New Drug Approvals

Home » Preclinical drugs » PNQ 201 from Advinus for for potential treatment of IBD.

PNQ 201 from Advinus for for potential treatment of IBD.

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

PAYPAL DONATIONS

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Blog Stats

  • 1,305,011 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,778 other followers

add to any

Share

formula I

PNQ 201

STRUCTURE COMING……

Adenosine A2b receptor antagonist

Advinus Therapeutics Ltd

KEEP WATCHING THIS POST……………

PNQ-201 is a proprietary orally active A2B Adenosine receptor (A2BAdoR) antagonist, currently in pre-clinical development for potential treatment of IBD. Advinus is looking for partnering/co-development opportunities.

A2BAdenosine Receptor (A2BAdoR) Antagonist PNQ-201 for IBD

Inflammatory Bowel Disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is a multifactorial disease of an etiology not fully understood. It includes chronic inflammation of the gut, characterized by dysfunction of mucosal immunity. Current oral therapies are ineffective, non-specific, and have significant adverse effects. As such, there is a large unmet medical need for the development of new and specific therapies for IBD.

Adenosine is a stimulator of pro-inflammatory effects in the gastro-intestinal tract. Adenosine regulates tissue function by activating its receptors: A1AdoR and A2AAdoR are high affinity receptors and A2BAdoR and A3AdoR are low affinity receptors. A2BAdoR is highly expressed in cecum and colon, with expression increased even further in epithelial cells in human and murine colitis. A2BAdoR, agonized by adenosine induces cytokine secretion at the mucosal surface, inflammatory cell infiltration into intestinal wall, focal crypt damage and ulceration. Therefore, A2BAdoR antagonists are expected to be beneficial in IBD patients.

PNQ-201 is a proprietary orally active A2BAdoR antagonist, currently in pre-clinical development for the potential treatment of IBD. PNQ-201 is a potent and selective A2B antagonist. It is selected for development on the basis of poor systemic bioavailability and high exposure in colon/cecum. Negligible systemic bioavailability and maximum exposure at the sites of action in the lower gastrointestinal tract is expected to offer maximum therapeutic benefits while minimizing potential side effects. PNQ-201 has shown a robust efficacy profile in standard models of IBD, namely, the mouse DSS-induced colitis model and the rat TNBS-induced colitis model. PNQ-201 was found to be safe in exploratory safety studies including a Drug Matrix Screen, mini-AMES test, and a 14- day repeat dose toxicology study in rats.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010103547&recNum=198&docAn=IN2010000145&queryString=(FP/Atherosclerosis)%20&maxRec=2268

Example 1 : 8-(l-Benzyl~lH-pyrazol-4-yl)-l-propyl-l,4,5,7-tetrahydro-purin-6-one

Step 1: l-Benzyl-lH-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-l,2,3,4-tetrahydro-pyrimidin-5-yl)-amide

A mixture of 5,6-diamino-3-propyl-lH-pyrimidine-2,4-dione (1.6g, 8.55mmol), 1-benzyl-lH-pyrazole-4-carboxylic acid (1.75g, 8.65mmol) in methanol (10ml) were cooled to 0 0C and added EDCLHCl (2.32g, 12.11mmol). The reaction mixture was stirred at 25 0C for 20 hours and the solvents were removed under reduced pressure. To this residue water (10ml) was added and the precipitate was filtered off, and was washed sequentially with cold water (20ml) and DCM (25ml) to obtain l-Benzyl-lH-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3 -propyl- 1 ,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (1.5 g, 47 %) as a pale yellow solid.

1HNMR^OOMHZ5 DMSO d6): δ 0.82 (t, J=7.6Hzs 3H); 1.46-1.51 (m, 2H); 3.64 (t, J=7.2Hz, 2H);^5.36 (s, 2H); 6.01 (s, 2H); 7.26-7.38 (m, 5H); 7.96 (s, IH); 8.31 (s, IH); 8.54 (s, IH); 10.43 (s, IH).

Step 2 : 8-(l-Benzyl-lH-pyrazol-4-yl)-2-chloro-l-propyH,7-dihydro-purin-6-one A mixture of l-benzyl-lH-pyrazole-4-carboxylicacid(6-amino-2,4-dioxo-3-propyl-l,2,3,4-tetrahydro-ρyrimidin-5-yl)-amide (0.5g, 13.5mmol)s POCl3 (10ml) and DMF (0.1ml) were heated at 125-130 0C for 20 hours. Reaction mixture was cooled to 20-25 0C. It was then concentrated under vacuum. The residue was triturated with diethyl ether, dried. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 2 to 4 % methanol in DCM as an eluent to obtain 8-( 1 -Benzyl- 1 H-pyrazol-4-yl)-2-chloro-l -propyl- l,7-dihydro-purin-6-one (0.04g, 8%) as a pale brown solid.

1HNMR^OOMHZ5 DMSO d6): δ 0.93 (t, J=7.6Hz, 3H); 1.67-1.73 (m, 2H); 4.15 (t, J=7.6Hz, 2H); 5.42 (s, 2H); 7.29-7.39 (m, 5H); 8.14 (s, IH); 8.49 (s, IH); 13.68 (bs, IH). Step 3: 8-(l-Benzyl-lH-pyrazol-4-yl)-l-propyl-l,7-dihydro-purin-6-one

A mixture of 8-(l -benzyl- lH-pyrazol-4-yl)-2-chloro-l -propyl- l,7-dihydro-purin-6-one (0.035 g, 0.094 mmol), Pd\C (10%) (0.025g), in ethanol (20ml) were stirred under hydrogen atmosphere for 20 hours. Reaction mixture was filtered through celite bed washed with methanol (20ml), and the solvents were removed under vacuum. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 2 to 4 % methanol in DCM as an eluent to obtain 8-(l-Benzyl-lH-pyrazol-4-yl)-l-propyl-l,7-dihydro-purin-6-one (0.012g, 39%) as off white solid.

1HNMR^OOMHZ, DMSO d6): δ 0.89 (t, J=7.2Hz, 3H); 1.66-1.72 (m, 2H); 3.94 (t, J=7.6Hz, 2H); 5.41 (s, 2H); 7.302-7.38 (m, 5H); 8.03 (s, IH); 8.16 (s, IH); 8.34 (s, IH).

PATENT

WO 2011055391

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011055391

Preparation 1: 2-chloro-8-cyclopentyl-l-propyI-l, 7-dihydro-purin-6-one:

Step 1: Cyclopentane carboxylic acid (6-amino-2,4-dioxo-3-propyl-l,2,3,4-tetra hydro-pyriniidin-S-y -amide

To a solution of 5, 6-diamino-3-propyI-lH-pyrimidine-2, 4-dione (0.6 g, 2.72 mmol) in methanol (50 ml) was added cyclopentane carboxylic acid (0.310 g, 2.72 mmol). The reaction mixture was cooled to 0°C and then l-ethyl-3(3′-dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HC1) (0.78 g, 4.1 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water. The solid was filtered and washed thoroughly with water followed by diethyl ether. The product obtained was dried under high vacuum. The crude product (0.40 g) was used for the next step without further purification.

Step 2: Preparation of 8-cyclopentyI-2-chloro-l-propyl-l, 7-dihydro-purin-6-one

To a suspension of cyclopentanecarboxylic acid (6-amino-2,4-dioxo-3-propyl- 1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.40 g, crude) obtained from step 1 in phosphorus oxychloride (25 ml) was added phosphorus pentachloride (0.10 g) and the resulting reaction mixture was refluxed overnight. Phosphorus oxychloride was evaporated under reduced pressure. The residue was slowly quenched with water. Ethyl acetate was added and the organic layer was separated and washed thoroughly with water followed by brine. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using dichloromethane, methanol (9:1) as the solvent system to give 0.075 g (19% over two steps) of the product as a white solid.

•H MR (400 MHz, DMSO d6): δ 0.9 (t, J = 8 Hz, 3H), 1.59-1.82 (m, 8H), 1.99 (m, 2H), 3.15 (t, J = 8 Hz, 1H), 4.12 (t, J = 8 Hz, 2H).

Preparations 2 to 7 were prepared following the experimental procedure as given for Preparation 1.

Preparation 2: 2-Chloro-8-cyclohexyl- 1 -propyl- 1 ,7-dihydro-purin-6-one,

Preparation 3: 2-Chloro-8-cyclopropyl-l -propyl- 1 ,7-dihydro-purin-6-one,

Preparation^ 2-Chloro-8-(hexahydro-2,5-methano-pentalen-3a-yl)-l -propyl- 1,7- dihydro-purin-6-one,

Preparation 5: 8-Bicyclo-[2.2.1]-hept-2-yl-2-chloro-l -propyl- 1, 7-dihydro-purin-6- one,

Preparation 6: 8-Adamantan-2-yl-2-chloro-l -propyl- 1, 7-dihydro-purin-6-one, Preparation7:3-[4-(2-Chloro-6-ox0-l-propyl-6,7-dihydro-lH-purin-8-yl)- bicyclo[2.2.2]oct-l-yl]-propionic acid.

Example 1: 8-Cyclopentyl-2-(3, 4-difluoro-phenoxy)-l-propyl-l, 7-dihydro-purin- 6-one:

To a solution of 8-cyclopentyl-2-chloro- 1 -propyl- l,7-dihydro-purin-6-one (0.06 g, 0.21 mmol) in N-methyl-2-pyrrolidone (0.2 ml) was added K2CO3 (0.044g, 0.32 mmol) followed by 3, 4-difluoro phenol and the reaction mixture was heated at 130 °C overnight. The reaction mixture was diluted with ethyl acetate and water. The layers were separated and ethyl acetate layer was washed with water. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using 3% methanol in DCM to give the product (0.015 g, 19 %) as a white solid.

‘HNMR (400 MHz, DMSO d6): δ 0.94 (t, J = 8 Hz, 3H), 1.59-1.74 (m, 6H), 1.94 (br.s, 2H), 3.12 (m, 2H), 4.09 (br. s, 2H), 7.21 (d, J = 8 Hz, 1H), 7.53-7.65 (m, 2H), 12.74 (br.s, 1H).


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Paypal Donate

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,778 other followers

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

Personal Links

View Full Profile →

TWITTER

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: