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Graphical abstract: The discovery of a potent series of carboxamide TRPA1 antagonists

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).

Image result for PFIZER

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.

Image result for SWAIN, Nigel AlanNigel Swain

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016067143&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

E8 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

PAPER

The discovery of a potent series of carboxamide TRPA1 antagonists

D. C. Pryde,*a   B. Marron,b   C. G. West,b   S. Reister,b   G. Amato,b  K. Yoger,b   K. Padilla,b   J. Turner,c   N. A. Swain,a   P. J. Cox,c  S. E. Skerratt,a   T. Ryckmans,d   D. C. Blakemore,a  J. Warmuse and   A. C. Gerlachb  
*Corresponding authors
aPfizer Worldwide Medicinal Chemistry, Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, UK
bIcagen, Inc., 4222 Emperor Boulevard, Suite 350, Durham, USA
cNeuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, UK
dPfizer Worldwide Medicinal Chemistry, Ramsgate Road, Sandwich, UK
ePfizer Worldwide Medicinal Chemistry, Neuroscience and Pain Research Unit, Groton, USA
Med. Chem. Commun., 2016, Advance Article

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.

Graphical abstract: The discovery of a potent series of carboxamide TRPA1 antagonists
str1  str2
 hydrochloride salt (69 mg, 82%). 1 H NMR (400 MHz, 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, 1H), 3.05–3.25 (m, 6H), 3.47–3.62 (m, 2H), 6.38 (br s, 1H), 7.20–7.40 (m, 9H), 7.80 (br m, 1H). MS m/z 509 [M + H]+ .

 

Image result for The discovery of a potent series of carboxamide TRPV1 antagonists

Discovery and development of TRPV1 antagonists

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


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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