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Posizolid in phase 2 for tuberculosis

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POSIZOLID

252260-02-9  CAS NO

(5R)-3-[4-[1-[(2S)-2,3-Dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluorophenyl]-5-(1,2-oxazol-3-yloxymethyl)-1,3-oxazolidin-2-one

AstraZeneca (Originator)

 

AZD-2563, AZD-5847

 

Posizolid, Posizolid [INN], SureCN374786, AC1L4U5J, AC1Q6O1X, CHEMBL131854, AZD-2563, AZD-5847   AR-1H7626, A820111
Molecular Formula: C21H21F2N3O7   Molecular Weight: 465.404146

Posizolid is an oxazolidinone antibiotic under investigation by AstraZeneca for the treatment of bacterial infections. At a concentration of 2 mg/L it inhibited 98% of all Gram-positive bacteria tested in vitro.[1]

 

Tuberculosis is a disease caused by Mycobacterium tuberculosis (Mtu), which in 1990 was declared a global epidemic by the World Health Organisation (WHO). It affects more than one third of the world’s population resulting in 8 million new patients and 2 million deaths every year. Also there exists a scenario called “Latent TB”, which occurs when germs remain in the body in a quiescent state but without any apparent effect on the health of the individual. In many cases this stage may last for many years or decades. In case of normal human being the chance of activation is 2-23% in a lifetime. However in case of immuno-compromised patients (like HIV) the chances of activation rise to 10% every year.

The current treatment of drug sensitive tuberculosis is at least six months long and requires a combination of isoniazid, rifampicin, pyrazinamide and ethambutol in the first two months followed by isoniazid and rifampicin for a period of four months. In recent years, drug resistance to these drugs has increased and the last of drugs for tuberculosis was introduced into clinical practice in the late 1960’s. The evolution of resistance could result in strains against which currently available antitubercular agents will be ineffective and treatment in such cases may last two years with no guarantee of cure. So there is an urgent need to introduce new drugs particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups and new treatment regimens to overcome not only rising drug resistance but also improve the overall treatment duration.

R. Sood et al (Infectious Disorders—Drug Targets 2006, 343-354) report that “Oxazolidinones are a new class of totally synthetic antibacterial agents with wide spectrum of activity against a variety of clinically significant susceptible and resistant bacteria. These compounds have been shown to inhibit translation at the initiation phase of protein synthesis. DuP-721, the first oxazolidinone showed good activity against M. tuberculosis when given orally or parenterally to experimental animals but was not developed further due to lethal toxicity in animal models. Later two oxazolidinones, PNU-100480 and Linezolid, demonstrated promising antimycobacterial activities in the murine model. While Linezolid has been approved for clinical use for broad spectrum area, PNU-100840 was not developed further. DA-7867 showed good in vitro and better in vivo efficacy than Linezolid but was poorly tolerated in rat toxicology studies. The antimycobacterial activity of AZD2563 has not been explored. RBx 7644 had modest antimycobacterial activity whilst RBx 8700 has potent antibacterial and concentration dependent activity against all slow growing mycobacteria. It demonstrated better activity than RBx 7644 against MDR strains of M. tuberculosis along with intracellular activity”.

In published patent application WO-99/64417 we disclose the compound

 

Figure US20120035219A1-20120209-C00001

 

ie. (5R)-3-[4-[1-[(2S)-2,3-dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluoro-phenyl]-5-(isoxazol-3-yloxymethyl)oxazolidin-2-one also known as AZD2563. As reported by R. Sood et al (op cit) the antimycobacterial activity of AZD2563 has not been explored.

In a first aspect of the invention we now provide (5R)-3-[4-[1-[(2S)-2,3-dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluoro-phenyl]-5-(isoxazol-3-yloxymethyl)oxazolidin-2-one or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, for use in the treatment of Mycobacterium tuberculosis.

The compound can form stable acid or basic salts, and in such cases administration of a compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described following.

Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, tosylate, α-glycerophosphate. fumarate, hydrochloride, citrate, maleate, tartrate and hydrobromide. Also suitable are salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl d-glucamine and amino acids such as lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. In one aspect of the invention the pharmaceutically-acceptable salt is the sodium salt.

Synthesis of 5R)-3-[4-[1-[(2S)-2,3-dihydroxypropanoyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-difluoro-phenyl]-5-(isoxazol-3-yloxymethyl)oxazolidin-2-one (AZD 2563) is disclosed in our published patent application WO-99/64417.

 

……………….

http://www.google.com/patents/WO1999064417A2?cl=en

Example 22: 5(R)-IsoxazoI-3-yloxymethyl-3-(4-(l-(2(S)-hvdroxy-3-phosphoryl- propanovD-l^^S^-tetrahvdropyrid^-vπ^^-difluorophenvDoxazolidin^-one

 

Figure imgf000071_0001

To a stiπed solution of the starting material Reference Example 15 (lOOmg, 0.15mmol) in dioxan (1ml) was added 4M HCl / dioxan (3ml). The solution was stiπed at ambient temperature for 30 mins. and then evaporated. The residue was triturated well with ether giving the title compound as a white powder (80mg, 96%).

NMR (300Mz. DMS0-d6): 2.43 (m, partially obscured), 3.6 – 4.35 (m, 8H), 4.35 – 4.60 (m, 3H), 5.09 (m, IH), 5.85 (s, IH), 6.30 (s, IH), 7.31 (d, 2H), 8.60 (s, IH). MS: ESP+ (M+H) = 546.

…………………….

EP 1082323; JP 2002517498; WO 9964417

The condensation of the protected 3,5-difluoroaniline (I) with 1-benzyl-4-piperidone (II) by means of BuLi in THF gives 4-(1-benzyl-4-hydroxypiperidin-4-yl)-3,5-difluoroaniline (III), which is dehydrated with refluxing conc. HCl to yield the tetrahydropyridine (IV). The reaction of (IV) with benzyl chloroformate in acetone/water affords the carbamate (V), which is cyclized with (R)-glycidyl butyrate (VI) by means of BuLi in THF to provide the oxazolidinone (VII). The condensation of (VII) with isoxazol-3-ol (VIII) by means of PPh3 and DIAD in THF gives the expected ether adduct (IX), which is debenzylated by reaction with 1-chloroethyl chloroformate in dichloromethane, yielding the free tetrahydropyridine derivative (X). The condensation of (X) with (S)-2,3-O-isopropylideneglyceric acid (XI) by means of DEC or DCC and TEA in dichloromethane affords the corresponding acyl tetrahydropyridine (XII), which is finally deprotected with HCl in THF to provide the target dihydroxy compound.

 

………………..

WO 0140236

The condensation of the protected 3,5-difluoroaniline (I) with 1-benzyl-4-piperidone (II) by means of BuLi in THF gives 4-(1-benzyl-4-hydroxypiperidin-4-yl)-3,5-difluoroaniline (III), which is dehydrated with refluxing conc. HCl to yield the tetrahydropyridine (IV). The reaction of (IV) with benzyl chloroformate in acetone/water affords the carbamate (V), which is cyclized with (R)-glycidyl butyrate (VI) by means of BuLi in THF to provide the oxazolidinone (VII). The condensation of (VII) with isoxazol-3-ol (VIII) by means of PPh3 and DIAD in THF gives the expected ether adduct (IX), which is debenzylated by reaction with 1-chloroethyl chloroformate in dichloromethane, yielding the free tetrahydropyridine derivative (X). The condensation of (X) with (S)-2,3-O-isopropylideneglyceric acid (XI) by means of DEC or DCC and TEA in dichloromethane affords the corresponding acyl tetrahydropyridine (XII), which is finally deprotected with HCl in THF to provide the target dihydroxy compound.

 

 

References

  1. Wookey, A.; Turner, P. J.; Greenhalgh, J. M.; Eastwood, M.; Clarke, J.; Sefton, C. (2004). “AZD2563, a novel oxazolidinone: definition of antibacterial spectrum, assessment of bactericidal potential and the impact of miscellaneous factors on activity in vitro”. Clinical Microbiology and Infection 10 (3): 247–254. doi:10.1111/j.1198-743X.2004.00770.xPMID 15008947.

 

  1. AstraZeneca. New tuberculosis drug trial begins in South Africa. Available online: http://www.astrazeneca.com/Research/news/Article/20121210–new-tuberculosis-drug-trial-begins-in-south-africa (accessed on 12 April 2013).
  2. Working Group on New TB Drugs. AZD5847 oxazolidinone. Available online: http://www.newtbdrugs.org/project.php?id=174 (accessed on 12 April 2013).
  3. National Institute of Allergy and Infectious Diseases (NIAID). Phase 2a EBA trial of AZD5847. Available online: http://www.clinicaltrials.gov/ct2/show/NCT01516203 (accessed on 12 April 2013).
  4. Villemagne, B.; Crauste, C.; Flipo, M.; Baulard, A.R.; Déprez, B.; Willand, N. Tuberculosis: The drug development pipeline at a glance. Eur. J. Med. Chem. 201251, 1–16, doi:10.1016/j.ejmech.2012.02.033.
2-10-2012
Compound for the Treatment of Tuberculosis

 

WO1993022298A1 * Apr 28, 1993 Nov 11, 1993 Hiroyuki Kawamura Oxazolidine derivative and pharmaceutically acceptable salt thereof
WO1993023384A1 * Apr 21, 1993 Nov 25, 1993 Michael Robert Barbachyn Oxazolidinones containing a substituted diazine moiety and their use as antimicrobials
WO1994022857A1 * Apr 7, 1994 Oct 13, 1994 Masakazu Fukushima Thiazolidine derivative and pharmaceutical composition containing the same
WO1997006791A1 * Aug 13, 1996 Feb 27, 1997 Scripps Research Inst METHODS AND COMPOSITIONS USEFUL FOR INHIBITION OF αvβ5 MEDIATED ANGIOGENESIS
WO1997009328A1 * Aug 13, 1996 Mar 13, 1997 David J Anderson Phenyloxazolidinones having a c-c bond to 4-8 membered heterocyclic rings
EP0645376A1 * Sep 15, 1994 Mar 29, 1995 MERCK PATENT GmbH Substituted 1-phenyl-oxazolidin-2-one derivatives, their preparation and their use as adhesion-receptor antagonists
EP0710657A1 * Oct 19, 1995 May 8, 1996 MERCK PATENT GmbH Antagonists of adhesion receptors

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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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