OCID 5090, Enmetazobactam

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2D chemical structure of 1001404-83-6

Unii-80vun7L00C.png

OCID 5090

Enmetazobactam

Beta-lactamase inhibitor.

AAI-101
RN: 1001404-83-6
UNII: 80VUN7L00C

Molecular Formula, C11-H14-N4-O5-S, Molecular Weight, 314.3206

(2S,3S,5R)-3-Methyl-3-((3-methyltriazol-3-ium-1-yl)methyl)-4,4,7-trioxo-4^6-thia-1-azabicyclo(3.2.0)heptane-2-carboxylate

  • 1H-1,2,3-Triazolium, 3-(((2S,3S,5R)-2-carboxy-3-methyl-4,4-dioxido-7-oxo-4-thia-1-azabicyclo(3.2.0)hept-3-yl)methyl)-1-methyl-, inner salt
  • Enmetazobactam

The Board of directors of Orchid Pharma Ltd has announced that the company had developed a new molecule known as OCID-5090, which was licensed to a company named Allecra Therapeutics, this molecule was undergoing the clinical trials and the company is happy to announce that the molecule has cleared the Phase 3 clinical trials.

Allecra Therapeutics would now either directly or through out license file for NDA of this molecule. Allecra has already out licensed the product to Haini Pharmaceuticals, China for the Chinese Territory at a value of $78mn plus royalties.

As per the IP Agreement between Orchid Pharma Limited and Allecra Therapeutics, Orchid is entitled to receive a Royalty of 6-8% on the worldwide sales of the product. Therefore, once the molecule is commercialised, Orchid can expect a regular stream of Royalty from Allecra. Further, the rights to develop and commercialise the molecule in India (which is under patent protection) remain with Orchid Pharma Limited, and the company is evaluating the various options to commercialise the product.

Orchid had developed a new molecule known as OCID-5090, which was licensed to a company named Allecra Therapeutics, this molecule was undergoing the clinical trials and the molecule has cleared the Phase 3 clinical trials.

Allecra Therapeutics would now either directly or through out license file for NDA of this molecule. Allecra has already out licensed the product to Haini Pharmaceuticals, China for the Chinese Territory at a value of $78mn plus royalties.

As per the IP Agreement between Orchid Pharma Limited and Allecra Therapeutics, Orchid is entitled to receive a Royalty of 6-8% on the worldwide sales of the product. Therefore, once the molecule is commercialised, Orchid can expect a regular stream of Royalty from Allecra. Further, the rights to develop and commercialise the molecule in India (which is under patent protection) remain with Orchid Pharma Limited, and the company is evaluating the various options to commercialise the product.

INVENTOR

senthil

Senthilkumar U P

ORCHID

Summary of Profile of Dr. U. P. Senthilkumar, R&D Centre, Orchid Pharma Ltd.
Dr. U. P. Senthilkumar Ph.D., the principal inventor of novel beta-lactamase inhibitor, OCID5090,
is currently serving as the senior vice-president at Orchid’s Research and Development Centre,
Chennai.
With illustrious credentials — top ranks in B.Sc. and M.Sc. degrees, first rank in the Graduate
Aptitude Test in Engineering (GATE), UGC-CSIR Junior Research Fellowship (JRF) and the
prestigious Dr. K.S. Krishnan Fellowship from the Department of Atomic Energy (DAE) and
publication of M.Sc. project work in the Indian Journal of Chemistry in 1987 — Mr. Senthilkumar
chose to pursue his doctoral research in synthetic organic chemistry with his mentor Prof.
Ramasubbu Jeyaraman at Bharathidasan University, Tiruchirapalli.
His research focus on the conformational preferences of sterically challenged novel N-Nitroso
heterocycles and their conformation dependent anti-cancer properties, led to the publication of 9
articles in reputed peer-reviewed international journals – a commendable accomplishment in the
90s.
After a brief post-doctoral stint on fluorescent dicyclopentapyridines, Dr. U. P. Senthilkumar joined
Torrent Research Centre at Ahmedabad and started his new endeavor of drug discovery on ACE
inhibitors. At the process research and development laboratory, he was actively involved in
asymmetric and stereo-selective synthesis of Active Pharmaceutical Ingredients (APIs), and
exploited the full potential of chiral prep-HPLC to realize the target molecules.
After joining Orchid Pharma Ltd., Chennai, Dr. Senthilkumar led the efforts in the development of
differentiated and patentable manufacturing processes for APIs related to both non-antibiotics
and beta-lactam antibiotics. He played a significant role in successfully implementing the
manufacturing processes overcoming several challenging problems. In addition, his scientific
insights and breath of understanding on the patent landscape were invaluable and impactful in
creating significant value to the organization and growth of the company in realizing the mission
to become a leader in the pharmaceutical generic business.
One finds more than 100 articles/patents/publications to his credit, which include inventions on
new drugs, drug-intermediates, products, processes, new synthetic routes, rearrangements and
novel polymorphs. As a Leadership Persona of the IP management team, he had exhibited a
thoroughness of the science/invention and meticulously executed the task of prosecution of few
hundred patents in many countries from both New Drug Discovery and Process Chemistry space.
All the successful effort earned Orchid Pharma Ltd the National Intellectual Property Award from
the Department of Industrial Policy and Promotion, Ministry of Commerce and Industry,
Government of India.
Through his executive and decision-making skills combined with scientific rationale and clarity,
Dr. Senthilkumar played significant role in the selection of products and creation of generic
product portfolio for Orchid, with unique IP strategies, analysis of patents, patent mapping,
designing & developing invalidation/non-infringing positions, and early launch opportunity,
including first-to-file (FTF) positioning. His appearance in the US courts, for deposition in couple
of patent litigations, and successful accomplishment of the same are testimony to his depth,
thoroughness of science and the ability to defend the invention with grit and professionalism.
Additionally, his effectual role in the first-to-launch of one of the large volume sterile penicillins
with regulatory exclusivity, achieved successfully by overcoming the citizen petition process in the
regulatory pathway, is another shining example of his leadership and scientific strength.
To support in-house projects as well as multinational pharma majors, Dr. Senthilkumar has taken
up CRAMS (Contract Research and Manufacturing Services) and CMC (Chemistry,
Manufacturing and Control) for new chemical entities. Besides, he passionately focused on novel beta-lactamase inhibitors and their antibiotic combinations that were envisaged by him to exhibit
potent activity against multi-drug resistant bacteria.
His dedicated effort brought a novel extended spectrum beta-lactamase inhibitor, OCID5090,
which was out-licensed to Allecra Inc. OCID5090/cefepime combination has completed
successfully the Phase III clinical trials for treating complicated urinary-track-infections (cUTI),
including acute pyelonephritis (AP), and rightfully, OCID5090 has gotten the US FDA fast track
designation as a Qualified Infectious Disease product (QIDP) that provides a five-year additional
market exclusivity and priority review.
His never-ending passion for research is infectious and roped him with academic institutions to
explore novel technologies including electron-beam irradiated heterogeneous catalysis. His
commendable knowledge on intellectual property is being utilized by the IP Cells of various
institutions as well as the Tamil Nadu State Technology Development and Promotion Centre.
A sincere student he is, Dr. Senthilkumar is also a founder-member of Prof. Ramasubbu
Jeyaraman Science Foundation (RJSF). Since 2011, he has been playing a significant role in
organizing several academic events (seminars, work-shops, invited lectures, state-level
proficiency tests, and research-orientation programs) for post-graduate chemistry students to
create passion for research. His concern and help for poor and rural students show his human
face.

SYN

 

PATENT

US 20080015156

https://patents.google.com/patent/US20080015156A1/en

    EXAMPLE 1Synthesis of 1-{[(2S,3S,5R)-2-Carboxy-3-methyl-4,4,7-trioxo-4-thia-1-azabicyclo[3.2.0]hept-3-yl]methyl}-3-methyl-1H-1,2,3-triazol-3-ium

  • [0050]
    Figure US20080015156A1-20080117-C00010
  • [0051]
    To a suspension of (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo-[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (25 g) in acetone (100 mL) at 25-30° C. was added slowly N,O-bis(silylacetamide) (18.6 g) with stirring. The reaction mixture was stirred at this temperature (25-30° C.) for 15-20 min. To the clear solution obtained, methyl iodide (100 mL) was added over a period of 15 min. and stirred at 25-30 min. for 24 h. The precipitated solid was separated by filtration and washed with acetone (25 mL). Wet weight of the solid obtained was 30 g.
  • [0052]
    The above wet solid was stirred with purified water (300 mL) at 10-15° C. for 2.5 h. To the resulted reaction mixture was added sodium thiosulfate (0.1 g) and stirred at 10-15° C. for 10-15 min. To the reaction mixture, dichloromethane (300 mL) was added, stirred and the organic layer separated. The aqueous layer was washed with a solution of Amberlite LA-2 resin (5% solution in dichloromethane twice, followed by dichloromethane twice. To the aqueous solution, activated carbon (1 g) was added, stirred for 15 min, filtered and washed with purified water (25 mL). The solution was filtered and lyophilized to get the title compound in pure form (10 g). 1H NMR (400 MHz, DMSO) δ ppm: 1.39 (s, 3H), 3.14 (dd, J=16.0, 1.3 Hz, 1H), 3.55 (dd, J=16.0, 4.2 Hz, 1H), 3.97 (s, 1H), 4.34 (s, 3H), 5.05 (dd, J=4.2, 1.3 Hz, 1H), 5.29 (d, J=14.7 Hz, 1H), 5.42 (d, J=14.7 Hz, 1H), 8.91 (d, J=1.3 Hz, 1H), 8.99 (d, J=1.3 Hz, 1H). Mass m/z: M+1 peak at 315. Alternatively the solution could be subjected to spray-drying to yield the title compound.

PATENT

WO 2012070071

IN 2010CH03555

US 20140057888

PATENT

WO 2015173378

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=7D714EA925DF9198DA8D15083DF88C7D.wapp2nB?docId=WO2015173378&tab=PCTDESCRIPTION

Scheme 1

Examples

Synthesis of (2535.5R)-3-methyl-3-((3-methyl-lH-1.2 -triazol-3-ium-l-yl)methvn-7-oxo-4-thia-l-azabicyclor3.2.01heptane-2-carboxylate 4,4-dioxide (4),

Compound (4) was prepared according to Scheme 2.

Scheme 2

i) Ν,Ο-bis-trimethylsilylacetamide, CH2CI2; ii) CH3OTf; iii) Na 2-ethylhexanoate

In a round bottom flask under nitrogen flow 100 g of Tazobactam acid (1) and 500 mL of Dichloromethane are loaded. The temperature is adjusted to +30/35°C then 37 g of Ν,Ο-Bis(trimethylsilyl) acetamide are loaded in 15-20 minutes maintaining the temperature to +35/42°C. The mixture is heated to reflux (+40/42°C) for 60 minutes. If the solution is not clear, N,0-Bis(trimethylsilyl) acetamide is loaded in small portions (0,5-1.0 g each) waiting 15 minutes every time till a clear solution containing intermediate (2) is obtained. 0.55 moles of N,0-Bis(trimethylsilyl) acetamide is used, with further 0.1-0.2 equivalents being added if the reaction is not complete.

Then the temperature is cooled down to 0/+5°C and 70 g of Methyl trifluoromethanesulfonate are loaded in 60-90 minutes maintaining the temperature at 0/+5°C. After 30 minutes the reaction is monitored by HPLC to control the disappearance of intermediate (2) and formation of intermediate (3). The reaction is monitored every 30 minutes until completion.

In a round bottom flask, under nitrogen, are loaded 500 mL of Ethanol and 55 g of Sodium 2-Ethylhexanoate and the temperature is adjusted to +20/25°C, then the reaction solution containing intermediate (3) is added in 60-90 minutes maintaining the temperature of +20/25 °C under vigorous stirring. The suspension is stirred for 30 minutes then is filtered and washed with 300 mL of Ethanol followed by 500 mL of Dichloromethane under nitrogen. The crude product (4) is dried under nitrogen flow till constant weight (150 g) is obtained. The crude product compound (4) was isolated as a solid product (HPLC assay = 70%, yield = 80%).

Purification of (2tS’,3^5^)-3-methyl-3-((3-methyl-lH-l,2,3-triazol-3-ium-l-yl)methyl)-7-oxo-4-thia-l-azabicyclor3.2.01heptane-2-carboxylate 4,4-dioxide (4)

In a round bottom flask 800 mL of Dimethylformamide are loaded, the temperature is adjusted to +20/25°C then crude Compound 4 (150g) obtained above is loaded using 100 mL of Dimethylformamide to facilitate the transfer. The mixture is stirred for 5 minutes and a solution is obtained, then and after a few minutes crystallization takes place. The suspension is stirred for about 3 hours, then is cooled to 0/+5°C and stirred for another 3 hours.

The solid is filtered and washed with 300 mL of Dimethylformamide pre-cooled to 0/+5°C. Compound 4 is then suspended in 700 mL of Ethyl acetate and the temperature is adjusted to +40/45°C. The suspension is stirred for 30 minutes then the solid is filtered and washed with 150 mL of Ethyl acetate pre-heated to +40/45°C. The suspension with

Ethyl acetate is repeated twice. Finally Compound 4 is dried under vacuum at +40°C till constant weight is achieved (66 g, HPLC assay = 99%, yield = 76%).

Compound 4 Sterile filtration and recrystallization Procedure

In a round bottom flask 350 mL of Methanol are loaded, the temperature is adjusted to +30/35°C then 100 g of Compound 4 are loaded and finally the flask is washed with 60 mL of Methanol. After 5-10 minutes a solution is obtained. The solution is diluted with 330 mL of acetone adjusting the temperature to +20/+25°C. The obtained solution is treated with 2,2 g of charcoal for 20 minutes then filtered using a 0.22microM filter and the filter is washed with a mixture of 13 mL of Methanol and 110 mL of Acetone. The temperature of the solution is adjusted to +30/35°C and under vigorous stirring 830 mL of Acetone are loaded in about 15-20 minutes. After stirring for 60 minutes at temperature of +30/35°C 1170 mL of Acetone are loaded in 45-60 minutes. Then the temperature is adjusted to +20/25 °C in about 30-60 minutes and maintained for 30 minutes. The obtained crystalline solid is filtered and washed with 430 mL of Acetone. Finally the product is dried under vacuum at +40°C till constant weight is achieved (83 g of Compound 4) are obtained with an HPLC assay = 98-99%, yield =t 80%).

Mr. Ram Gopal Agarwal

Chairman and Non-Executive Director

He is a decisive and action oriented visionary who took over a sick pesticide Company named Northern Mineral Pvt. Ltd. in 1980 and transformed it today into a Rs 1000 Crore organization called Dhanuka Agritech Ltd.

Mr. Mridul Dhanuka

Whole-Time Director

He is associated with Dhanuka Group Ltd. since 2005. He was responsible in successfully realigning the entire supply chain vertical from procurement to sales. At Orchid, he hopes to replicate the Group’s success and put another feather in Dhanuka cap.

Mr. Manish Dhanuka

Managing Director

Mr. Manish Dhanuka is the Director of Orchid Pharma Ltd. He has the vision to rejuvenate Orchid Pharma Ltd. and take it on a fruitful path. His wide-ranging experience of handling operations, commercial, marketing and finance in the manufacturing industry.

CLIP

image

Orchid Chemicals & Pharmaceuticals, or Orchid Pharma since its recent name change in 2015, was established in 1992 in Chennai to manufacture antibiotics, and entered drug discovery in 2001 with projects in the areas of anti-infectives and treatments for pain.32197 In 2002, the company engaged in a joint venture to develop US-based firm Bexel Biotechnology’s BLX-1002, an oral, non-PPAR AMPK activator for the treatment of diabetes,198 later repositioned for NASH (2012), but no further progress has been reported recently.197 In 2008, Orchid invested in Diakron Pharmaceuticals, a US-based company that had an exclusive license to MSD′s investigational oral anticoagulant drug, a direct thrombin inhibitor later known as DPOC-4088 (or DP-4088),199 which reached Phase 1 clinical studies in Europe in 2012 (Supporting Information Table 6b, entries 5–6).200 The company’s own internal discovery efforts had a broad therapeutic focus, covering infectious diseases, inflammation, pain, oncology, metabolic disorders, and CNS diseases. OCID-2987,197201 a PDE4 inhibitor for the treatment of inflammatory disorders such as COPD, completed successfully Phase 1 studies in Europe in 2012, and OCID-4681 29,202203 a histone deacetylase (HDAC) inhibitor for cancer had received approval in 2011 for Phase 1 studies for solid tumors in India, but we assume both have been abandoned, as cancer and inflammation are not mentioned in the company’s latest annual reports.197 Two additional compounds were abandoned at the preclinical stage: OCID-5005, a STAT-3/IL-6 inhibitor for oncology, and a unnamed Th1/Th2 cytokine synthesis inhibitor for inflammation (Supporting Information Table 2a, entries 134–138).197 Financial issues led Orchid, as of 2009, to sell parts of its business to Hospira (now part of Pfizer). As a consequence, no progress has been reported on its discovery programs since 2010, and no further NCE patent application has been published since 2012. However, in 2013 Orchid licensed its broad-spectrum β-lactamase inhibitor OCID-5090, a zwitterionic N-methylated tazobactam derivative, to the German Allecra Therapeutics for a 20 % stake in the company, for use in combination with antibiotics to treat multidrug-resistant gram negative bacteria.204207 Allecra’s lead compound AAI202, a combination of cefepime and AAI101/OCID-5090 30, is currently in Phase 1 studies in France.208209

 

Dr. B. Gopalan - PredOmix TechnologiesPredOmix Technologies

Dr. B. Gopalan

Scientific Advisor

Dr. Gopalan is a synthetic organic chemist with extensive experience in the field of drug discovery and development. After completing his PhD from University of Madras, he went to Harvard University where he worked with the Nobel Laureate, Prof. E.J. Corey, as a post-doctoral fellow. Subsequent to this he joined Syntex Research Inc. in California to work on the synthesis of unnatural amino acids. After a year, he moved to Bristol-Meyers Squibb, Princeton, New Jersey, to contribute to their program on novel antibiotics and ACE inhibitors. Dr. Gopalan then moved back to India in 1982 to join the Drug Discovery Research Division of Boots Pharmaceuticals (India) Ltd. in Mumbai. Over his decade long stint there he contributed extensively to their drug discovery program, and one of the product candidates that he developed went up to Phase-2 clinical trials in both USA and UK. He then moved to Sun Pharma Advanced Research Center as Vice-President and, after a year, took up the position as General Manager at Glaxo (India) Ltd. in 1993. Here, he worked in a broad range of areas that included process development, synthesis of impurities of APIs, and generation of small molecule libraries to support drug discovery efforts to Glaxo, France. In 1999 he took over as Senior Vice President of the Drug Discovery Chemistry Division of Glenmark Pharmaceuticals Ltd. where he was involved in the design and development of inhibitors for PDE IV and DPP IV, as well as agonists for CB2. After a 6-year stint at Glenmark, Dr. Gopalan joined Matrix Laboratories Ltd. as CSO and Executive Vice-President, where he successfully helped to develop novel and selective inhibitors for PDE4 and DPP4. Five years later he became CSO and Executive Director of Orchid Pharmaceuticals Ltd in Chennai. He served in this capacity for close to a decade, contributing extensively to drug design and development in the broad segments of oncology, anti-infectives, and anti-inflammatory & metabolic disorders. Since 2017, Dr. Gopalan has been associated with CSIR-Indian Institute of Chemical Technology as a Scientific Advisor.

Dr. Gopalan’s illustrious career is endowed with numerous successes. He has been inventor, or co-inventor, of several drugs or candidate drugs. These include the novel potassium channel blockers BTS-67582 (BTI-2927) for tpe-2 diabetes, the PDE IV inhibitors Oglemilast (COPD) and Revamilast (RA); DPP IV inhibitor Melogliptin; a selective Cannaboid-2 agonist Tedalinib (Neuropathic pain); a Beta lactamase inhibitor Enmetazobactum (OCID-5090); OCID-18034 (an inhibitor of KPC enzyme); and OCID-18174 (an inhibitor of P. arugenosa). Most of these compounds were out-licensed to major international pharmaceutical companies such as Forest Laboratories Inc. USA, Teijin of Japan, Merck KGaA of Germany, Allecra of Switzerland, and Merck & Co. USA. Dr.Gopalan has 34 publications in National and International Journals, has contributed a Chapter,Co-authored with Professor K.K.Balasubramanian (IITM) on Applications of Click Chemistry in Drug Discovery and Development in a Book on Click reaction in Organic Synthesis, published by Wiley-VCH VERLAG GmbH &Co,KGaA, Weinheim,Germany,Chapter 2, p 25-70,2016, edited by Prof. S. Chandrasekharan (IISc,Bangalore) & 51 Patents.

Commensurate with his achievements, Dr. Gopalan has also received many awards. The more prominent of these include Inventor’s award by Glenmark (2004), Ranbaxy Science Foundation Award in Pharmaceutical Sciences (2005), and the Lifetime Achievement Award in the Field of Chemistry from Vels University (2011).

 

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//////////OCID 5090, AAI-101, AAI 101,  Enmetazobactam, ORCHID, Allecra Therapeutics, PHASE 3

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