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

 

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.

compd 2 and 1

OR

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

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

compd 3.above both str are same(6S,9aS)-N-Benzyl-6-(4-hydroxybenzyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxoperhydropyrazino[1,2-a]pyrimidine-1-carboxamide

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

Prism Biolab Corporation

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

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

OR

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

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.

1

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

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

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

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

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LUMACAFTOR SPECTRAL VISIT

LUMACAFTOR
VX 809

3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic Acid
CAS No.:	936727-05-8
Synonyms:	VX-809 (Lumacaftor); VX-809; Lumacaftor; 3-(6-{[1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonyl]-amino}-3-methyl-pyridin-2-yl)-benzoic acid; 3-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid;
Formula:	C24H18F2N2O5
Exact Mass:	452.11800

SMILLES....    Cc1ccc(nc1c2cccc(c2)C(=O)O)NC(=O)C3(CC3)c4ccc5c(c4)OC(O5)(F)F

NMR................http://file.selleckchem.com/downloads/nmr/S156503-VX-809-HNMR-Selleck.pdf
syn.....http://newdrugapprovals.org/2013/07/28/3274/

 PATENT

 http://www.google.com/patents/EP2639222A1?cl=en

• Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) directly from benzoate.

  
• A solution of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70 ± 10 °C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50 °C and the mixture stirred. The mixture is then heated to 70 ± 10 °C until the level of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 as an off-white solid.

• 1HNMR spectra of Compound 1 are shown in Figures 9-11 (Figures 9 and 10 depict Compound 1 in Form I in a 50 mg/mL, 0.5 methyl cellulose-polysorbate 80 suspension, and Figure 11 depicts Compound 1 as an HCl salt).
• Table 3 below recites additional analytical data for Compound 1.
• Table 3.

  Cmpd. No.	LC/MS M+1	LC/RTmin	NMR
  1	453.3	1.93	H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m, 1H), 7.74-7.72 (m, 1H), 7.60-7.55 (m, 2H), 7.41-7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H)

1H NMR PREDICT

 
13C NMR PREDICT




CAS NO. 936727-05-8, 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid C-NMR spectral analysis

COSY PREDICT

13C NMR PREDICT

WO2002096421A1 *	May 22, 2002	Dec 5, 2002	Neurogen Corp	5-substituted-2-arylpyridines as crf1 modulators
WO2004072038A1 *	Feb 10, 2004	Aug 26, 2004	Vertex Pharma	Processes for the preparation of n-heteroaryl-n-aryl-amines by reacting an n-aryl carbamic acid ester with a halo-heteroaryl and analogous processes
WO2007056341A1	Nov 8, 2006	May 18, 2007	Vertex Pharma	Heterocyclic modulators of atp-binding cassette transporters

Patent

http://www.google.co.in/patents/US8124781












Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid (Compound 1)

A slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl (1 eq) in water (10 vol) is stirred at ambient temperature. A sample is taken after stirring for 24 hours. The sample is filtered and the solid washed with water (2×). The solid sample is submitted for DSC analysis. When DSC analysis indicates complete conversion to Compound 1, the solid is collected by filtration, washed with water (2×1.0 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60° C. with a slight N₂ bleed to afford Compound 1 as an off-white solid (98% yield).

Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid (Compound 1) Using Water and Base

To a slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl (1 eq) in water (10 vol) stirred at ambient temperature is added 50% w/w aq. NaOH (2.5 eq). The mixture is stirred for NLT 15 min or until a homogeneous solution. Concentrated HCl (4 eq) is added to crystallize Compound 1. The mixture is heated to 60° C. or 90° C. if needed to reduce the level of the t-butylbenzoate ester. The mixture is heated until HPLC analysis indicates NMT 0.8% (AUC) t-butylbenzoate ester. The mixture is then cooled to ambient and the solid is collected by filtration, washed with water (3×3.4 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60° C. with a slight N₂ bleed to afford Compound 1 as an off-white solid (97% yield).

Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid (Compound 1) Directly from Benzoate

A solution of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70±10° C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50° C. and the mixture stirred. The mixture is then heated to 70±10° C. until the level of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2×3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60° C. with a slight N₂ bleed to afford Compound 1 as an off-white solid.

syn.....http://newdrugapprovals.org/2013/07/28/3274/


syn.....http://newdrugapprovals.org/2013/07/28/3274/


syn.....http://newdrugapprovals.org/2013/07/28/3274/

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GSK 923295

GSK-923295A

1088965-37-0

Synonym: GSK-923295; GSK 923295; GSK923295.

CENP-E Inhibitor

IUPAC/Chemical name: 

3-Chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide

3-​chloro-​N-​[(1S)​-​2-​[[2-​(dimethylamino)​acetyl]​amino]​-​1-​[[4-​[8-​[(1S)​-​1-​hydroxyethyl]​imidazo[1,​2-​a]​pyridin-​2-​yl]​phenyl]​methyl]​ethyl]​-​4-​(1-​methylethoxy)​- Benzamide,

3-Chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[1-(N,N-dimethylglycinamido)-3-[4-[8-[1(S)-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl]phenyl]propan-2(S)-yl]-4-isopropoxybenzamide

C32H38ClN5O4
Exact Mass: 591.26123
Molecular Weight: 592.12822
Elemental Analysis: C, 64.91; H, 6.47; Cl, 5.99; N, 11.83; O, 10.81

Kinesin-like protein KIF11 inhibitor; Centromere protein E inhibitor
GSK-923295 is a novel antimitotic inhibitor of centromere-associated protein E (CENP-E) with potential anticancer activity. GSK923295A demonstrated significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts.

Organic Process Research & Development (2010), 14(5), 1254-1263

Org. Process Res. Dev., 2010, 14 (5), pp 1254–1263

DOI: 10.1021/op100186c

http://pubs.acs.org/doi/abs/10.1021/op100186c

The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}−4-[(1-methylethyl)oxy]benzamide (GSK923295A) is described. The existing route to GSK923295A was expensive, nonrobust, used nonideal reagents, and consistently struggled to deliver the API needed for clinical studies. The new synthesis commences from the readily available l-phenylalaninol, which is smoothly converted through to GSK923295A using key Friedel−Crafts acylation as well as selective acylation chemistries. Downstream chemistry to GSK923295A is both high yielding and robust, and the resulting process has been demonstrated first on the kilo scale and subsequently in the pilot plant where 55 kg was successfully prepared. The resulting process is simple, uses cheaper raw materials, is greener in that it avoids using aluminum, tin, and bromination chemistries, and obviates the need for chromatographic purification. Also discussed are the route derived impurities, how they were unambiguously prepared to confirm structure and processing amendments to control their formation, and enhancements to the new process to facilitate future processing.

¹H NMR (400 MHz, CD₃OD) δ_H 1.34 (6H, d, J = 6.0, (CH₃)₂), 1.59 (3H, d, J = 7.0, CH₃CH), 2.21 (6H, s, N(CH₃)₂), 2.87−3.01 (4H, m, CH₂Ph and CH₂N(CH₃)₂), 3.49 (2H, m, CH₂NPhthal), 4.50 (1H, m, CHNH), 4.70 (1H, m, (CH₃)₂CHO)), 5.49 (1H, q, J = 7.0, CHOH), 6.88 (1H, t, J = 7.0, H-j), 7.08 (1H, d, J = 7.5, H-b), 7.33−7.37 (3H, m, H-k and H-d), 7.63 (1H, dd, J = 7.5 and 2.0, H-c), 7.78 (1H, s, H-a), 7.83 (2H, d, J = 7.0, H-e), 8.09 (1H, m, H-h), 8.27 (1H, d, J = 8.0, H-i);

¹³C NMR (100 MHz, CD₃OD) δ_C 22.2, 24.1, 39.3, 43.8, 46.1, 53.0, 63.7, 66.2, 73.0, 110.4, 113.8, 115.3, 121.2, 124.5, 126.1, 127.5, 128.4, 128.5, 130.6, 130.7, 133.3, 136.0, 139.4, 145.1, 146.1, 157.6, 168.5 and 173.6;

HRMS (ESI⁺) m/z calculated for [M+H]⁺ C₃₂H₃₉N₅O₄Cl 592.2691, found 592.2684.

IH NMR PREDICT

13 C NMR PREDICT

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