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VNRX-7145

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CAS 1842399-68-1

MF C19 H26 B N O7

MW 391.22

2H-1,2-Benzoxaborin-8-carboxylic acid, 3,4-dihydro-2-hydroxy-3-[(1-oxopropyl)amino]-, (2-ethyl-1-oxobutoxy)methyl ester, (3R)-

The VNRX-7145 combination is now in Phase I studies to treat resistant urinary tract infections.

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VNRX-7145

PATENT

WO 2015191907

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015191907

ntibiotics are the most effective drugs for curing bacteria-infectious diseases clinically. They have a wide market due to their advantages of good antibacterial effect with limited side effects. Among them, the beta-lactam class of antibiotics (for example, penicillins, cephalosporins, and carbapenems) is widely used because they have a strong bactericidal effect and low toxicity.

[0005] To counter the efficacy of the various beta-lactams, bacteria have evolved to produce variants of beta-lactam deactivating enzymes called beta-lactamases, and in the ability to share this tool inter- and intra-species. These beta-lactamases are categorized as“serine” or“metallo” based, respectively, on presence of a key serine or zinc in the enzyme active site. The rapid spread of this mechanism of bacterial resistance can severely limit beta-lactam treatment options in the hospital and in the community.

SCHEME 1

SCHEME 2

SCHEME 3

[00390] Alternatively, (II) can be obtained by treatment of (I) with hydrochloric acid (around 3-5 Molar in dioxane) in an alcohol solvent such as methanol, ethanol, or n-butanol at a temperature between room temperature and 120 ºC (SCHEME 4).

SCHEME 4

SCHEME 5

EXAMPLE 62: (R)-2-Hydroxy-3-propionylamino-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid

Step 1. Synthesis of 2-Methoxy-3-[2-propionylamino-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester.

[00540] Prepared from [(1S)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-chloro-ethyl]boronic acid (+) pinanediol ester and propionic acid following the procedure in Step 2 of Example 1. The crude product was purified by flash chromatography on silica gel (25-100% EtOAc/Hexane). ESI-MS m/z 486 (MH)+.

Step 2. Synthesis of (R)-2-Hydroxy-3-propionylamino-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid.

[00541] Prepared from 2-Methoxy-3-[2-propionylamino-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester following the procedure described in Step 3 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 264 (MH)+

CLIP

https://cen.acs.org/pharmaceuticals/drug-discovery/Drug-structures-displayed-first-time-in-Orlando/97/web/2019/04?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN

Candidate: VNRX-7145

20190404lnp1-vnrx7145.jpg

Credit: Tien Nguyen/C&EN

Presenter: Christopher John Burns, president and chief executive officer of VenatoRx Pharmaceuticals

Target: β-lactamases

Disease: Resistant urinary tract infections

Reporter’s notes: Having unveiled an antibacterial candidate at last spring’s first time disclosures session, Burns was back with another, this time the molecule can be taken orally. Both VenatoRx (pronounced Ven-a-tor-ix) compounds resuscitate the activity of β-lactam drugs, which make up more than 60% of all antibiotics prescribed. Unfortunately, many bacteria have grown resistant to these antibiotics. The new compounds rescue the old antibacterials by inhibiting β-lactamases, enzymes that chew up the antibiotics. To test the activity of new β-lactamase-targeting compounds, the researchers settled on several “sentinel” bacteria strains. Then to find a candidate with oral bioavailability, the team focused on molecules with low polarity and low molecular weight. They found VNRX-7145, developed as a prodrug in which esterases in the liver clip off the tips of the molecule to reveal the active drug. VNRX-5133, disclosed at last year’s meeting, had to be delivered intravenously along with another IV-antibiotic Cefepime, and targeted serine and metallo β-lactamases. The new oral candidate VNRX-7145 inhibits serine β-lactamases with Ceftibuten as its partner. The VNRX-7145 combination is now in Phase I studies to treat resistant urinary tract infections.

////////////VNRX-7145, VNRX7145, VNRX 7145, Phase I, VenatoRx

CCC(CC)C(=O)OCOC(=O)c1cccc2C[C@H](NC(=O)CC)B(O)Oc12

CCC(CC)C(=O)OCOC(=O)c1cccc2C[C@H](NC(=O)CC)B(O)Oc12

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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 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 Open superstar 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 30 year tenure till date Dec 2017, Around 35 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, 50 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 19 lakh plus views on New Drug Approvals Blog in 216 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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