7 Hz, 1H), 7.27 (d, J=7 Hz, 2H), 7.34 (t, J=8 Hz, 2H), 7.55 (d d, J=8, 4 Hz, 1H), 7.60 (brd, J=6 Hz, 1H), 7.62 (dd, J=8, 7 Hz, 1H), 7.88 (dd, J=8,1 Hz, 1H), 8.38 (dd, J=8, 2 Hz, 1H), 8.90 (dd, J =4, 2 Hz, 1H).

…………………………………………………………………….

SEE

http://www.google.co.in/patents/WO2009148192A1?cl=en

SYNTHESIS OF COMPD 2

PART A

Synthesis Part A

step A

(S)-benzyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate

Reaction of the foll……………….N-methoxy-N-methylamine hydrochloride, 1N sodium hydroxide , (S)-2-(benzyloxycarbonylamino)propanoic acidand 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride to obtain

(S)-benzyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate.

STEP B

(S)-benzyl 1,1-diethoxypropan-2-ylcarbamate

Reaction of the foll……………….(S)-benzyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate, 2M lithium aluminium hydride in tetrahydrofuran solution to obtain (S)-benzyl 1,1-diethoxypropan-2-ylcarbamate

STEP C

(S)-1,1-diethoxypropan-2-amine

Reaction of the foll……………….(S)-benzyl 1,1-diethoxypropan-2-ylcarbamate, 5% palladium on carbon title compound . (S)-1,1-diethoxypropan-2-amine,

STEP D

(S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine,

Reaction of the foll……………….(S)-1,1-diethoxypropan-2-amine,was reacted with 8-Quinolinecarboaldehyde to obtain the title

compound (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine

PART B

STEP E

(9H-fluoren-9-yl)methyl (S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylcarbamate

Reaction of the foll………………. (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tertbutoxyphenyl)propanoic acid to obtain the title compound (9H-fluoren-9-yl)methyl (S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylcarbamate

STEP f

(S)-2-amino-3-(4-tertbutoxyphenyl)-N-((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide INT A

Reaction of the foll………………. (9H-fluoren-9-yl)methyl (S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylcarbamate and piperidine to
obtain the title compound (S)-2-amino-3-(4-tertbutoxyphenyl)-N-((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide INT A

PART C

STEP g

ethyl 2-(1-methylhydrazinyl)acetate

Reaction of the foll……………….methylhydrazine 7 was reacted with ethyl 2-bromoacetate 1to obtain the title compound

STEP h
ethyl 2-(1-Methyl-2-(benzylcarbamoyl)hydrazinyl)acetate

Reaction of the foll………………. ethyl 2-(1-methylhydrazinyl)acetateand benzyl isocyanate to obtain the title
compound ethyl 2-(1-Methyl-2-(benzylcarbamoyl)hydrazinyl)acetate

STEP i
2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid

Reaction of the foll………………. ethyl 2-(1-allyl-2-
(benzylcarbamoyl)hydrazinyl)acetate and lithium hydroxide monohydrate to obtain the title compound 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid

STEP j
N-benzyl-2-(2-((S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-
diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylamino)-2-oxoethyl)-2-
methylhydrazinecarboxamide……… precursor

Reaction of the foll………………. 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid and (S)-2-amino-3-(4-tert-butoxyphenyl)-N-((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide ( INT A )yielded the title compound ie the precursor

PART D

THIS PRECURSOR GIVES FINAL PRODUCT

Synthesis of (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-
dimethyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-
carboxamide ……….final

fOLL reactants……….. N-benzyl-2-(2-((S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-1-oxopropan-2-ylamino)-2-oxoethyl)-2-methylhydrazinecarboxamide, ie the precursor and 10%-water/HCOOH gave (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro-1Hpyrazino[2,1-c][1,2,4]triazine-1-carboxamide

RT 4.22; Mass 578.9

COMPD 3

(6S,9aS)-N-Benzyl-6-(4-hydroxybenzyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxoperhydropyrazino[1,2-a]pyrimidine-1-carboxamide

SEE

US 6762185

……………………………..

SEE

http://www.google.com/patents/WO2012141038A1?cl=en

novel compounds, agent for inducing differentiation into hepatocytes of mesenchymal stem cells, Wnt / β- catenin signaling pathway inhibitor, method for producing hepatocytes with them on hepatocytes such as by their production.

Liver disease is said to be Japan’s national disease, a large number of patients suffering from liver disease. In addition, the annual number of deaths from hepatocellular carcinoma amounts to about 30 004 thousand people. Recently, hepatocellular cancer outcome is improved by advances in treatment, but the increase of advanced cancer, with hepatic dysfunction cirrhosis to merge, so-called hepatic failure death has increased. Liver failure therapy, although liver transplantation is ideal, it is difficult in Japan to obtain sufficient donors, it is necessary to develop a liver regeneration therapy with stem cells.

As stem cells that have the potential to differentiate into liver cells, bone marrow cells, tissue stem cells, such as umbilical cord blood cells can be expected.Therefore, a number of research institutions, for the realization of by regenerative medicine liver cell transplantation treatment of chronic liver failure patient, to differentiate human tissue stem cells into functional hepatocytes, truly clinically applicable efficient differentiation induction technology you are conducting research and development with the goal of developing a.

For example, in the laboratory of Shioda Professor of Tottori University Graduate School of Medicine, reported that the Wnt / β- catenin signaling pathway were differentiated into hepatocytes showed that suppressed by RNA interference at the time of induction of differentiation from human mesenchymal stem cells into hepatocytes you are (Non-Patent Document 1 and Non-Patent Documents 3-5).Furthermore, studies to induce differentiation of hepatocytes in other institutions have been conducted (Non-Patent Document 2, Patent Documents 1 and 2).

On the other hand, recently, from 4,000 or more screening of large compound libraries, Wnt / β- catenin signaling pathway inhibitory low molecular compound 5 types have been identified (Non-Patent Documents 6-9).

Kohyo 2009-535035 JP Patent Publication No. 2010-75631

Atsushi Yanagitani et al., ” retinoic Acid Receptor Dominant Level Negative Form Causes steatohepatitis and Liver Tumors in Transgenic Mice “, Hepatology, Vol. 40, No. 2, 2004, P. 366-375 Seoyoung Park et al.,”Hexachlorophene Inhibits Wnt / beta-catenin Pathway by Promoting Siah-Mediated beta-catenin Degradation “, Mol Pharmacol Vol. 70, No. 3, 960-966, 2006 Yoko Yoshida et al.,” A role of Wnt / beta-catenin Signals in hepatic fate Specification of human umbilical cord blood-derived mesenchymal stem cells “, Am J Physiol Gastrointest Liver Physiol 293:. G1089-G1098, 2007 Shimomura T et al,” Hepatic differentiation of human bone marrow-derived UE7T-13 cells: Effects of cytokines and CCN family Gene expression “, Hepatol Res., 37, 1068-79, 2007 Ishii K et al.,” Hepatic differentiation of human bone marrow-derived mesenchymal stem cells by tetracycline-regulated Hepatocyte Nuclear factor 3Beta “Hepatology, 48, 597- 606, 2008 Maina Lepourcelet et al., ” Small-molecule Antagonists of the oncogenic Tcf / beta-catenin protein complex “, CANCER CELL, JANUARY 2004, VOL. 5, 91-102 Emami KH et al.,” A Small molecule inhibitor of beta-catenin / CREB-binding protein Transcription “, Proc Natl Acad Sci US A. 2004 Aug 24; 101 (34):.. 12682-7 Jufang Shan et al,”Identification of a Specific Inhibitor of the Dishevelled PDZ Domain ” , Biochemistry 2005 Nov 29; 44 (47):.. 15495-503 Trosset JY et al, ” Inhibition of protein-protein Interactions: the discovery of beta-catenin Druglike Inhibitors by combining virtual and Biophysical Screening . “, Proteins 2006 Jul 1 ; 64 (1): 60-7

However, the conventional techniques described above literature, had a room for improvement in the following points.
Patent Documents 1 and 2, it has been described for proteins to induce stem cells from Hikimomiki cells, due to the use of the protein formulation as a differentiation inducing agent, a room for further improvement in terms of stability and safety and there was.

Non-Patent Document 1 and Non-Patent Document 3 to 5, and have reported that induced differentiated hepatocytes from human mesenchymal stem cells, the use of siRNA as a differentiation inducing agent, such as stability and safety there is room for further improvement in the surface. Non-Patent Document 2, 6 to 9, is not described with respect to method of inducing differentiation into hepatocytes.

The present invention has been made in view of the above circumstances, and an object thereof is to provide an effective low-molecular compounds that induce differentiation into hepatocytes from mesenchymal stem cells. Or, it is intended that the low-molecular compound was used to provide a secure differentiation inducing method is excellent from the mesenchymal stem cell differentiation efficiency of liver cells.

According to the present invention, there is provided formula (1) and one or more compounds selected from the group of compounds represented by the formula (2), a salt thereof or a solvate thereof.

<Example 1> synthetic ICG-001 of synthesis (1) ICG-001 of the IC-2 is an oligopeptide having two rings of β- turn mimic structure in central skeleton, and transcription by β-catenin / Tcf complex can function as a potent antagonist for activation has been reported (Drug Discov. Today 2005, 10, 1467-1474). Synthesis of ICG-001 in accordance with the literature (Tetrahedron 2007, 63, 12912-12916), was subjected to examination.

(1-1) of Compound 1 Synthesis 1-naphtaldehyde (Wako Pure Chemical) (1.56 g, 10 mmol) and 2,2-diethoxyethanamine (Tokyo Kasei Kogyo) (1.33 g, 10 mmol) were mixed 100 I was stirred 20 min at ^o C. After cooling to room temperature, diluted with EtOH (20 _mL), was added portionwise NaBH 4 (0.38 g, 10 mmol), at room temperature, and stirred for 16 h. After completion of the reaction, was distilled off by concentration under reduced pressure EtOH, the product was extracted with AcOEt. The resulting product was purified by silica gel column chromatography (hexane / AcOEt = 5/1) to give the to give compound 1 (2.29 g, 8.5 mmol, 85%).

(1-2) Synthesis of Compound 3 Fmoc-L-Tyr (t-Bu) -OH (0.87 g, 1.9 mmol) in DMF (7 mL) solution of a condensing agent HATU (0.76 g, 2.0 mmol) and diisopropylethylamine (DIEA) (0.35 mL, 2.0 mmol) was added and after stirring for 20 min, compound 1 (0.54 g, a 2.0 mmol) was added, at room temperature, 16 h the mixture was stirred. After the reaction, DMF was distilled off by concentration under reduced pressure, and the resulting product was purified by column chromatography (hexane / AcOEt = 10/1), compound 2 was obtained (1.33 g, 1.9 mmol, 93%). The resulting compound 2 (1.33 g, 1.9 mmol) was dissolved in _CH 2 _Cl 2 (20 mL), was added diethylamine (DEA) (10 ml, excess), at room temperature, was 2 h stirring.After confirming the completion of the reaction by TLC, vacuum was distilled off _{CH 2} Cl 2 by concentration, the resulting product was purified by silica gel column chromatography (AcOEt), to give compound 3 (0.92 g, 1. 8 mmol, 92%).

(1-3) Synthesis Fmoc-β-Ala-OH (0.53 g, 1.7 mmol) of compound 5 in DMF (8 mL) solution of a condensing agent HATU (0.70 g, 1.8 mmol) and diisopropylethylamine (DIEA) (0.32 mL, 1.8 mmol) was added and after stirring for 20 min, compound 3 (0.92 g, 1.8 mmol) was added, at room temperature, and stirred for 14 h. After the reaction, DMF was distilled off by concentration under reduced pressure, the resulting product was purified by column chromatography (hexane / AcOEt = 1/1), compound 4 was obtained (1.2 g, 1.5 mmol, 82%). Obtained compound 4 (1.2 g, 1.5 mmol) was dissolved in _CH 2 _Cl 2 (20 mL), was added diethylamine (DEA) (9 mL, excess), at room temperature, and stirred for 1 h. After confirming the completion of the reaction by TLC, was distilled off _{CH 2} Cl 2 by concentration under reduced pressure, and the resulting product was purified by silica gel column chromatography (AcOEt / EtOH = 1/1), to give compound 5 (0 .66 g, 1.2 mmol, 80%).

(1-4) synthetic compounds 5 (0.66 g, 1.2 mmol) of compound 7 _{CH 2} Cl 2 of solution (8 mL) to benzylisocyanate (0.16 g, 1.2 mmol) of _{CH 2} Cl 2 solution (8 mL) was added, at room temperature, and stirred for 12 h. After confirming the completion of the reaction by TLC, was distilled off _{CH 2} Cl 2 by concentration under reduced pressure, and the resulting product was purified by column chromatography (AcOEt / EtOH = 1/1), to give compound 6 (0. 59 g, 0.85 mmol, 73%). The obtained compound 6 (0.59 g, 0.85 mmol) at room temperature in the formic acid (9 ml), I was stirred 20 h. Was evaporated formic acid by concentration under reduced pressure, the resulting product was purified by column chromatography (AcOEt), Compound 7a to (ICG-001) was obtained as a white solid (0.26 g, 0.48 mmol, 57 %).
The resulting product, MS spectra and ^were identified from the 1 H NMR spectrum (with the literature value) (Fig. 1).

WO2006101858A1 *	Mar 15, 2006	Sep 28, 2006	Inst Chemical Genomics	Alpha-helix mimetics and methods relating to the treatment of fibrosis
WO2009148192A1 *	Jun 5, 2009	Dec 10, 2009	Prism Biolab Corporation	Alpha helix mimetics and methods relating thereto
WO2012068299A2 *	Nov 16, 2011	May 24, 2012	University Of Southern California	Cbp/catenin antagonists for enhancing asymmetric division of somatic stem cells

SEE https://www.google.com/patents/WO2014061827A1?cl=en

one more compd

compd 4

https://www.google.com/patents/WO2014061827A1?cl=en

STRUCTURE 4

4-(((6S,9S,9aS)-l-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-ylmethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazin-6-yl)methyl)phenyl dihydrogen phosphate

STRUCTURE 5

(6S,9S,9aS)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinolin-8-yImethyl)octahydro- 1 H-pyrazino[2, 1 -c] [ 1 ,2,4]triazine- 1 -carboxamide.

Cas 1422253-37-9

2H-Pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide, hexahydro-6-[(4-hydroxyphenyl)methyl]-2,9-dimethyl-4,7-dioxo-N-(phenylmethyl)-8-(8-quinolinylmethyl)-, (6S,9S,9aS)-

Structure can represented as

Will be updated

coming

CONCLUSION ………………….SEEMS TO ME THAT COMPD 4 IS PRI 724 NAD COMPD 3 IS ICG 001……ERROR EMAIL ME amcrasto@gmail.com, call +919323115463 india

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Japanese filing for Amgen’s PCSK9 inhibitor Repatha

March 23, 2015 7:39 am / Leave a comment

Amgen has filed its closely watched PCSK9 inhibitor Repatha (evolocumab) in Japan for the treatment of high cholesterol.

Repatha is an investigational fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver’s ability to remove low-density lipoprotein cholesterol (LDL-C), or ‘bad’ cholesterol, from the blood.

Evolocumab
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	PCSK9
Clinical data
Legal status	Investigational
Routes of administration	Subcutaneous injection
Identifiers
CAS Registry Number	1256937-27-5
ATC code	C10AX13
Chemical data
Formula	C₆₂₄₂H₉₆₄₈N₁₆₆₈O₁₉₉₆S₅₆
Molecular mass	141.8 kDa

Evolocumab^[1] (also known as compound number AMG-145 or AMG145)^[2] is a monoclonal antibody designed for the treatment of hyperlipidemia.^[3] Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9).

PCSK9 is a protein that targets LDL receptors for degradation and thereby reduces the liver’s ability to remove LDL-C, or “bad” cholesterol, from the blood.

Evolocumab, being developed by Amgen scientists, is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of the liver to remove LDL-C from the blood.

Clinical trials

Two trials have been in progress as at mid-2014:

On 23 January 2014 Amgen announced that the Phase 3 GAUSS-2 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2) trial evaluating evolocumab in patients with high cholesterol who cannot tolerate statins met its co-primary endpoints: the percent reduction from baseline in low-density lipoprotein cholesterol (LDL-C) at week 12 and the mean percent reduction from baseline in LDL-C at weeks 10 and 12. The mean percent reductions in LDL-C, or “bad” cholesterol, compared to ezetimibe were consistent with results observed in the Phase 2 GAUSS study.^[4]^[5]

The GAUSS-2 trial evaluated safety, tolerability and efficacy of evolocumab in 307 patients with high cholesterol who could not tolerate effective doses of at least two different statins due to muscle-related side effects. Patients were randomly assigned to one of four treatment groups: subcutaneous evolocumab 140 mg every two weeks and oral placebo daily; subcutaneous evolocumab 420 mg monthly and oral placebo daily; subcutaneous placebo every two weeks and oral ezetimibe 10 mg daily; or subcutaneous placebo monthly and oral ezetimibe 10 mg daily.

Safety was generally balanced across treatment groups. The most common adverse events (> 5 percent in evolocumab combined group) were headache (7.8 percent evolocumab; 8.8 percent ezetimibe), myalgia (7.8 percent evolocumab; 17.6 percent ezetimibe), pain in extremity (6.8 percent evolocumab; 1.0 percent ezetimibe), and muscle spasms (6.3 percent evolocumab; 3.9 percent ezetimibe).

Cholesterol-lowering treatment with a statin as part of follow-up care can help reduce a patient’s risk after myocardial infarction, ischaemic stroke or TIA.

The FOURIER Phase 3 clinical study http://www.fourierstudy.com/ seeks to find out whether lowering cholesterol by an additional 50% might reduce this risk even further. Several sites in the UK are part of this very large clinical study, lasting up to five years, and it is hoped that the study will help guide future clinical practice.

Evolocumab (also formerly known as AMG145, from Amgen) binds to PCSK9, a natural protein produced by the liver. By binding to PCSK9, evolocumab allows the LDL receptor (a protein present in the liver) to move LDL-cholesterol out of the bloodstream more efficiently. This study is designed to see whether treatment of dyslipidemia with evolocumab in people who have experienced a prior myocardial infarction, ischaemic stroke or TIA, and who are taking a highly effective dose of a statin, reduces the risk of recurring or additional cardiovascular events. Participants in this study have clinically evident cardiovascular disease.

READ AT

https://newdrugapprovals.org/2014/03/19/amgen-drug-evolocumab-hits-endpoint-of-cholesterol-reduction/

MY EARLIER ARTICLE

DR ANTHONY CRASTO

https://newdrugapprovals.org/

References

World Health Organization (2012). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 108” (PDF). WHO Drug Information 26 (4).
2
Sheridan, C (2013). “Phase 3 data for PCSK9 inhibitor wows”. Nature Biotechnology 31 (12): 1057–8. doi:10.1038/nbt1213-1057. PMID 24316621. edit
3
Statement On A Nonproprietary Name Adopted By The USAN Council – Evolocumab
4
Estel Grace Masangkay, “Amgen Phase III GAUSS-2 Trial of Evolocumab (AMG 145) Meets Co-Primary Endpoints Of LDL Cholesterol Reduction”, Bioresearch Online (January 24 2014)
5

Pierson, Ransdell (17 March 2014). “Amgen drug meets goal for those with high genetic cholesterol”. Associated Press. Retrieved 19 March 2014.

CS 3150, angiotensin II receptor antagonist, for the treatment or prevention of such hypertension and heart disease

March 13, 2015 4:50 am / 1 Comment on CS 3150, angiotensin II receptor antagonist, for the treatment or prevention of such hypertension and heart disease

CS-3150, (XL550)

CS 3150, angiotensin II receptor antagonist, for the treatment or prevention of such hypertension and heart disease similar to olmesartan , losartan, candesartan , valsartan, irbesartan, telmisartan, eprosartan,

Cas name 1H-Pyrrole-3-carboxamide, 1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-, (5S)-

CAS 1632006-28-0 for S conf

MF C₂₂ H₂₁ F₃ N₂ O₄ S

MW 466.47

(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

CAS 1632006-28-0 for S configuration

1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide

(S) -1- (2- hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide

(+/-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide, CAS 880780-76-7

(+)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide..1072195-82-4

(-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide..1072195-83-5

WO 2014168103

WO 2008126831

WO2008 / 126831 (US Publication US2010-0093826)http://www.google.co.in/patents/EP2133330A1?cl=en

WO 2015012205

WO 2006012642..compound A;..http://www.google.com/patents/WO2006012642A2?cl=en

WO2006 / 012642 (US Publication US2008-0234270)

WO 2015030010…http://www.google.com/patents/WO2015030010A1?cl=en

Originator Exelixis
Developer Daiichi Sankyo Company..

Daiichi Sankyo Company,Limited, 第一三共株式会社
Class Antihypertensives; Small molecules
Mechanism of Action Mineralocorticoid receptor antagonists

	Daiichi Sankyo Company,Limited, 第一三共株式会社

JAPAN PHASE 2……….Phase 2 Study to Evaluate Efficacy and Safety of CS-3150 in Patients with Essential Hypertension

http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-121921

Phase II Diabetic nephropathies; Hypertension

01 Jan 2015 Daiichi Sankyo initiates a phase IIb trial for Diabetic nephropathies in Japan (NCT02345057)
01 Jan 2015 Daiichi Sankyo initiates a phase IIb trial for Hypertension in Japan (NCT02345044)
01 May 2013 Phase-II clinical trials in Diabetic nephropathies in Japan (PO)
　Currently, angiotensin II receptor antagonists and calcium antagonists are widely used as a medicament for the treatment or prevention of such hypertension or heart disease.

　Mineralocorticoid receptor (MR) (aldosterone receptor) has been known to play an important role in the control of body electrolyte balance and blood pressure, spironolactone having a steroid structure, MR antagonists such as eplerenone, are known to be useful in the treatment of hypertension-heart failure.

　Renin – angiotensin II receptor antagonists are inhibitors of angiotensin system is particularly effective in renin-dependent hypertension, and show a protective effect against cardiovascular and renal failure. Also, the calcium antagonists, and by the function of the calcium channel antagonizes (inhibits), since it has a natriuretic action in addition to the vasodilating action, is effective for hypertension fluid retention properties (renin-independent) .

　Therefore, the MR antagonist, when combined angiotensin II receptor antagonists or calcium antagonists, it is possible to suppress the genesis of multiple hypertension simultaneously, therapeutic or prophylactic effect of the stable and sufficient hypertension irrespective of the etiology is expected to exhibit.

　Also, diuretics are widely used as a medicament for the treatment or prevention of such hypertension or heart disease. Diuretic agent is effective in the treatment of hypertension from its diuretic effect. Therefore, if used in combination MR antagonists and diuretics, the diuretic effect of diuretics, it is possible to suppress the genesis of multiple blood pressure at the same time, shows a therapeutic or prophylactic effect of the stable and sufficient hypertension irrespective of the etiology it is expected.

　1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide (hereinafter, compound ( I)) is, it is disclosed in Patent Documents 1 and 2, hypertension, for the treatment of such diabetic nephropathy are known to be useful.

CS-3150 (XL550) is a small-molecule antagonist of the mineralocorticoid receptor (MR), a nuclear hormone receptor implicated in a variety of cardiovascular and metabolic diseases. MR antagonists can be used to treat hypertension and congestive heart failure due to their vascular protective effects. Recent studies have also shown beneficial effects of adding MR antagonists to the treatment regimen for Type II diabetic patients with nephropathy. CS-3150 is a non-steroidal, selective MR antagonist that has the potential for the treatment of hypertension, congestive heart failure, or end organ protection due to vascular damage.

Useful as a mineralocorticoid receptor (MR) antagonist, for treating hypertension, cardiac failure and diabetic nephropathy. It is likely to be CS-3150, a non-steroidal MR antagonist, being developed by Daiichi Sankyo (formerly Sankyo), under license from Exelixis, for treating hypertension and diabetic nephropathy (phase 2 clinical, as of March 2015). In January 2015, a phase II trial for type 2 diabetes mellitus and microalbuminuria was planned to be initiated later that month (NCT02345057).

Exelixis discovered CS-3150 and out-licensed the compound to Daiichi-Sankyo. Two phase 2a clinical trials, one in hypertensive patients and the other in type 2 diabetes with albuminuria, are currently being conducted in Japan by Daiichi-Sankyo.

Mineralocorticoid receptor (MR) (aldosterone receptor) has been known to play an important role in the control of body electrolyte balance and blood pressure, spironolactone having a steroid structure, MR antagonists such as eplerenone, are known to be useful in the treatment of hypertension-heart failure.

Daiichi Sankyo (formerly Sankyo), under license from Exelixis, is developing CS-3150 (XL-550), a non-steroidal mineralocorticoid receptor (MR) antagonist, for the potential oral treatment of hypertension and diabetic nephropathy, microalbuminuria , By October 2012, phase II development had begun ; in May 2014, the drug was listed as being in phase IIb development . In January 2015, a phase II trial for type 2 diabetes mellitus and microalbuminuria was planned to be initiated later that month. At that time, the trial was expected to complete in March 2017 .

Exelixis, following its acquisition of X-Ceptor Therapeutics in October 2004 , was investigating the agent for the potential treatment of metabolic disorders and cardiovascular diseases, such as hypertension and congestive heart failure . In September 2004, Exelixis expected to file an IND in 2006. However, it appears that the company had fully outlicensed the agent to Sankyo since March 2006 .

Description	Small molecule antagonist of the mineralocorticoid receptor (MR)
Molecular Target	Mineralocorticoid receptor
Mechanism of Action	Mineralocorticoid receptor antagonist
Therapeutic Modality	Small molecule

In January 2015, a multi-center, placebo-controlled, randomized, 5-parallel group, double-blind, phase II trial (JapicCTI-152774; NCT02345057; CS3150-B-J204) was planned to be initiated later that month in Japan, in patients with type 2 diabetes mellitus and microalbuminuria, to assess the efficacy and safety of different doses of CS-3150 compared to placebo. At that time, the trial was expected to complete in March 2017; later that month, the trial was initiated in the Japan

By October 2012, phase II development had begun in patients with essential hypertension

By January 2011, phase I trials had commenced in Japan

Several patents WO-2014168103,

WO-2015012205 and WO-2015030010

XL-550, claimed in WO-2006012642,

………………………………………………………………….

http://www.google.co.in/patents/EP2133330A1?cl=en

(Example 3)(+/-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

After methyl 4-methyl-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxylate was obtained by the method described in Example 16 of WO 2006/012642 , the following reaction was performed using this compound as a raw material.
Methyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (1.4 g, 4.9 mmol) was dissolved in methanol (12 mL), and a 5 M aqueous sodium hydroxide solution (10 mL) was added thereto, and the resulting mixture was heated under reflux for 3 hours. After the mixture was cooled to room temperature, formic acid (5 mL) was added thereto to stop the reaction. After the mixture was concentrated under reduced pressure, water (10 mL) was added thereto to suspend the resulting residue. The precipitated solid was collected by filtration and washed 3 times with water. The obtained solid was dried under reduced pressure, whereby 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (1.1 g, 83%) was obtained as a solid. The thus obtained solid was suspended in dichloromethane (10 mL), oxalyl chloride (0.86 mL, 10 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 2 hours. After the mixture was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL), and 4-(methylsulfonyl)aniline hydrochloride (1.0 g, 4.9 mmol) and N,N-diisopropylethylamine (2.8 mL, 16 mmol) were sequentially added to the solution, and the resulting mixture was heated under reflux for 18 hours. After the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and acetonitrile (10 mL) and 3 M hydrochloric acid (100 mL) were added to the residue. A precipitated solid was triturated, collected by filtration and washed with water, and then, dried under reduced pressure, whereby 4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (1.4 g, 89%) was obtained as a solid.
¹H-NMR (400 MHz, DMSO-d6) δ11.34 (1H, brs,), 9.89 (1H, s), 7.97 (2H, d, J = 6.6 Hz), 7.87-7.81 (3H, m), 7.73 (1H, t, J = 7.4 Hz), 7.65-7.61 (2H, m), 7.44 (1H, d, J = 7.8 Hz), 3.15 (3H, s), 2.01 (3H, s).
Sodium hydride (0.12 g, 3 mmol, 60% dispersion in mineral oil) was dissolved in N,N-dimethylformamide (1.5 mL), and 4-methyl -N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (0.47 g, 1.1 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (0.14 g, 1.2 mmol) was added thereto, and the resulting mixture was stirred at room temperature. After 1 hour, sodium hydride (40 mg, 1.0 mmol, oily, 60%) was added thereto again, and the resulting mixture was stirred for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (12 mg, 0.11 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration, and the filtrate was concentrated again. To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added, and the resulting mixture was stirred at 60°C for 16 hours. The reaction was cooled to room temperature, and then dissolved in ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained.
¹H-NMR (400 MHz, CDCl₃) δ: 7.89-7.79 (m, 6H), 7.66-7.58 (m, 2H), 7.49 (s, 1H), 7.36 (d, 1H, J = 7.4Hz), 3.81-3.63 (m, 4H), 3.05 (s, 3H), 2.08 (s, 3H).
HR-MS (ESI) calcd for C₂₂H₂₂F₃N₂O₄S [M+H]⁺, required m/z: 467.1252, found: 467.1246.
Anal. calcd for C₂₂H₂₁F₃N₂O₄S: C, 56.65; H, 4.54; N, 6.01; F, 12.22; S, 6.87. found: C, 56.39; H, 4.58; N, 5.99; F, 12.72; S, 6.92.

(Example 4)

Optical Resolution of Compound of Example 3

Resolution was performed 4 times in the same manner as in Example 2, whereby 74 mg of Isomer C was obtained as a solid from a fraction containing Isomer C (t_R = 10 min), and 71 mg of Isomer D was obtained as a solid from a fraction containing Isomer D (t_R = 11 min).
Isomer C: (+)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide
[α]_D ²¹: +7.1° (c = 1.0, EtOH) .
¹H-NMR (400 MHz, CDCl₃) δ: 7.91 (s, 1H), 7.87-7.79 (m, 5H), 7.67-7.58 (m, 2H), 7.51 (s, 1H), 7.35 (d, 1H, J = 7.0 Hz), 3.78-3.65 (m, 4H), 3.05 (s, 3H), 2.07 (s, 3H).
HR-MS (ESI) calcd for C₂₂H₂₂F₃N₂O₄S [M+H]⁺, required m/z: 467.1252, found: 467.1260.
Retention time: 4.0 min.
Isomer D: (-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide
[α]_D ²¹: -7.2° (c = 1.1, EtOH) .
¹H-NMR (400 MHz, CDCl₃) δ: 7.88-7.79 (m, 6H), 7.67-7.58 (m, 2H), 7.50 (s, 1H), 7.36 (d, 1H, J = 7.5 Hz), 3.79-3.65 (m, 4H), 3.05 (s, 3H), 2.08 (s, 3H).
HR-MS (ESI) calcd for C₂₂H₂₂F₃N₂O₄S [M+H]⁺, required m/z: 467.1252, found: 467.1257.
Retention time: 4.5 min.

……………………………………………….

WO 2014168103

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014168103

　Step B: pyrrole derivative compounds (A ‘)

[Of 16]

(Example 1) 2-bromo-1- [2- (trifluoromethyl) phenyl] propan-1-one

[Of 19]

　1- [2- (trifluoromethyl) phenyl] propan-1-one 75 g (370 mmol) in t- butyl methyl ether (750 mL), and I was added bromine 1.18 g (7.4 mmol). After confirming that the stirred bromine color about 30 minutes at 15 ~ 30 ℃ disappears, cooled to 0 ~ 5 ℃, was stirred with bromine 59.13 g (370 mmol) while keeping the 0 ~ 10 ℃. After stirring for about 2.5 hours, was added while maintaining 10 w / v% aqueous potassium carbonate solution (300 mL) to 0 ~ 25 ℃, was further added sodium sulfite (7.5 g), was heated to 20 ~ 30 ℃. The solution was separated, washed in the resulting organic layer was added water (225 mL), to give t- butyl methyl ether solution of the title compound and the organic layer was concentrated under reduced pressure (225 mL).

　¹ H NMR (400 MHz, CDCl ₃ ) delta: 1.91 (3H, D, J = 4.0 Hz), 4.97 (1H, Q, J = 6.7 Hz), 7.60 ~ 7.74 (4H, M).

(Example 2) 2-cyano-3-methyl-4-oxo-4- [2- (trifluoromethyl) phenyl] butanoate

[Of 20]

　2-bromo-1- [2- (trifluoromethyl) phenyl] propan-1 / t- butyl methyl ether solution (220 mL) in dimethylacetamide (367 mL), ethyl cyanoacetate obtained in Example 1 53.39 g (472 mmol), potassium carbonate 60.26 g (436 mmol) were sequentially added, and the mixture was stirred and heated to 45 ~ 55 ℃. After stirring for about 2 hours, 20 is cooled to ~ 30 ℃, water (734 mL) and then extracted by addition of toluene (367 mL), washed by adding water (513 mL) was carried out in the organic layer (2 times implementation). The resulting organic layer was concentrated under reduced pressure to obtain a toluene solution of the title compound (220 mL).

　¹ H NMR (400 MHz, CDCl ₃ ) delta: 1.33 ~ 1.38 (6H, M), 3.80 ~ 3.93 (2H, M), 4.28 ~ 4.33 (2H, M), 7.58 ~ 7.79 (4H, M).

(Example 3) 2-chloro-4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl

[Of 21]

　The 20 ~ 30 ℃ 2-cyano-3-methyl-4-oxo-4 was obtained [2- (trifluoromethyl) phenyl] butanoate in toluene (217 mL) by the method of Example 2 ethyl acetate (362 mL) Te, after the addition of thionyl chloride 42.59 g (358 mmol), cooled to -10 ~ 5 ℃, was blown hydrochloric acid gas 52.21 g (1432 mmol), further concentrated sulfuric acid 17.83 g (179 mmol) was added, and the mixture was stirred with hot 15 ~ 30 ℃. After stirring for about 20 hours, added ethyl acetate (1086 mL), warmed to 30 ~ 40 ℃, after the addition of water (362 mL), and the layers were separated. after it separated organic layer water (362 mL) was added for liquid separation, and further 5w / v% was added for liquid separation aqueous sodium hydrogen carbonate solution (362 mL).

　Subsequently the organic layer was concentrated under reduced pressure, the mixture was concentrated under reduced pressure further added toluene (579 mL), was added toluene (72 mL), and cooled to 0 ~ 5 ℃. After stirring for about 2 hours, the precipitated crystals were filtered, and washed the crystals with toluene which was cooled to 0 ~ 5 ℃ (217 mL). The resulting wet goods crystals were dried under reduced pressure at 40 ℃, the title compound was obtained (97.55 g, 82.1% yield).

　¹ H NMR (400 MHz, CDCl ₃ ) delta: 1.38 (3H, t, J = 7.1 Hz), 2.11 (3H, s), 4.32 (2H, Q, J = 7.1 Hz), 7.39 (1H, D, J = 7.3 Hz), 7.50 ~ 7.62 (2H, m), 7.77 (1H, d, J = 8.0 Hz), 8.31 (1H, br).

(Example 4) 4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl

[Of 22]

　Example obtained by the production method of the three 2-chloro-4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylate 97.32 g (293 mmol) in ethanol (662 mL), tetrahydrofuran (117 mL), water (49 mL), sodium formate 25.91 g (381 mmol) and 5% palladium – carbon catalyst (water content 52.1%, 10.16 g) was added at room temperature, heated to 55 ~ 65 ℃ the mixture was stirred. After stirring for about 1 hour, cooled to 40 ℃ less, tetrahydrofuran (97 mL) and filter aid (KC- flock, Nippon Paper Industries) 4.87 g was added, the catalyst was filtered and the residue using ethanol (389 mL) was washed. The combined ethanol solution was used for washing the filtrate after concentration under reduced pressure, and with the addition of water (778 mL) was stirred for 0.5 hours at 20 ~ 30 ℃. The precipitated crystals were filtered, and washed the crystals with ethanol / water = 7/8 solution was mixed with (292 mL). The resulting wet goods crystals were dried under reduced pressure at 40 ℃, the title compound was obtained (86.23 g, 98.9% yield).

　¹ H NMR (400 MHz, CDCl ₃ ) delta: 1.35 (3H, t, J = 7.1 Hz), 2.18 (3H, s), 4.29 (2H, M), 7.40 ~ 7.61 (4H, M), 7.77 (1H, d, J = 7.9 Hz), 8.39 (1H, br).

(Example 5) (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl

[Of 23]

　N to the fourth embodiment of the manufacturing method by the resulting 4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylate 65.15 g (219 mmol), N- dimethylacetamide ( 261 mL), ethylene carbonate 28.95 g (328.7 mmol), 4- dimethylaminopyridine 2.68 g (21.9 mmol) were sequentially added at room temperature, and heated to 105 ~ 120 ℃, and the mixture was stirred. After stirring for about 10 hours, toluene was cooled to 20 ~ 30 ℃ (1303 mL), and the organic layer was extracted by adding water (326 mL). Subsequently, was washed by adding water (326 mL) to the organic layer (three times). The resulting organic layer was concentrated under reduced pressure, ethanol (652 mL) was added, and was further concentrated under reduced pressure, ethanol (130 mL) was added to obtain an ethanol solution of the title compound (326 mL).

　¹ H NMR (400 MHz, CDCl ₃ ) delta: 1.35 (3H, t, J = 7.1 Hz), 1.84 (1H, Broad singlet), 2.00 (3H, s), 3.63 ~ 3.77 (4H, M), 4.27 (2H , m), 7.35 ~ 7.79 (5H, m).

(Example 6) (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid

[Of 24]

　Obtained by the method of Example 5 (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl / ethanol (321 mL) solution in water (128.6 mL), was added at room temperature sodium hydroxide 21.4 g (519 mmol), and stirred with heating to 65 ~ 78 ℃. After stirring for about 6 hours, cooled to 20 ~ 30 ℃, after the addition of water (193 mL), and was adjusted to pH 5.5 ~ 6.5, while maintaining the 20 ~ 30 ℃ using 6 N hydrochloric acid. was added as seed crystals to the pH adjustment by a liquid (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid 6.4 mg , even I was added to water (193mL). Then cooled to 0 ~ 5 ℃, again, adjusted to pH 3 ~ 4 with concentrated hydrochloric acid and stirred for about 1 hour. Then, filtered crystals are precipitated, and washed the crystals with 20% ethanol water is cooled to 0 ~ 5 ℃ (93 mL). The resulting wet product crystals were dried under reduced pressure at 40 ℃, to give the title compound (64.32 g, 95.0% yield). ¹ H NMR (400 MHz, DMSO-D ₆ ) delta: 1.87 (3H, s), 3.38 ~ 3.68 (4H, M), 7.43 ~ 7.89 (5H, M).

(Example 7)

(S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid quinine salt
(7-1) (S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid quinine salt
obtained by the method of Example 6 the (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid 50.00 g (160 mmol), N, N- dimethylacetamide (25 mL), ethyl acetate (85 mL) was added and dissolved at room temperature (solution 1).

　Quinine 31.05 g (96 mmol) in N, N- dimethylacetamide (25 mL), ethyl acetate (350 mL), was heated in water (15 mL) 65 ~ 70 ℃ was added, was added dropwise a solution 1. After about 1 hour stirring the mixture at 65 ~ 70 ℃, and slowly cooled to 0 ~ 5 ℃ (cooling rate standard: about 0.3 ℃ / min), and stirred at that temperature for about 0.5 hours. The crystals were filtered, 5 ℃ using ethyl acetate (100 mL) which was cooled to below are washed crystals, the resulting wet product crystals was obtained and dried under reduced pressure to give the title compound 43.66 g at 40 ℃ (Yield 42.9%). Furthermore, the diastereomeric excess of the obtained salt was 98.3% de. ¹ H NMR (400 MHz, DMSO-D ₆ ) delta: 1.30 ~ 2.20 (10H, M), 2.41 ~ 2.49 (2H, M), 2.85 ~ 3.49 (6H, M), 3.65 ~ 3.66 (1H, M), 3.88 (3H, s), 4.82 (1H, broad singlet), 4.92 ~ 5.00 (2H, m), 5.23 ~ 5.25 (1H, m), 5.60 (1H, br), 5.80 ~ 6.00 (1H, m), 7.36 ~ 7.92 (9H, M), 8.67 (1H, D, J = 4.6 Hz) (7-2) (S)-1-(2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3 diastereomeric excess of the carboxylic acid quinine salt HPLC measurements (% de) 　that the title compound of about 10 mg was collected, and the 10 mL was diluted with 50v / v% aqueous acetonitrile me was used as a sample solution.

　Column: DAICEL CHIRALPAK IC-3 (4.6 mmI.D. × 250 mm, 3 μm)
mobile phase A: 0.02mol / L phosphorus vinegar buffer solution (pH 3)
mobile phase B: acetonitrile
solution sending of mobile phase: mobile phase A and I indicates the mixing ratio of mobile phase B in Table 1 below.

[Table 1]

　　Detection: UV 237 nm
flow rate: about 0.8 mL / min
column temperature: 30 ℃ constant temperature in the vicinity of
measuring time: about 20 min
Injection volume: 5 μL
diastereomeric excess (% de), the title compound (retention time about 12 min), was calculated by the following equation using a peak area ratio of R-isomer (retention time of about 13 min).
% De = {[(the title compound (S body) peak area ratio) – (R body peak area ratio)] ÷ [(the title compound (S body) peak area ratio) + (R body peak area ratio)]} × 100

(Example 8)

(S) -1- (2- hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole 3-carboxamide (Compound (A))
(8-1) (S)-1-(2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole -3 – carboxylic acid
obtained by the method of Example 7 (S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid (8α, 9R) -6′- methoxycinnamate Conan-9-ol 40.00 g (63 mmol) in ethyl acetate (400 mL), was added 2N aqueous hydrochloric acid (100 mL) was stirred at room temperature and separated . The resulting organic layer was concentrated under reduced pressure (120 mL), and added ethyl acetate (200 mL), and further concentrated under reduced pressure to obtain a solution containing the title compound (120 mL).

(8-2) N – {[4- (methylsulfonyl) phenyl] amino} oxamic acid 2 – ((S) -3- methyl-4 – {[4- (methylsulfonyl) phenyl] carbamoyl} -2- [ 2- (trifluoromethyl) phenyl] -1H- pyrrol-1-yl) ethyl
ethyl acetate (240 mL), was mixed tetrahydrofuran (80 mL) and oxalyl chloride 20.72 g (163 mmol), and cooled to 10 ~ 15 ℃ was. Then the resulting solution was added while keeping the 10 ~ 15 ℃ Example (8-1) and stirred for about 1 hour by heating to 15 ~ 20 ℃. After stirring, acetonitrile (120 mL) and pyridine 2.46 g (31 mmol) was added and the reaction mixture was concentrated under reduced pressure (120 mL), acetonitrile (200 mL) was added and further concentrated under reduced pressure (120 mL).

　After completion concentration under reduced pressure, acetonitrile (200 mL) was added and cooled to 10 ~ 15 ℃ (reaction 1).

　Acetonitrile (240mL), pyridine 12.39 g (157 mmol), 4- were successively added (methylsulfonyl) aniline 26.85 g (157 mmol), the reaction solution 1 was added while maintaining the 10 ~ 15 ℃, the 20 ~ 25 ℃ and the mixture was stirred and heated to about 1 hour.

　The resulting reaction solution in acetonitrile (40 mL), 2 N hydrochloric acid water (120 mL), was added sodium chloride (10.0 g) was stirred, and the layers were separated. Again, 2N aqueous hydrochloric acid to the organic layer (120 mL), was added sodium chloride (10.0 g) was stirred, and the layers were separated. After filtering the resulting organic layer was concentrated under reduced pressure (400 mL). Water (360 mL) was added to the concentrated liquid, after about 1 hour stirring, the crystals were filtered, washed with 50v / v% aqueous acetonitrile (120 mL), wet product of the title compound (undried product, 62.02 g) and obtained. ¹ H NMR (500 MHz, DMSO-D ₆ ) delta: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.81 (t, 1H), 4.12 (t, 1H), 4.45 ( t, 2H, J = 5.81 Hz), 7.62 (t, 1H, J = 4.39 Hz), 7.74 (t, 2H, J = 3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J = 6.94 , 2.13 Hz), 7.97 (DD, 2H, J = 6.80, 1.98 Hz), 8.02 (DD, 2H), 10.03 (s, 1H), 11.19 (s, 1H)

(8-3) (S)-1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide (Compound (A)) 　( the resulting wet product crystals 8-2), t- butyl methyl ether (200 mL), acetonitrile (40 mL), 48w / w potassium hydroxide aqueous solution (16 g) and water (200 mL) was added, I was stirred for about 2 hours at 25 ~ 35 ℃. After stirring, and the mixture is separated, the resulting organic layer was concentrated under reduced pressure (120 mL), ethanol (240 mL) was added and further concentrated under reduced pressure (120 mL). After completion concentration under reduced pressure, ethanol (36 mL), and heated in water (12 mL) was added 35 ~ 45 ℃, while maintaining the 35 ~ 45 ℃ was added dropwise water (280 mL), and was crystallized crystals. After cooling the crystal exudates to room temperature, I was filtered crystal. Then washed with crystals 30v / v% aqueous ethanol solution (80 mL), where it was dried under reduced pressure at 40 ℃, the title compound was obtained in crystalline (26.26 g, 89.7% yield). Moreover, the enantiomers of the resulting crystals was 0.3%.

¹ H NMR (400 MHz, CDCl ₃ ) delta: 1.74 (1H, Broad singlet), 2.08 (3H, s), 3.04 (3H, s), 3.63 ~ 3.80 (4H, M), 7.36 (1H, D, J = 7.2 Hz), 7.48 (1H, s), 7.58 ~ 7.67 (2H, M), 7.77 ~ 7.90 (6H, M).

(8-4) (S)-1-(2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole -3- HPLC method for measuring the amount enantiomer carboxamide (%) 　and collected the title compound of about 10 mg is, what was the 10 mL was diluted with 50v / v% aqueous acetonitrile to obtain a sample solution.

see

(Example 12) (S) -1- (2- hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole 3-carboxamide (Compound (A)) Preparation of 2

(12-1) (S)-1-(2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H – pyrrole-3-carboxylic acid
obtained by the method of Example 7 (S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole 3-carboxylic acid (8α, 9R) -6′- methoxycinnamate Conan-9-ol 10.00 g (16 mmol) in t- butyl methyl ether (90 mL), water (10 mL) 36w / w% aqueous hydrochloric acid ( 5 mL) was added and stirring at room temperature and separated. The resulting organic layer was concentrated under reduced pressure (30 mL), was added ethyl acetate (50 mL), and further concentrated under reduced pressure to obtain a solution containing the title compound (30 mL).

(12-2) N – {[4- (methylsulfonyl) phenyl] amino} oxamic acid 2 – ((S) -3- methyl-4 – {[4- (methylsulfonyl) phenyl] carbamoyl} -2- [ 2- (trifluoromethyl) phenyl] -1H- pyrrol-1-yl) ethyl
ethyl acetate (50 mL), was mixed with tetrahydrofuran (20 mL) and oxalyl chloride 5.18 g (41 mmol), and cooled to 0 ~ 5 ℃ was.Then the resulting solution was added in Examples while maintaining the 0 ~ 5 ℃ (12-1), and the mixture was stirred for 6 hours at 0 ~ 10 ℃. After stirring, acetonitrile (30 mL) and pyridine 0.62 g (8 mmol) was added and the reaction mixture was concentrated under reduced pressure (30 mL), acetonitrile (50 mL) was added, and further concentrated under reduced pressure (30 mL).

　After concentration under reduced pressure end, is added acetonitrile (10 mL) and oxalyl chloride 0.10 g (1 mmol), and cooled to 0 ~ 5 ℃ (reaction 1).

　Acetonitrile (30mL), pyridine 3.15 g (40 mmol), 4- were successively added (methylsulfonyl) aniline 6.71 g (39 mmol), the reaction solution 1 was added while maintaining the 10 ~ 15 ℃, the 20 ~ 25 ℃ and the mixture was stirred and heated to about 1 hour.

　Insolubles from the resulting reaction solution was filtered, washed with acetonitrile (10 mL), and stirred for about 2 hours the addition of water (15 mL), followed by dropwise addition of water (75 mL) over about 1 hour . After about 1 hour stirring the suspension was filtered crystals were washed with 50v / v% aqueous acetonitrile (20 mL), wet product of the title compound (undried product, 15.78 g) to give a. ¹ H NMR (500 MHz, DMSO-D ₆ ) delta: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.81 (t, 1H), 4.12 (t, 1H), 4.45 ( t, 2H, J = 5.81 Hz), 7.62 (t, 1H, J = 4.39 Hz), 7.74 (t, 2H, J = 3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J = 6.94 , 2.13 Hz), 7.97 (DD, 2H, J = 6.80, 1.98 Hz), 8.02 (DD, 2H), 10.03 (s, 1H), 11.19 (s, 1H)

(12-3) (S)-1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide (Compound (A)) 　( the resulting wet product crystals 12-2), t- butyl methyl ether (50 mL), acetonitrile (10 mL), 48w / w potassium hydroxide aqueous solution (4 g) and water (50 mL) was added, 15 I was about 2 hours of stirring at ~ 25 ℃. After stirring, and the mixture is separated, the resulting organic layer was concentrated under reduced pressure (30 mL), was added ethanol (60 mL), was further concentrated under reduced pressure (30 mL). After completion concentration under reduced pressure, ethanol (14 mL), after addition of water (20 mL), was added a seed crystal, and was crystallized crystals. After dropwise over about 1 hour water (50 mL), and about 1 hour stirring, and crystals were filtered off. Then washed with crystals 30v / v% aqueous ethanol solution (10 mL), where it was dried under reduced pressure at 40 ℃, the title compound was obtained in crystal (6.36 g, 87.0% yield). Moreover, the enantiomers of the resulting crystals was 0.05%. Enantiomers amount, I was measured by the method of (Example 8-4). ¹ H NMR (400 MHz, CDCl ₃ ) delta: 1.74 (1H, Broad singlet), 2.08 (3H, s), 3.04 (3H, s), 3.63 ~ 3.80 (4H, M), 7.36 (1H, D, J = 7.2 Hz), 7.48 (1H, s), 7.58 ~ 7.67 (2H, m), 7.77 ~ 7.90 (6H, m).

………………………………………………

Patent literature

Patent Document 1: International Publication WO2006 / 012642 (US Publication US2008-0234270)
Patent Document 2: International Publication WO2008 / 056907 (US Publication US2010-0093826)
Patent Document 3: Pat. No. 2,082,519 JP (US Patent No. 5,616,599 JP)
Patent Document 4: Pat. No. 1,401,088 JP (US Pat. No. 4,572,909)
Patent Document 5: US Pat. No. 3,025,292

Angiotensin II receptor 桔抗 agent

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015012205&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Angiotensin II receptor 桔抗 agent used as the component (A), olmesartan medoxomil, olmesartan cilexetil, losartan, candesartan cilexetil, valsartan, biphenyl tetrazole compounds such as irbesartan, biphenyl carboxylic acid compounds such as telmisartan, eprosartan, agile Sultan, and the like, preferably, a biphenyl tetrazole compound, more preferably, olmesartan medoxomil, is losartan, candesartan cilexetil, valsartan or irbesartan, particularly preferred are olmesartan medoxomil, losartan or candesartan cilexetil, Most preferably, it is olmesartan medoxomil.

　Olmesartan medoxomil, JP-A-5-78328, US Patent No. 5,616,599
is described in Japanese or the like, its chemical name is (5-methyl-2-oxo-1,3-dioxolen-4-yl ) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1 – in [2 ‘(1H- tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate, Yes, olmesartan medoxomil of the present application includes its pharmacologically acceptable salt.

OLMESARTAN

　Losartan (DUP-753) is, JP 63-23868, is described in US Patent No. 5,138,069 JP like, and its chemical name is 2-butyl-4-chloro-1- [2 ‘ – The (1H- tetrazol-5-yl) biphenyl-4-ylmethyl] -1H- is imidazol-5-methanol, application of losartan includes its pharmacologically acceptable salt (losartan potassium salt, etc.).

LOSARTAN

　Candesartan cilexetil, JP-A-4-364171, EP-459136 JP, is described in US Patent No. 5,354,766 JP like, and its chemical name is 1- (cyclohexyloxycarbonyloxy) ethyl-2 ethoxy-1- [2 ‘one (1H- tetrazol-5-yl) -4-Bife~eniru ylmethyl] -1H- benzimidazole-7-carboxylate is a salt application of candesartan cilexetil, which is a pharmacologically acceptable encompasses.

　Valsartan (CGP-48933), the JP-A-4-159718, are described in EP-433983 JP-like, and its chemical name, (S) -N- valeryl -N- [2 ‘- (1H- tetrazol – It is a 5-yl) biphenyl-4-ylmethyl) valine, valsartan of the present application includes its pharmacologically acceptable ester or a pharmacologically acceptable salt thereof.

　Irbesartan (SR-47436), the Japanese Patent Publication No. Hei 4-506222, is described in JP WO91-14679 publication, etc., its chemical name, 2-N–butyl-4-spiro cyclopentane-1- [2′ The (tetrazol-5-yl) biphenyl-4-ylmethyl] -2-imidazoline-5-one, irbesartan of the present application includes its pharmacologically acceptable salts.

　Eprosartan (SKB-108566) is described in US Patent No. 5,185,351 JP etc., the chemical name, 3- [1- (4-carboxyphenyl-methyl) -2-n- butyl – imidazol-5-yl] The 2-thienyl – methyl-2-propenoic acid, present in eprosartan, the carboxylic acid derivatives, pharmacologically acceptable ester or a pharmacologically acceptable salt of a carboxylic acid derivative (eprosartan mesylate, encompasses etc.).

　Telmisartan (BIBR-277) is described in US Patent No. 5,591,762 JP like, and its chemical name is 4 ‘- [[4 Mechiru 6- (1-methyl-2-benzimidazolyl) -2 – is a propyl-1-benzimidazolyl] methyl] -2-biphenylcarboxylic acid, telmisartan of the present application includes its carboxylic acid derivative, a pharmacologically acceptable ester or a pharmacologically acceptable salt thereof of carboxylic acid derivatives .

　Agile Sultan, is described in Patent Publication No. 05-271228 flat JP, US Patent No. 5,243,054 JP like, and its chemical name is 2-ethoxy-1 {[2 ‘- (5-oxo-4,5-dihydro 1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl} -1H- benzo [d] imidazole-7-carboxylic acid (2-Ethoxy-1 {[2 ‘- (5- oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] is a methyl} -1H-benzo [d] imidazole-7-carboxylic acid).

Vibegron ビベグロン

October 6, 2014 7:30 am / Leave a comment

Chemical structure for Vibegron (USAN)

Vibegron, MK-4618, KRP 114V

update FDA APPROVED 12/23/2020, GEMTESA, To treat overactive bladder

UNII-M5TSE03W5U; M5TSE03W5U; D10433

1190389-15-1; cas no

Molecular Formula: C₂₆H₂₈N₄O₃ Molecular Weight: 444.52552

Merck Sharp & Dohme Corp. INNOVATOR

phase 2 for the treatment of overactive bladder

(6S)-N-[4-([(2S,5R)-5-[(R)-Hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide

(6S)-N-[4-[[(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidine-6-carboxamide

Target-based Actions Beta 3 adrenoceptor agonist
Indications Overactive bladder; Urinary incontinence

UPDATE 2018/9/21 pmda Beova JAPAN 2018Kyorin Pharmaceutical, under license from Merck, is developing vibegron (phase II, September 2014) for the treating of overactive bladder. In July 2014, Merck has granted to Kyorin an exclusive license to develop, manufacture and commercialize vibegron in Japan.

MK-4618 is being developed in phase II clinical trials at Merck & Co. for the treatment of overactive bladder. The company had been developing the compound for the treatment of endocrine disorders and hypertension; however, recent progress reports are not available at present.

In 2014, Merck licensed the product to Kyorin for development and commercialization in Japan.

The function of the lower urinary tract is to store and periodically release urine. This requires the orchestration of storage and micturition reflexes which involve a variety of afferent and efferent neural pathways, leading to modulation of central and peripheral neuroeffector mechanisms, and resultant coordinated regulation of sympathetic and parasympathetic components of the autonomic nervous system as well as somatic motor pathways. These proximally regulate the contractile state of bladder (detrusor) and urethral smooth muscle, and urethral sphincter striated muscle.

β Adrenergic receptors (βAR) are present in detrusor smooth muscle of various species, including human, rat, guinea pig, rabbit, ferret, dog, cat, pig and non-human primate. However, pharmacological studies indicate there are marked species differences in the receptor subtypes mediating relaxation of the isolated detrusor; β1AR predominate in cats and guinea pig, β2AR predominate in rabbit, and β3AR contribute or predominate in dog, rat, ferret, pig, cynomolgus and human detrusor. Expression of βAR subtypes in the human and rat detrusor has been examined by a variety of techniques, and the presence of β3AR was confirmed using in situ hybridization and/or reverse transcription-polymerase chain reaction (RT-PCR). Real time quantitative PCR analyses of β1AR, β2AR and β3AR mRNAs in bladder tissue from patients undergoing radical cystectomy revealed a preponderance of β3AR mRNA (97%, cf 1.5% for β1AR mRNA and 1.4% for β2AR mRNA). Moreover, β3AR mRNA expression was equivalent in control and obstructed human bladders. These data suggest that bladder outlet obstruction does not result in downregulation of β3AR, or in alteration of β3AR-mediated detrusor relaxation. β3AR responsiveness also has been compared in bladder strips obtained during cystectomy or enterocystoplasty from patients judged to have normal bladder function, and from patients with detrusor hyporeflexia or hyperreflexia. No differences in the extent or potency of β3AR agonist mediated relaxation were observed, consistent with the concept that the β3AR activation is an effective way of relaxing the detrusor in normal and pathogenic states.

Functional evidence in support of an important role for the β3AR in urine storage emanates from studies in vivo. Following intravenous administration to rats, the rodent selective β3AR agonist CL316243 reduces bladder pressure and in cystomeric studies increases bladder capacity leading to prolongation of micturition interval without increasing residual urine volume.

Overactive bladder is characterized by the symptoms of urinary urgency, with or without urgency urinary incontinence, usually associated with frequency and nocturia. The prevalence of OAB in the United States and Europe has been estimated at 16 to 17% in both women and men over the age of 18 years. Overactive bladder is most often classified as idiopathic, but can also be secondary to neurological condition, bladder outlet obstruction, and other causes. From a pathophysiologic perspective, the overactive bladder symptom complex, especially when associated with urge incontinence, is suggestive of detrusor overactivity. Urgency with or without incontinence has been shown to negatively impact both social and medical well-being, and represents a significant burden in terms of annual direct and indirect healthcare expenditures. Importantly, current medical therapy for urgency (with or without incontinence) is suboptimal, as many patients either do not demonstrate an adequate response to current treatments, and/or are unable to tolerate current treatments (for example, dry mouth associated with anticholinergic therapy). Therefore, there is need for new, well-tolerated therapies that effectively treat urinary frequency, urgency and incontinence, either as monotherapy or in combination with available therapies. Agents that relax bladder smooth muscle, such as β3AR agonists, are expected to be effective for treating such urinary disorders.

PATENT

http://www.google.com/patents/WO2013062881A1?cl=en

Figure imgf000013_0001

EXAMPLE 3

To a three neck flask equipped with a N₂ inlet, a thermo couple probe was charged pyrrolidine i-11 (10.0 g), sodium salt i-12 (7.87 g), followed by IPA (40 mL) and water (24 mL). 5 N HC1 (14.9 mL) was then slowly added over a period of 20 min to adjust pH = 3.3- 3.5, maintaining the batch temperature below 35 °C. Solid EDC hydrochloride (7.47 g) was charged in portions over 30 min. The reaction mixture was aged at RT for additional 0.5 – 1 h, aqueous ammonia (14%) was added dropwise to pH ~8.6. The batch was seeded and aged for additional 1 h to form a slurry bed. The rest aqueous ammonia (14%, 53.2 ml total) was added dropwise over 6 h. The resulting thick slurry was aged 2-3 h before filtration. The wet-cake was displacement washed with 30% IPA (30 mL), followed by 15% IPA (2 x 20mL) and water (2 X 20mL). The cake was suction dried under N₂ overnight to afford 14.3 g of compound of Formula (I)-

1H NMR (DMSO) δ 10.40 (s, NH), 7.92 (d, J = 6.8, 1H), 7.50 (m, 2H), 7.32 (m, 2H), 7.29 (m, 2H), 7.21 (m, 1H), 7.16 (m, 2H), 6.24 (d, J = 6.8, 1H), 5.13 (dd, J = 9.6, 3.1, 1H), 5.08 (br s, OH), 4.22 (d, J = 7.2, 1H), 3.19 (p, J = 7.0, 1H), 3.16-3.01 (m, 3H), 2.65 (m, 1H), 2.59-2.49 (m, 2H), 2.45 (br s, NH), 2.16 (ddt, J = 13.0, 9.6, 3.1, 1H), 1.58 (m, 1H), 1.39 (m, 1H), 1.31-1.24 (m, 2H).

¹³C NMR (DMSO) δ 167.52, 165.85, 159.83, 154.56, 144.19, 136.48, 135.66, 129.16, 127.71, 126.78, 126.62, 119.07, 112.00, 76.71, 64.34, 61.05, 59.60, 42.22, 31.26, 30.12, 27.09, 23.82.

HPLC method – For monitoring conversion

Column: XBridge C18 cm 15 cm x 4.6 mm, 3.5 μιη particle size;

Column Temp. : 35 °C; Flow rate: 1.5 mL/min; Detection: 220 nm;

Mobile phase: A. 5 mM Na₂B40₇.10 H20 B: Acetonitrile

Gradient:

HPLC method – For level of amide epimer detection

Column: Chiralpak AD-H 5 μηι, 250 mm x 4.6 mm.

Column Temp: 35 °C; Flow rate: 1.0 mL/min; Detection: 250 nm;

Mobile phase: Isocratic 30% Ethanol in hexanes + 0.1% isobutylamine

PATENT

WO 2009124167

http://www.google.com/patents/WO2009124167A1?cl=en

EXAMPLE 103

(6y)-N-r4-({(^‘25′. 5R)-5-r(^‘R)-hvdroxy(^‘phenvnmethyl1pyrrolidin-2-yl}methvnphenyl1-4-oxo- 4,6J,8-tetrahydropyiτolori,2-α1pyrimidine-6-carboxamide

ter?-butyl(2R. 55^f)-2-rCR)-hvdroxy(^‘phenvnmethyl1-5-r4-(^‘{r(^‘65^f)-4-oxo-4.6.7.8-

tetrahydropyrrolof 1.2-alpyrimidin-6- yl]carbonyl} amino)benzyl]pyrrolidine- 1 – carboxylate

To a solution of i-13a (21.4 g, 55.9 mmol) in N,N-dimethylformamide (100 ml) at O⁰C was added [(65)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-α]pyrimidine-6-carboxylic acid (11.1 g, 61.5 mmol), followed by 1 -hydroxybenzotriazole (i-44, 7.55 g, 55.9 mmol), N-(3- dimethylaminopropyl)-N^l-ethylcarbodiimide hydrochloride (16.1 g, 84.0 mmol) and N,N- diisopropylethylamine (29.2 ml, 168 mmol). The reaction mixture was stirred from O⁰C to ambient temperature for 2 h. Water (600 ml) was added and it was extracted with dichloromethane (600 ml x 2). The combined organic layers were dried over Na₂SO₄. After removal of the volatiles, the residue was purified by using a Biotage Horizon® system (0-5% then 5% methanol with 10% ammonia/dichloromethane mixture) to afford the title compound which contained 8% of the minor diastereomer. It was further purified by supercritical fluid chromatography (chiral AS column, 40% methanol) to afford the title compound as a pale yellow solid (22.0 g, 72%). ¹H NMR (CDCl₃): δ 9.61 (s, IH), 7.93 (d, J = 6.6 Hz, IH), 7.49 (d, J = 8.4 Hz, 2H), 7.35-7.28 (m, 5H), 7.13 (d, J = 8.5 Hz, 2H), 6.40 (d, J = 6.7 Hz, IH), 5.36 (d, J = 8.6 Hz, IH), 4.38 (m, IH), 4.12-4.04 (m, 2H), 3.46 (m,lH), 3.15-3.06 (m, 2H), 2.91 (dd, J = 13.1, 9.0 Hz, IH), 2.55 (m, IH), 2.38 (m, IH), 1.71-1.49 (m, 13H). LC-MS 567.4 (M+23).

(6S)-N-\4-( U2S. 5R)-5-r(R)-hvdroxy(phenyl)methyl1pyrrolidin-2-

yl}methyl)phenyl1-4-oxo-4,6J,8-tetrahvdropyrrolori,2-α1pyrimidine-6- carboxamide

To a solution of the intermediate from Step A (2.50 g, 4.59 mmol) in dichloromethane (40 ml) was added trifluoroacetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 1.5 h. After removal of the volatiles, saturated NaHCCh was added to make the PH value to 8-9. The mixture was then extracted with dichloromethane. The combined organic layers were dried over Na₂SO₄. After concentration, crystallization from methanol/acetonitrile afforded the title compound as a white solid (1.23g, 60%). ¹H NMR (DMSO-Cl₆): δ 10.40 (s, IH), 7.91 (d, J = 6.7 Hz, IH), 7.49 (d, J = 8.3 Hz, 2H), 7.32-7.26 (m, 4H), 7.21 (m, IH), 7.15 (d, J = 8.4 Hz, 2H), 6.23 (d, J = 6.7 Hz, IH), 5.11 (dd, J = 9.6, 2.9 Hz, IH), 5.10 (br, IH), 4.21 (d, J = 7.1 Hz, IH), 3.20-3.00 (m, 4H), 2.66-2.51 (m, 3H), 2.16 (m, IH), 1.57 (m, IH), 1.38 (m, IH), 1.29-1.23 (m, 2H). LC-MS 445.3 (M+l).

Using the Biological Assays described above, the human β3 functional activity of Example 103 was determined to be between 11 to 100 nM.

PATENT

CHECK STRUCTURE…………….CAUTION

http://www.google.com/patents/US8247415

Figure US08247415-20120821-C00547

Figure US08247415-20120821-C00015

CAUTION…………….

Example 103(6S)-N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidine-6-carboxamide

Step A: tert-butyl(2R,5S)-2-[(R)-hydroxy(phenyl)methyl]-5-[4-({[(6S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidin-6-yl]carbonyl}amino)benzyl]pyrrolidine-1-carboxylate

To a solution of i-13a (21.4 g, 55.9 mmol) in N,N-dimethylformamide (100 ml) at 0° C. was added [(6S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidine-6-carboxylic acid (11.1 g, 61.5 mmol), followed by 1-hydroxybenzotriazole (i-44, 7.55 g, 55.9 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (16.1 g, 84.0 mmol) and N,N-diisopropylethylamine (29.2 ml, 168 mmol). The reaction mixture was stirred from 0° C. to ambient temperature for 2 h. Water (600 ml) was added and it was extracted with dichloromethane (600 ml×2). The combined organic layers were dried over Na₂SO₄. After removal of the volatiles, the residue was purified by using a Biotage Horizon® system (0-5% then 5% methanol with 10% ammonia/dichloromethane mixture) to afford the title compound which contained 8% of the minor diastereomer. It was further purified by supercritical fluid chromatography (chiral AS column, 40% methanol) to afford the title compound as a pale yellow solid (22.0 g, 72%). ¹H NMR (CDCl₃): δ 9.61 (s, 1H), 7.93 (d, J=6.6 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.35-7.28 (m, 5H), 7.13 (d, J=8.5 Hz, 2H), 6.40 (d, J=6.7 Hz, 1H), 5.36 (d, J=8.6 Hz, 1H), 4.38 (m, 1H), 4.12-4.04 (m, 2H), 3.46 (m, 1H), 3.15-3.06 (m, 2H), 2.91 (dd, J=13.1, 9.0 Hz, 1H), 2.55 (m, 1H), 2.38 (m, 1H), 1.71-1.49 (m, 13H). LC-MS 567.4 (M+23).

Step B: (6S)-N-[4-({(2S,5R)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)phenyl]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-α]pyrimidine-6-carboxamide

To a solution of the intermediate from Step A (2.50 g, 4.59 mmol) in dichloromethane (40 ml) was added trifluoroacetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 1.5 h. After removal of the volatiles, saturated NaHCO₃was added to make the PH value to 8-9. The mixture was then extracted with dichloromethane. The combined organic layers were dried over Na₂SO₄. After concentration, crystallization from methanol/acetonitrile afforded the title compound as a white solid (1.23 g, 60%). ¹H NMR (DMSO-d₆): δ 10.40 (s, 1H), 7.91 (d, J=6.7 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.32-7.26 (m, 4H), 7.21 (m, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.23 (d, J=6.7 Hz, 1H), 5.11 (dd, J=9.6, 2.9 Hz, 1H), 5.10 (br, 1H), 4.21 (d, J=7.1 Hz, 1H), 3.20-3.00 (m, 4H), 2.66-2.51 (m, 3H), 2.16 (m, 1H), 1.57 (m, 1H), 1.38 (m, 1H), 1.29-1.23 (m, 2H). LC-MS 445.3 (M+1).

Using the Biological Assays described above, the human β3 functional activity of Example 103 was determined to be between 11 to 100 nM.

PATENT

WO2014150639

http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014150639&recNum=4&docAn=US2014023858&queryString=EN_ALL:nmr%20AND%20PA:merck&maxRec=11148

Step 6. Preparation of Compound 1-7 from Compound 1-6 and Compound A-2

To a three neck flask equipped with a N₂ inlet, a thermo couple probe was charged pyrrolidine hemihydrate 1-6 (10.3 g), sodium salt A-2 (7.87 g), followed by IPA (40 mL) and water (24 mL). 5 N HC1 (14.9 mL) was then slowly added over a period of 20 minutes to adjust pH = 3.3-3.5, maintaining the batch temperature below 35°C. Solid EDC hydrochloride (7.47 g) was charged in portions over 30 minutes. The reaction mixture was aged at RT for additional 0.5 – 1 hour, aqueous ammonia (14%) was added dropwise to pH -8.6. The batch was seeded and aged for additional 1 hour to form a slurry bed. The rest aqueous ammonia (14%, 53.2 ml total) was added dropwise over 6 hours. The resulting thick slurry was aged 2-3 hours before filtration. The wet-cake was displacement washed with 30% IPA (30 mL), followed by 15% IPA (2 x 20mL) and water (2 X 20mL). The cake was suction dried under N₂ overnight to afford 14.3 g of compound 1-7.

¹³C NMR (DMSO) δ 167.52, 165.85, 159.83, 154.56, 144.19, 136.48, 135.66, 129.16, 127.71, 126.78, 126.62, 119.07, 112.00, 76.71, 64.34, 61.05, 59.60, 42.22, 31.26, 30.12, 27.09, 23.82.

The crystalline freebase anhydrous form I of Compound 1-7 can be characterized by XRPD by

PATENT

WO-2014150633
Merck Sharp & Dohme Corp
Process for preparing stable immobilized ketoreductase comprises bonding of recombinant ketoreductase to the resin in a solvent. Useful for synthesis of vibegron intermediates. For a concurrent filling see WO2014150639, claiming the method for immobilization of ketoreductase. Picks up from WO2013062881, claiming the non enzymatic synthesis of vibegron and intermediates.

PAPER

Discovery of Vibegron: A Potent and Selective β₃ Adrenergic Receptor Agonist for the Treatment of Overactive Bladder

Scott D. Edmondson^*,

Merck Research Laboratories, 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States

J. Med. Chem., Article ASAP

DOI: 10.1021/acs.jmedchem.5b01372

Publication Date (Web): December 27, 2015

*Telephone: (908) 740-0287. E-mail scott.edmondson@merck.com.

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01372

http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01372/suppl_file/jm5b01372_si_001.pdf

The discovery of vibegron, a potent and selective human β₃-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β₃-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β₃-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure–activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.

Reference
1		H.P. Kaiser, et al., “Catalytic Hydrogenation of Pyrroles at Atmospheric Pressure“, J. Org. Chem., vol. 49, No. 22, p. 4203-4209 (1984).

A study of the efficacy and safety of MK-4618 in patients with overactive bladder (OAB) (MK-4618-008 EXT1) (NCT01314872)
ClinicalTrials.gov Web Site 2011, April 28

WO2011043942A1 *	Sep 27, 2010	Apr 14, 2011	Merck Sharp & Dohme Corp.	Combination therapy using a beta 3 adrenergic receptor agonist and an antimuscarinic agent
US20090253705 *	Apr 2, 2009	Oct 8, 2009	Richard Berger	Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
US20110028481 *	Apr 2, 2009	Feb 3, 2011	Richard Berger	Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists

Citing Patent	Filing date	Publication date	Applicant	Title
US8642661	Aug 2, 2011	Feb 4, 2014	Altherx, Inc.	Pharmaceutical combinations of beta-3 adrenergic receptor agonists and muscarinic receptor antagonists
US8653260	Jun 20, 2012	Feb 18, 2014	Merck Sharp & Dohme Corp.	Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
US20120202819 *	Sep 27, 2010	Aug 9, 2012	Merck Sharp & Dohme Corporation	Combination therapy using a beta 3 adrenergic receptor agonists and an antimuscarinic agent

US20020028835	Jul 12, 2001	Mar 7, 2002	Baihua Hu	Cyclic amine phenyl beta-3 adrenergic receptor agonists
US20070185136	Feb 2, 2007	Aug 9, 2007	Sanofi-Aventis	Sulphonamide derivatives, their preparation and their therapeutic application
US20110028481	Apr 2, 2009	Feb 3, 2011	Richard Berger	Hydroxymethyl pyrrolidines as beta 3 adrenergic receptor agonists
WO2003072572A1	Feb 17, 2003	Sep 4, 2003	Jennifer Anne Lafontaine	Beta3-adrenergic receptor agonists


US8247415	8-22-2012	Hydroxymethyl pyrrolidines as [beta]3 adrenergic receptor agonists

////////////C1CC(NC1CC2=CC=C(C=C2)NC(=O)C3CCC4=NC=CC(=O)N34)C(C5=CC=CC=C5)O

Japan First to Approve Alectinib アレクチニブ塩酸塩 (AF 802) for ALK+ NSCLC

July 8, 2014 4:08 am / 3 Comments on Japan First to Approve Alectinib アレクチニブ塩酸塩 (AF 802) for ALK+ NSCLC

Alectinib (AF802, CH5424802, RG7853, RO5424802)

CAS 1256580-46-7 FREE

1256589-74-8 (Alectinib Hydrochloride)

9-Ethyl-6,11-dihydro-6,6-dimethyl-8-[4-(4-morpholinyl)-1-piperidinyl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile

Formula:	C₃₀H₃₄N₄O₂
M.Wt:	482.62

Mechanism of Action:ALK inhibitor
Indication:Non-small cell lung cancer (NSCLC)
Current Status:Phase II (US,EU,UK), NDA(Japan)
Company:中外製薬株式会社 (Chugai), Roche

Japan First to Approve Alectinib for ALK+ NSCLC

http://www.dddmag.com/news/2014/07/japan-first-approve-alectinib-alk-nsclc?et_cid=4034150&et_rid=523035093&type=headline

Roche announced that the Japanese Ministry of Health, Labor and Welfare (MHLW) has approved alectinib for the treatment of people living with non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase fusion gene-positive (ALK+). The approval was based on results from a Japanese Phase 1/2 clinical study (AF-001JP) for people whose tumors were advanced, recurrent or could not be removed completely through surgery (unresectable).

Company	Chugai Pharmaceutical Co. Ltd.
Description	Anaplastic lymphoma kinase (ALK) inhibitor
Molecular Target	Anaplastic lymphoma kinase (ALK)
Mechanism of Action	Anaplastic lymphoma kinase (Ki-1) (ALK) inhibitor
Therapeutic Modality	Small molecule

Latest Stage of Development	Registration
Standard Indication	Non-small cell lung cancer (NSCLC)
Indication Details	Treat advanced ALK-positive non-small cell lung cancer (NSCLC); Treat non-small cell lung cancer (NSCLC); Treat unresectable progressive or recurrent ALK-positive non-small cell lung cancer (NSCLC)
Regulatory Designation	U.S. – Breakthrough Therapy (Treat advanced ALK-positive non-small cell lung cancer (NSCLC)); Japan – Orphan Drug (Treat advanced ALK-positive non-small cell lung cancer (NSCLC)); Japan – Orphan Drug (Treat unresectable progressive or recurrent ALK-positive non-small cell lung cancer (NSCLC)); Japan – Standard Review (Treat advanced ALK-positive non-small cell lung cancer (NSCLC))
Partner	Roche

Alectinib (also known as CH5424802,RO5424802), a second generation oral inhibitor of anaplastic lymphoma kinase (ALK), is being developed by Chugai and Roche for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC) that has progressed on Xalkori (Crizotinib).

Alectinib was discovered by Chugai Pharmaceutical Co. Ltd. Chugai became a subsidiary of Roche in 2002 and the Swiss group currently owns 59.9 percent of the company.

On October 8, 2013, Chugai Pharmaceutical announced that it has filed a new drug application to Japan’s Ministry of Health, Labour and Welfare (MHLW) for alectinib hydrochloride for the treatment of ALK fusion gene positive non-small cell lung cancer (NSCLC).

IT is a potent and selective ALK inhibitor with IC50 of 1.9 nM.Alterations in the anaplastic lymphoma kinase (ALK) gene have been implicated in human cancers. Among these findings, the fusion gene comprising EML4 and ALK has been identified in non-small cell lung cancer (NSCLC) and fusion of ALK to NPM1 has been observed in anaplastic large cell lymphoma (ALCL). The possibility of targeting ALK in human cancer was advanced with the launch of crizotinib for NSCLC in the U.S. in 2011. The development of resistance to crizotinib in tumors, however, has led to the need for second-generation ALK inhibitors. One of these, alectinib hydrochloride, has been found to be an orally active, potent and highly selective ALK inhibitor with activity in ALK-driven tumor models. Alectinib has shown preclinical activity against cancers with ALK gene alterations, including NSCLC cells expressing the EML4-ALK fusion and ALCL cells expressing the NPM-ALK fusion. Alectinib was well tolerated and active in a phase I/II study conducted in Japan in patients with ALK-rearranged advanced NSCLC and in patients with ALK-positive NSCLC who had progressed on crizotinib. Alectinib has been submitted for approval in Japan for the treatment of ALK fusion gene-positive NSCLC and is in phase I/II development for ALK-rearranged NSCLC in the U.S.

……………..

………………….

WO2012023597

http://www.google.fm/patents/WO2012023597A1?cl=en

(Preparation 30)
Compound F6-20
9 – ethyl-6, 6 – dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) -11 – oxo-6 ,11 – dihydro-5H-benzo [b] carbazol-3 – carbonitrile

Under the same conditions as the synthesis of the compound B3-13-1, and the title compound was synthesized from compound F5-49.
¹ H-NMR (400MHz, DMSO-D ₆₎ ^δ: 12.70 (1H, s), 8.32 (1H, d, J = 7.9 Hz), 8.04 (1H, s), 8.00 (1H, s), 7.61 (1H , d, J = 8.5 Hz), 7.34 (1H, s), 3.64-3.57 (4H, m), 3.27-3.18 (2H, m), 2.82-2.66 (4H, m), 2.39-2.28 (1H, m ), 1.96-1.87 (2H, m), 1.76 (6H, s), 1.69-1.53 (2H, m), 1.29 (3H, t, J = 7.3 Hz)
LCMS: m / z 483 [M ⁺ H] +
HPLC retention time: 1.98 minutes (analysis conditions U)

Hydrochloride 9 of compound F6-20 – ethyl-6, 6 – dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) -11 – oxo-6 ,11 – dihydro-5H-benzo [b I was dissolved at 60 ℃ in a mixture of 10 volumes of methyl ethyl ketone, 3 volumes of water and acetic acid volume 4-carbonitrile -] carbazol-3. I was dropped hydrochloric acid (2N) 1 volume of solution. After stirring for 30 minutes at 60 ℃, and the precipitated solid was filtered and added dropwise to 25 volume ethanol, 9 – Dry ethyl -6,6 – dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) I got a one-carbonitrile hydrochloride – 11 – oxo-6 ,11 – dihydro-5H-benzo [b] carbazol-3. Ethyl-6, 6 – 9 – obtained dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) -11 – oxo-6 ,11 – dihydro-5H-benzo [b] carbazol-3 – I was pulverized with a jet mill carbonitrile monohydrochloride.
¹ H-NMR (400MHz, DMSO-D ₆₎ ^δ: 12.78 (1H, s), 10.57 (1H, br.s), 8.30 (1H, J = 8.4 Hz), 8.05 (1H, s), 7.99 (1H , s), 7.59 (1H, d, J = 7.9 Hz), 7.36 (1H, s) ,4.02-3 .99 (2H, m) ,3.84-3 .78 (2H, m) ,3.51-3 .48 (2H, m), 3.15-3.13 (1H, s) ,2.83-2 .73 (2H, s) ,2.71-2 .67 (2H, s) ,2.23-2 .20 (2H, m) ,1.94-1 .83 (2H, m), 1.75 (6H, s ), 1.27 (3H, t, J = 7.5 Hz)
FABMS: m / z 483 [M ⁺ H] +

I was dissolved at 90 ℃ to 33 volume dimethylacetamide F6-20 F6-20 mesylate. Was added to 168 volumes mesylate solution (2 N) 1.2 volume, ethyl acetate solution was stirred for 4 hours. The filtered crystals were precipitated, and dried to obtain a F6-20 one mesylate. I was milled in a jet mill F6-20 one mesylate salt was obtained.

……………………

Journal of Medicinal Chemistry, 54(18), 6286-6294; 2011

http://pubs.acs.org/doi/abs/10.1021/jm200652u

WO2002043704A1 *	30 Nov 2001	6 Jun 2002	Yasuki Kato	Composition improved in solubility or oral absorbability
WO2008051547A1 *	23 Oct 2007	2 May 2008	Cephalon Inc	Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and c-met inhibitors
WO2009073620A2 *	1 Dec 2008	11 Jun 2009	Newlink Genetics	Ido inhibitors
WO2010143664A1 *	9 Jun 2010	16 Dec 2010	Chugai Seiyaku Kabushiki Kaisha	Tetracyclic compound
JP2008280352A				Title not available
JP2009100783A				Title not available
JPH0892090A *				Title not available

References

1: Ignatius Ou SH, Azada M, Hsiang DJ, Herman JM, Kain TS, Siwak-Tapp C, Casey C, He J, Ali SM, Klempner SJ, Miller VA. Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib. J Thorac Oncol. 2014 Apr;9(4):549-53. doi: 10.1097/JTO.0000000000000094. PubMed PMID: 24736079.

2: Gouji T, Takashi S, Mitsuhiro T, Yukito I. Crizotinib can overcome acquired resistance to CH5424802: is amplification of the MET gene a key factor? J Thorac Oncol. 2014 Mar;9(3):e27-8. doi: 10.1097/JTO.0000000000000113. PubMed PMID: 24518097.

3: Latif M, Saeed A, Kim SH. Journey of the ALK-inhibitor CH5424802 to phase II clinical trial. Arch Pharm Res. 2013 Sep;36(9):1051-4. doi: 10.1007/s12272-013-0157-8. Epub 2013 May 23. Review. PubMed PMID: 23700294.

4: Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, Hida T, Yamamoto N, Yoshioka H, Harada M, Ohe Y, Nogami N, Takeuchi K, Shimada T, Tanaka T, Tamura T. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol. 2013 Jun;14(7):590-8. doi: 10.1016/S1470-2045(13)70142-6. Epub 2013 Apr 30. PubMed PMID: 23639470.

5: Kinoshita K, Asoh K, Furuichi N, Ito T, Kawada H, Hara S, Ohwada J, Miyagi T, Kobayashi T, Takanashi K, Tsukaguchi T, Sakamoto H, Tsukuda T, Oikawa N. Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). Bioorg Med Chem. 2012 Feb 1;20(3):1271-80. doi: 10.1016/j.bmc.2011.12.021. Epub 2011 Dec 22. PubMed PMID: 22225917.

6: Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, Aoki Y. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011 May 17;19(5):679-90. doi: 10.1016/j.ccr.2011.04.004. PubMed PMID: 21575866.

Gadgeel S, Ou SH, Chiappori A, et al: A phase I dose escalation study of a new ALK inhibitor, CH542480202, in ALK+ non-small cell lung cancer patients who have failed crizotinib. Abstract O16.06. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013.

Ou SH, Gadgeel S, Chiappori AA, et al: Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer patients in an ongoing phase I/II study. Abstract O16.07. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013.

Kinoshita, Kazuhiro et al,Preparation of tetracyclic compounds such as 11-oxo-5,6-dihydrobenzo[b]carbazole-3-carbonitrile derivatives as anaplastic lymphoma kinase (ALK) inhibitors,Jpn. Kokai Tokkyo Koho, 2012126711, 05 Jul 2012

Furumoto, Kentaro et al, Composition containing tetracyclic compound and dissolution aid (４環性化合物を含む組成物), PCT Int. Appl., WO2012023597, 23 Feb 2012, Also published as CA2808210A1, CN103052386A, EP2606886A1, EP2606886A4, US20130143877

Kinoshita, Kazutomo et al,Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802), Bioorganic & Medicinal Chemistry, 20(3), 1271-1280; 2012

Kinoshita, Kazutomo et al,9-Substituted 6,6-Dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors, Journal of Medicinal Chemistry, 54(18), 6286-6294; 2011

Kinoshita, Kazuhiro et al, Preparation of tetracyclic compounds such as 11-oxo-5,6-dihydrobenzo[b]carbazole-3-carbonitrile derivatives as anaplastic lymphoma kinase (ALK) inhibitors,Jpn. Tokkyo Koho, 4588121, 24 Nov 2010

Japan approves world’s first PD-1 drug, nivolumab

July 8, 2014 3:27 am / 1 Comment on Japan approves world’s first PD-1 drug, nivolumab

Japan approves world's first PD-1 drug, nivolumab

Ono Pharmaceutical Co has become the first company in the world to get an approval for a PD-1 checkpoint inhibitor, as regulators in Japan gave the green light to nivolumab, developed with Bristol-Myers Squibb, as a treatment for melanoma.

http://www.pharmatimes.com/Article/14-07-07/Japan_approves_world_s_first_PD-1_drug_nivolumab.aspx

old article cut paste

NIVOLUMAB

Anti-PD-1;BMS-936558; ONO-4538

PRONUNCIATION nye vol’ ue mab
THERAPEUTIC CLAIM Treatment of cancer
CHEMICAL DESCRIPTION
A fully human IgG4 antibody blocking the programmed cell death-1 receptor (Medarex/Ono Pharmaceuticals/Bristol-Myers Squibb)
MOLECULAR FORMULA C6362H9862N1712O1995S42
MOLECULAR WEIGHT 143.6 kDa

SPONSOR Bristol-Myers Squibb
CODE DESIGNATION MDX-1106, BMS-936558
CAS REGISTRY NUMBER 946414-94-4

Bristol-Myers Squibb announced promising results from an expanded phase 1 dose-ranging study of its lung cancer drug nivolumab

Nivolumab (nye vol’ ue mab) is a fully human IgG4 monoclonal antibody designed for the treatment of cancer. Nivolumab was developed by Bristol-Myers Squibb and is also known as BMS-936558 and MDX1106.^[1] Nivolumab acts as an immunomodulator by blocking ligand activation of the Programmed cell death 1 receptor.

A Phase 1 clinical trial ^[2] tested nivolumab at doses ranging from 0.1 to 10.0 mg per kilogram of body weight, every 2 weeks. Response was assessed after each 8-week treatment cycle, and were evaluable for 236 of 296 patients. Study authors concluded that:”Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.”^[3]

Phase III clinical trials of nivolumab are recruiting in the US and EU.^[4]

Statement On A Nonproprietary Name Adopted By The USAN Council – Nivolumab, American Medical Association.
A Phase 1b Study of MDX-1106 in Subjects With Advanced or Recurrent Malignancies (MDX1106-03), NIH.
Topalian SL, et al. (June 2012). “Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer”. New England Journal of Medicine 366. doi:10.1056/NEJMoa1200690. Lay summary – New York Times.
Nivolumab at ClinicalTrials.gov, A service of the U.S. National Institutes of Health.

The PD-1 blocking antibody nivolumab continues to demonstrate sustained clinical activity in previously treated patients with advanced non-small cell lung cancer (NSCLC), according to updated long-term survival data from a phase I trial.

Survival rates at one year with nivolumab were 42% and reached 24% at two years, according to the median 20.3-month follow up. Additionally, the objective response rate (ORR) with nivolumab, defined as complete or partial responses by standard RECIST criteria, was 17% for patients with NSCLC. Results from the updated analysis will be presented during the 2013 World Conference on Lung Cancer on October 29.

“Lung cancer is very difficult to treat and there continues to be a high unmet medical need for these patients, especially those who have received multiple treatments,” David R. Spigel, MD, the program director of Lung Cancer Research at the Sarah Cannon Research Institute and one of the authors of the updated analysis, said in a statement.

“With nivolumab, we are investigating an approach to treating lung cancer that is designed to work with the body’s own immune system, and these are encouraging phase I results that support further investigation in larger scale trials.”

In the phase I trial, 306 patients received intravenous nivolumab at 0.1–10 mg/kg every-other-week for ≤12 cycles (4 doses/8 week cycle). In all, the trial enrolled patients with NSCLC, melanoma, renal cell carcinoma, colorectal cancer, and prostate cancer.

The long-term follow up focused specifically on the 129 patients with NSCLC. In this subgroup, patients treated with nivolumab showed encouraging clinical activity. The participants had a median age of 65 years and good performance status scores, and more than half had received three or more prior therapies. Across all doses of nivolumab, the median overall survival was 9.9 months, based on Kaplan-Meier estimates.

In a previous update of the full trial results presented at the 2013 ASCO Annual Meeting, drug-related adverse events of all grades occurred in 72% of patients and grade 3/4 events occurred in 15%. Grade 3/4 pneumonitis related to treatment with nivolumab emerged early in the trial, resulting in 3 deaths. As a result, a treatment algorithm for early detection and management was developed to prevent this serious side effect.

Nivolumab is a fully human monoclonal antibody that blocks the PD-1 receptor from binding to both of its known ligands, PD-L1 and PD-L2. This mechanism, along with early data, suggested an associated between PD-L1 expression and response to treatment.

In separate analysis presented at the 2013 World Conference on Lung Cancer, the association of tumor PD-L1 expression and clinical activity in patients with NSCLC treated with nivolumab was further explored. Of the 129 patients with NSCLC treated with nivolumab in the phase I trial, 63 with NSCLC were tested for PD-L1 expression by immunohistochemistry (29 squamous; 34 non-squamous).

Bayer HealthCare has obtained approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for its Nexavar (sorafenib) for treatment of patients with unresectable differentiated thyroid carcinoma.

June 26, 2014 4:14 am / 1 Comment on Bayer HealthCare has obtained approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for its Nexavar (sorafenib) for treatment of patients with unresectable differentiated thyroid carcinoma.

Sorafenib

(4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide)

BAY 43-9006

Bayer HealthCare has obtained approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for its Nexavar (sorafenib) for treatment of patients with unresectable differentiated thyroid carcinoma.

http://www.pharmaceutical-technology.com/news/newsbayers-nexavar-receives-japanese-approval-4300422?WT.mc_id=DN_News

Nexavar’s approval in Japan is supported by data from the multicentre, placebo-controlled Phase III DECISION (‘stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer’) study.

The international Phase III DECISION study, which randomised a total of 417 patients, met its primary endpoint of extended progression-free survival. Safety and tolerability profile of sorafenib was generally consistent with the known profile of sorafenib.

The most common treatment-emergent adverse events in the sorafenib arm were hand-foot skin reaction, diarrhea, alopecia, weight loss, fatigue, hypertension and rash.

Nexavar was awarded orphan drug status by the MHLW for thyroid carcinoma in September 2013.

Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar),^[1] is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), and radioactive iodine resistant advanced thyroid carcinoma.

Medical uses

At the current time sorafenib is indicated as a treatment for advanced renal cell carcinoma (RCC), unresectable hepatocellular carcinomas (HCC) and thyroid cancer.^[2]^[3]^[4]^[5]

Kidney cancer

An article in The New England Journal of Medicine, published January 2007, showed compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear cell renal cell carcinoma in whom previous therapy has failed. The median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01).^[6] A few reports described patients with stage IV renal cell carcinomas that were successfully treated with a multimodal approach including neurosurgical, radiation, and sorafenib.^[7] This is one of two TGA-labelled indications for sorafenib, although it is not listed on the Pharmaceutical Benefits Scheme for this indication.^[5]^[8]

Liver cancer

At ASCO 2007, results from the SHARP trial^[9] were presented, which showed efficacy of sorafenib in hepatocellular carcinoma. The primary endpoint was median overall survival, which showed a 44% improvement in patients who received sorafenib compared to placebo (hazard ratio 0.69; 95% CI, 0.55 to 0.87; p=0.0001). Both median survival and time to progression showed 3-month improvements. There was no difference in quality of life measures, possibly attributable to toxicity of sorafenib or symptoms related to underlying progression of liver disease. Of note, this trial only included patients with Child-Pugh Class A (i.e. mildest) cirrhosis. The results of the study appear in the July 24, 2008, edition of The New England Journal of Medicine. Because of this trial Sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.^[10]

In a randomized, double-blind, phase II trial combining sorafenib with doxorubicin, the median time to progression was not significantly delayed compared with doxorubicin alone in patients with advanced hepatocellular carcinoma. Median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone.^[10] A prospective single-centre phase II study which included the patients with unresectable hepatocellular carcinoma (HCC)concluding that the combination of sorafenib and DEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib.^[11] This is the only indication for which sorafenib is listed on the PBS and hence the only Government-subsidised indication for sorafenib in Australia.^[8] Along with renal cell carcinoma, hepatocellular carcinoma is one of the TGA-labelled indications for sorafenib.^[5]

Thyroid cancer

A phase 3 clinical trial has started recruiting (November 2009) to use sorafenib for non-responsive thyroid cancer.^[12] The results were presented at the ASCO 13th Annual Meeting and are the base for FDA approval. The Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The Phase 3 DECISION trial showed significant improvement in progression-free survival but not in overall survival. However, as is known, the side effects were very frequent, specially hand and foot skin reaction.^[13]

Adverse effects

Adverse effects by frequency
Note: Potentially serious side effects are in bold.
Very common (>10% frequency)

Lymphopenia
Hypophosphataemia^{[Note 1]}
Haemorrhage^{[Note 2]}
Hypertension^{[Note 3]}
Diarrhea
Rash
Alopecia (hair loss; occurs in roughly 30% of patients receiving sorafenib)
Hand-foot syndrome
Pruritus (itchiness)
Erythema
Increased amylase
Increased lipase
Fatigue
Pain^{[Note 4]}
Nausea
Vomiting^{[Note 5]}^[14]

Common (1-10% frequency)

Leucopoenia^{[Note 6]}
Neutropoenia^{[Note 7]}
Anaemia^{[Note 8]}
Thrombocytopenia^{[Note 9]}
Anorexia (weight loss)
Hypocalcaemia^{[Note 10]}
Hypokalaemia^{[Note 11]}
Depression
Peripheral sensory neuropathy
Tinnitus^{[Note 12]}
Congestive heart failure
Myocardial infarction^{[Note 13]}
Myocardial ischaemia^{[Note 14]}
Hoarseness
Constipation
Stomatitis^{[Note 15]}
Dyspepsia^{[Note 16]}
Dysphagia^{[Note 17]}
Dry skin
Exfoliative dermatitis
Acne
Skin desquamation
Arthralgia^{[Note 18]}
Myalgia^{[Note 19]}
Renal failure^{[Note 20]}
Proteinuria^{[Note 21]}
Erectile dysfunction
Asthenia (weakness)
Fever
Influenza-like illness

Transient increase in transaminase

Uncommon (0.1-1% frequency)

Folliculitis
Infection
Hypersensitivity reactions^{[Note 22]}
Hypothyroidism^{[Note 23]}
Hyperthyroidism^{[Note 24]}
Hyponatraemia^{[Note 25]}
Dehydration
Reversible posterior leukoencephalopathy
Hypertensive crisis
Rhinorrhoea^{[Note 26]}
Interstitial lung disease-like events^{[Note 27]}
Gastro-oesophageal reflux disease (GORD)
Pancreatitis^{[Note 28]}
Gastritis^{[Note 29]}
Gastrointestinal perforations^{[Note 30]}
Increase in bilirubin leading, potentially, to jaundice^{[Note 31]}
Cholecystitis^{[Note 32]}
Cholangitis^{[Note 33]}
Eczema
Erythema multiforme^{[Note 34]}
Keratoacanthoma^{[Note 35]}
Squamous cell carcinoma
Gynaecomastia (swelling of the breast tissue in men)
Transient increase in blood alkaline phosphatase
INR abnormal
Prothrombin level abnormal
bulbous skin reaction^[15]

Rare (0.01-0.1% frequency)

QT interval prolongation^{[Note 36]}
Angiooedema^{[Note 37]}
Anaphylactic reaction^{[Note 38]}
Hepatitis^{[Note 39]}
Radiation recall dermatitis
Stevens-Johnson syndrome^{[Note 40]}
Leucocytoclastic vasculitis
Toxic epidermal necrolysis^{[Note 41]}
Nephrotic syndrome
Rhabdomyolysis^{[Note 42]}

Mechanism of action

Sorafenib is a small molecular inhibitor of several tyrosine protein kinases (VEGFR and PDGFR) and Raf kinases (more avidly C-Raf than B-Raf).^[16]^[17] Sorafenib also inhibits some intracellular serine/threonine kinases (e.g. C-Raf, wild-type B-Raf and mutant B-Raf).^[10] Sorafenib treatment induces autophagy,^[18] which may suppress tumor growth. However, autophagy can also cause drug resistance.^[19]

History

Renal cancer

Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005,^[20] and received European Commission marketing authorization in July 2006,^[21] both for use in the treatment of advanced renal cancer.

Liver cancer

The European Commission granted marketing authorization to the drug for the treatment of patients with hepatocellular carcinoma(HCC), the most common form of liver cancer, in October 2007,^[22] and FDA approval for this indication followed in November 2007.^[23]

In November 2009, the UK’s National Institute of Clinical Excellence declined to approve the drug for use within the NHS in England, Wales and Northern Ireland, stating that its effectiveness (increasing survival in primary liver cancer by 6 months) did not justify its high price, at up to £3000 per patient per month.^[24] In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS Scotland, for the same reason.^[24]

In March 2012, the Indian Patent Office granted a domestic company, Natco Pharma, a license to manufacture generic Sorafenib, bringing its price down by 97%. Bayer sells a month’s supply, 120 tablets, of Nexavar for280000 (US$4,700). Natco Pharma will sell 120 tablets for 8800 (US$150), while still paying a 6% royalty to Bayer.^[25]^[26] Under Indian Patents Act, 2005 and the World Trade Organisation TRIPS Agreement, the government can issue a compulsory license when a drug is not available at an affordable price.^[27]

Thyroid Cancer

As of November 22, 2013, sorafenib has been approved by the FDA for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment.^[28]

Research

Lung

In some kinds of lung cancer (with squamous-cell histology) sorafenib administered in addition to paclitaxel and carboplatin may be detrimental to patients.^[29]

Brain (Recurrent Glioblastoma)

There is a phase I/II study at the Mayo Clinic^[30] of sorafenib and CCI-779 (temsirolimus) for recurrent glioblastoma.

Desmoid Tumor (Aggressive Fibromatosis)

A study performed in 2011 showed that Sorafenib is active against Aggressive fibromatosis. This study is being used as justification for using Sorafenib as an initial course of treatment in some patients with Aggressive fibromatosis.^[31]

Nexavar Controversy

In January 2014, Bayer’s CEO stated that Nexavar was developed for “western patients who [could] afford it”. At the prevailing prices, a kidney cancer patient would pay $96,000 (£58,000) for a year’s course of the Bayer-made drug. However, the cost of the Indian version of the generic drug would be around $2,800 (£1,700).^[32]

Notes

Low blood phosphate levels
Bleeding; including serious bleeds such as intracranial and intrapulmonary bleeds
High blood pressure
Including abdominal pain, headache, tumour pain, etc.
Considered a low (~10-30%) risk chemotherapeutic agent for causing emesis)
Low level of white blood cells in the blood
Low level of neutrophils in the blood
Low level of red blood cells in the blood
Low level of plasma cells in the blood
Low blood calcium
Low blood potassium
Hearing ringing in the ears
Heart attack
Lack of blood supply for the heart muscle
Mouth swelling, also dry mouth and glossodynia
Indigestion
Not being able to swallow
Sore joints
Muscle aches
Kidney failure
Excreting protein [usually plasma proteins] in the urine. Not dangerous in itself but it is indicative kidney damage
Including skin reactions and urticaria (hives)
Underactive thyroid
Overactive thyroid
Low blood sodium
Runny nose
Pneumonitis, radiation pneumonitis, acute respiratory distress, etc.
Swelling of the pancreas
Swelling of the stomach
Formation of a hole in the gastrointestinal tract, leading to potentially fatal bleeds
Yellowing of the skin and eyes due to a failure of the liver to adequately cope with the amount of bilirubin produced by the day-to-day actions of the body
Swelling of the gallbladder
Swelling of the bile duct
A potentially fatal skin reaction
A fairly benign form of skin cancer
A potentially fatal abnormality in the electrical activity of the heart
Swelling of the skin and mucous membranes
A potentially fatal allergic reaction
Swelling of the liver
A potentially fatal skin reaction
A potentially fatal skin reaction
The rapid breakdown of muscle tissue leading to the build-up of myoglobin in the blood and resulting in damage to the kidneys

Sorafenib
Systematic (IUPAC) name


4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide
Clinical data
Trade names	Nexavar
AHFS/Drugs.com	monograph
MedlinePlus	a607051
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	D (AU) D (US)
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	38–49%
Protein binding	99.5%
Metabolism	Hepatic oxidation and glucuronidation (CYP3A4 & UGT1A9-mediated)
Half-life	25–48 hours
Excretion	Faeces (77%) and urine (19%)
Identifiers
CAS number	284461-73-0
ATC code	L01XE05
PubChem	CID 216239
DrugBank	DB00398
ChemSpider	187440
UNII	9ZOQ3TZI87
KEGG	D08524
ChEBI	CHEBI:50924
ChEMBL	CHEMBL1336
Synonyms	Nexavar Sorafenib tosylate
PDB ligand ID	BAX (PDBe, RCSB PDB)
Chemical data
Formula	C₂₁H₁₆Cl F₃N₄O₃
Mol. mass	464.825 g/mol

4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-Λ/²-methylpyridine-2- carboxamide is commonly known as sorafenib (I). Sorafenib is prepared as its tosylate salt. Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis.

Sorafenib, marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received “Fast Track” designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer). It is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor.

Sorafenib and pharmaceutically acceptable salts thereof is disclosed in WO0042012. Sorafenib is also disclosed in WO0041698. Both these patents disclose processes for the preparation of sorafenib.

WO0042012 and WO0041698 describe the process as given in scheme I which comprises reacting picolinic acid (II) with thionyl chloride in dimethyl formamide (DMF) to form acid chloride salt (III). This salt is then reacted with methylamine dissolved in tetrahydrofuran (THF) to give carboxamide (IV). This carboxamide when further reacted with 4- aminophenol in anhydrous DMF and potassium tert-butoxide 4-(2-(N-methylcarbamoyl)-4- pyridyloxy)aniline (V) is formed. Subsequent reaction of this aniline with 4-chloro-3- (trifluoromethyl) phenyl isocyanate (Vl) in methylene chloride yields sorafenib (I). The reaction is represented by Scheme I as given below.

Scheme I

Picolini

Sorafenib (I)

WO2006034796 also discloses a process for the preparation of sorafenib and its tosylate salt. The process comprises reacting 2-picolinic acid (II) with thionyl chloride in a solvent inert toward thionyl chloride without using dimethyl formamide to form acid chloride salt (III). This acid salt on further reaction with aqueous solution methylamine or gaseous methylamine gives compound (IV). Compound (IV) is then reacted with 4-aminophenol with addition of a carbonate salt in the presence of a base to yield compound (V).

Compound (V) can also be obtained by reacting compound (IV) with 4-aminophenol in the presence of water with addition of a phase transfer catalyst. Compound (V) when reacted with 4-chloro-3-(trifluoromethyl) phenyl isocyanate (Vl) in a non-chlorinated organic solvent, inert towards isocyanate gives sorafenib (I). Sorafenib by admixing with p- toluenesulfonic acid in a polar solvent gives sorafenib tosylate (VII). The reaction is represented by Scheme Il as given below.

Scheme Il

A key step in the synthesis of sorafenib is the formation of the urea bond. The processes disclosed in the prior art involve reactions of an isocyanate with an amine. These isocyanate compounds though commercially available are very expensive. Further synthesis of isocyanate is very difficult which requires careful and skillful handling of reagents.

Isocyanate is prepared by reaction of an amine with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) or trichloromethyl chloroformate (diphosgene). Isocyanate can also be prepared by using a hazardous reagent such as an azide. Also, the process for preparation of an isocyanate requires harsh reaction conditions such as strong acid, higher temperature etc. Further, this isocyanate is reacted with an amine to give urea.

Reactions of isocyanates suffer from one or more disadvantages. For example phosgene or phosgene equivalents are hazardous and dangerous to use and handle on a large scale. These reagents are also not environment friendly. Isocyanates themselves are thermally unstable compounds and undergo decomposition on storage and they are incompatible with a number of organic compounds. Thus, the use of isocyanate is not well suited for industrial scale application.

Sorafenib and its pharmaceutically acceptable salts and solvates are reported for the first time in WO0041698 (corresponding US 03139605) by Bayer. In the literature only one route is disclosed for the preparation of sorafenib. According to this route (Scheme-I), picolinic acid of formula III is reacted with thionyl chloride to give the 4-chloro derivative which on treatment

VII

Scheme-I with methanol gave the methyl ester of formula V. Compound of formula V is reacted with methylamine to get the corresponding amide of formula VL Compound of formula VI is reacted with 4-aminophenol to get the ether derivative of formula VII. Compound of formula VII is reacted with 4-chloro-3-trifluoromethylphenylisocyante to get sorafenib base of formula I. Overall yield of sorafenib in this process is 10% from commercially available 2-picolinic acid of formula II. Main drawback in this process is chromatographic purification of the intermediates involved in the process and low yield at every step.

Donald Bankston’s (Org. Proc. Res. Dev., 2002, 6, 777-781) development of an improved synthesis of the above basic route afforded sorafenib in an overall yield of 63% without involving any chromatographic purification. Process improvements like reduction of time in thionyl chloride reaction; avoid the isolation of intermediates of formulae IV and V₅ reduction of base quantity in p-aminophenol reaction, etc lead to the simplification of process and improvement in yield of final compound of formula I.

Above mentioned improvements could not reduce the number of steps in making sorafenib of formula-I. In the first step all the raw materials are charged and heated to target temperature (72°C). Such a process on commercial scale will lead to sudden evolution of gas emissions such as sulfur dioxide and hydrogen chloride. Also, in the aminophenol reaction two bases (potassium carbonate and potassium t-butoxide) were used in large excess to accomplish the required transformation.

A scalable process for the preparation of sorafenib is disclosed in WO2006034796. In this process also above mentioned chemistry is used in making sorafenib of formula I. In the first step, catalytic quantity. of DMF used in the prior art process is replaced with reagents like hydrogen bromide, thionyl bromide and sodium bromide. Yield of required product remained same without any advantages from newly introduced corrosive reagents. Process improvements like change of solvents, reagents, etc were applied in subsequent steps making the process scalable. Overall yield of sorafenib is increased to 74% from the prior art 63% yield. Purity of sorafenib is only 95% and was obtained as light brown colored solid.

Main drawbacks in this process are production of low quality sorafenib and requirement of corrosive and difficult to handle reagents such as thionyl bromide and hydrogen bromide. Also, there is no major improvement in the yield of sorafenib.

Sorafenib tosylate ( Brand name: Nexavar ®, BAY 43-9006 other name, Chinese name: Nexavar, sorafenib, Leisha Wa) was Approved by U.S. FDA for the treatment of advanced kidney cancer in 2005 and liver cancer in 2007 .

Sorafenib, co-Developed and co-marketed by Germany-based Bayer AG and South San Francisco-based Onyx Pharmaceuticals , is an Oral Multi-kinase inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRbeta, Kit, RET and Raf-1.

In March 2012 Indian drugmaker Natco Pharma received the first compulsory license ever from Indian Patent Office to make a generic Version of Bayer’s Nexavar despite the FACT that Nexavar is still on Patent. This Decision was based on the Bayer Drug being too expensive to most patients. The Nexavar price is expected to drop from $ 5,500 per person each month to $ 175, a 97 percent decline. The drug generated $ 934 million in global sales in 2010, according to India’s Patent Office.

Sorafenib tosylate

Chemical Name: 4-Methyl-3-((4 – (3-pyridinyl)-2-pyrimidinyl) amino)-N-(5 – (4-methyl-1H-imidazol-1-yl) -3 – (trifluoromethyl) phenyl) benzamide monomethanesulfonate, Sorafenib tosylate

CAS Number 475207-59-1 (Sorafenib tosylate ) , 284461-73-0 (Sorafenib)

References for the Preparation of Sorafenib References

1) Bernd Riedl, Jacques Dumas, Uday Khire, Timothy B. Lowinger, William J. Scott, Roger A. Smith, Jill E. Wood, Mary-Katherine Monahan, Reina Natero, Joel Renick, Robert N. Sibley; Omega-carboxyaryl Substituted diphenyl Ureas as RAF kinase inhibitors ; U.S. Patent numberUS7235576
2) Rossetto, Pierluigi; Macdonald, Peter, Lindsay; Canavesi, Augusto; Process for preparation of sorafenib and Intermediates thereof , PCT Int. Appl., WO2009111061
3) Lögers, Michael; gehring, Reinhold; Kuhn, Oliver; Matthäus, Mike; Mohrs, Klaus; müller-gliemann, Matthias; Stiehl, jürgen; berwe, Mathias; Lenz, Jana; Heilmann, Werner; Process for the preparation of 4 – {4 – [( {[4-chloro-3-(TRIFLUOROMETHYL) phenyl] amino} carbonyl) amino] phenoxy}-N-methylpyridine-2-carboxamide , PCT Int. Appl., WO2006034796
4) Shikai Xiang, Liu Qingwei, Xieyou Rong, sorafenib preparation methods, invention patent application Publication No. CN102311384 , Application No. CN201010212039
5) Zhao multiply there, Chenlin Jie, Xu Xu, MASS MEDIA Ji Yafei; sorafenib tosylate synthesis ,Chinese Journal of Pharmaceuticals , 2007 (9): 614 -616

Preparation of Sorafenib Tosylate (Nexavar) Nexavar, sorafenib Preparation of methyl sulfonate

Sorafenib (Sorafenib) chemical name 4 – {4 – [({[4 – chloro -3 – (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy}-N-methyl-pyridine -2 – formamide by Bayer (Bayer) research and development, in 2005 the U.S. Food and Drug Administration (FDA) approval. Trade name Nexavar (Nexavar). This product is an oral multi-kinase inhibitor, for the treatment of liver cancer and kidney cancer.

Indian Patent Office in March this year for Bayer’s Nexavar in liver and kidney cancer drugs (Nexavar) has released a landmark “compulsory licensing” (compulsory license). Indian Patent Office that due to the high price Nexavar in India, the vast majority of patients can not afford the drug locally, thus requiring local Indian pharmaceutical company Natco cheap Nexavar sales. Nexavar in 2017 before patent expiry, Natco pay only Bayer’s pharmaceutical sales to 6% royalties. The move to make Nexavar patent drug prices, the supply price from $ 5,500 per month dropped to $ 175, the price reduction of 97%. Compulsory licensing in India for other life-saving drugs and patent medicines overpriced open a road, the Indian Patent Office through this decision made it clear that the patent monopoly does not guarantee that the price is too high. Nexavar is a fight against advanced renal cell carcinoma, liver cancer cure. In China, a box of 60 capsules of Nexavar price of more than 25,000 yuan. In accordance with the recommended dose, which barely enough to eat half of patients with advanced cancer. In September this year India a patent court rejected Bayer Group in India cheap drugmaker emergency appeal. Indian government to refuse patent medicine overpriced undo “compulsory licensing rules,” allowing the production of generic drugs Nexavar.

Sorafenat by Natco – Sorafenib – Nexavar – India natco Nexavar

Chemical Synthesis of Sorafenib Tosylate (Nexavar)

Sorafenib tosylate (brand name :Nexavar®, other name BAY 43-9006, was approved by US FDA for the treatment of kidney cancer in 2005 and advanced liver cancer in 2007.

US Patent US7235576, WO2006034796, WO2009111061 and Faming Zhuanli Shenqing(CN102311384) disclosed processes for preparation of sorafenib base and its salt sorafenib tosylate.

References

1)Bernd Riedl, Jacques Dumas, Uday Khire, Timothy B. Lowinger, William J. Scott, Roger A. Smith, Jill E. Wood, Mary-Katherine Monahan, Reina Natero, Joel Renick, Robert N. Sibley; Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors; US patent numberUS7235576
2)Rossetto, pierluigi; Macdonald, peter, lindsay; Canavesi, augusto; Process for preparation of sorafenib and intermediates thereof, PCT Int. Appl., WO2009111061
3)Lögers, michael; gehring, reinhold; kuhn, oliver; matthäus, mike; mohrs, klaus; müller-gliemann, matthias; stiehl, jürgen; berwe, mathias; lenz, jana; heilmann, werner; Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide, PCT Int. Appl., WO2006034796CN102311384, CN201010212039

Full Experimental Details for the preparation of Sorafenib Tosylate (Nexavar)

Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temp. for 2 h. The contents were treated with 4-chloro- N -methyl-2-pyridinecarboxamide (15.0 g, 87.9mmol) and K2CO3 (6.50 g, 47.0 mmol) and then heated at 80°C. for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4×1000 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35°C. for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g, 84%):. 1H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA’BB’ quartet, J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 8.44 (d, J = 5.5 Hz; 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H)+).

Synthesis of 4-{4-[({[4-Chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide (sorafenib)

4-(4-Aminophenoxy)-N-methyl-2-pyridinecarboxamide (52.3 kg, 215 mol) is suspended in ethyl acetate (146 kg) and the suspension is heated to approx. 40° C. 4-Chloro-3-trifluoromethylphenyl isocyanate (50 kg, 226 mol), dissolved in ethyl acetate (58 kg), is then added to such a degree that the temperature is kept below 60° C. After cooling to 20° C. within 1 h, the mixture is stirred for a further 30 min and the product is filtered off. After washing with ethyl acetate (30 kg), the product is dried under reduced pressure (50° C., 80 mbar). 93 kg (93% of theory) of the title compound are obtained as colorless to slightly brownish crystals. m.p. 206-208° C. 1H-NMR (DMSO-d6, 500 MHz): δ =2.79 (d, J=4.4 Hz, 3H, NCH3); 7.16 (dd, J=2.5, 5.6 Hz, 1H, 5-H); 7.18 (d, J=8.8 Hz, 2H, 3′-H, 5′-H); 7.38 (d, J=2.4 Hz, 1H, 3-H); 7.60-7.68 (m, 4H, 2′-H, 6′-H, 5″-H, 6″-H); 8.13 (d, J=1.9 Hz, 1H, 2″-H); 8.51 (d, J=5.6 Hz, 1H, 6-H); 8.81 (d, J=4.5 Hz, 1H, NHCH3); 9.05 (br. s, 1H, NHCO); 9.25 (br. s, 1H, NHCO) MS (ESI, CH3CN/H2O): m/e=465 [M+H]+.

Synthesis of Sorafenib Tosylate (Nexavar)

4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide (sorafenib) (50g, 0.1076 mol) is suspended in ethyl acetate (500 g) and water (10g). The mixture is heated to 69°C within 0.5 h, and a filtered solution of p-toluenesulfonic acid monohydrate (3.26 g, 0.017 mol) in a mixture of water (0.65 g) and ethyl acetate (7.2 g) is added. After filtration a filtered solution of p-toluenesulfonic acid monohydrate (22g, 0.11 mol) in a mixture of ethyl acetate (48 g) and water (4.34 g) is added. The mixture is cooled to 23°C within 2 h. The product is filtered off, washed twice with ethyl acetate (92.5 g each time) and dried under reduced pressure. The sorafenib tosylate (65.5 g, 96% of theory) is obtained as colorless to slightly brownish crystals.

…………………..

http://www.google.com/patents/EP2195286A2?cl=en

Example 22: Synthesis of Sorafenib

Phenyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (100 g, 0.3174 mol) and 4-(4- aminophenoxy)-N-methylpicolinamide (77.14 g, 0.3174 mol) were dissolved in N₁N- dimethyl formamide (300 ml) to obtain a clear reaction mass. The reaction mass was agitated at 40-45⁰C for 2-3 hours, cooled to room temperature and diluted with ethyl acetate (1000 ml). The organic layer was washed with water (250 ml) followed by 1N HCI (250ml) and finally with brine (250 ml). The organic layer was separated, dried over sodium sulfate and degassed to obtain solid. This solid was stripped with ethyl acetate and finally slurried in ethyl acetate (1000 ml) at room temperature. It was then filtered and vacuum dried to give (118 g) of 4-(4-(3-(4-chloro-3- (trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base).

Example 23: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)urea (Compound 4)

Sodium cyanate (1.7 g, 0.02mol) was dissolved in water (17ml) at room temperature to obtain a clear solution. This solution was then charged drop wise to the clear solution of 3- trifluoromethyl-4-chloroaniline (5 g, 0.025 mol) in acetic acid (25 ml) at 40°C-45°C within 1- 2 hours. The reaction mass was agitated for whole day and cooled gradually to room temperature. The obtained solid was filtered washed with water and vacuum dried at 50⁰C to afford the desired product (5.8 g) i.e. 1-(4-chloro-3-(trifluoromethyl)phenyl)urea.

Example 24: Synthesis of Sorafenib

1-(4-chloro-3-(trifluoromethyl) phenyl)urea (15 g, 0.0628 mol), 1 ,8- diazabicyclo[5.4.0]undec-7-ene (11.75 ml, 0.078 mol) and 4-(4-aminophenoxy)-N- methylpicolinamide (15.27 g, 0.0628 mol) were mixed with dimethyl sulfoxide (45 ml) and the reaction mass was then heated to 110-120⁰C for 12-18 hours. The reaction mass was cooled to room temperature and quenched in water (250 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in acetonitrile (150 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido) phenoxy)-N-methylpicolinamide (sorafenib base) (17.5 g).

………………………..

http://www.google.com/patents/WO2009054004A2?cl=en

http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2009054004A2&KC=A2&FT=D&date=20090430&DB=EPODOC&locale=en_gb

Figure imgf000006_0002

EXAMPLES

Example 1

Preparation of l-(4-chloro-3-(trifluoromethyl)phenyI)-3-(4-hydroxyphenyl)urea Into a 250 ml, four-necked RB flask was charged 1O g of 4-aminophenol and 100 ml of toluene. A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyante (20.4 g) in toluene (50 ml) was added to the reaction mass at 25-30⁰C. The reaction mass was stirred at room temperature for 16 h. The reaction mass was filtered and washed the. solid with 50 ml of toluene. The wet material was dried in the oven at 50-60°C to get 29.8 g of title compound as white solid. M.P. is 218-222°C. IR (KBr): 3306, 1673, 1625, 1590, 1560, 1517, 1482, 1435, 1404, 1328, 1261, 1182, 1160, 1146, 1125, 1095, 1032, 884, 849, 832, 812, 766, 746, 724, 683, 539 and 434 cm^“1.

Example 2 Preparation of sorafenib tosylate

Into a 100 ml, three-necked RB flask was charged 2.0 g of l-(4-chloro-3- (trifluoromethyl)-phenyl)-3-(4-hydroxyphenyl)urea and 10 ml of DMF. Potassium tert- butoxide (2.3 g) was added to the reaction mass and stirred for 45 min at RT. 4-Chlro-N- methylpicolinamide (1.14 g) and potassium carbonate (0.42 g) were added to the reaction mass and heated to 80°C. The reaction mass was maintained at 80-85°C for 8 h and cooled to 30°C. The reaction mass was poured into water and extracted with ethyl acetate. Ethyl acetate layer was washed with water, brine and dried over sodium sulphate. Solvent was distilled of under reduced pressure.

The crude compound (4.7 g) was dissolved in 10 ml of IPA and added 1.9 g of p- toluenesulfonic acid. The reaction mass was stirred at RT for 15 h and filtered. The wet solid was washed with 10 ml of IPA and dried at 50-60°C to get 3.4 g of title compound as off-white crystalline solid.

…………………..

A Scaleable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer

Donald Bankston,*Jacques Dumas,Reina Natero,Bernd Riedl,Mary-Katherine Monahan, andRobert Sibley

Bayer Research Center, Pharmaceutical Division, 400 Morgan Lane, West Haven, Connecticut 06516, U.S.A.

Org. Proc. Res. Dev., 2002, 6 (6), pp 777–781

DOI: 10.1021/op020205n

http://pubs.acs.org/doi/abs/10.1021/op020205n

Urea 3 (BAY 43–9006), a potent Raf kinase inhibitor, was prepared in four steps with an overall yield of 63%. Significant process research enabled isolation of each intermediate and target without chromatographic purification, and overall yield increases >50% were observed compared to those from previous methods. This report focuses on improved synthetic strategies for production of scaled quantities of 3 for preclinical, toxicological studies. These improvements may be useful to assemble other urea targets as potential therapeutic agents to combat cancer.

Synthesis of N-[4-Chloro-3-(trifluoromethyl)phenyl]({4-[2-(N-methyl-carbamoyl)(4-pyridyloxy)]phenyl}amino)carboxamide (3, BAY 43–9006).

A suspension of 9 (67.00 g, 275.43 mmol) in methylene chloride ———————-DELETE………………………………The solids were washed with methylene chloride (2 × 50 mL) and dried under vacuum for 4 h at 35 °C to afford 3 (118.19 g, 254.27 mmol, 92%) as an off-white solid.

Mp = 210−212 °C.

¹H NMR (DMSO-d₆, 300 MHz):

δ 2.77 (d, J = 4.8 Hz, 3H, −NHCH₃);

7.16 (m, 3H, aromatic);

7.37 (d, J = 2.5 Hz, 1H, aromatic);

7.62 (m, 4H, aromatic);

8.11 (d, J = 2.5 Hz, 1H, aromatic);

8.49 (d, J = 5.5 Hz, 1H, aromatic);

8.77 (br d, 1H, −NHCH₃);

8.99 (s, 1H, −NHCO−); 9.21 (s, 1H, −NHCO−).

Mass spectrum (HPLC/ES): m/e = 465 (M + 1).

Anal. Calcd for C₂₁H₁₆N₄ClF₃O₃: C, 54.26; H, 3.47; N, 12.05. Found: C, 54.11; H, 3.49; N, 12.03.

HPLC (ELS) purity >98%: t_R = 3.5 min.

Synthesis of N-[4-Chloro-3-(trifluoromethyl)phenyl]({4-[2-(N-methyl-carbamoyl)(4-pyridyloxy)]phenyl}amino)carboxamide (3, BAY 43–9006): Use of CDI.

A solution of 11 (1.25 g, 6.39 mmol) in methylene chloride———————-DELETED……………………. high vacuum at 35 °C for 2 h to afford 3 (2.55 g, 5.49 mmol, 91%) as a white solid. Proton NMR and mass-spectral data were consistent with structure.

Anal. Calcd for C₂₁H₁₆N₄ClF₃O₃: C, 54.26; H, 3.47; N, 12.05; Cl, 7.63. Found: C, 54.24; H, 3.31; N, 12.30; Cl, 7.84.

Mp (differential scanning calorimetry, 10 °C/min): 205.6 °C;

no polymorphs observed.

References

“FDA Approves Nexavar for Patients with Inoperable Liver Cancer” (Press release). FDA. November 19, 2007. Retrieved November 10, 2012.
“Nexavar (sorafenib) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 26 December 2013.
“NEXAVAR (sorafenib) tablet, film coated [Bayer HealthCare Pharmaceuticals Inc.]”. DailyMed. Bayer HealthCare Pharmaceuticals Inc. November 2013. Retrieved 26 December 2013.
“Nexavar 200mg film-coated tablets – Summary of Product Characteristics (SPC) – (eMC)”. electronic Medicines Compendium. Bayer plc. 27 March 2013. Retrieved 26 December 2013.
“PRODUCT INFORMATION NEXAVAR® (sorafenib tosylate)” (PDF). TGA eBusiness Services. Bayer Australia Ltd. 12 December 2012. Retrieved 26 December 2013.
Escudier, B; Eisen, T; Stadler, WM; Szczylik, C; Oudard, S; Siebels, M; Negrier, S; Chevreau, C; Solska, E; Desai, AA; Rolland, F; Demkow, T; Hutson, TE; Gore, M; Freeman, S; Schwartz, B; Shan, M; Simantov, R; Bukowski, RM (January 2007). “Sorafenib in advanced clear-cell renal-cell carcinoma”. New England Journal of Medicine 356 (2): 125–34. doi:10.1056/NEJMoa060655. PMID 17215530.
Walid, MS; Johnston, KW (October 2009). “Successful treatment of a brain-metastasized renal cell carcinoma”. German Medical Science 7: Doc28. doi:10.3205/000087. PMC 2775194. PMID 19911072.
“Pharmaceutical Benefits Scheme (PBS) -SORAFENIB”. Pharmaceutical Benefits Scheme. Australian Government Department of Health. Retrieved 27 December 2013.
Llovet, et al. (2008). “Sorafenib in Advanced Hepatocellular Carcinoma” (PDF). New England Journal of Medicine 359 (4): 378–90.
Keating GM, Santoro A (2009). “Sorafenib: a review of its use in advanced hepatocellular carcinoma”. Drugs 69 (2): 223–40. doi:10.2165/00003495-200969020-00006. PMID 19228077.
Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF (October 2011). “Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma”. J. Clin. Oncol. 29 (30): 3960–7. doi:10.1200/JCO.2011.37.1021. PMID 21911714.
“Phase 3 Trial of Nexavar in Patients With Non-Responsive Thyroid Cancer”^{[dead link]}
[1]
“Chemotherapy-Induced Nausea and Vomiting Treatment & Management”. Medscape Reference. WebMD. 3 July 2012. Retrieved 26 December 2013.
Hagopian, Benjamin (August 2010). “Unusually Severe Bullous Skin Reaction to Sorafenib: A Case Report”. Journal of Medical Cases 1 (1): 1–3. doi:10.4021/jmc112e. Retrieved 11 February 2014.
Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M (January 2009). “CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations”. Oncogene 28 (1): 85–94. doi:10.1038/onc.2008.362. PMC 2898184. PMID 18794803.
Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (October 2008). “Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling”. Mol. Cancer Ther. 7 (10): 3129–40. doi:10.1158/1535-7163.MCT-08-0013. PMID 18852116.
Zhang Y (Jan 2014). “Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways.”. J Mol Med Rep 9 (1): 83–90. PMID 24213221.
Gauthier A (Feb 2013). “Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update..”. Hepatol Res 43 (2): 147–154. doi:10.1111/j.1872-034x.2012.01113.x. PMID 23145926.
FDA Approval letter for use of sorafenib in advanced renal cancer
European Commission – Enterprise and industry. Nexavar. Retrieved April 24, 2007.
“Nexavar® (Sorafenib) Approved for Hepatocellular Carcinoma in Europe” (Press release). Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. October 30, 2007. Retrieved November 10, 2012.
FDA Approval letter for use of sorafenib in inoperable hepatocellular carcinoma
“Liver drug ‘too expensive‘“. BBC News. November 19, 2009. Retrieved November 10, 2012.
http://www.ipindia.nic.in/ipoNew/compulsory_License_12032012.pdf
“Seven days: 9–15 March 2012”. Nature 483 (7389): 250–1. 2012. doi:10.1038/483250a.
“India Patents (Amendment) Act, 2005”. WIPO. Retrieved 16 January 2013.
[2]
“Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients”
ClinicalTrials.gov NCT00329719 Sorafenib and Temsirolimus in Treating Patients With Recurrent Glioblastoma
“Activity of sorafenib against desmoid tumor/deep fibromatosis”
“‘We didn’t make this medicine for Indians… we made it for western patients who can afford it‘“. Daily Mail Reporter. 24 Jan 2014.

External links

Nexavar.com – Manufacturer’s website
Prescribing Information – includes data from the key studies justifying the use of sorafenib for the treatment of kidney cancer (particularly clear cell renal cell carcinoma, which is associated with the von Hippel-Lindau gene)
Patient Information from FDA
Sorafenib in Treating Patients With Soft Tissue Sarcomas
Sorafenib Sunitinib differences – diagram
ClinicalTrials.gov NCT00217399 – Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
Cipla launches Nexavar generic at 1/10 of Bayer’s price

Reference
1	*	D. BANKSTON ET AL.: “A Scalable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer” ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 6, no. 6, 2002, pages 777-781, XP002523918 cited in the application
2	*	PAN W ET AL: “Pyrimido-oxazepine as a versatile template for the development of inhibitors of specific kinases” BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 15, no. 24, 15 December 2005 (2005-12-15), pages 5474-5477, XP025314229 ISSN: 0960-894X [retrieved on 2005-12-15]

Citing Patent	Filing date	Publication date	Applicant	Title
WO2011036647A1	Sep 24, 2010	Mar 31, 2011	Ranbaxy Laboratories Limited	Process for the preparation of sorafenib tosylate
WO2011036648A1	Sep 24, 2010	Mar 31, 2011	Ranbaxy Laboratories Limited	Polymorphs of sorafenib acid addition salts
WO2011058522A1	Nov 12, 2010	May 19, 2011	Ranbaxy Laboratories Limited	Sorafenib ethylsulfonate salt, process for preparation and use
WO2011092663A2	Jan 28, 2011	Aug 4, 2011	Ranbaxy Laboratories Limited	4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-n2-methylpyridine-2-carboxamide dimethyl sulphoxide solvate
WO2011113367A1 *	Mar 17, 2011	Sep 22, 2011	Suzhou Zelgen Biopharmaceutical Co., Ltd.	Method and process for preparation and production of deuterated ω-diphenylurea
US8552197	Nov 12, 2010	Oct 8, 2013	Ranbaxy Laboratories Limited	Sorafenib ethylsulfonate salt, process for preparation and use
US8604208	Sep 24, 2010	Dec 10, 2013	Ranbaxy Laboratories Limited	Polymorphs of sorafenib acid addition salts
US8609854	Sep 24, 2010	Dec 17, 2013	Ranbaxy Laboratories Limited	Process for the preparation of sorafenib tosylate
US8618305	Jan 28, 2011	Dec 31, 2013	Ranbaxy Laboratories Limited	Sorafenib dimethyl sulphoxide solvate
US8669369	Mar 17, 2011	Mar 11, 2014	Suzhou Zelgen Biopharmaceutical Co., Ltd.	Method and process for preparation and production of deuterated Ω-diphenylurea

Taltirelin Талтирелин for Treatment of Neurodegenerative Diseases,

May 15, 2014 4:22 am / Leave a comment

Taltirelin Талтирелин

N-{[(4S)-1-methyl-2,6-dioxohexahydropyrimidin-4-yl]carbonyl}-L-histidyl-L-prolinamide

(S)-1-Methyl-4,5-dihydroorotyl-L-histidyl-L-prolinamide
(S)-N-(1-Methyl-2,6-dioxohexahydropyrimidin-4-ylcarbonyl)-L-histidyl-L-prolinamide

launched 2000 by Mitsubishi Tanabe Pharma

Tanabe Seiyaku Co., Ltd.

103300-74-9
201677-75-0

Taltirelin tetrahydrate, Taltirelin hydrate, 201677-75-0, TA 0910

Molecular Formula: C₁₇H₃₁N₇O₉ Molecular Weight: 477.46954

LS-185116
D01925

N-{[(4S)-1-methyl-2,6-dioxohexahydropyrimidin-4-yl]carbonyl}-L-histidyl-L-prolinamide tetrahydrate

Taltirelin (marketed under the tradename Ceredist) is a thyrotropin-releasing hormone (TRH) analog, which mimics the physiological actions of TRH, but with a much longer half-life and duration of effects,^[1] and little development of tolerance following prolonged dosing.^[2] It has nootropic,^[3] neuroprotective^[4] and analgesic effects.^[5]

Taltirelin is primarily being researched for the treatment of spinocerebellar ataxia; limited research has also been carried out with regard to other neurodegenerative disorders, e.g., spinal muscular atrophy.^[6]^[7]^[8]

Taltirelin is a thyrotropin-releasing hormone (TRH) analog that was first commercialized by Tanabe Seiyaku (now Mitsubishi Tanabe Pharma) in Japan in 2000 for the oral treatment of ataxia due to spinocerebellar degeneration.

In 2008, the company filed a regulatory application seeking approval of taltirelin orally disintegrating tablets for the treatment of spinocerebellar degeneration, and in 2009 the approval was received for this formulation.

TRH is a tripeptide hormone that stimulates the release of thyroid-stimulating hormone and prolactin by the anterior pituitary. TRH is produced by the hypothalamus and travels across the median eminence to the pituitary via the hypophyseal portal system.

Taltirelin (TAL) is a thyrotropin-releasing hormone (TRH) analog that is approved for use in humans in Japan. In this study, we characterized TAL binding to and signaling by the human TRH receptor (TRH-R) in a model cell system. We found that TAL exhibited lower binding affinities than TRH and lower signaling potency via the inositol-1,4,5-trisphosphate/calcium pathway than TRH. However, TAL exhibited higher intrinsic efficacy than TRH in stimulating inositol-1,4,5-trisphosphate second messenger generation. This is the first study that elucidates the pharmacology of TAL at TRH-R and shows that TAL is a superagonist at TRH-R

……………………………

Synthesis and central nervous system actions of thyrotropin-releasing hormone analogues containing a dihydroorotic acid moiety
J Med Chem 1990, 33(8): 2130\

http://pubs.acs.org/doi/abs/10.1021/jm00170a013

………………

http://www.google.com/patents/US4665056

EXAMPLE 2

(1) 1.56 g of 1-methyl-L-4,5-dihydroorotic acid and 1.15 g of N-hydroxysuccinimide are dissolved in 30 ml of dimethylformamide, and 2.06 g of dicyclohexylcarbodiimide are added thereto at 0° C. The mixture is stirred at room temperature for 2 hours. The solution thus obtained is hereinafter referred to as “Solution A”. On the other hand, 3.43 g of benzyl L-histidyl-L-prolinate.2HCl are dissolved in dimethylformamide, and 1.67 g of triethylamine are added thereto. The mixture is stirred at 0° C. for 20 minutes, and insoluble materials are filtered off. The filtrate is added to “Solution A”, and the mixture is stirred at 0° C. for 4 hours and then at 10° C. for one day. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure at 40° C. to remove dimethylformamide. The residue is dissolved in water, and insoluble materials are filtered off. The filtrate is adjusted to pH 8 with sodium bicarbonate and then passed through a column packed with CHP-20P resin. The column is washed with 500 ml of water, 500 ml of 20% methanol and 300 ml of 50% methanol, successively. Then, the desired product is eluted with 70% methanol. The fractions which are positive to the Pauly’s reaction are collected from the eluate and concentrated under reduced pressure, whereby 3.65 g of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate are obtained as an oil.

IRν_max ^chloroform (cm^-1) 3300, 1725, 1680.

650 mg of the product obtained above are dissolved in 1 N-HCl and then lyophilized to give 690 mg of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate.HCl.H₂ O as powder.

[α]_D ²² : -39.8° (C=0.5, H₂ O).

IRν_max ^nujol (cm^-1): 1720, 1640-1680.

NMR (DMSO-d₆, δ): 1.7-2.4 (m, 4H), 2.90 (s, 3H), 2.4-3.9 (m, 6H), 3.9-4.2 (m, 1H), 4.3-4.5 (m, 1H), 4.6-5.0 (m, 1H), 5.09 (s, 2H), 7.2-7.5 (m, 5H), 8.96 (s, 1H).

Mass (m/e): 496 (M⁺).

(2) 700 mg of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate are dissolved in 20 ml of methanol, and 20 mg of palladium-black are added thereto. The mixture is stirred at room temperature for 3 hours in hydrogen gas. 20 ml of water are added to the reaction mixture, and the catalyst is filtered off. The filtrate is evaporated to remove solvent. The residue is crystallized with methanol, whereby 290 mg of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-proline.5/4 H₂ O are obtained.

M.p.: 233°-236° C. (decomp.).

[α]_D ²⁰ : -17.2° (C=0.5, H₂ O).

IRν_max ^nujol (cm^-1): 1715, 1680, 1630.

NMR (D₂ O, δ): 1.7-2.4 (m, 4H), 2.6-3.9 (m, 6H), 3.03 (s, 3H), 4.0-4.45 (m, 2H), 4.95 (t, 1H), 7.27 (s, 1H), 8.57 (s, 1H).

(3) A mixture of 4.29 g of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-proline, 1.15 g of N-hydroxysuccinimide, 2.26 g of dicyclohexylcarbodiimide and 30 ml of dimethylformamide is stirred at 0° C. for 40 minutes and at room temperature for 80 minutes. 30 ml of 15% ammonia-methanol are then added to the mixture at 0° C., and the mixture is stirred at 0° C. for 30 minutes and at room temperature for one hour. Insoluble materials are filtered off, and the filtrate is evaporated to remove dimethylformamide. The residue is dissolved in 20 ml of water, and insoluble materials are again filtered off. The filtrate is adjusted to pH 8 with sodium bicarbonate and then passed through a column packed with CHP-20P resin. After the column is washed with 2 liters of water, the desired product is eluted with 10% methanol. The fractions which are positive to the Pauly’s reaction are collected and concentrated under reduced pressure. The residue is dissolved in 10 ml of water, and allowed to stand in a refrigerator. Crystalline precipitates are collected by filtration, washed with water, and then dried at 25° C. for one day, whereby 3.3 g of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinamide.7/2 H₂ O are obtained.

M.p.: 72°-75° C.

[α]_D ²⁵ : -13.6° (C=1, H₂ O).

IRν_max ^nujol (cm^-1): 3400, 3250, 1710, 1660, 1610, 1540.

References

Fukuchi, I.; Asahi, T.; Kawashima, K.; Kawashima, Y.; Yamamura, M.; Matsuoka, Y.; Kinoshita, K. (1998). “Effects of taltirelin hydrate (TA-0910), a novel thyrotropin-releasing hormone analog, on in vivo dopamine release and turnover in rat brain”. Arzneimittel-Forschung 48 (4): 353–359. PMID 9608876.
Asai, H.; Asahi, T.; Yamamura, M.; Yamauchi-Kohno, R.; Saito, A. (2005). “Lack of behavioral tolerance by repeated treatment with taltirelin hydrate, a thyrotropin-releasing hormone analog, in rats”. Pharmacology Biochemistry and Behavior 82 (4): 646–651. doi:10.1016/j.pbb.2005.11.004. PMID 16368129.
Yamamura, M.; Suzuki, M.; Matsumoto, K. (1997). “Synthesis and pharmacological action of TRH analog peptide (Taltirelin)”. Nihon yakurigaku zasshi. Folia pharmacologica Japonica. 110 Suppl 1: 33P–38P. PMID 9503402.
Urayama, A.; Yamada, S.; Kimura, R.; Zhang, J.; Watanabe, Y. (2002). “Neuroprotective effect and brain receptor binding of taltirelin, a novel thyrotropin-releasing hormone (TRH) analogue, in transient forebrain ischemia of C57BL/6J mice”. Life Sciences 72 (4–5): 601–607. doi:10.1016/S0024-3205(02)02268-3. PMID 12467901.
Tanabe, M.; Tokuda, Y.; Takasu, K.; Ono, K.; Honda, M.; Ono, H. (2009). “The synthetic TRH analogue taltirelin exerts modality-specific antinociceptive effects via distinct descending monoaminergic systems”. British Journal of Pharmacology 150 (4): 403–414. doi:10.1038/sj.bjp.0707125. PMC 2189720. PMID 17220907.
Takeuchi, Y.; Miyanomae, Y.; Komatsu, H.; Oomizono, Y.; Nishimura, A.; Okano, S.; Nishiki, T.; Sawada, T. (1994). “Efficacy of Thyrotropin-Releasing Hormone in the Treatment of Spinal Muscular Atrophy”. Journal of Child Neurology 9 (3): 287–289. doi:10.1177/088307389400900313. PMID 7930408.
Tzeng, A. C.; Cheng, J.; Fryczynski, H.; Niranjan, V.; Stitik, T.; Sial, A.; Takeuchi, Y.; Foye, P.; Deprince, M.; Bach, J. R. (2000). “A study of thyrotropin-releasing hormone for the treatment of spinal muscular atrophy: A preliminary report”. American journal of physical medicine & rehabilitation / Association of Academic Physiatrists 79 (5): 435–440. doi:10.1097/00002060-200009000-00005. PMID 10994885.
Kato, Z.; Okuda, M.; Okumura, Y.; Arai, T.; Teramoto, T.; Nishimura, M.; Kaneko, H.; Kondo, N. (2009). “Oral Administration of the Thyrotropin-Releasing Hormone (TRH) Analogue, Taltireline Hydrate, in Spinal Muscular Atrophy”. Journal of Child Neurology 24 (8): 1010–1012. doi:10.1177/0883073809333535. PMID 19666885.
- EP 168 042 (Tanabe Seiyaku; appl. 10.7.1985; GB-prior. 10.7.1984).
- JP 62 234 029 (Tanabe Seiyaku; J-prior. 27.12.1985).
- Suzuki, M. et al.: J. Med. Chem. (JMCMAR) 33 (8), 2130-2137 (1990).

External links

(Japanese) Ceredist セレジスト錠 (PDF) Mitsubishi Tanabe Pharma. October 2007.

SITAFLOXACIN …………Antibacterial [DNA-gyrase inhibitor]

March 30, 2014 5:11 am / Leave a comment

7-[(4S)-4-Amino-6-azaspiro[2.4]heptan-6-yl]-8-chloro-6-fluoro-1-[(2S)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid

(1R-(1a(S*),2a))-7-(7-Amino-5-azaspiro[2.4]hept-5-yl)-8-chloro-6-fluoro-1-(2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic Acid

SYNTHESIS……….http://www.drugfuture.com/synth/syndata.aspx?ID=176447

127254-10-8 [RN]

127254-10-8(ACETATE)

127254-12-0 [RN]

163253-35-8 [RN] MAY BE CORRECT SESQUIHYDRATE

163253-36-9 (HEMIHYDRATE)

163253-37-0 (MONOHYDRATE)

Sitafloxacin isomer II, DU-6859a, STFX, 127254-12-0, 127254-10-8, 163253-35-8

Molecular Formula: C₁₉H₁₈ClF₂N₃O₃ Molecular Weight: 409.814326

DU 6859A
DU-6859a
Sitafloxacin
UNII-9TD681796G

Sitafloxacin (INN; also called DU-6859a) is a fluoroquinolone antibiotic^[1] that shows promise in the treatment of Buruli ulcer. The molecule was identified by Daiichi Sankyo Co., which brought ofloxacin and levofloxacin to the market. Sitafloxacin is currently marketed in Japan by Daiichi Sankyo under the tradename Gracevit.

Sitafloxacin is a new-generation, broad-spectrum oral fluoroquinolone antibiotic.It is very active against many Gram-positive, Gram-negative and anaerobic clinical isolates, including strains resistant to other fluoroquinolones, was recently approved in Japan for the treatment of respiratory and urinary tract infections. Sitafloxacin is active against methicillin-resistant staphylococci, Streptococcus pneumoniae and other streptococci with reduced susceptibility to levofloxacin and other quinolones and enterococci

163253-35-8

C19-H18-Cl-F2-N3-O3.3/2H2-O

427.833

AU 8933702; EP 0341493; JP 1990231475; JP 1995300416; JP 1999124367; JP 1999124380; US 5587386; US 5767127
The condensation of 3-chloro-2,4,5-trifluorobenzoylacetic acid ethyl ester (I) with (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) and ethyl orthoformate (II) in hot acetic anhydride gives (1R,2S)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(2-fluorocyclopropylamino)acrylic acid ethyl ester (IV). The cyclization of (IV) by means of NaH yields the quinolone (V), which is hydrolyzed with HCl to the free acid (VI). The condensation of (VI) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) by means of triethylamine in refluxing acetonitrile affords the protected final product (VIII), which is finally deprotected with trifluoroacetic acid and anisole.

The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) is obtained as follows: 1) The cyclization of butadiene (IX) with dibromofluoromethane by means of BuONa, followed by oxidation with KMnO4, esterification with ethanol – sulfuric acid and reduction with tributyltin hydride gives 2-fluorocyclopropanecarboxylic acid ethyl ester as a cis/trans mixture (X), which is separated by crystallization. The cis-racemic-isomer (XI) is hydrolyzed with NaOH to the corresponding acid (XII), which is condensed with (R)-alpha-methylbenzylamine (XIII) by means of diphenyl chlorophosphate to give the mixture of diastereomers (XIV). This mixture is separated by crystallization, yielding pure (1S,2S)-2-fluoro-N-[alpha(R)-methylbenzyl]cyclopropanecarboxamide (XV), which is hydrolyzed with HCl to the corresponding free acid (XVI). Finally, this compound is converted into (III) by treatment with diphenylphosphoryl azide in refluxing tert-butanol.

b) The intermediate 7(S)-(tert-Butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) can also be obtained as follows: 1) The cyclopropanation of ethyl acetoacetate (XXXI) with 1,2-dibromoethane (XXXII) by means of K2CO3 in DMF gives 1-acetylcyclopropane-1-carboxylic acid ethyl ester (XXXIII), which is brominated with Br2 in ethanol yielding the bromoacetyl derivative (XXXIV). The cyclization of (XXXI) with (R)-alpha-methylbenzylamine (XIII) by means of triethylamine affords 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione (XXXV), which by reaction with hydroxylamine is converted into the monooxime (XXXVI). The reduction of (XXXVI) with H2 over RaNi in methanol affords 7-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptan-4-one as a diastereomeric mixture (XXXVII) + (XXXVIII), which is separated by column chromatography. The reduction of the (7S)-isomer (XXXVIII) with LiAlH4 in THF gives 7(S)-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane (XXXIX), which is protected in the usual way to the tert-butoxycarbonyl derivative (XL). Finally, this compound is debenzylated to (VII) by hydrogenation with H2 over Pd/C in ethanol.

b) The intermediate 7(S)-(tert-Butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) can also be obtained as follows: 2) The reaction of 1-acetylcyclopropane-1-carboxylic acid ethyl ester (XXXIII) with (R)-alpha-methylbenzylamine (XIII) by means of NaOH and ethyl chloroformate gives the corresponding amide (XLI), which by reaction with ethylene glycol and p-toluenesulfonic acid is converted into the ethylene ketal (XLII). The bromination of (XLII) with Br2 in dioxane affords the bromomethyl dioxolane (XLIII), which is finally cyclized to 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione (XXXV), already obtained as an intermediate in the preceding synthesis.

The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) can also be obtained as follows: 3) A study of the influence of different substituents in the cis/trans ratio of the cyclopropanation process has been performed. The general method is as follows: the reaction of benzylamine (XXIII) with acetaldehyde and trichloromethyl chloroformate gives the N-benzyl-N-vinylcarbamoyl chloride (XXIV), which by treatment with alcohol yields the N-vinylcarbamate (XXV). The cyclopropanation of (XXV) with fluorodiiodomethane and diethyl zinc as before preferentially affords the cis-N-(2-fluorocyclopropyl)carbamate (XXVI), which is purified by crystallization. The hydrogenolysis of (XXVI) with H2 over Pd/C in acetic acid gives cis-racemic-2-fluorocyclopropylamine (XXVII), which is submitted to optical resolution with L-menthyl chloroformate to afford pure (1R,2S)-isomer (XXII). Finally, this compound is converted into (III) with tert-butoxycarbonyl anhydride as before.

References

Anderson, DL. (Jul 2008). “Sitafloxacin hydrate for bacterial infections.”. Drugs Today (Barc) 44 (7): 489–501. doi:10.1358/dot.2008.44.7.1219561.PMID 18806900.
Chem Pharm Bull 1998,46(4),587
J Med Chem 1994,37(20),3344
Drugs Fut 1994,19(9),827
33rd Intersci Conf Antimicrob Agents Chemother (Oct 17-20, New Orleans) 1993,Abst 975
Tetrahedron Lett 1992,33(24),3487-90

Keating GM (April 2011). “Sitafloxacin: in bacterial infections”. Drugs 71 (6): 731–44. doi:10.2165/11207380-000000000-00000.PMID 21504249.

(Japanese) Gracevit グレースビット (PDF) Daiichi Sankyo Co. January 2008.

US8129533	3-7-2012	Method for Production of Quinolone-Containing Lyophilized Preparation
US7304075	12-5-2007	Stabilized liquid preparation
US2007196504	8-24-2007	PHARMACEUTICAL COMPOSITION
US2007148235	6-29-2007	PHARMACEUTICAL COMPOSITION
US2005152975	7-15-2005	Pharmaceutical composition
US6861071	3-2-2005	Highly absorptive solid preparation
US2004132756	7-9-2004	Highly absorbable solid preparation
US2004022848	2-6-2004	Medicinal composition
WO9964037	12-17-1999	NOVEL THERAPEUTIC AGENTS THAT MODULATE ENZYMATIC PROCESSES

Japanese Pharmacopoeia and Japanese GMP Regulations available online

March 7, 2014 3:08 am / 1 Comment on Japanese Pharmacopoeia and Japanese GMP Regulations available online

Japanese Pharmacopoeia and Japanese GMP Regulations available online

On Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) website, you can download documents on GMP as well as on marketing authorisations for medicinal products. An English version of the Japanese Pharmacopoeia (JP) is also available. You will find the direct links in the News.

On Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) website, you can find in the section “Regulations and Procedures” under the heading “GMP” requirements regarding the inspection of manufacturers of medicinal products and APIs who want to introduce their products into Japan.

Now, a document was supplemented in January 2014 which describes which documents have to be submitted to the Japanese Agency within a pre-approval inspection and/ or a periodical post-approval inspection.

Go to the PMDA webpage to get more information.

There, you can also access the current Japanese Pharmacopoeia Sixteenth Edition in English.

Source: PMDA, Japan

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