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The United States Pharmacopeia (USP) is currently undertaking further steps towards a comprehensive analytical lifecycle approach by publishing a draft of a new General Chapter <1210> Statistical Tools for Procedure Validation and two Stimuli Articles regarding Analytical Target Profile and AnalyticalControl Strategy in Pharmacopeial Forum. Read more about the life cycle concept for analytical procedures.
Following the recently announced elaboration of a new general chapter <1220> “The Analytical Procedure Lifecycle” the United States pharmacopeia (USP) is now proceeding in its approach for a comprehensive analytical lifecycle concept. A further step towards this approach is the draft of a new USP General Chapter <1210> Statistical Tools for Procedure Validation which has been published in Pharmacopeial Forum (PF) 42(5) in September 2016. Comment deadline is November 30, 2016.
Additionally, two Stimuli Articles regarding “Analytical Control Strategy” and “Analytical…
View original post 624 more words
Ibipinabant
| cas 464213-10-3; UNII-O5CSC6WH1T; BMS-646256; SLV-319; |
| Molecular Formula: | C23H20Cl2N4O2S |
|---|---|
| Molecular Weight: | 487.4015 g/mol |
(4S)-5-(4-chlorophenyl)-N-(4-chlorophenyl)sulfonyl-N’-methyl-4-phenyl-3,4-dihydropyrazole-2-carboximidamide
1H-Pyrazole-1-carboximidamide, 3-(4-chlorophenyl)-N’-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N-methyl-4-phenyl-, (4S)-
(4S)-3-(4-Chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N’-methyl-4-phenyl-1H-pyrazole-1-carboximidamide
1H-Pyrazole-1-carboximidamide, 3-(4-chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N‘-methyl-4-phenyl-, (4S)-
(-)-(4S)-N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine
4S)-(−)-3-(4-Chlorophenyl)-N-methyl-N‘-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine
It was originally developed by Solvay, which was acquired by Abbott in 2010.
SLV 319, UNII:O5CSC6WH1T, (S)-SLV 319, BMS 646256, JD 5001
Ibipinabant, also known as BMS-646256, JD-5001 and SLV-319, is a potent and highly selective CB1 antagonist. It has potent anorectic effects in animals, and was researched for the treatment of obesity, although CB1 antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB1 antagonists
Ibipinabant (SLV319, BMS-646,256) is a drug used in scientific research which acts as a potent and highly selective CB1antagonist.[1] It has potent anorectic effects in animals,[2] and was researched for the treatment of obesity, although CB1 antagonists as a class have now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel CB1 antagonists.[3][4][5]
| Inventors | Josephus H.M. Lange, Cornelis G Kruse,Jacobus Tipker, Jan Hoogendoorn |
| Applicant | Solvay Pharmaceuticals B.V. |
PATENT
WO 2002076949
https://www.google.com/patents/WO2002076949A1?cl=en
Example IV
(-)-(4S)-N-methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5- dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine
(-)-(4S)-N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine (7.16 gram, 0.0147 mol)) ([α25 D] = -150°, c = 0.01 , MeOH) (melting point: 169-170 °C) was obtained via chiral chromatographic separation of racemic N-methyl-N’-((4-chlorophenyl)sulfonyl)-3- (4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1 -carboxamidine (18 gram, 0.037 mol) using a Chiralpak AD, 20 μm chiral stationary phase. The mobile phase consisted of a mixture of hexane/ethanol (80/20 (v/v)) and 0.1 % ammonium hydroxide (25 % aqueous solution).
Example III N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-1 H-pyrazole-1 -carboxamidine
Part A: To a solution of N-((4-chlorophenyl)sulfonyl)carbamic acid methyl ester (CAS: 34543-04-9) (2.99 gram, 12.0 mmol) and pyridine (4 ml) in 1 ,4-dioxane (20 ml) is added 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole (3.39 gram, 13.2 mmol) and the resulting mixture is stirred for 4 hours at 100 °C After concentration in vacuo the residue is dissolved in dichloromethane, successively washed with water, 1 N HCI and water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to a volume of 20 ml. Methyl-tert-butyl ether (60 ml) is added and the resulting solution is concentrated to a volume of 20 ml. The formed crystals are collected by filtration and recrystallised from methyl-te/τ-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1 H- pyrazole-1-carboxamide (4J5 gram, 76 % yield) Melting point: 211-214 °C
Part B: A mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro- 4-phenyl-1 H-pyrazole-1 -carboxamide (3.67 gram, 7J5 mmol) and phosphorus pentachloride (1.69 gram, 8.14 mmol) in chlorobenzene (40 ml) is heated at reflux for 1 hour. After thorough concentration in vacuo, the formed N-((4- chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1 H-pyrazole-1- carboximidoyl chloride is suspended in dichloromethane and reacted with cold methylamine (1.5 ml). After stirring at room temperature for 1 hour, the mixture is concentrated in vacuo. The residue is crystallised from diethyl ether to give N-methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- 1 H-pyrazole-1 -carboxamidine (2.29 gram, 61 % yield). Melting point: 96-98 °C(dec).
PATENT
WO 2008074816
https://google.com/patents/WO2008074816A1?cl=en
PAPER
An expedient atom-efficient synthesis of the cannabinoid CB1receptor inverse agonist ibipinabant
http://www.sciencedirect.com/science/article/pii/S0040403911000955
http://dx.doi.org/10.1016/j.tetlet.2011.01.068
A novel synthetic route to the highly selective and orally active cannabinoid CB1 receptor inverse agonist ibipinabant is described which combines the use of inexpensive, commercially available reagents and mild reaction conditions with a high degree of atom-efficiency. The method is expected to enable the rapid synthesis of a variety of sulfonylguanidines.
PAPER
JD-5006 and JD-5037: Peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities
http://dx.doi.org/10.1016/j.bmcl.2012.08.004
http://www.sciencedirect.com/science/article/pii/S0960894X12009936
Reagents and conditions: (a) ArylSO2NHCO2CH3, toluene, reflux, 3–6 h, 30–95%; (b) PCl5, chlorobenzene, reflux, 2–4 h, 50–90%; (c) NH2Me.HCl, Et3N, CH2Cl2, ice-bath to rt, 16–20 h, 30–70%; (d) X = CO2Et/X′ = CO2H: LiOH, H2O/THF(1:3), 50%; X′ = CO2H/X′ = CONH2, (1) IBCF, NMM, CH2Cl2, (2) NH3/THF, 60%; X′ = CO2H/X′ = CONHOH, (1) IBCF, NMM, CH2Cl2, (2) NH2OH·HCl, NMM, CH2Cl2, 40%; X = OCH2CO2Et/OCH2CO2H: LiOH, H2O/THF(1:3), rt, 50%; X′ = OCH2CO2H/X′ = OCH2CONH2: (1) IBCF, NMM, CH2Cl2, (2) NH3/THF, 30%; X = NO2:/X′ = NHCOCH3: (1) Fe/HCl, EtOH, H2O, reflux 1–2 h, 90%; (2) Ac2O, pyr, CH2Cl2, rt, 8 h, 90%; X = NO2:/X′ = NHCO2Et: (1) Fe/HCl, EtOH, H2O, reflux 1–2 h, 90%; (2) ClCO2Et, pyr, CH2Cl2, 0 °C to rt, 8 h, 90%
Clip
http://molpharm.aspetjournals.org/content/87/2/197.full.pdf
Paper
Lange et al (2005) Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity. Bioorg.Med.Chem.Lett. 15 4794. PMID: 16140010.
http://www.sciencedirect.com/science/article/pii/S0960894X05010139
http://dx.doi.org/10.1016/j.bmcl.2005.07.054
Paper
Lange et al (2004) Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB1 cannabinoid receptor antagonists. J.Med.Chem. 47 627. PMID:14736243.
A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB1 and hCB2) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitroCB1 antagonistic activities and in general exhibited high CB1 vs CB2 receptor subtype selectivities. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C4 position as 4S. Bioanalytical studies revealed a high CNS−plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB1 receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH2 moiety with a -NHCH3 group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80
] = −150°, c = 0.01, MeOH; mp 171−172 °C; 
] = + 150°, c = 0.01, MeOH; mp 171−172 °C; 1H NMR (400 MHz, DMSO-d6) δ 2.94 (d, J = 4 Hz, 3H), 3.96 (dd, J = 11 and 4 Hz, 1H), 4.46 (t, J = 11 Hz, 1H), 5.05 (dd, J = 11 and 4 Hz, 1H), 7.20−7.35 (m, 5H), 7.45 (dt, J = 8 and 2 Hz, 2H), 7.53 (dt, J = 8 and 2 Hz, 2H), 7.77 (dt,J = 8 and 2 Hz, 2H), 7.82 (dt, J = 8 and 2 Hz, 2H), 8.19 (br d, J = 4 Hz, 1H); HRMS (C23H21Cl2N4O2S) [M+H]+: found m/z 487.0749, calcd 487.0762. Anal. (C23H20Cl2N4O2S) C, H, N.Paper
changed to
Process for the second pilot-plant implementation
Process parameter ranges and typical results from approximately 20 lab experiments conducted on the process shown in Scheme
Figure 3. Ishikawa diagram for the API step, highlighting factors that potentially affect the enantiomeric purity of the product. Factors shown in blue were accounted for in the sulfonylation reaction and distillative crystallization models. Factors shown in red were not included in the models
| process parameter | min. value | max. value | # of “levels” |
|---|---|---|---|
| sulfonylation reaction model | |||
| temp. (°C) | 5 | 35 | 7 |
| 4-chlorobenzenesulfonyl chloride (equiv) | 1.0 | 1.2 | 6 |
| conc. (mL/g) | 5 | 10 | 6 |
| reaction time (h) | 2 | 5 | 4 |
| distillative crystallization model | |||
| pressure (mbar) | 300 | 1013 | 6 |
| residual 2(AP) | 0.05 | 2.0 | 6 |
| distillation time (h) | 8 | 48 | 4 |
| distillation end point (wt % EtOH) | 90 | 98 | 3 |
1: Schirris TJ, Ritschel T, Herma Renkema G, Willems PH, Smeitink JA, Russel FG. Mitochondrial ADP/ATP exchange inhibition: a novel off-target mechanism underlying ibipinabant-induced myotoxicity. Sci Rep. 2015 Sep 29;5:14533. doi: 10.1038/srep14533. PubMed PMID: 26416158; PubMed Central PMCID: PMC4586513.
2: Chorvat RJ, Berbaum J, Seriacki K, McElroy JF. JD-5006 and JD-5037: peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities. Bioorg Med Chem Lett. 2012 Oct 1;22(19):6173-80. doi: 10.1016/j.bmcl.2012.08.004. Epub 2012 Aug 20. PubMed PMID: 22959249.
3: Tomlinson L, Tirmenstein MA, Janovitz EB, Aranibar N, Ott KH, Kozlosky JC, Patrone LM, Achanzar WE, Augustine KA, Brannen KC, Carlson KE, Charlap JH, Dubrow KM, Kang L, Rosini LT, Panzica-Kelly JM, Flint OP, Moulin FJ, Megill JR, Zhang H, Bennett MJ, Horvath JJ. Cannabinoid receptor antagonist-induced striated muscle toxicity and ethylmalonic-adipic aciduria in beagle dogs. Toxicol Sci. 2012 Oct;129(2):268-79. doi: 10.1093/toxsci/kfs217. Epub 2012 Jul 21. PubMed PMID: 22821849.
4: Dawes J, Allenspach C, Gamble JF, Greenwood R, Robbins P, Tobyn M. Application of external lubrication during the roller compaction of adhesive pharmaceutical formulations. Pharm Dev Technol. 2013 Feb;18(1):246-56. doi: 10.3109/10837450.2012.705299. Epub 2012 Jul 20. PubMed PMID: 22813432.
5: Leane MM, Sinclair W, Qian F, Haddadin R, Brown A, Tobyn M, Dennis AB. Formulation and process design for a solid dosage form containing a spray-dried amorphous dispersion of ibipinabant. Pharm Dev Technol. 2013 Mar-Apr;18(2):359-66. doi: 10.3109/10837450.2011.619544. Epub 2012 Jan 23. PubMed PMID: 22268601.
6: Rohrbach K, Thomas MA, Glick S, Fung EN, Wang V, Watson L, Gregory P, Antel J, Pelleymounter MA. Ibipinabant attenuates β-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight. Diabetes Obes Metab. 2012 Jun;14(6):555-64. doi: 10.1111/j.1463-1326.2012.01563.x. Epub 2012 Feb 24. PubMed PMID: 22268426.
7: Lynch CJ, Zhou Q, Shyng SL, Heal DJ, Cheetham SC, Dickinson K, Gregory P, Firnges M, Nordheim U, Goshorn S, Reiche D, Turski L, Antel J. Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels. Am J Physiol Endocrinol Metab. 2012 Mar 1;302(5):E540-51. doi: 10.1152/ajpendo.00258.2011. Epub 2011 Dec 13. PubMed PMID: 22167524; PubMed Central PMCID: PMC3311290.
8: Gamble JF, Leane M, Olusanmi D, Tobyn M, Supuk E, Khoo J, Naderi M. Surface energy analysis as a tool to probe the surface energy characteristics of micronized materials–a comparison with inverse gas chromatography. Int J Pharm. 2012 Jan 17;422(1-2):238-44. doi: 10.1016/j.ijpharm.2011.11.002. Epub 2011 Nov 10. PubMed PMID: 22100516.
9: Sinclair W, Leane M, Clarke G, Dennis A, Tobyn M, Timmins P. Physical stability and recrystallization kinetics of amorphous ibipinabant drug product by fourier transform raman spectroscopy. J Pharm Sci. 2011 Nov;100(11):4687-99. doi: 10.1002/jps.22658. Epub 2011 Jun 16. PubMed PMID: 21681752.
10: Gamble JF, Tobyn M, Dennis AB, Shah T. Roller compaction: application of an in-gap ribbon porosity calculation for the optimization of downstream granule flow and compactability characteristics. Pharm Dev Technol. 2010 Jun;15(3):223-9. doi: 10.3109/10837450903095342. PubMed PMID: 22716462.
11: Zhang H, Patrone L, Kozlosky J, Tomlinson L, Cosma G, Horvath J. Pooled sample strategy in conjunction with high-resolution liquid chromatography-mass spectrometry-based background subtraction to identify toxicological markers in dogs treated with ibipinabant. Anal Chem. 2010 May 1;82(9):3834-9. doi: 10.1021/ac100287a. PubMed PMID: 20387806.
12: Lange JH, van der Neut MA, den Hartog AP, Wals HC, Hoogendoorn J, van Stuivenberg HH, van Vliet BJ, Kruse CG. Synthesis, SAR and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles as potent cannabinoid CB(1) receptor antagonists. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1752-7. doi: 10.1016/j.bmcl.2010.01.049. Epub 2010 Jan 20. PubMed PMID: 20137935.
References
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| US9174965 | 2015-11-03 | Pyrimidinylpiperidinyloxypyridone analogues as GPR119 modulators |
| US2015133479 | 2015-05-14 | PYRIMIDINYLPIPERIDINYLOXYPYRIDONE ANALOGUES AS GPR119 MODULATORS |
| US8940716 | 2015-01-27 | Bicyclic heteroaryl compounds as GPR119 modulators |
| US8853205 | 2014-10-07 | Heteropyrrole analogs acting on cannabinoid receptors |
| US8729084 | 2014-05-20 | Benzofuranyl analogues as GPR119 modulators |
| US2014080788 | 2014-03-20 | NOVEL BICYCLIC NITROGEN CONTAINING HETEROARYL TGR5 RECEPTOR MODULATORS |
| US8513265 | 2013-08-20 | [6, 6] and [6, 7]-bicyclic GPR119 G protein-coupled receptor agonists |
| US8513424 | 2013-08-20 | Pyridone GPR119 G protein-coupled receptor agonists |
| US8476283 | 2013-07-02 | [6, 5]â??bicyclic GPR119 G protein-coupled receptor agonists |
| US8314095 | 2012-11-20 | [6, 6] and [6, 7]-bicyclic GPR119 G protein-coupled receptor agonists |
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
4S-(−)-3-(4-chlorophenyl)-N-methyl-N’-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine
|
|
| Identifiers | |
| CAS Number | 464213-10-3  |
| ATC code | none |
| PubChem | CID 9826744 |
| ChemSpider | 24765166  |
| UNII | O5CSC6WH1T |
| KEGG | D09349 |
| ChEMBL | CHEMBL158784 |
| Chemical data | |
| Formula | C24H22Cl2N4O2S |
| Molar mass | 501.427 |
///////// 464213-10-3, UNII-O5CSC6WH1T, BMS-646256, SLV-319, Ibipinabant, JD 5001, solvay, abbott
c2cc(Cl)ccc2C1=NN(C(NC)=NCS(=O)(=O)c3ccc(Cl)cc3)CC1c4ccccc4
IPI-549
CAS 1693758-51-8
MF : C30H24N8O2
Molecular Weight: 528.576
(S)-2-amino-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
| Latest Stage of Development | Phase I |
| Standard Indication | Solid tumors |
| Indication Details | Treat solid tumors |
IPI-549 is a potent and selective phosphoinositide-3-kinase (PI3Kγ) Inhibitor as an Immuno-Oncology Clinical Candidate (Kd = 0.29 nM). Bioactivity data of IPI-549: biochemcial IC50 (nM) for PI3K isoform: 3200 (α); 3500 (β); 16 (γ); and >8400 (δ) respectively. Cellar IC50 (nM) of IPI549 for PI3K isoform: 250 (α); 240 (β); 1.6 (γ); and 180 (δ) respectively. IPI-549 shows >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.
Patent
WO 2015051244
https://www.google.co.in/patents/WO2015051244A1?cl=en
Scheme 1
Scheme 2
Example 1
[00657] Compound 4 was prepared in 3 steps from compound A according to the following procedures:
Compound A was prepared according to Method A. It was coupled to 2-((tert-butoxycarbonyl)amino)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid according to the following procedure: Compound A (27.4 mmol, 1.0 equiv), HOBt hydrate (1.2 equiv), 2-((tert-butoxycarbonyl)amino)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (1.05 equiv) and
EDC (1.25 equiv) were added to a 200 mL round bottomed flask with a stir bar. N,N-Dimethylformamide (50 mL) was added and the suspension was stirred at RT for 2 min. Hunig’s base (4.0 equiv) was added and after which the suspension became homogeneous and was stirred for 22h resulting in the formation of a solid cake in the reaction flask. The solid mixture was added to water (600 mL) and stirred for 3h. The resulting cream colored solid was filtered and washed with water (2 x 100 mL) and dried. The solid was then dissolved in methylene chloride (40 mL) after which trifluoroacetic acid (10 equiv, 20 mL) was added and the reaction was stirred for 30 min at RT after which there is no more starting material by LC/MS analysis. The solution was then concentrated and coevaporated with a mixture of methylene choride/ethanol (1 : 1 v/v) and then dried under high vacuum overnight. The resulting solid was triturated with 60 mL of ethanol for lh and then collected via vacuum filtration. The beige solid was then neutralized with sodium carbonate solution (100 mL) and then transferred to a separatory funnel with methylene chloride (350 mL). The water layer was extracted with an additional 100 mL of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to provide a pale yellow solid that was purified using flash silica gel chromatography (Combiflash, 24g column, gradient of 0-5% methanol/methylene chloride) to provide amide B. ESI-MS m/z: 459.4 [M+H]+.
[00658] Amide B was placed in a sealed tube (0.67 mmol, 1.0 equiv) followed by dichlorobis(acetonitrile)palladium (15 mol%), X-Phos (45 mol%), and cesium carbonate (3.0 equiv) Propionitrile (5 mL) was added and the mixture was bubbled with Ar for 1 min. 4-Ethynyl-l -methyl- lH-pyrazole (1.24 equiv) was added and the resulting orange mixture was sealed and stirred in an oil bath at 85 oC for 1.5h. The resulting brownish-black mixture was allowed to cool at which point there was no more SM by LC/MS analysis. The mixture was then filtered through a short plug of cotton using acetonitrile and methylene chloride. The combined filtrates were concentrated onto silica gel and purified using flash silica gel chromatography (Combiflash, 4g column, gradient of 0-5% methylene chloride/methanol). The resulting material was further purified by reverse phase HPLC (15-90%o acetonitrile with 0.1%o formic acid/water with 0.1%o formic water) to provide desired compound 4. ESI-MS m/z: 529.5 [M+H]+.
PAPER
WO 2015143012
https://www.google.com/patents/WO2015143012A1?cl=en
PAPER
IPI-549 NMR 1H
IPI-549 13C NMR
IPI-549 ASSAY
Compound 1 is coupled to 4-ethynyl-1-methyl-1H-pyrazole using the general procedure outlined above to provide compound 26 IPI-549, in 70% yield with >98% enantiomeric purity.
IPI-549
1H NMR (400 MHz, DMSO-d6) δ 8.92 (dd, J = 6.8, 1.7 Hz, 1H), 8.55 (dd, J = 4.5, 1.7 Hz, 1H), 8.00 (d, J=6.8 Hz, 1H), 8.00 (s, 1H), 7.69 – 7.54 (m, 5H), 7.53 – 7.43 (m, 3H), 7.41 – 7.35 (m, 1H), 7.01 (dd, J = 6.7, 4.5 Hz, 1H), 6.74 (s, 1H), 6.42 (s, 2H), 4.56 (quin, J = 6.8 Hz, 1H).), 3.82 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H).
13C NMR (101 MHz, DMSO-d6) δ 162.73, 161.19, 160.93, 150.06, 147.51, 146.74, 141.05, 138.09, 137.81, 135.42, 133.66, 132.56, 131.90, 129.51, 129.24, 129.20, 129.17, 128.50, 126.16, 123.41, 123.31, 107.88, 102.44, 101.15, 90.40, 87.06, 85.94, 44.88, 38.62, 20.69.
ESI-HRMS: calcd for 529.2095 C30H25N8O2 (M+H)+ , found 529.2148.
[]D 22: +447.8o (c 1.007, DMSO)
COMPD1
compound 1 in 95% yield.
1H NMR (400 MHz, CDCl3) 8.41 (dd, J = 6.8, 1.7 Hz, 1H), 8.37 (dd, J = 4.4, 1.7 Hz, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.50-7.34 (m, 5H), 7.34-7.27 (m, 2H), 6.76 (dd, J = 7.1, 4.9 Hz, 1H), 6.57 (s, 1H), 5.54 (broad s, 2H), 4.79 (quin, J = 6.9 Hz, 1H), 1.36 (d, J = 6.5 Hz, 3H);
ESI-HRMS: calcd for C24H20ClN6O2 459.1331 (M+H)+ , found 459.1386. HPLC Purity: 96% AUC.
Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.
http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00238
CLIP
Infinity Expands Pipeline with Addition of IPI-549, an Immuno-Oncology Development Candidate for the Treatment of Solid Tumors
– IPI-549, a Selective PI3K-Gamma Inhibitor, Targets the Immune-Suppressive Tumor Microenvironment –
– Preclinical Data for IPI-549 Presented at CRI-CIMT-EATI-AACR – The Inaugural International Cancer Immunotherapy Conference –
CAMBRIDGE, Mass.–(BUSINESS WIRE)–Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) today announced the expansion of its pipeline with the addition of IPI-549, an orally administered immuno-oncology development candidate that selectively inhibits phosphoinositide-3-kinase gamma (PI3K-gamma), for the treatment of solid tumors. Preclinical data demonstrating the potential of IPI-549 to disrupt the immune-suppressive tumor microenvironment and enable a heightened anti-tumor immune response are being presented today at CRI-CIMT-EATI-AACR – The Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival Meeting in New York City. IPI-549 was discovered at Infinity and is expected to enter Phase 1 clinical development in early 2016.
“Infinity is committed to developing first-in-class and best-in-class medicines, and the expansion of our pipeline with the addition of IPI-549 represents an important step toward fulfilling our vision of building a sustainable biopharmaceutical company that brings meaningful medicines to patients”
“Infinity is committed to developing first-in-class and best-in-class medicines, and the expansion of our pipeline with the addition of IPI-549 represents an important step toward fulfilling our vision of building a sustainable biopharmaceutical company that brings meaningful medicines to patients,” stated Vito Palombella, Ph.D., Infinity’s chief scientific officer. “Infinity’s ability to internally develop a selective PI3K-gamma inhibitor provides us with a unique opportunity to explore the impact that PI3K-gamma inhibition has on disrupting the tumor microenvironment. We look forward to initiating the first clinical study of IPI-549 in patients with solid tumors.”
“I have had the pleasure of collaborating with Infinity’s discovery team and am excited to have worked with IPI-549 in my laboratory,” Jedd Wolchok, M.D., Ph.D., chief of Melanoma and Immunotherapeutics Service, Lloyd J. Old/Ludwig Chair in Clinical Investigation Department of Medicine and Ludwig Center, at Memorial Sloan Kettering Cancer Center and the principal investigator for the planned Phase 1 clinical study of IPI-549. “IPI-549 is a novel, small molecule immuno-oncology agent, and I am looking forward to leading the Phase 1 study for this program.”
IPI-549 inhibits immune suppressive macrophages within the tumor microenvironment, whereas other immunotherapies such as checkpoint modulators more directly target immune effector cell function. As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially complementary approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.
Preclinical Data for IPI-549 Presented at CRI-CIMT-EATI-AACR – The Inaugural International Cancer Immunotherapy Conference
Today at the AACR meeting in New York City Infinity researchers are presenting preclinical data for IPI-549 in a poster entitled, “The potent and selective phosphoinositide-3-kinase-gamma inhibitor, IPI-549, inhibits tumor growth in murine syngeneic solid tumor models through alterations in the immune suppressive microenvironment.”
In vitro data showed that IPI-549 blocks both the migration of murine myeloid cells and the differentiation of myeloid cells to the M2 phenotype, which is a type of myeloid cell known to promote cancer growth and suppress anti-tumor immune responses. In vivo data in murine solid tumor models demonstrated that IPI-549 treatment also decreased tumor-associated myeloid cells found in the immune suppressive microenvironment. Additionally, IPI-549 treatment increased the number of intratumoral CD8+T-cells, which are known to play a role in inhibiting tumor growth.
IPI-549 has demonstrated dose-dependent, single-agent, anti-tumor activity in multiple solid tumor models, including murine models of lung, colon and breast cancer. Additionally, mice treated with IPI-549 in combination with checkpoint inhibitors showed greater tumor growth inhibition than either treatment as a monotherapy. Preclinical in vivo data also demonstrated that T-cells are required for the anti-tumor activity of IPI-549, which is a hallmark of immunotherapy.
Further details about the IPI-549 development program will be provided at Infinity’s R&D Day on Tuesday, October 6, 2015. R&D Day will be held in New York City from 7:30 a.m. to 12:00 p.m. ET. The event will be webcast beginning at 8:00 a.m. ET and can be accessed in the Investors/Media section of Infinity’s website, www.infi.com. A replay of the event will also be available.
Infinity is also developing duvelisib, an investigational, oral, dual inhibitor of PI3K-delta and PI3K-gamma. The PI3K pathway is also known to play a critical role in regulating the growth and survival of certain types of blood cancers. The investigational agent is being evaluated in registration-focused studies, including DYNAMOTM, a Phase 2 study in patients with refractory indolent non-Hodgkin lymphoma, DYNAMO+R, a Phase 3 study in patients with previously treated follicular lymphoma, and DUOTM, a Phase 3 study in patients with relapsed/refractory chronic lymphocytic leukemia. Duvelisib is an investigational compound and its safety and efficacy have not been evaluated by the U.S. Food and Drug Administration or any other health authority.
About Infinity Pharmaceuticals, Inc.
Infinity is an innovative biopharmaceutical company dedicated to discovering, developing and delivering best-in-class medicines to people with difficult-to-treat diseases. Infinity combines proven scientific expertise with a passion for developing novel small molecule drugs that target emerging disease pathways. For more information on Infinity, please refer to the company’s website at www.infi.com.
Clip
Background: IPI-549 is a potential first-in-class potent and selective PI3K-γ inhibitor being developed as a novel orally administered immuno-oncology therapeutic in multiple cancer indications. Preclinical studies demonstrate a role for PI3K-γ in polarization of immune suppressive myeloid cells in the tumor microenvironment. Inhibition of PI3K-γ by IPI-549 enhanced antitumor immune responses and inhibited tumor growth in syngeneic solid tumor preclinical models. In addition, IPI-549 in combination with immune checkpoint inhibitors showed increased tumor growth inhibition compared to each single agent in multiple pre-clinical models. These data served as the scientific foundation for initiating a clinical trial testing IPI-549 as a potential immuno-oncology therapy. This first-in-human clinical study will evaluate the safety and tolerability, and determine the recommended Phase 2 dose (RP2D) of IPI-549 when administered as a monotherapy and in combination with pembrolizumab (NCT02637531) in solid tumors. Methods: This multi-part Phase 1/1b open-label trial will initiate with monotherapy dose escalation cohorts consisting of an accelerated dose escalation phase followed by a standard phase with a 3+3 design. Evaluation of the PK, PD, and safety data in these cohorts will lead to the determination of the maximum tolerated dose (MTD) and RP2D of IPI-549 monotherapy. Subsequently, combination dose escalation cohorts will be initiated in which the combination of IPI-549 and pembrolizumab will be evaluated. Expansion cohorts evaluating the safety, PK, PD, and preliminary clinical activity of IPI-549 as a monotherapy and in combination with pembrolizumab will occur following the dose escalation phase. All subjects in the trial will have advanced and/or metastatic carcinoma or melanoma, and will have failed to respond to standard therapies. Combination expansion cohorts will recruit subjects with non-small cell lung cancer or melanoma who must have received an anti-PD-1 or anti-PD-L1 antibody as their most recent treatment. This trial is currently enrolling patients in the US. Clinical trial information: NCT02637531
Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate
Catherine A. Evans, Tao Liu, André Lescarbeau, Somarajan J. Nair, Louis Grenier, Johan A. Pradeilles, Quentin Glenadel, Thomas Tibbitts, Ann M. Rowley, Jonathan P. DiNitto, Erin E. Brophy, Erin L. O’Hearn, Janid A. Ali, David G. Winkler, Stanley I. Goldstein, Patrick O’Hearn, Christian M. Martin, Jennifer G. Hoyt, John R. Soglia, Culver Cheung, Melissa M. Pink, Jennifer L. Proctor, Vito J. Palombella, Martin R. Tremblay, and Alfredo C. Castro
Publication Date (Web): July 22, 2016 (Letter)
DOI: 10.1021/acsmedchemlett.6b00238
///////immuno-oncology, IPI-549, isoform selectivity, neutrophil migration, phosphoinositide-3-kinase, PI3K-gamma inhibitor, IPI 549, IPI549. PRECLINICAL
O=C1N(C2=CC=CC=C2)C([C@@H](NC(C3=C(N=CC=C4)N4N=C3N)=O)C)=CC5=CC=CC(C#CC6=CN(C)N=C6)=C51
PF-04745637
cas 1917294-46-2
MW 509.00, MF C27 H32 Cl F3 N2 O2
Cyclopentanecarboxamide, 1-(4-chlorophenyl)-N-[2-[4-hydroxy-4-(trifluoromethyl)-1-piperidinyl]-3-phenylpropyl]-
rac-1-(4-Chlorophenyl)-N-f2-r4-hvdroxy-4-(trifluoromethyl)piperidin-1-vn-3-phenylpropyDcyclopentanecarboxamide
|
PRODUCT PATENT WO-2016067143-A1
|
| Applicants: | PFIZER INC. [US/US]; 235 East 42nd Street New York, New York 10017 (US) |
| Inventors: | SWAIN, Nigel Alan; (GB). PRYDE, David Cameron; (GB). RAWSON, David James; (GB). RYCKMANS, Thomas; (GB). SKERRATT, Sarah Elizabeth; (GB). AMATO, George Salvatore; (US). MARRON, Brian Edward; (US). REISTER, Steven Michael; (US). |
TrpA1 is a member of the Transient Receptor Potential (Trp) family of ion channels. It was first described as being activated in response to noxious cold. It is activated by a number of exogenous chemical compounds and some endogenous inflammatory mediators. It has also been reported to be activated in response to mechanical stress.
There is substantial evidence for the involvement of TrpA1 in the physiology of pain, including neuropathic and inflammatory pain, and in pruritus (itch). For example, see:
Bautista, D.M. et al., “TRPA 1: A Gatekeeper for Inflammation” , Annu. Rev. Physiol.2013, 75, 181-200;
Bishnoi, M. & Premkumar, L.S., “Changes in TRP Channels Expression in Painful
Conditions”, Open Pain Journal 2013, 6(Suppl. 1), 10-22;Brederson, J.-D. et al., “Targeting TRP channels for pain relief, Eur. J. Pharmacol.2013, 716, 61-76;
Radresa, O. et al., “Roles of TRPAI in Pain Pathophysiology and Implications for the Development of a New Class of Analgesic Drugs”, Open Pain Journal 2013, 6(Suppl. 1), 137-153; and Toth, B.I. & Biro, T., “TRP Channels and Pruritus” , Open Pain Journal 2013, 6(Suppl.1), 62-80.
There is a continuing interest in finding new compounds that interact with TrpA1.
Nigel SwainE8 that is 1-(4-chlorophenyl)-/V-[2-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-3-phenylpropyl]-cyclopentanecarboxamide, or a pharmaceutically acceptable salt thereof. This compound is represented by formula (lE).
Example 1
rac-1-(4-Chlorophenyl)-N-f2-r4-hvdroxy-4-(trifluoromethyl)piperidin-1-vn-3-phenylpropyDcyclopentanecarboxamide
Method 1
To a solution of rac-1-(1-amino-3-phenylpropan-2-yl)-4-(trifluoromethyl)piperidin-4-ol (Preparation 2, 50 mg, 0.214 mmol) in DMF (1 mL) was added 1-(4-chlorophenyl)cyclopentanecarboxylic acid (37 mg, 0.165 mmol), DIPEA (0.035 mL, 0.198 mmol) and EDCI (38 mg, 0.198 mmol), followed by HOBt (30 mg, 0.198 mmol) and the reaction was stirred at room temperature for 18 hours. Water was added and the reaction stirred for a further 2 hours. DCM was added with further stirring for 1 hour followed by elution through a phase separation cartridge. The organic filtrate was concentrated in vacuo. The residue was dissolved in MeOH and treated with ethereal HCI with standing for 18 hours. The resulting suspension was filtered and triturated with EtOAc, heptanes and TBME to afford the title compound as the hydrochloride salt (69 mg, 82%).
1H NMR (400MHz, DMSO-d6): δ ppm 1.50-1.60 (m, 4H), 1.70-1.90 (m, 4H), 2.15-2.25 (m, 2H), 2.40-2.48 (m, 2H), 2.70-2.80 (m, 1 H), 3.05-3.25 (m, 6H), 3.47-3.62 (m, 2H), 6.38 (br s, 1 H), 7.20-7.40 (m, 9H), 7.80 (br m, 1 H).
MS m/z 509 [M+H]+
Example 1 may also be prepared according to the following method:
A mixture of 1-(4-chlorophenyl)cyclopentanecarboxylic acid (25.7 g, 114 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid-hexafluoro phosphate (49.4 g, 130 mmol) and N,N-diisopropylethylamine (40 mL, 229 mmol) in DMF (475 mL) was stirred at room temperature for 15 minutes. To this mixture was added a solution of 1-(1-amino-3-phenylpropan-2-yl)-4-(trifluoromethyl)piperidin-4-ol (Preparation 2, 31.4 g, 104 mmol) in DMF (200 mL). The reaction was stirred at room temperature for 18 hours before partitioning between EtOAc (600 mL) and saturated aqueous sodium hydrogen carbonatesolution (600 mL). The aqueous layer was washed with EtOAc (2 x 600 mL). The combined organic layers were washed with water (600 mL), brine (600 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0: 1 to 1 : 1 EtOAc: heptanes to afford the title compound (44 g, 76%).
1H NMR (400MHz, CDCI3): δ ppm 1.35 (br s, 1 H), 1.49-1.85 (m, 6H), 1.90-1.99 (m, 2H), 2.25-2.55 (m, 7H), 2.56-2.70 (m, 1 H), 2.75-3.00 (m, 4H), 3.23-3.31 (m, 1 H), 5.87 (br s, 1 H), 7.07 (d, 2H), 7.16-7.30 (m, 7H).
MS m/z 509 [M+H]+
Examples 2 and 3
IS) and (R)-1-(4-Chlorophenyl)-N-f2-r4-hvdroxy-4-(trifluoromethyl)piperidin-1-vn-3-phenylpropyl)cyclopentanecarboxamide
Example 2
To a suspension of (S)-1-(1-amino-3-phenylpropan-2-yl)-4-(trifluoromethyl)piperidin-4-ol (Preparation 3, 70 mg, 0.232 mmol) and 1-(4-chlorophenyl)cyclopentanecarboxylic acid (57.3 mg, 0.255 mmol) in acetonitrile (0.8 mL) was added triethylamine (0.133 mL, 0.928 mmol) followed bypropylphosphonic anhydride (50% wt solution in EtOAc, 0.21 mL, 0.35 mmol). The reaction was stirred at room temperature for 1.5 hours after which the solution was purified directly by silica gel column chromatography eluting with 0-30% EtOAc in heptanes to afford the title compound (75 mg, 64%).
[a]D20 = +9.6 in DCM [20 mg/mL]
ee determination:
Column: ChiralTech AD-H, 250×4.6 mm, 5 micron.
Mobile phase A: CO2; Mobile phase B: MeOH with 0.2% ammonium hydroxide Gradient: 5% B at 0.00 mins, 60% B at 9.00 mins; hold to 9.5 mins and return to 5% B at 10 mins. Flow rate 3 mL/min.
Rt = 5.047 minutes, ee = 95%
Example 2 may also be prepared from rac-1-(4-chlorophenyl)-N-{2-[4-hydroxy-4- (trifluoromethyl)piperidin-1-yl]-3-phenylpropyl}cyclopentanecarboxamide(Example 1).
The racemate was separated into two enantiomers using preparative chiral chromatography as described below:
Chiralpak IA, 4.6x250mm, 5 micron.
Mobile phase: Hexane:DCM:EtOH:DEA 90:8:2:0.1
Flow rate: 1 mL/min
Rt = 8.351 minutes and Rt = 10.068 minutes
The first eluting isomer is Example 2: (S)-1-(4-chlorophenyl)-N-{2-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]-3-phenylpropyl}cyclopentanecarboxamide. ee = 100% The second eluting isomer is Example 3: (R)-1-(4-chlorophenyl)-N-{2-[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]-3-phenylpropyl}cyclopentanecarboxamide. ee = 99.62% The compound of Example 2 prepared from the chiral separation method is identical by a-rotation and retention time to the compound of Example 2 prepared as the single enantiomer described above.
MS m/z 509 [M+H]+
1H NMR (400MHz, DMSO-d6): δ 1.30-1.80 (m, 10H), 2.20-2.30 (m, 1 H), 2.35-2.60 (m, 6H), 2.65-2.85 (m, 4H), 3.00-3.15 (m, 1 H), 5.50 (br s, 1 H), 6.95-7.00 (m, 1 H), 7.05-7.15 (m, 2H), 7.20-7.35 (m, 6H) ppm
DOI: 10.1039/C6MD00387G, http://pubs.rsc.org/en/Content/ArticleLanding/2016/MD/C6MD00387G?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract
. Please note PF-6667294 is Compound 4 and PF-4746537 is Compound 8.
A series of potent and selective carboxamide TRPA1 antagonists were identified by a high throughput screen. Structure–activity relationship studies around this series are described, resulting in a highly potent example of the series. Pharmacokinetic and skin flux data are presented for this compound. Efficacy was observed in a topical cinnamaldehyde flare study, providing a topical proof of pharmacology for this mechanism. These data suggest TRPA1 antagonism could be a viable mechanism to treat topical conditions such as atopic dermatitis.
https://en.wikipedia.org/wiki/Discovery_and_development_of_TRPV1_antagonists
/////////////PF-04745637, PF 04745637, PF04745637, PFIZER, PRECLINICAL, TRPV1 antagonists, atopic dermatitis, 1917294-46-2
c1(ccccc1)CC(CNC(=O)C3(c2ccc(cc2)Cl)CCCC3)N4CCC(CC4)(O)C(F)(F)F
DDD 107498, DDD 498
PATENT WO 2013153357, US2015045354
6-Fluoro-2-[4-(morpholinomethyl)phenyl]-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide
6-Fluoro-2-[4-(4-morpholinylmethyl)phenyl]-N-[2-(1-pyrrolidinyl)ethyl]-4-quinolinecarboxamide
4-Quinolinecarboxamide, 6-fluoro-2-[4-(4-morpholinylmethyl)phenyl]-N-[2-(1-pyrrolidinyl)ethyl]-
CAS 1469439-69-7
CAS 1469439-71-1 SUCCINATE
| MF C27H31FN4O2 | |
| MW | 462.559043 g/mol |
|---|
| Inventors | Ian Hugh Gilbert, Neil Norcross, Beatriz Baragana Ruibal, Achim Porzelle |
| Original Assignee | University Of Dundee |
BCDD, College of Life Sciences, University of Dundee, DD1 5EH, UK
Tel: +44 (0) 1382-386240
Agreement further diversifies MMV’s partner base, strengthening our antimalarial research and development portfolio
Photo © Merck Serono
Merck Serono, the biopharmaceutical business of Merck, and MMV announced today that an agreement has been signed for Merck Serono to obtain the rights to the investigational antimalarial compound DDD107498 from MMV. This agreement underscores the commitment of Merck Serono to provide antimalarials for the most vulnerable populations in need.
“This agreement strengthens our Global Health research program and our ongoing collaboration with Medicines for Malaria Venture,” said Luciano Rossetti, Executive Vice President, Global Head of Research & Development at Merck Serono. “MMV is known worldwide for its major contribution to delivering innovative antimalarial treatments to the most vulnerable populations suffering from this disease, and at Merck Serono we share this goal.”
DDD107498 originated from a collaboration between MMV and the University of Dundee Drug Discovery Unit, led by Prof. Ian Gilbert and Dr. Kevin Read. The objective of the clinical program is to demonstrate whether the investigational compound exerts activity on a number of malaria parasite lifecycle stages, and remains active in the body long enough to offer potential as a single-dose treatment against the most severe strains of malaria.
While development and commercialization of the compound is under Merck Serono’s responsibility, MMV will provide expertise in the field of malaria drug development, including its clinical and delivery expertise, and provide access to its public and private sector networks in malaria-endemic countries.
Merck Serono has a dedicated Global Health R&D group working to address key unmet medical needs related to neglected diseases, such as schistosomiasis and malaria, with a focus on pediatric populations in developing countries. Its approach is based on public-private partnerships and collaborations with leading global health institutions and organizations in both developed and developing countries.
“Working with partners like Merck Serono is critical to the progress of potential antimalarial compounds, like DDD107498, through the malaria drug pipeline,” said Dr. Timothy Wells, Chief Scientific Officer at MMV. “Their Global Health Program is gaining momentum and we need more compounds to tackle malaria, a disease that places a huge burden on the world’s most vulnerable populations. DDD107498 holds great promise and we look forward to working with the Merck Serono team through the development phase.”
According to the World Health Organization, there were an estimated 198 million cases of malaria worldwide in 2013, and an estimated 584,000 deaths, primarily in young children from the developing world. The launch of the not-for-profit research foundation, MMV, in 1999 and a number of collaborations and partnerships, including those with Merck Serono, has contributed to reducing the major gap in malaria R&D investment and subsequent dearth of new medicines.
“It’s hugely encouraging to see the German pharmaceutical industry increasing their engagement in the development of novel antimalarials,” said global malaria expert Prof. Dr. Peter Kremsner, Director of the Institute for Tropical Medicine at the University of Tübingen, Germany. “The Merck Serono and MMV collaboration to develop DDD107498 is a great step. It’s a compound that offers lots of promise so I’m excited to see how it progresses.
Scientists have discovered an antimalarial compound that could treat malaria patients in a single dose and help prevent the spread of the disease from infected people.
The compound DDD107498 also has the potential to treat patients with malaria parasites resistant to current medications, researchers say.
Scientists hope it could lead to treatments and protection against the disease, which claimed almost 600,000 lives amid 200 million reported cases in 2013.
The compound was identified through a collaboration between the University of Dundee’s drug discovery unit (DDU) and the Medicines for Malaria Venture (MMV), a separate organisation.
The compound is now undergoing further safety testing with a view to entering human clinical trials within the next year.
Details of the discovery have been published in the journal Nature.
Professor Ian Gilbert, head of chemistry at the DDU, who led the team that discovered the compound, said: “The publication describes the discovery and profiling of this exciting new compound.
“It reveals that DDD107498 has the potential to treat malaria with a single dose, prevent the spread of malaria from infected people and protect a person from developing the disease in the first place.
“There is still some way to go before the compound can be given to patients. However, we are very excited by the progress that we have made.”
The World Health Organisation reports that there were 200 million clinical cases of malaria in 2013, with 584,000 people dying from the disease. Most of these deaths were children under the age of five and pregnant women.
MMV chief executive officer Dr David Reddy said: “Malaria continues to threaten almost half of the world’s population – the half that can least afford it.
“DDD107498 is an exciting compound since it holds the promise to not only treat but also protect these vulnerable populations.
“The collaboration to identify and progress the compound, led by the drug discovery unit at the University of Dundee, drew on MMV’s network of scientists from Melbourne to San Diego.”The publication of the research is an important step and a clear testament to the power of partnership.”
MMV selected DDD107498 to enter preclinical development in October 2013 following the recommendation of its expert scientific advisory committee.
Since then, with MMV’s leadership, large quantities of the compound have been produced and it is undergoing further safety testing with a view to entering human clinical trials within the next year.
Merck Serono has recently obtained the right to develop and, if successful, commercialise the compound, with the input of MMV’s expertise in the field of malaria drug development and access and delivery in malaria-endemic countries.
Dr Michael Chew from the Wellcome Trust, which provides funding for the DDU and MMV, said: “The need for new antimalarial drugs is more urgent than ever before, with emerging strains of the parasite now showing resistance against the best available drugs.
“These strains are already present at the Myanmar-Indian border and it’s a race against time to stop resistance spreading to the most vulnerable populations in Africa.
“The discovery of this new antimalarial agent, which has shown remarkable potency against multiple stages of the malaria lifecycle, is an exciting prospect in the hunt for viable new treatments.”
PAPER
Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy
// https://tpc.googlesyndication.com/pagead/js/r20160906/r20110914/abg.js//
A single-dose treatment against malaria worked in mice to cure them of the disease. The drug also worked to block infection in healthy mice and to stop transmission, according to a study published in Nature today. The fact that the drug can act against so many stages of malaria is pretty new, but what’s even more exciting is the compound’s mode of action: it kills malaria in a completely new way, researchers say. The feature would make it a welcome addition to our roster of antimalarials — a roster that’s threatened by drug resistance.
RESEARCHERS SIFTED THROUGH A LIBRARY OF ABOUT 4,700 COMPOUNDS TO FIND THIS ONE
Malaria is an infectious disease that’s transmitted through mosquito bites; it’s also a leading cause of death in a number of developing countries. Approximately 3.4 billion people live in areas where malaria poses a real threat. As a result, there were 207 million cases of malaria in 2012 — and 627,000 deaths. There are drugs that can be used to prevent malaria, and even treat it, but drug resistance is halting the use of certain treatments in some areas.
Searching for a new drug is all about trial and error. To find this particular compound, researchers sifted through a library of about 4,700 compounds, testing them to see if they were capable of killing the malaria parasite in a lab setting. When they found something that worked, they tweaked the drug candidate to see if it could perform more effectively. “We went through a lot of these cycles of testing and designing new compounds,” says Ian Gilbert, a medicinal chemist at the University of Dundee in the UK, and a co-author of the study. “Eventually we optimized to the compound which is the subject of the paper.” For now, that compound’s unwieldy name is DDD107498.
To make sure DDD107498 really had potential, the researchers tested it on mice that had already been infected with malaria. A single dose was enough to provoke a 90 percent reduction in the number of parasites in their blood. The scientists also gave the compound to healthy mice that were subsequently exposed to malaria. DDD107498 helped the mice evade infection with a single dose, but it’s unclear how long that effect would last in humans. Finally, the researchers looked at whether the compound could prevent the transmission from an infected mouse to a mosquito. A day after receiving the treatment, mice were put in contact with mosquitoes. The scientists noted a 91 percent reduction in infected mosquitoes.
“IT HAS THE ABILITY TO BE A ONE-DOSE [DRUG], IN COMBINATION WITH ANOTHER MOLECULE.”
“What’s exciting about this molecule is obviously the fact that it has the ability to be a one-dose [drug], in combination with another molecule to cure blood stage malaria,” says Kevin Read, a drug researcher also at the University of Dundee and a co-author of the study. The fact that the compound has the ability to block transmission and protect against infection is equally thrilling. But the way in which DDD107498 kills malaria might be its most interesting feature. It halts the production of proteins — which are necessary for the parasite’s survival. No other malaria drug does that right now, Read says. “So, in principle, there’s no resistance out there already to this mechanism.”
The drug hasn’t been tested in humans yet, so it may not be nearly as good in the field. But Read says DDD107498 looks promising. “From all the pre-clinical or non-clinical data we’ve generated, it is comparable or better than any of the current marketed anti-malarials in those studies.” And at $1 per treatment, the price of the drug should fall “within the range of what’s acceptable,” he says.
“It looks like an excellent study, and the results look very important,” says Philip Rosenthal, a malaria drug researcher at The University of California-San Francisco who didn’t participate in the study. This is a big shift for Rosenthal’s field. Five years ago, “we had very little going on in anti-malarial drug discovery,” he says. Now, there’s quite a bit going on for malaria researchers, and a number of promising compounds are moving along. DDD107498 “is another player, and it’s got a number of positive features,” he says.
OTHER TREATMENTS HAVE TO BE TAKEN FOR A FEW DAYS
One of the features is the drug’s potency. It’s very active against cultured malaria parasites, Rosenthal says. But what’s perhaps most intriguing about DDD107498 is that the drug works against the mechanism that enables protein synthesis the malaria parasite’s cells. No other malaria drug does that right now, Read says. “Considering challenges of treating malaria, which is often in rural areas and developing countries, a single dose would be a big plus,” he says. “In addition, because of it’s long half life, it may also work to prevent malaria with once a week dosing, which is also a benefit.”
Still, no drug is perfect. The data suggests that DDD107498 doesn’t kill malaria as quickly as some other drugs, Rosenthal says. And when the researchers tested it to see how long it might take for resistance to develop, the results weren’t as promising as he would like. The parasites figured out a way to become resistant to the compound “relatively easily,” he says. That shouldn’t be “deal-killer,” however. “Its slow onset of action probably means it should be combined with a faster-acting drug,” he says.
BUT IT’S SLOW-ACTING
The compound is going through safety testing now. If everything goes well, it should hit human trials within the next year, Read says. Chances are, it will have to be used in combination with other malaria drugs, Gilbert says. “All anti-malarials are given in combination because it slows down resistance.”
“When you’re treating infectious diseases, you know that drug resistance is always a potential problem, so having a number of choices to treat malaria is a good thing,” Rosenthal says. In this case, the drug’s new mode of action may hold lead to an entirely new weapon against malaria. “Obviously it’s got a long way to go,” Read says. But the compound is “very exciting,” nonetheless.
// https://tpc.googlesyndication.com/pagead/js/r20160906/r20110914/abg.js//
//
SCHEME 1
SCHEME 2
Preparation 4Yield: 54% Preparation 3
Yield: 27%
SCHEME 4 B
Yield: 72% Yield: 70% Preparation 6
Example 1 : 6-Fluoro-2-r4-(morpholinomethyl)phenyll-N-(2-pyrrolidin-1-ylethyl)quinoline- 4-carboxamide, Example compound 1 in Scheme 2
In a sealed microwave tube, a suspension of 2-chloro-6-fluoro-N-(2-pyrrolidin-1- ylethyl)quinoline-4-carboxamide (preparation 4) (2.00 g, 6 mmol), [4- (morpholinomethyl)phenyl]boronic acid, hydrochloride, available from UORSY, (3.20 g, 12 mmol), potassium phosphate (2.63 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.19 mmol) in DMF/Water 3/1 (40 ml) was heated at 130°C under microwave irradiation for 30 min. The reaction was filtered through Celite™ and solvents were removed under reduced pressure. The resulting residue was taken up in DCM (150 ml) and washed twice with NaHC03 saturated aqueous solution (2 x 100 ml). The organic layer was separated, dried over MgS04and concentrate to dryness under reduced pressure. The reaction crude was purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 1 min hold 100% A, followed by a 30 min ramp to 10 % B, and then 15 min hold at 10% B. The fractions containing product were pooled together and concentrated to dryness under vacuum to obtain the desired product as an off-white solid (1 g). The product was dissolved in methanol (100 ml) and 3-mercaptopropyl ethyl sulfide Silica (Phosphonics, SPM-32, 60- 200 uM) was added. The suspension was stirred at room temperature over for 2 days and then at 50°C for 1 h. After cooling to room temperature, the scavenger was filtered off and washed with methanol (30 ml). The solvent was removed under reduced pressure and the product was further purified by preparative HPLC. The fractions containing product were pooled together and freeze dried to obtain the desired product as a white solid (0.6 g, 1.3 mmol, Yield 20%).
1 H NMR (500 MHz; CDCI3) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J = 5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J = 5.4 Hz, J = 1 1.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1 H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J = 8.2 Hz), 8.21 (dd, 1 H, J = 5.5 Hz, J = 9.2 Hz) ppm . 19 F NMR (407.5 MHz; CDCI3) δ -11 1.47 ppm. Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.7 min, m/z 463 (M+H)+ HRMS (ES+) found 463.2501 [M+H]+, C27H32F1 N402 requires 463.2504.
Example 2: 6-Fluoro-2-[4-(morpholinomethyl)phenyl1-N-(2-pyrrolidin-1-ylethyl)quinoline- 4-carboxamide; fumaric acid salt, compound (IB) in Scheme 2
The starting free base (example 1) (0.58 g, 1 mmol) was dissolved in dry ethanol (10 ml) and added dropwise to a stirred solution of fumaric acid (0.15 g, 1 mmol) in dry ethanol (9 ml). The mixture was stirred at room temperature for 1 h. The white precipitate was filtered, washed with ethanol (20 ml) and then dissolved in 10 ml of water and freeze dried to obtain the desired salt as a white solid (0.601 g, 1 mmol, Yield 82%).
1 H NMR (500 MHz; d6-DMSO) δ 1.83-1.86 (m, 4H), 2.41 (brs, 4H), 2.94 (brs, 4H), 3.03 (t, 2H, J = 6.2 Hz), 3.57 (s, 2H), 3.60-3.65 (m, 6H), 6.47 (s, 2H), 7.51 (d, 2H, J = 8.25), 7.74-7.78 (m, 1 H), 8.06 (dd, 1 H, J = 2.9 Hz, J = 10.4 Hz), 8.17 (dd, 1 H, J = 5.7 Hz, J = 9.3 Hz), 8.24-8.26 (m, 3H), 9.24 (t, 1 H, J = 5.5 Hz) ppm. 19 F NMR (407.5 MHz; d6- DMSO) δ -112.30 ppm.
Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.3 min, m/z 463 (M+H)+
Example 1A: Alternative synthesis of 6-fluoro-2-[4-(morpholinomethyl)phenyl1-N-(2- pyrrolidin-1-ylethyl)quinoline-4-carboxamide, Example compound 1A in Scheme 4
To a stirred suspension of 6-fluoro-2-[4-(morpholinomethyl)phenyl]quinoline-4-carboxylic acid (preparation 7) (2.20 g, 6 mmol) in DCM (100 ml) at room temperature, 2-chloro- 4,6-dimethoxy-1 ,3,5-triazine (CDMT) (1.26 g, 7 mmol) and 4-methylmorpholine (NMO) (1.33 ml, 12 mmol) were added. The reaction mixture was stirred at room temperature for 1 h and then 2-pyrrolidin-1-ylethanamine (0.77 ml, 6 mmol) was added and stirred at room temperature for further 3 h. The reaction mixture was washed with NaHC03 saturated aqueous solution (2x 100 ml) and the organic phase was separated, dried over MgS04 and concentrated under reduced pressure. The resulting residue was absorbed on silica gel and purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 2 min hold 100% A followed by a 30 min ramp to 10 %B and then 15 min hold at 10%B. The desired fractions were concentrated to dryness under vacuum to obtain the crude product as a yellow solid (95% purity by LCMS). The sample was further purified by a second column chromatography using a 40 g silica gel cartridge, eluting with DCM (Solvent A) and 10% NH3-MeOH in DCM (Solvent B) and the following gradient: 2 min hold 100% A, followed by a 10 min ramp to 23 % B and then 15 min hold at 23% B. The desired fractions were concentrated to dryness under vacuum to obtain product as a white solid (1 g). Re-crystallisation form acetonitrile (18 ml) yielded the title compound as a white solid (625 mg, 1.24 mmol, 20%).
1 H NMR (500 MHz; CDCI3) δ 1.81-1.84 (m, 4H), 2.50-2.52 (m, 4H), 2.63 (brs, 4H), 2.82 (t, 2H, J = 5.9 Hz), 3.61 (s, 2H), 3.71 (dd, 2H, J = 5.4 Hz, J = 1 1.4 Hz), 3.74-3.76 (m, 4H), 6.84 (brs, 1 H), 7.52-7.57 (m, 3H), 7.97-8.00 (m, 2H), 8.13 (d, 2H, J = 8.2 Hz), 8.21 (dd, 1 H, J = 5.5 Hz, J = 9.2 Hz) ppm .
1 H NMR (500 MHz; d6-DMSO) δ 1.72-1.75 (m, 4H), 2.41 (brs, 4H), 2.56 (brs, 4H), 2.67 (t, 2H, J = 6.6 Hz), 3.49-3.52 (m, 2H), 3.56 (s, 2H), 3.60-3.61 (m, 4H), 7.52 (d, 2H, J = 8.3 Hz), 7.73-7.77 (m, 1 H), 8.07 (dd, 1 H, J = 2.9 Hz, J = 10.4 Hz), 8.18-8.21 (m, 2H), 8.26 (d, 2H , J = 8.3 Hz), 8.85 (t, 1 H, J = 6.6 Hz) ppm.
13C NMR (125 MHz; d6-DMS03) 5 23.2, 38.4, 53.2, 53.5, 54.5, 62.1 , 66.2, 109.0, 109.1 , 1 17.3, 120.1 , 120.3, 124.1 , 124.2, 127.1 , 129.4, 132.2, 132.3, 136.8, 139.9, 142.8, 145.2, 155.3, 159.0, 161 .0, 166.1 ppm.
19 F NM R (500 MHz; d6-DMSO) δ -1 12.47 ppm.
Purity by LCMS (UV Chromatogram, 190-450nm) 99 %, rt = 5.0 min, m/z 463 (M+H)+
Putting a stop to malaria: Phenotypic screening against malaria parasites, hit identification, and efficient lead optimization have delivered the preclinical candidate antimalarial DDD107498. This molecule is distinctive in that it has potential for use as a single-dose cure for malaria and shows a unique broad spectrum of activity against the liver, blood, and mosquito stages of the parasite life cycle.
Medicinal Chemistry
I am a medicinal chemist and my research interests are in the design and synthesis of potential drugs. The mainstay of my work is synthetic medicinal chemistry as part of the Drug Discovery Unit (DDU). Where possible we make extensive use of molecular modeling to guide our synthetic efforts. I have a particular interests in the following aspects of drug discovery:
Neglected diseases such as human African trypanosomiasis, leishmaniasis and malaria.
Chemical validation of drug targets, including novel targets for which there is little or no precedence for drug discovery.
Novel approaches to and paradigms for drug discovery.
Mode of action studies and target identification.
I am Head of Chemistry in the DDU. Our main focuses are on neglected diseases and novel drug targets. The neglected diseases we are tackling are malaria, tuberculosis and the kinetoplastid diseases. We use both target-based approaches and phenotypic approaches (whole parasite screening). We have had particular success in validating the enzyme N-myristoyltransferase as a drug target in human African trypanosomiasis, and in identifying and optimising phenotypic hits. In our novel targets area, we aim to validate novel areas of biology as potential drug targets.
///////////DDD107498, DDD 107498, PRECLINICAL, DUNDEE, MALARIA, DDD 498, Achim Porzelle, Ian Gilbert, MERCK SERENO, Beatriz Baragaña, Medicines for Malaria Venture, University of Dundee, Neil Norcross, 1469439-69-7, 1469439-71-1 , SUCCINATE
Fc1ccc2nc(cc(c2c1)C(=O)NCCN1CCCC1)-c1ccc(cc1)CN1CCOCC1
1, 2-Bis(4-(4-4-nitrophenyl)piperazin-1-yl)ethanone
| Molecular Formula: | C22H26N6O5 |
|---|---|
| Molecular Weight: | 454.47904 g/mol |
CAS 330633-91-5
CDRI-?
1, 2-Bis(4-(4-4-nitrophenyl)piperazin-1-yl)ethanone
In the quest for novel scaffolds for the management of androgen sensitive prostatic disorders like prostate cancer and benign prostatic hyperplasia, a series of twenty-six aryl/heteroaryl piperazine derivatives have been described. Three compounds, 8a, 8c and 9a, exhibited good activity profiles against an androgen sensitive prostate cancer cell line (LNCaP) with EC50values of 9.8, 7.6 and 11.2 μM, respectively. These compounds caused a decrease in luciferase activity and a decline in PSA and Ca2+ levels, which are indicative of their anti-androgenic and α1A-adrenergic receptor blocking activities, respectively.
Compound 9a reduced the prostate weight of rats (47%) and in pharmacokinetic analysis at 10 mg kg−1 it demonstrated an MRT of ∼14 h post dose, exhibiting high levels in prostate. Compound 9a docked in a similar orientation to hydroxyflutamide on an androgen receptor and showed strong π–π interactions. These findings reveal that compound 9a is a promising candidate for management of prostatic disorders with anti-androgenic and α1A-blocking activities.
DOI: 10.1039/C6MD00426A, http://pubs.rsc.org/en/Content/ArticleLanding/2016/MD/C6MD00426A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract
1, 2-Bis(4-(4-4-nitrophenyl)piperazin-1-yl)ethanone (9a) To the mixture of 8a (0.3 g, 1.06 mmol) and Et3N (0.3 mL, 2.12 mmol) in CHCl3 (5 mL) was added 1-(4-nitrophenyl)piperazine (7a, 0.320 g, 1.59 mmol) in 5 mL CHCl3 dropwise within 1 h. After complete addition reaction mixture was further stirred in an oil bath at 80-85 °C for 15 h. The reaction mixture was cooled, washed with water (5 mL × 3) and the organic layer was separated. Combined organic layer was dried (anhyd. Na2SO4 and concentrated under reduced pressure in rotavapor. The solid obtained was purified by recrystallization using EtOAc/Hexane which furnished yellow crystals (yield 81%);
mp: 156-157 °C; IR (KBr) (cm-1): 3019, 2399, 1640, 1597, 1506, 1423, 1330;
1H NMR (400 MHz, CDCl3): 8.14-8.09 (4H, m), 6.84-6.81 (4H, m), 3.84-3.83 (4H, m), 3.49-3.44 (8H, m), 3.33 (2H, s), 2.72 (4H, t, J = 5.0 Hz);
13C NMR (75.4 MHz, CDCl3): 167.7, 154.7, 154.3, 138.8, 138.4, 125.9, 125.8, 112.9, 112.7, 60.8, 52.5, 46.9, 46.7, 44.6;
HRMS (ESI positive) m/z calcd. for C22H26N6O5 [M+H]+ : 455.2043, found: 455.2034;
Anal calcd. for C22H26N6O5: C, 58.14; H, 5.77; N, 18.49, found: C, 58.31; H, 5.92; N, 18.66.
SONAL GUPTA
Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram ext., Lucknow-226031, India
Dr. VISHNU LAL SHARMA
http://www.cdriindia.org/VL_Sharma.htm
| Dr. VISHNU LAL SHARMA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Senior Principal Scientist (CSIR-CDRI ) / Professor (AcSIR) |
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 From left to right upper row: Dr. S.T.V.S. Kiran Kumar, Dr. Lalit Kumar, Dr. V.L. Sharma, Dr. Nand Lal, Dr. Amit Sarswat Lower row: Dhanaraju Mandalapu, Sonal Gupta, Mrs. Tara Rawat (S.T.O.), Dr. Veenu bala, Dr. Santosh Jangir |
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From left to right upper row: Dr. S.T.V.S. Kiran Kumar, Dr. Lalit Kumar, Dr. V.L. Sharma, Dr. Nand Lal, Dr. Amit Sarswat
Lower row: Dhanaraju Mandalapu, Sonal Gupta, Mrs. Tara Rawat (S.T.O.), Dr. Veenu bala, Dr. Santosh Jangir
///////////aryl piperazine, androgen sensitive prostatic disorders, 330633-91-5, CDRI-?
c1(ccc(cc1)[N+]([O-])=O)N2CCN(CC2)C(=O)CN3CCN(CC3)c4ccc(cc4)[N+]([O-])=O
| Almorexant; ACT-078573; (R)-2-((S)-6,7-Dimethoxy-1-(4-(trifluoromethyl)phenethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-methyl-2-phenylacetamide; |
Almorexant (INN, codenamed ACT-078573) is an orexin antagonist, functioning as a competitive receptor antagonist of the OX1 and OX2 orexin receptors, which was being developed by the pharmaceutical companies Actelion and GSK for the treatment of insomnia. Development of the drug was abandoned in January 2011.[1]
Development
Originally developed by Actelion, from 2007 almorexant was being reported as a potential blockbuster drug, as its novel mechanism of action (orexin receptor antagonism) was thought to produce better quality sleep and fewer side effects than the traditionalbenzodiazepine and z drugs which dominated the multibillion-dollar insomnia medication market.[2][3]
In 2008, pharmaceutical giant GlaxoSmithKline bought the development and marketing rights for almorexant from Actelion for an initial payment of $147 million.[4] The deal was worth a potential $3.2billion if the drug were to successfully complete clinical development and obtain FDA approval.[5] GSK and Actelion continued to develop the drug together, and completed a Phase IIIclinical trial in November 2009.[6]
However, in January 2011 Actelion and GSK announced they were abandoning the development of almorexant because of its side effect profile.[1][7]
Almorexant is a competitive, dual OX1 and OX2 receptor antagonist and selectively inhibits the functional consequences of OX1 and OX2 receptor activation, such as intracellular Ca2+ mobilization.
PAPER
http://pubs.rsc.org/en/content/articlelanding/2013/ob/c3ob40655e#!divAbstract
An enantioselective synthesis of almorexant, a potent antagonist of human orexin receptors, is presented. The chiral tetrahydroisoquinoline core structure was prepared via iridium-catalysed asymmetric intramolecular allylic amidation. Further key catalytic steps of the synthesis include an oxidative Heck reaction at room temperature and a hydrazine-mediated organocatalysedreduction.
https://www.google.com/patents/EP2227454A2?cl=en
Reaction scheme 5:
7*CH3COOH
Step 11 : synthesis of (2R)-2-{(-/S)-6,7-dimethoxy-1 -[2-(4-thfluoromethyl-phenyl)- ethyl]-3,4-dihydro-1 /-/-isoquinolin-2-yl}-Λ/-methyl-2-phenyl-acetamide (compound 8)
To the solution of the compound 7 in MIBK are added 1.2 equivalents of the compound 6, 1.1 equivalents caustic soda and 1.1 equivalents potassium carbonate and heated to 70-90 0C. After full conversion the solution is cooled to RT and water is added. Phase separation is followed by a second washing of the organic phase with water and again phase separation. Step 12: synthesis of (2R)-2-{(-/S)-6,7-dimethoxy-1 -[2-(4-trifluoromethyl-phenyl)- ethyl]-3,4-dihydro-1 /-/-isoquinolin-2-yl}-/\/-nnethyl-2-phenyl-acetannide hydrochloride acid (compound I)
To the organic phase of step 11 is added 1 equivalent aqueous hydrochloric acid and then the water removed by azeotropic distillation in vacuo. The precipitate is dissolved by addition of 2-propanol at 75 0C. Concentration of the solution leads to crystallisation and the suspension is then cooled to RT. To ensure complete crystallisation, the suspension is aged at RT, then filtered and washed with a MIBK-2-propanol mixture. The product is dried in vacuo at 50 0C.
PAPER
Several methods are presented for the enantioselective synthesis of the tetrahydroisoquinoline core of almorexant (ACT-078573A), a dual orexin receptor antagonist. Initial clinical supplies were secured by the Noyori Ru-catalyzed asymmetric transfer hydrogenation (Ru-Noyori ATH) of the dihydroisoquinoline precursor. Both the yield and enantioselectivity eroded upon scale-up. A broad screening exercise identified TaniaPhos as ligand for the iridium-catalyzed asymmetric hydrogenation with a dedicated catalyst pretreatment protocol, culminating in the manufacture of more than 6 t of the acetate salt of the tetrahydroisoquinoline. The major cost contributor was TaniaPhos. By switching the dihydroisoquinoline substrate of the Ru-Noyori ATH to its methanesulfonate salt, the ATH was later successfully reduced to practice, delivering several hundreds of kilograms of the tetrahydroisoquinoline, thereby reducing the catalyst cost contribution significantly. The two methods are compared with regard to green and efficiency metrics.
References
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| Systematic (IUPAC) name | |
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(2R)-2-[(1S)- 6,7-dimethoxy- 1-{2-[4-(trifluoromethyl)phenyl]ethyl}- 3,4-dihydroisoquinolin-2(1H)-yl]- N-methyl- 2-phenylacetamide
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| Clinical data | |
| Routes of administration |
Oral |
| Pharmacokinetic data | |
| Metabolism | Hepatic |
| Identifiers | |
| CAS Number | 871224-64-5 |
| ATC code | none |
| PubChem | CID 23727689 |
| IUPHAR/BPS | 2886 |
| ChemSpider | 21377865 |
| UNII | 9KCW39P2EI |
| ChEMBL | CHEMBL455136 |
| Chemical data | |
| Formula | C29H31F3N2O3 |
| Molar mass | 512.6 g/mol (free base) |
///////Almorexant, ACT-078573
CNC(=O)C(C1=CC=CC=C1)N2CCC3=CC(=C(C=C3C2CCC4=CC=C(C=C4)C(F)(F)F)OC)OC
SR48692 (Meclinertant)
Reminertant; SR 48692
CAS [146362-70-1]
SEE…...https://newdrugapprovals.org/2014/12/31/meclinertant-sr48692/
2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)pyrazole-3-carbonyl]amino]adamantane-2-carboxylic acid
Meclinertant (SR-48692) is a drug which acts as a selective, non-peptide antagonist at the neurotensin receptor NTS1, and was the first non-peptide antagonist developed for this receptor.[1][2] It is used in scientific research to explore the interaction between neurotensin and other neurotransmitters in the brain,[3][4][5][6][7][8] and produces anxiolytic, anti-addictive and memory-impairing effects in animal studies.[9][10][11][12]
CLIP
Methods for the synthesis of pharmaceuticals have improved over the years, however, the technology and tools used to perform synthetic operations have remained the same. Batch-mode processes are still common but many improvements can be made by using modern technologies. Recently, the use of machine-assisted protocols has increased, with flow-based chemical synthesis being extensively investigated. Under dynamic flow regimes, mixing and heat transfer can be more accurately controlled, the use of solid-phase reagents and catalysts can facilitate purification, and tedious downstream processes (workup, extraction, and purification) are reduced.
Steven V. Ley and co-workers, University of Cambridge, UK, have been evaluating the utility of flow-based syntheses to accelerate multistep routes to highly complex, medically relevant compounds, in this case Meclinertant (SR48692, pictured). They show that new technologies can help to overcome many synthetic issues of the existing batch process. In this case, flow chemistry has allowed control of exothermic events, controlled the superheating of solvents, and streamlined the synthesis by allowing reaction telescoping. It has also helped to prevent back mixing and the accumulation of byproducts. The use of polymer-supported reagents has simplified downstream processing and enhanced the safety of reactions, and in-line monitoring can track hazardous intermediates.
These new technologies have been shown to be powerful synthetic tools, although care must be taken not to convert them to expensive solutions to nonexistent problems.
http://community.dur.ac.uk/i.r.baxendale/papers/ChemEurJ2013.19.7917.pdf
A Machine-Assisted Flow Synthesis of SR48692: A Probe for the Investigation of Neurotensin Receptor-1,
Claudio Battilocchio, Benjamin J. Deadman, Nikzad Nikbin, Matthew O. Kitching, Ian R. Baxendale, Steven V. Ley,
Chem. Eur. J. 2013.
DOI: 10.1002/chem.201300696
2-[1-(7-Chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido]adamantane-2-carboxylic acid (1):
Polymer-supported sulfonic acid (QP-SA; 0.6 g, 2.4 mmol) was added to a solution of tert-butyl 2-[1- (7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido]adamantane-2-carboxylate (13; 30 mg, 0.05 mmol) in dichloromethane and the reaction was stirred at RT for 18 h. The QP-SA was filtered off and the filtrate concentrated in vacuo to provide the title compound as white crystals (yield 25 mg, 0.04 mmol, 86%).
M.p. 219–222 deg C;
1 H NMR (400 MHz, CDCl3, 25 deg C): d=8.91 (d, 1H, J=4.6 Hz), 8.15 (d, 1H, J=2.1 Hz), 7.78 (d, 1H, J=9.1 Hz), 7.68 (dd, 1H, J=2.1, 9.1 Hz), 7.28 (d, 1H, J=4.7 Hz), 7.24 (t, 1H, J=8.5 Hz), 7.91 (s, 1H), 6.52 (d, 2H, J=8.5 Hz), 3.42 (s, 6H), 2.64–2.56 (m, 2H), 2.17–2.05 (m, 2H), 2.04–1.92 (m, 2H), 1.82–1.71 (m, 2H), 1.71–1.61 (m, 4H), 1.61–1.50 ppm (m, 2H);
13C NMR (100 MHz, CDCl3, 25 deg C): d=173.3(C), 159.9 (C), 157.5 (C), 157.5 (C), 151.8 (CH), 149.1 (C), 143.4 (C), 139.2 (C), 134.8 (C), 131.9 (CH), 128.0 (CH), 127.7 (CH), 125.9 (CH), 122.2 (C), 118.6 (CH), 109.6 (CH), 105.8 (C), 104.0 (CH), 55.4 (CH3), 55.3 (C), 37.4 (CH2), 33.6 (CH2), 32.8 (CH2), 31.9 (CH), 26.5 (CH), 26.2 ppm (CH);
FT-IR (neat): 3405, 2922, 1728, 1674, 1591, 1527, 1474, 1433, 1379, 1357, 1288, 1251, 1206, 1101, 1077, 1031, 1006, 957, 882, 865, 823, 779, 725, 682 cm1 ;
LCMS: tR =5.29 min, m/z [M+H]+: 587.46;
HRMS (ESI): m/z calcd for C32H32N4O5Cl+: 587.2061, found 587.2053; the structure was unambiguously confirmed by single X-ray crystallography; space group P1¯: a= 10.249, b=11.718, c=12.634 ; a=76.6, b=72.9, g=76.4o
CLIP AND ITS OWN REFERENCES
Although batch processes remain the most used procedure for running chemical reactions, the use of machine-assisted flow methodologies(24) enables an improved efficiency and high throughput. A direct comparison between conventional batch preparation and flow multistep synthesis of selective neurotensine probe SR48692 (Meclinertant) was reported by Ley and co-workers in 2013 (Scheme 6).(25)
In this case study, the authors investigated whether flow technology could accelerate a multistep synthesis (i.e., higher yields or lower reaction times) and overcome many synthetic issues (i.e., solid precipitation or accumulation of byproducts). The initial Claisen condensation between ketone 31 and ethyl glyoxalate in the presence of NaOEt as base and EtOH as solvent in batch is run at room temperature and product 32 is obtained in 60% yield after 3 h stirring.
Superheating (heat above solvent boiling point) the reaction in flow provided a faster alternative: using a 52 mL PFA reactor coil at 115 °C with a residence time of 22 min gave the corresponding product 32 in 74% yield. In order to solve some problems of solid accumulation an ad-hoc pressurized stainless-steel tank (5 bar, nitrogen) was designed; it allowed to run the reaction continuously without any precipitation or blockage.
The following reaction between 32 and commercially available hydrazine 33 was performed in DMF in the presence of concentrated H2SO4. After 52 min of residence time at 140 °C into a 52 mL PFA reactor coil the crude mixture was treated with an Na2CO3 aq. and then inline extracted through a semipermeable membrane with CH2Cl2. After crystallization, pyrazole ester 34 was isolated in 89% yield.
The corresponding reaction in batch was conducted in DMF under microwaves irradiation at 140 °C for 2 h. Running the reaction in batch on the same scale as in flow (3.58 mmol) gave product 34 in a lower yield (70%). The subsequent hydrolysis was performed combining a THF solution of ester 34 and 3 M aqueous KOH. The reaction was performed inside a 14 mL PFA reactor coil heated at 140 °C with a residence time of 14 min.
Upon treatment with 3 M HCl aq., acid 35 precipitated, and it was isolated by filtration in 90% yield. In this case, the corresponding batch hydrolysis afforded product 35 with the same yield (90%); however, a longer reaction time (1.5 h) was required. The final amide formation was performed by reacting acid 35 (activated as acyl chloride) and protected amino alcohol 37through a telescoped synthesis. Triphosgene 36 (a safer substitute for phosgene) was found to be the best acid activator.
Triphosgene decomposition occurred in the presence of DIPEA at 100 °C into a stainless steel heat exchanger, where phosgene was generated. The crude mixture, containing also acid 35, then passed into a 2.5 mL stainless steel reactor coil at 25 °C, to complete the formation of the corresponding acyl chloride. An inline Flow-IR spectrometer(26)was used to monitor the formation of phosgene without exposing the operator to the toxic gas during analysis. As soon as acyl chloride was formed it was reacted with protected amino alcohol 37.
The amide formation took place into a 14 mL stainless steel reactor coil at 100 °C with a residence time of 75 s. Amide 38 was isolated in 85% yield after quenching with NH4Cl and extraction with AcOEt. For obvious safety concerns, avoiding the handling of phosgene and the isolation of highly reactive acyl chloride intermediate represent a remarkable improvement with respect to batch procedure.
Finally, meclinertant 39 was obtained after deprotection of ester38 by using a polymer-supported sulfonic acid. The last synthetic step was conducted in batch on a small scale; however, it could be easily transferred to flow mode by using a column packed with commercially available polymer-supported sulfonic acid.
24 Ley, S. V.; Fitzpatrick, D. E.; Myers, R. M.; Battilocchio, C.; Ingham, R. J. Angew. Chem., Int. Ed. 2015, 54, 2, DOI: 10.1002/anie.201501618
25.Battilocchio, C.; Deadman, B. J.; Nikbin, N.; Kitching, M. O.; Baxendale, I. C.; Ley, S. V. Chem. – Eur. J. 2013, 19, 7917, DOI: 10.1002/chem.201300696
CLIP AND ITS OWN REFERENCES
The choice of the flow reactor also plays a key role in the synthesis of meclinertant (SR48692, 103), which is a potent probe for investigating neurotensin receptor-1 [92]. The flow synthesis of this challenging compound was reported in 2013 and aims to evaluate the benefits of flow chemistry in order to avoid shortcomings of previous batch synthesis efforts particularly in regard to scale up [93].
The investigation first involved the preparation of the key acetophenone starting material 112 which although commercially available was expensive and could be generated from 1,3-cyclohexadione (104). The sequence consisted of O-acetylation, a Steglich rearrangement, oxidation and a final methylation reaction.
As the use of flow chemistry had already improved the O-acetylation during scale-up tests (130 mmol) by avoiding exotherms, it was anticipated that the subsequent Steglich rearrangement could be accomplished in flow using catalytic DMAP instead of stoichiometric AlCl3 as precedented (Scheme 19).
This was eventually realised by preparing a monolithic flow reactor functionalised with DMAP that proved far superior to commercially available DMAP on resin. Employing the monolithic reactor cleanly catalysed the rearrangement step when a solution of 106 was passed through the reactor at elevated temperature (100 °C, 20 min residence time).
The resulting triketone 107 was telescoped into an iodine mediated aromatisation, followed by high temperature mono-methylation using dimethyl carbonate/dimethylimidazole as a more benign alternative to methyl iodide at scale.
The subsequent Claisen condensation step between ketone 112 and diethyl oxalate (113) was reportedly hampered by product precipitation and clogging problems, thus a pressure chamber was developed [94] that would act as a pressure regulator allowing this step to be scaled up in flow in order to provide 114 on multigram scale (134 g/h).
A Knorr pyrazole formation between 114 and commercially available hydrazine 115 had previously been found difficult to scale up in batch (the yield dropped from 87% to 70%) and was thus translated into a high temperature flow protocol (140 °C) delivering the desired product 116 in 89% yield (Scheme 20).
Ester hydrolysis and a triphosgene (118) mediated amide bond formation between acid 117 and adamantane-derived aminoester119 [95] completed this flow synthesis. Meclinertant (103) was subsequently obtained after batch deprotection using polymer supported sulfonic acid.
Overall, this study showcases how flow chemistry can be applied to gain benefits when faced with problems during mesoscale synthesis of a complex molecule. However, despite the successful completion of this campaign, it could be argued that the development time required for such a complex molecule in flow can be protracted; therefore both synthetic route and available enabling technologies should be carefully examined before embarking upon such an endeavour.
| 92 Myers, R. M.; Shearman, J. W.; Kitching, M. O.; Ramos-Montoya, A.; Neal, D. E.; Ley, S. V. ACS Chem. Biol. 2009, 4, 503–525. doi:10.1021/cb900038e |
| 93. | Battilocchio, C.; Deadman, B. J.; Nikbin, N.; Kitching, M. O.; Baxendale, I. R.; Ley, S. V.Chem. – Eur. J. 2013, 19, 7917–7930. doi:10.1002/chem.201300696 |
| 94. | Deadman, B. J.; Ley, S. V.; Browne, D. L.; Baxendale, I. R.; Ley, S. V.Chem. Eng. Technol. 2015, 38, 259–264. doi:10.1002/ceat.201400445 |
| 95. | Battilocchio, C.; Baxendale, I. R.; Biava, M.; Kitching, M. O.; Ley, S. V.Org. Process Res. Dev. 2012, 16, 798–810. doi:10.1021/op300084z |
and Ian R. Baxendale Corresponding author email| EP 0477049; FR 2665898; JP 1992244065; US 5420141; US 5607958; US 5616592; US 5635526; US 5744491; US 5744493 | |
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|
| The condensation of 2′,6′-dimethoxyacetophenone (I) with diethyl oxalate (II) by means of sodium methoxide in refluxing methanol gives the dioxobutyrate (III), which is cyclized with 7-chloroquinoline-4-hydrazine (IV) in refluxing acetic acid yielding the pyrazole derivative (V). The hydrolysis of the ester group of (V) with KOH in refluxing methanol/water affords the corresponding carboxylic acid (VI), which is finally treated with SOCl2 in refluxing toluene and condensed with 2-aminoadamantane-2-carboxylic acid. | |
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| US5420141 | 1995-05-30 | 3-amidopyrazole derivatives, process for preparing these and pharmaceutical composites containing them |
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|
| Systematic (IUPAC) name | |
|---|---|
|
2-([1-(7-Chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carbonyl]amino)admantane-2-carboxylic acid
|
|
| Identifiers | |
| CAS Number | 146362-70-1 |
| PubChem | CID 119192 |
| IUPHAR/BPS | 1582 |
| UNII | 5JBP4SI96H |
| ChEMBL | CHEMBL506981 |
| Chemical data | |
| Formula | C32H31ClN4O5 |
| Molar mass | 587.064 |
. PMID 8380498.. PMID 17356568.//////////////////////Flow synthesis, Meclinertant, SR48692, Reminertant, SR 48692, 146362-70-1
COC1=C(C(=CC=C1)OC)C2=CC(=NN2C3=C4C=CC(=CC4=NC=C3)Cl)C(=O)NC5(C6CC7CC(C6)CC5C7)C(=O)O
SNS 032, BMS-387032
N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide
Cas 345627-80-7, MP 165-167° C
M.Wt:380.53, Formula:C17H24N4O2S2
SNS 032, BMS-387032 HYDROCHLORIDE
| Formula | C17H24N4O2S2 . HCl |
|---|---|
| MW | 380.5 . 36.5 |
| CAS | 345627-90-9 |
A potent and selective Cdk inhibitor
Potent inhibitor of cyclin-dependent kinases (cdks) 9, 2 and 7 (IC50 values are 4, 38 and 62 nM respectively). Displays no activity against 190 additional kinases (IC50 >1000 nM). Arrests the cell cycle at G2/M; inhibits transcription, proliferation and colony formation, and induces apoptosis in RPMI-8226 multiple myeloma cells. Prevents tumor cell-induced VEGF secretion and in vitro angiogenesis. SNS-032 (BMS-387032) has firstly been described as a selective inhibitor of CDK2 with IC50 of 48 nM in cell-free assays and is 10- and 20-fold selective over CDK1/CDK4. It is also found to be sensitive to CDK7/9 with IC50 of 62 nM/4 nM, with little effect on CDK6. Phase 1.
Quality Control & MSDS
COA NMR HPLC Datasheet SDS/MSDS
SNS-032 (BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDKs) 2, 7, and 9 [1], with IC50 values of 38 nM, 62 nM and 4 nM, respectively [2].
CDKs mean a family of serine/threonine kinases regulating cell cycle process. Some CDKs are related to transcription control and are often perturbed in cancer cells [3].
Decrease in the phosphorylation at Ser5 and Ser2 in the C-terminal domain (CTD) of RNA Pol II can indicate the inhibition to CDK9 and CDK7 [1]. Chronic lymphocytic leukemia (CLL) cells treated with SNS-032 for 6 or 24 hours showed a decrease in the phosphorylation of Ser2 and Ser5 of the CTD of RNA Pol II, this appeared to be both time- and concentration- dependent, and remarkably consistent among samples. For the phosphorylation of Ser2, the inhibition of SNS-032 was greater than that for the phosphorylation of Ser5, this was consistent with the fact that IC50 for the inhibition of CDK9 was lower compared with that for the inhibition of CDK7 (4 nM vs 62 nM). After 6 hours of SNS-032 exposure, protein levels of CDK7 and CDK9 were stable, but declined at 24 hours [4].
In patients with chronic lymphocytic leukemia (CLL), infusion of SNS-032 in a total dose of 75 mg/m2 resulted in a decrease in the phosphorylation at Ser5 and Ser2 in the C-terminal domain of RNA Pol II. This indicated the inhibition to Cdk9 and Cdk7 by SNS-032. This inhibition was first seen 2 hours after the beginning of the infusion with SNS-032, was pronounced after 6 hours and returned to baseline after 24 hours [1].
The cell cycle-regulated cyclin-dependent kinases (CDKs), CDK1, 2, and 4 have been extensively studied as potential therapeutic targets in cancer. Recent research has additionally underscored the potential role of several constitutively active CDKs including CDK7 and 9 as cancer targets. Phosphorylation of the c-terminal domain (CTD) of RNA Polymerase II by CDK7 and 9 are critical steps in transcriptional regulation. Inhibition of these kinases is predicted to have the greatest effect on the expression of proteins with short t½ and short-lived mRNA, including proteins involved in apoptotic regulation. CDK7 also activates cell-cycle CDKs 1, 2, 4 and 6. SNS-032 (formerly BMS-387032) has previously been described as a selective inhibitor of CDK2 with potent antitumor activity in animal models. Here we show that in addition to inhibition of CDK2, SNS-032 also inhibits CDK7/cyclinH and CDK9/cyclinT at low nanomolar concentrations in biochemical assays. The compound is highly selective for CDK inhibition; in a panel of 208 kinases, only four non-CDK proteins were inhibited by >50% at 1 μM SNS-032. The cellular pharmacology of SNS- 032 mirrors the biochemical data. Cells treated with SNS-032 show a rapid cell cycle arrest and onset of cell death that corresponds with inhibition of multiple substrates of CDK2, 7, and 9. For instance, inhibition of Rb phosphorylation, accumulation of cyclin E protein and cell-cycle arrest at GI and G2 are observed in multiple cell lines in a time and dose-dependent manner, consistent with inhibition of CDK2 and CDK7. Furthermore, SNS-032 inhibits CDK9-mediated phosphorylation of Ser2 in the CTD with an IC50 = 200 nM. Corresponding with inhibition of RNA polymerase II, the short half-life, anti-apoptotic protein Mcl-1 is rapidly depleted from cells, coincident with the phosphorylation of p53. Expression of Mcl-1 is a candidate predictor of aggressive disease and resistance to chemotherapy in CLL and is essential for survival of B-cell lymphoma and multiple myelomas, supporting the use of SNS-032 as a treatment for these diseases. SNS-032, a selective inhibitor of multiple CDKs involved in apoptosis and cell cycle regulation, has potential for antitumor activity in both solid and hematological cancers. SNS-032 is currently in phase 1 clinical studies.
SNS-032, was designed as a selective CDK2 inhibitor. Here, we show that in addition to CDK2, CDK 7 and 9 inhibitory activities also contribute to the biological activity of the molecule. The CDK2/cyclin E complex regulates entry of cells into S phase by phosphorylating Rb, a negative regulator of the transcription factor E2F. CDK2 phosphorylates a number of additional substrates, including cyclin E, signaling its degradation. Inhibiting CDK2 should therefore arrest cells in G1 and stabilize cyclin E. The cellcycle CDKs (CDK1, 2 4 and 6) are activated by phosphorylation by CDK7/cyclin H (also called CAK). Inhibition of CDK7 would therefore also result in cell-cycle arrest at multiple points in the cell cycle due to failure to activate the cell cycle CDKs. CDK 7 and 9 activate transcription by phosphorylating the CTD of RNA pol II. Inhibition of CTD phosphorylation has been shown to inhibit transcription and reduce expression of short lived proteins, including those involved in apoptosis regulation. Stalling of RNA polymerase has also been shown to activate p53, leading to apoptosis. Thus, the CDK7 and 9 inhibitory activities of SNS-032 are expected to cause cytotoxicity via induction of apoptosis.
SNS-032 is a selective CDK inhibitor, preferentially targeting CDK2, CDK7 and CDK9 in vitro. • In cell models, SNS-032 shows dual activity, targeting both cell cycle progression and apoptosis pathway proteins. • SNS-032 Inhibited CDK9 and 7-mediated phosphorylation of ser 2 and ser 5 of the CTD of RNA pol II and in turn downregulates the antiapoptotic protein Mcl-1. • SNS-032 induced a cell cycle arrest, and increased cyclin E levels are consistent with inhibition of cell cycle CDKs • Mcl-1 is a key survival factor in many B-cell malignancies. SNS-032 is being pursed as treatment for these diseases.
| Biological Activity | ||||||
|---|---|---|---|---|---|---|
| Description | SNS-032 is a novel, potent and selective CDK inhibitor of CDK2, CDK7 and CDK9 with IC50 of 38 nM, 62 nM and 4 nM, respectively. | |||||
| Targets | CDK2 | CDK7 | CDK9 | |||
| IC50 | 38 nM | 62 nM | 4 nM [1] | |||
| In Vitro | SNS-032 has low sensitivity to CDK1 and CDK4 with IC50 of 480 nM and 925 nM, respectively. SNS-032 effectively kills chronic lymphocytic leukemia cells in vitro regardless of prognostic indicators and treatment history. Compared with flavopiridol and roscovitine, SNS-032 is more potent, both in inhibition of RNA synthesis and at induction of apoptosis. SNS-032 activity is readily reversible; removal of SNS-032 reactivates RNA polymerase II, which led to resynthesis of Mcl-1 and cell survival. [1] SNS-032 inhibits three dimensional capillary network formations of endothelial cells. SNS-032 completely prevents U87MG cell–mediated capillary formation of HUVECs. In addition, SNS-032 significantly prevents the production of VEGF in both cell lines, SNS-032 prevents in vitro angiogenesis, and this action is attributable to blocking of VEGF. Preclinical studies have shown that SNS-032 induces cell cycle arrest and apoptosis across multiple cell lines. [2] SNS-032 blocks the cell cycle via inhibition of CDKs 2 and 7, and transcription via inhibition of CDKs 7 and 9. SNS-032 activity is unaffected by human serum. [3]SNS-032 induces a dose-dependent increase in annexin V staining and caspase-3 activation. At the molecular level, SNS-032 induces a marked dephosphorylation of serine 2 and 5 of RNA polymerase (RNA Pol) II and inhibits the expression of CDK2 and CDK9 and dephosphorylated CDK7. [4] | |||||
| In Vivo | SNS-032 prevents tumor cell-induced VEGF secretion in a tumor coculture model. [2] SNS-032, a new CDK inhibitor, is more selective and less cytotoxic and has been shown to prolong stable disease in solid tumors. [4] | |||||
| Clinical Trials | SNS-032 currently in phase I clinical trial for chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). | |||||
| Description | SNS-032 is a selective inhibitor of CDK2 with IC50 of 48 nM. | |||||
| Targets | CDK2 | CDK7 | CDK9 | |||
| IC50 | 48 nM | 62 nM | 4 nM | |||
CLIP
http://www.mdpi.com/1420-3049/19/9/14366/htm#B39-molecules-19-14366
SNS032, previously called BMS-387032, has been developed by Sunesis. This compound, which contains a thiazole unit, selectively inhibits CDK2 (IC50: 38 nM), CDK7 (IC50: 62 nM) and CDK9 (IC50: 4 nM) [39]. Preclinical studies demonstrated that SNS032 was able to inhibit cell cycle activity along with transcription [20].
SNS032 is in phase I clinical trials for the treatment of chronic lymphoid leukemia along with multiple myeloma, and the mode of administration is intravenous [39]. The purpose is to evaluate the dose-escalation of SNS-032 along with its safety, pharmacokinetics, pharmacodynamic activity and clinical efficacy. Biomarker analyses demonstrated mechanism-based pharmacodynamic activity with inhibition of CDK7 and CDK9, although limited clinical activity in heavily pretreated patients was observed [39].
Tong, W.G.; Chen, R.; Plunkett, W.; Siegel, D.; Sinha, R.; Harvey, R.D.; Badros, A.Z.; Popplewell, L.; Coutre, S.; Fox, J.A.; et al. Phase I and pharmacologic study of SNS-032, a potent and selective CDK2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. ASCO Annual Meeting. J. Clin. Oncol. 2010, 28, 3015–3022.
![Image result for N-(Cycloalkylamino)acyl-2-aminothiazole Inhibitors of Cyclin-Dependent Kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a Highly Efficacious and Selective Antitumor Agent,](https://journals.prous.com/journals/dof/20083311/html/df330932/images/sch01.gif)
SNS-032 (formerly BMS-387032) is a small-molecule cyclin-dependent kinase (CDK) inhibitor currently in phase I clinical trials for the treatment of B-cell malignancies and advanced solid tumors. Preclinical studies have shown that SNS-032 is a specific and potent inhibitor of CDK2, 7 and 9 which induces cell cycle arrest and apoptosis in tumor cell lines. It was shown to inhibit in vitro angiogenesis and prostaglandin E2 (PGE2) production, both strongly associated with tumorigenesis. Phase I clinical trials support the safety and tolerability of SNS-032 as evaluated in dose-escalation studies. The compound is currently administered by i.v. infusion but has shown promising potential for oral delivery.
![Image result for N-(Cycloalkylamino)acyl-2-aminothiazole Inhibitors of Cyclin-Dependent Kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a Highly Efficacious and Selective Antitumor Agent,](https://journals.prous.com/journals/dof/20083311/html/df330932/images/sch02.gif)
NMR
CLIP
![Image result for N-(Cycloalkylamino)acyl-2-aminothiazole Inhibitors of Cyclin-Dependent Kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a Highly Efficacious and Selective Antitumor Agent,](https://i0.wp.com/www.rcsb.org/pdb/images/56H_600.gif)
![Image result for N-(Cycloalkylamino)acyl-2-aminothiazole Inhibitors of Cyclin-Dependent Kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a Highly Efficacious and Selective Antitumor Agent,](https://i0.wp.com/www.mdpi.com/ijms/ijms-14-21805/article_deploy/html/images/ijms-14-21805f2-1024.png)
The structures of representative protein kinases inhibitors based on the aminopyrazole scaffold.http://www.mdpi.com/1422-0067/14/11/21805/htm
CLIP
N-(Cycloalkylamino)acyl-2-aminothiazole Inhibitors of Cyclin-Dependent Kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a Highly Efficacious and Selective Antitumor Agent,
N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 {N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032}, has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC50 = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC50 = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5−7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a sc/ip A2780 human ovarian carcinoma xenograft model.
CLIP
http://pubs.rsc.org/en/content/articlehtml/2016/md/c6md90040b
Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine 25 was also shown to have high potency against the CDK9 enzyme (3 nM).
DOI: 10.1039/C6MD00159A
COMPD 25
1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.21 (s, 1H), 8.74 (d, J = 0.9 Hz, 1H), 8.62 (dd, J = 8.2, 1.5 Hz, 1H), 8.56 (dd, J = 4.7, 1.5 Hz, 1H), 8.16-8.13 (m, 2H), 7.64 (br d, J = 8.6 Hz, 1H), 7.52-7.47 (m, 2H), 4.14 (t, J = 5.9 Hz, 2H), 2.66 (t, J = 5.9 Hz, 2H), 2.47-2.42 (m, 4H), 1.53-1.47 (m, 4H), 1.42 – 1.33 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 160.74, 158.32, 156.72, 154.88, 150.74, 146.47, 145.38, 143.74, 134.21, 125.02, 124.16, 122.29, 119.60, 114.32, 94.06, 66.49, 57.35, 54.35, 25.54, 23.88. HRMS (ESI+ ): calcd for C22H25N8O (M + H)+ , 417.2146; found 417.2163.
NOTE, THERE IS ERROR IN STRUCTURE ABOVE OF SNS 032
References:
[1]. Tong W.G., Chen R., Plunkett W., et al. Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma. Journal of Clinical Oncology, 2010, 28(18):3015- 3022.
[2]. Chipumuro E., Marco E., Christensen C.L., et al. CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer. Cell, 2014, 159:1-14.
[3]. Meng H., Jin Y.M., Liu H., et al. SNS-032 inhibits mTORC1/mTORC2 activity in acute myeloid leukemia cells and has synergistic activity with perifosine against Akt. Journal of Hematology & Oncology, 2013, 6:18.
[4]. Chen R., Wierda W.G., Chubb S., et al. Mechanism of action of SNS032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood, 2009, 113(19):4637-4645.Chen et al (2010) Responses in mantle cell lymphoma cells to SNS-032 depend on the biological context of each cell line. Cancer Res. 70 6587. PMID: 20663900.
Conroy et al (2009) SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples. Cancer Chemother.Pharmacol. 64 723. PMID: 19169685.
Ali et al (2007) SNS-032 prevents tumor cell-induced angiogenesis by inhibiting vascular endothelial growth factor. Neoplasia 9 370. PMID: 17534442.
Misra et al (2004) N-(Cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J.Med.Chem. 47 1719. PMID: 15027863.
CC(C)(C)C1=CN=C(O1)CSC2=CN=C(S2)NC(=O)C3CCNCC3
Continuous Flow Stereoselective Synthesis of (S)-Warfarin
The same catalytic packed-bed reactor was used for the preparation of (S)-warfarin 107 under continuous flow conditions (Scheme ).A solution of 4-OH-coumarin 104, benzalacetone105, and trifluoroacetic acid as a cocatalyst in dioxane was flowed into the reactor containing the polystyrene-supported 9-amino-epi-quinine 122. With a residence time of 5 h at 50 °C, we were able to isolate the product in up to 90% yield and up to 87% ee. Further studies are needed in order to optimize the reaction under continuous flow conditions; however, the proposed protocol already offers the possibility to extend catalyst’s lifetime, longer than in batch mode, further suggesting interesting future applications for the catalytic reactors.
The Pericàs group published the stereoselective Michael addition of ethyl nitroacetate to benzalacetone promoted by polystyrene-supported 9-amino-9-deoxy-epi-quinine 126 under continuous flow conditions. It should be pointed out that the polystyrene in our hands is a highly reticulated, insoluble polymer, while the polystyrene used by the Pericàs group is a swelling resin; a careful choice of the reaction solvent should be done, as this may affect the reaction course. The functionalized resin was packed into a Teflon tube between two plugs of glass wool. The reaction was run by pumping a solution of the two reagents and benzoic acid as a cocatalyst in CHCl3 (chosen after careful solvent screening) at 30 °C for 40 min residence time. Notably, 3.6 g (12.9 mmol) of the desired adducts were collected in 21 h of operation in roughly 1/1 dr and 97/98% ee.
Porta, R.; Benaglia, M.; Puglisi, A. Unpublished results.
Izquierdo, J.; Ayats, C.; Henseler, A. H.; Pericàs, M. A. Org. Biomol. Chem. 2015, 13, 4204, DOI: 10.1039/C5OB00325C
DOI: 10.1039/C5OB00325C
A polystyrene (PS)-supported 9-amino(9-deoxy)epi quinine derivative catalyzes Michael reactions affording excellent levels of conversion and enantioselectivity using different nucleophiles and structurally diverse enones. The highly recyclable, immobilized catalyst has been used to implement a single-pass, continuous flow process (residence time: 40 min) that can be operated for 21 hours without significant decrease in conversion and with improved enantioselectivity with respect to batch operation. The flow process has also been used for the sequential preparation of a small library of enantioenriched Michael adducts.
Synthesis:
There are 3 types of Warfarin:
1. Racemic Warfarin
2. S-Warfarin
3. R-Warfarin
As there are different types different synthetic routes are required. Firstly, looking at the racemic Warfarin followed by the asymetric Warfarin (S- and R- Warfarin).
The usual synthetic route for racemic Warfarin involves a base/acid catalysed Michael condensation reaction of 4-hydroxycoumarin with benzalacetone. These reactants are either refluxed in water for approximately 4-8 hours or refluxed with pyridine which gives a saturated yield. The mechanism is shown below:
The yield when this reaction is reflux with water is 48%.
During recent years it has been found that one of the possible enantiomers usually has a pharmacological profile that is superior to the racemate. Hence pharmaceutical companies have been replacing exisiting racemic drugs with their pure enantiomeric form.
In the case of Warfarin it was found that S-Warfarin is the superior enantiomer being 6 times more active than R-Warfarin. There are 2 main methods to form a pure enantiomeric form of Warfarin.
1. Asymmetric hydrogenation: This was developed by DuPont Merk Pharmaceutical. It involves the a DuPHOS-Rh(I) catalysed hydrogenation of racemic Warfarin to give the desired enantiomer. Below is the reaction scheme for this synthesis:
This exclusive product is then used in the rest of the synthesis. First reacting it with NaOH to form the sodium salt of the product:
This, then, depending on the enantiomer that is desired, the sodium salt is hydrogenated using either (R,R)-Et-DuPHOS-Rh(I) or (S,S)-Et-DuPHOS-Rh(I) to give S-Warfarin and R-Warfarin respectively:
This route gives enantioselectivities of 82-86% e.e in methanol and 88% e.e in 3:2 isopropanol-methanol. Acidification and a single recrystallisation of the crude product gave R- and S- Warfarin in >98% e.e.
2. Hetero-Diels-Alder cycloaddition: This method was developed in 2001 and the key feature is that it does not use racemic Warfarin as a starting material. Instead it involves a hetero-Diels-Alder cycloaddition of a iso-propenyl ether to 4-hydroxycoumarin (via the use of dry dioxane and a Tietze Base with 5A Molecular sieves at a temperature of 80ºC):
Here S-Warfarin has been synthesised with an e.e of 95%.
General Data:
| Chemical Names: |
|
| Formula: |
C19H16O4 |
| CAS Number: |
81-81-2
|
| Molecular Weight: |
308.33
|
| Structure: |
 |
| Isomers: |
Optical Isomers: S-Warfarin and R-Warfarin
|
| Melting Point /ºC : |
161
|
| Optical Rotation: |
S-Warfarin : -25.5 ± 1º
R-Warfarin : +24.8 ± 1º |
Tautomerization of warfarin substructures, whose combination generates 40 distinct tautomeric forms of warfarin
13 C NMR spectrum (A) and 1 H NMR spectrum (B) of warfarin. Arrows indicate peaks from the open-chain form of warfarin though the intensity is very low. See Figure 1 for numbering of the C atoms. H1(R) and H1(S) are connected to C15; H2 and H3 are connected to C13; and H4 is bonded to C3.
| (R)-(+)-Warfarin |
Warfarin is optically active, and from the time of it’s discovery it was recognised that the two enantiomers were clinically different in their effect as a drug. So establishing the absolute configuration of the two isomers was a priority.
| R-Warfarin
|
S-Warfarin
|
| RR-Warfarin
|
SS-Warfarin
|
| RS-Warfarin
|
SR-Warfarin
|
The stereochemical assignment of (−)-(S)-warfarin was initially achieved by relating it to (−)-(R)-beta-phenylcaproic acid through a series of reactions not involving the asymmetric center {B.D.West, S.Preis, C.H.Schroder, & K.P.Link, J.Amer.Chem.Soc.,1961,83, 2676}. This assignment was confirmed by a determination of the crystal and molecular structure, and using the anomalous scattering of oxygen, and absolute configuration of (−)-(S)-Warfarin was measured {E.J.Valente, W.F.Trager and L.H.Jensen, Acta Cryst. 1975. B31, 954}.
The primary feature of the structure of (−)-warfarin is the hemiketal ring formed by cyclization of the side-chain keto function and the phenolic hydroxyl in the 4 position of the coumarin ring system. The crystal structure of racemic warfarin has the same feature. In solution n.m.r. spectra shows that the hemiketal is present in acetone solution.
The hemiketal bonding is rather weak. Thus the bond lengths within the hemiketal show that the atoms retain some of the characteristic of an open side chain keto group.
In the open chain keto form warfarin has two isomers, R andS, however the hemiketal introduces a second assymmetric center, so that we can have RR,SS, RS, and SR forms. The crystal structure determination favoured the SS enantiomer in the crystal studied.
The S-isomer is very much more potent than the R isomer in both rats and humans.The S-isomer is stereoselectively oxidized to the inactive 7-hydroxywarfarin, and the keto-group of the R-isomer is stereospecifically reduced to the slightly active R,S-alcohol. Both isomers are oxidized to the inactive 6-hydroxywarfarin.
It is evident that we are dealing with a very complex system indeed; the presence of the hemiketal adds four more enantiomers to the complexity pot. Recent work has unravelled some more of the mechanisms behind the Vitamin K1 antagonism of Warfarin.
In 1883 Hans von Pechmann and Carl Duisberg {H. v Pechmann, and C. Duisberg, Ber., 1883, 16, 2119} found that phenols condense with beta-ketonic esters in the presence of sulphuric acid, giving coumarin derivatives.
With R1=OH we have 4-hydroxycoumarin, the starting material for the preparation of Warfarin
The reaction is also catalysed by the presence of a Lewis acid such aluminium(III) chloride or other strong Brönstedt acids such as methanesulphonic acid to form a coumarin. The acid catalyses trans-esterification as well as keto-enol tautomerisation.
Bismuth(III) chloride, also a Pechmann catalyst, provides a recent procedure for 4-substituted coumarins.{ An Efficient and Practical Procedure for the Synthesis of 4-Substituted Coumarins Surya K. De*, Richard A. Gibbs, Synthesis, 2005, 1231.}
In another Pechmann condensation synthesis, the ionic liquid 1-butyl-3-methylimidazolium chloroaluminate ([bmim]Cl.2AlCl3) plays the dual role of solvent and Lewis acid catalyst for the reaction of phenols with ethyl acetoacetate leading to coumarin derivatives. Here, the reaction time is reduced drastically even at ambient conditions. {M. K. Potdar, S. S. Mohile, M. M. Salunkhe, Tetrahedron Lett., 2001, 42, 9285}
Solid acid catalysts with the H+ attached to the polymer surface such as Nafion 417 or Amberlyst IR120 can be used. Thus resorcinol reacts with ethyl acetoacetate in boiling toluene in the presence of Nafion sheet to form the coumarin 7-hydroxy-4-methylcoumarin. This preparation forms the basis of a student organic chemistry experiment at Penn State University. In this case the coumarin, {also named, 7-hydroxy-4-methyl-2H-benzo[b]-pyran-2-one} is not a blood thinner but is a drug used in bile therapy, Hymecromone. The material is also, in highly purified form a laser dye, and the starting material for some insecticides!
Reaction of 4-hydroxycoumarin with benzylacetone underMichael reactionconditions gives racaemic warfarin.
Imidazolidinone compounds – MacMillan organocatalysts – enable a stereoselective preparation for this reaction
There has been a recent flurry of interest in such assymetric preparation, well cataloged byWikipedia, references 17 to 22. The last reference even puts the stereoselective preparation into the second year undergraduate chemistry laboratory as an innovative ‘green chemistry’ experiment:
This is a complex biochemical and medical subject, certainly beyond the simple chemistry required for a molecule of the month! Warfarin acts as a Vitamin K antagonist, that is it blocks the action of vitamin K epoxide reductase.
This vitamin is found in brassicas, spinach, parsley, and other green vegetables, avocado pairs are also rich in Vitamin K1.
For Vitamin K2, n signifies a number of five-carbon side chain units, hence MK-n, and except for MK4, is synthesised by gut bacteria. Both vitamins are fat soluble, the “K” deriving from the German “koagulation”. German researchers discovered the K vitamins, and that they are involved in blood clotting.
Vitamin K is a cofactor in the synthesis of blood clotting factors II, VII, IX and X*, this step occurs in the liver and involves the gammacarboxylation of the first 10 glutamic acid residues in the amino-terminal region of the prothrombin clotting factor to generategamma-carboxyglutamate. The gamma-carboxyglutamatee amino acid groups can chelate Ca2+ better than ten replaced glutamate residues, thus providing binding sites for four Vitamin Ks onto the phospholipid membrane during coagulation. The clotting occurs via a cascade*, a kind of biochemical chain reaction. {See Biochemistry by Stryer for the terminology}
To work, the Vitamin K must be reduced to its quinol or hydroquinone form. This is achieved with Vitamin K Oxide reductase, which is the step inhibited by S-warfarin, being some three times more potent than R-warfarin. S-warfarin is metabolized primarily by the CYP2C9 enzyme of the cytochrome P450 system. The R-warfarin is metabolized by the two cytochrome P450 enzymes, CP1A4Y and CYP3A4. Warfarin is very soluble in water, and is absorbed into the blood stream within 90 minutes of taking the pills.
So far as the enantiomers are concerned, racaemic warfarin has a half life of around 40 hours, the two enantiomers, having half lives: R-warfarin, 45 hours; S-warfarin, 29 hours.
During my review for MoTM, necessarily hurried, I have not been able to find out if the hemiketal, with the four enantiomers is involved. That the hemiketal is weak is shown by the crystal structure study, so, in any case these enantiomers will have short half lives. It all adds to the complexity.
An application of an asymmetric synthesis with a DuPhos ligand is the hydrogenation of dehydrowarfarin to warfarin:[9]
The first practical asymmetric synthesis of R and S-Warfarin Andrea Robinson and Hui-Yin Li John Feaster Tetrahedron Letters Volume 37, Issue 46, 11 November 1996, Pages 8321-8324doi:10.1016/0040-4039(96)01796-0
//////////////////////Continuous Flow, Stereoselective Synthesis, (S)-Warfarin, FLOW CHEMISTRY, FLOW SYNTHESIS
![1,2-bis[4-(4-nitrophenyl)piperazin-1-yl]ethanone.png](https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=2867018&t=l "A structure of 1,2-bis[4-(4-nitrophenyl)piperazin-1-yl]ethanone")
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