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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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AZITHROMYCIN, アジスロマイシン;


Azithromycin

Azithromycin structure.svg

ChemSpider 2D Image | Azithromycin | C38H72N2O12

AZITHROMYCIN

C38H72N2O12,

748.9845

アジスロマイシン;

CAS: 83905-01-5
PubChem: 51091811
ChEBI: 2955
ChEMBL: CHEMBL529
DrugBank: DB00207
PDB-CCD: ZIT[PDBj]
LigandBox: D07486
NIKKAJI: J134.080H
CAS Registry Number: 83905-01-5
CAS Name: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-a-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-b-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one
Additional Names: N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A; 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A
Molecular Formula: C38H72N2O12
Molecular Weight: 748.98
Percent Composition: C 60.94%, H 9.69%, N 3.74%, O 25.63%
Literature References: Semi-synthetic macrolide antibiotic; related to erythromycin A, q.v. Prepn: BE 892357; G. Kobrehel, S. Djokic, US 4517359 (1982, 1985 both to Sour Pliva); of the crystalline dihydrate: D. J. M. Allen, K. M. Nepveux, EP 298650eidemUS 6268489 (1989, 2001 both to Pfizer). Antibacterial spectrum: S. C. Aronoff et al., J. Antimicrob. Chemother. 19, 275 (1987); and mode of action: J. Retsema et al., Antimicrob. Agents Chemother. 31, 1939 (1987). Series of articles on pharmacology, pharmacokinetics, and clinical experience: J. Antimicrob. Chemother. 31, Suppl. E, 1-198 (1993). Clinical trial in prevention of Pneumocystis carinii pneumonia in AIDS patients: M. W. Dunne et al., Lancet 354, 891 (1999). Review of pharmacology and clinical efficacy in pediatric infections: H. D. Langtry, J. A. Balfour, Drugs 56, 273-297 (1998).
Properties: Amorphous solid, mp 113-115°. [a]D20 -37° (c = 1 in CHCl3).
Melting point: mp 113-115°
Optical Rotation: [a]D20 -37° (c = 1 in CHCl3)
Derivative Type: Dihydrate
CAS Registry Number: 117772-70-0
Manufacturers’ Codes: CP-62993; XZ-450
Trademarks: Azitrocin (Pfizer); Ribotrex (Fabre); Sumamed (Pliva); Trozocina (Sigma-Tau); Zithromax (Pfizer); Zitromax (Pfizer)
Properties: White crystalline powder. mp 126°. [a]D26 -41.4° (c = 1 in CHCl3).
Melting point: mp 126°
Optical Rotation: [a]D26 -41.4° (c = 1 in CHCl3)
Therap-Cat: Antibacterial.

Azithromycin is an antibiotic used for the treatment of a number of bacterial infections.[3] This includes middle ear infectionsstrep throatpneumoniatraveler’s diarrhea, and certain other intestinal infections.[3] It can also be used for a number of sexually transmitted infections, including chlamydia and gonorrhea infections.[3] Along with other medications, it may also be used for malaria.[3] It can be taken by mouth or intravenously with doses once per day.[3]

Common side effects include nauseavomitingdiarrhea and upset stomach.[3] An allergic reaction, such as anaphylaxisQT prolongation, or a type of diarrhea caused by Clostridium difficile is possible.[3] No harm has been found with its use during pregnancy.[3] Its safety during breastfeeding is not confirmed, but it is likely safe.[4] Azithromycin is an azalide, a type of macrolide antibiotic.[3] It works by decreasing the production of protein, thereby stopping bacterial growth.[3]

Azithromycin was discovered 1980 by Pliva, and approved for medical use in 1988.[5][6] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[7] The World Health Organization classifies it as critically important for human medicine.[8] It is available as a generic medication[9] and is sold under many trade names worldwide.[2] The wholesale cost in the developing world is about US$0.18 to US$2.98 per dose.[10] In the United States, it is about US$4 for a course of treatment as of 2018.[11] In 2016, it was the 49th most prescribed medication in the United States with more than 15 million prescriptions.[12]

Medical uses

Azithromycin is used to treat many different infections, including:

  • Prevention and treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease due to H. influenzaeM. catarrhalis, or S. pneumoniae. The benefits of long-term prophylaxis must be weighed on a patient-by-patient basis against the risk of cardiovascular and other adverse effects.[13]
  • Community-acquired pneumonia due to C. pneumoniaeH. influenzaeM. pneumoniae, or S. pneumoniae[14]
  • Uncomplicated skin infections due to S. aureusS. pyogenes, or S. agalactiae
  • Urethritis and cervicitis due to C. trachomatis or N. gonorrhoeae. In combination with ceftriaxone, azithromycin is part of the United States Centers for Disease Control-recommended regimen for the treatment of gonorrhea. Azithromycin is active as monotherapy in most cases, but the combination with ceftriaxone is recommended based on the relatively low barrier to resistance development in gonococci and due to frequent co-infection with C. trachomatis and N. gonorrhoeae.[15]
  • Trachoma due to C. trachomatis[16]
  • Genital ulcer disease (chancroid) in men due to H. ducrey
  • Acute bacterial sinusitis due to H. influenzaeM. catarrhalis, or S. pneumoniae. Other agents, such as amoxicillin/clavulanate are generally preferred, however.[17][18]
  • Acute otitis media caused by H. influenzaeM. catarrhalis or S. pneumoniae. Azithromycin is not, however, a first-line agent for this condition. Amoxicillin or another beta lactam antibiotic is generally preferred.[19]
  • Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy[20]

Bacterial susceptibility

Azithromycin has relatively broad but shallow antibacterial activity. It inhibits some Gram-positive bacteria, some Gram-negative bacteria, and many atypical bacteria.

A strain of gonorrhea reported to be highly resistant to azithromycin was found in the population in 2015. Neisseria gonorrhoeae is normally susceptible to azithromycin,[21] but the drug is not widely used as monotherapy due to a low barrier to resistance development.[15] Extensive use of azithromycin has resulted in growing Streptococcus pneumoniae resistance.[22]

Aerobic and facultative Gram-positive microorganisms

Aerobic and facultative Gram-negative microorganisms

Anaerobic microorganisms

Other microorganisms

Pregnancy and breastfeeding[edit source]

No harm has been found with use during pregnancy.[3] However, there are no adequate well-controlled studies in pregnant women.[23]

Safety of the medication during breastfeeding is unclear. It was reported that because only low levels are found in breast milk and the medication has also been used in young children, it is unlikely that breastfed infants would suffer adverse effects.[4] Nevertheless, it is recommended that the drug be used with caution during breastfeeding.[3]

Airway diseases

Azithromycin appears to be effective in the treatment of COPD through its suppression of inflammatory processes.[24] And potentially useful in asthma and sinusitis via this mechanism.[25] Azithromycin is believed to produce its effects through suppressing certain immune responses that may contribute to inflammation of the airways.[26][27]

Adverse effects

Most common adverse effects are diarrhea (5%), nausea (3%), abdominal pain (3%), and vomiting. Fewer than 1% of people stop taking the drug due to side effects. Nervousness, skin reactions, and anaphylaxis have been reported.[28] Clostridium difficile infection has been reported with use of azithromycin.[3] Azithromycin does not affect the efficacy of birth control unlike some other antibiotics such as rifampin. Hearing loss has been reported.[29]

Occasionally, people have developed cholestatic hepatitis or delirium. Accidental intravenous overdose in an infant caused severe heart block, resulting in residual encephalopathy.[30][31]

In 2013 the FDA issued a warning that azithromycin “can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm.” The FDA noted in the warning a 2012 study that found the drug may increase the risk of death, especially in those with heart problems, compared with those on other antibiotics such as amoxicillin or no antibiotic. The warning indicated people with preexisting conditions are at particular risk, such as those with QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or those who use certain drugs to treat abnormal heart rhythms.[32][33][34]

Pharmacology

Mechanism of action

Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. Nucleic acid synthesis is not affected.[23]

Pharmacokinetics

Azithromycin is an acid-stable antibiotic, so it can be taken orally with no need of protection from gastric acids. It is readily absorbed, but absorption is greater on an empty stomach. Time to peak concentration (Tmax) in adults is 2.1 to 3.2 hours for oral dosage forms. Due to its high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma due to ion trapping and its high lipid solubility.[citation needed] Azithromycin’s half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.[35]

Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours.[35] Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, about 6% of the administered dose appears as unchanged drug in urine.

History

A team of researchers at the pharmaceutical company Pliva in ZagrebSR CroatiaYugoslavia, — Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski, and Zrinka Tamburašev, led by Dr. Slobodan Đokić — discovered azithromycin in 1980.[6] It was patented in 1981. In 1986, Pliva and Pfizer signed a licensing agreement, which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva put its azithromycin on the market in Central and Eastern Europe under the brand name Sumamed in 1988. Pfizer launched azithromycin under Pliva’s license in other markets under the brand name Zithromax in 1991.[36] Patent protection ended in 2005.[37]

Society and culture

Zithromax (azithromycin) 250 mg tablets (CA)

Cost

It is available as a generic medication.[9] The wholesale cost is about US$0.18 to US$2.98 per dose.[10] In the United States it is about US$4 for a course of treatment as of 2018.[11] In India, it is about US$1.70 for a course of treatment.[citation needed]

Available forms

Azithromycin is commonly administered in film-coated tablet, capsule, oral suspensionintravenous injection, granules for suspension in sachet, and ophthalmic solution.[2]

Usage

In 2010, azithromycin was the most prescribed antibiotic for outpatients in the US,[38] whereas in Sweden, where outpatient antibiotic use is a third as prevalent, macrolides are only on 3% of prescriptions.[39]

Solved: Using Push Arrows To Show Mechanisms, Show How To ...
Antibiotics | Free Full-Text | From Erythromycin to Azithromycin ...

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References

  1. Jump up to:ab “Azithromycin Use During Pregnancy”Drugs.com. 2 May 2019. Retrieved 24 December 2019.
  2. Jump up to:abcdef “Azithromycin International Brands”. Drugs.com. Archived from the original on 28 February 2017. Retrieved 27 February 2017.
  3. Jump up to:abcdefghijklm “Azithromycin”. The American Society of Health-System Pharmacists. Archived from the original on 5 September 2015. Retrieved 1 August 2015.
  4. Jump up to:ab “Azithromycin use while Breastfeeding”Archived from the original on 5 September 2015. Retrieved 4 September 2015.
  5. ^ Greenwood, David (2008). Antimicrobial drugs : chronicle of a twentieth century medical triumph (1. publ. ed.). Oxford: Oxford University Press. p. 239. ISBN9780199534845Archived from the original on 5 March 2016.
  6. Jump up to:ab Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 498. ISBN9783527607495.
  7. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ^ World Health Organization (2019). Critically important antimicrobials for human medicine (6th revision ed.). Geneva: World Health Organization. hdl:10665/312266ISBN9789241515528. License: CC BY-NC-SA 3.0 IGO.
  9. Jump up to:ab Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. ISBN9781284057560.
  10. Jump up to:ab “Azithromycin”International Drug Price Indicator Guide. Retrieved 4 September 2015.
  11. Jump up to:ab “NADAC as of 2018-05-23”Centers for Medicare and Medicaid Services. Retrieved 24 May 2018.
  12. ^ “The Top 300 of 2019”clincalc.com. Retrieved 22 December2018.
  13. ^ Taylor SP, Sellers E, Taylor BT (2015). “Azithromycin for the Prevention of COPD Exacerbations: The Good, Bad, and Ugly”. Am. J. Med128 (12): 1362.e1–6. doi:10.1016/j.amjmed.2015.07.032PMID26291905.
  14. ^ Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, Musher DM, Niederman MS, Torres A, Whitney CG (2007). “Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults”. Clin. Infect. Dis. 44 Suppl 2: S27–72. doi:10.1086/511159PMID17278083.
  15. Jump up to:ab “Gonococcal Infections – 2015 STD Treatment Guidelines”Archived from the original on 1 March 2016.
  16. ^ Burton M, Habtamu E, Ho D, Gower EW (2015). “Interventions for trachoma trichiasis”Cochrane Database Syst Rev11 (11): CD004008. doi:10.1002/14651858.CD004008.pub3PMC4661324PMID26568232.
  17. ^ Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Ashok Kumar K, Kramper M, Orlandi RR, Palmer JN, Patel ZM, Peters A, Walsh SA, Corrigan MD (2015). “Clinical practice guideline (update): adult sinusitis”. Otolaryngol Head Neck Surg152 (2 Suppl): S1–S39. doi:10.1177/0194599815572097PMID25832968.
  18. ^ Hauk L (2014). “AAP releases guideline on diagnosis and management of acute bacterial sinusitis in children one to 18 years of age”. Am Fam Physician89 (8): 676–81. PMID24784128.
  19. ^ Neff MJ (2004). “AAP, AAFP release guideline on diagnosis and management of acute otitis media”. Am Fam Physician69 (11): 2713–5. PMID15202704.
  20. ^ Randel A (2013). “IDSA Updates Guideline for Managing Group A Streptococcal Pharyngitis”. Am Fam Physician88 (5): 338–40. PMID24010402.
  21. ^ The Guardian newspaper: ‘Super-gonorrhoea’ outbreak in Leeds, 18 September 2015Archived 18 September 2015 at the Wayback Machine
  22. ^ Lippincott Illustrated Reviews : Pharmacology Sixth Edition. p. 506.
  23. Jump up to:ab “US azithromycin label”(PDF). FDA. February 2016. Archived(PDF) from the original on 23 November 2016.
  24. ^ Simoens, Steven; Laekeman, Gert; Decramer, Marc (May 2013). “Preventing COPD exacerbations with macrolides: A review and budget impact analysis”. Respiratory Medicine107 (5): 637–648. doi:10.1016/j.rmed.2012.12.019PMID23352223.
  25. ^ Gotfried, Mark H. (February 2004). “Macrolides for the Treatment of Chronic Sinusitis, Asthma, and COPD”CHEST125 (2): 52S–61S. doi:10.1378/chest.125.2_suppl.52SISSN0012-3692PMID14872001.
  26. ^ Zarogoulidis, P.; Papanas, N.; Kioumis, I.; Chatzaki, E.; Maltezos, E.; Zarogoulidis, K. (May 2012). “Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases”. European Journal of Clinical Pharmacology68 (5): 479–503. doi:10.1007/s00228-011-1161-xISSN1432-1041PMID22105373.
  27. ^ Steel, Helen C.; Theron, Annette J.; Cockeran, Riana; Anderson, Ronald; Feldman, Charles (2012). “Pathogen- and Host-Directed Anti-Inflammatory Activities of Macrolide Antibiotics”Mediators of Inflammation2012: 584262. doi:10.1155/2012/584262PMC3388425PMID22778497.
  28. ^ Mori F, Pecorari L, Pantano S, Rossi M, Pucci N, De Martino M, Novembre E (2014). “Azithromycin anaphylaxis in children”. Int J Immunopathol Pharmacol27 (1): 121–6. doi:10.1177/039463201402700116PMID24674687.
  29. ^ Dart, Richard C. (2004). Medical Toxology. Lippincott Williams & Wilkins. p. 23.
  30. ^ Tilelli, John A.; Smith, Kathleen M.; Pettignano, Robert (2006). “Life-Threatening Bradyarrhythmia After Massive Azithromycin Overdose”. Pharmacotherapy26 (1): 147–50. doi:10.1592/phco.2006.26.1.147PMID16506357.
  31. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 132–133.
  32. ^ Denise Grady (16 May 2012). “Popular Antibiotic May Raise Risk of Sudden Death”The New York TimesArchived from the original on 17 May 2012. Retrieved 18 May 2012.
  33. ^ Ray, Wayne A.; Murray, Katherine T.; Hall, Kathi; Arbogast, Patrick G.; Stein, C. Michael (2012). “Azithromycin and the Risk of Cardiovascular Death”New England Journal of Medicine366(20): 1881–90. doi:10.1056/NEJMoa1003833PMC3374857PMID22591294.
  34. ^ “FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms”. FDA. 12 March 2013. Archived from the original on 27 October 2016.
  35. Jump up to:ab “Archived copy”Archived from the original on 14 October 2014. Retrieved 10 October 2014.
  36. ^ Banić Tomišić, Z. (2011). “The Story of Azithromycin”Kemija U Industriji60 (12): 603–617. ISSN0022-9830Archived from the original on 8 September 2017.
  37. ^ “Azithromycin: A world best-selling Antibiotic”http://www.wipo.int. World Intellectual Property Organization. Retrieved 18 June 2019.
  38. ^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (April 2013). “U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine368 (15): 1461–1462. doi:10.1056/NEJMc1212055PMID23574140.
  39. ^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (September 2013). “More on U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine369 (12): 1175–1176. doi:10.1056/NEJMc1306863PMID24047077.

External links

Keywords: Antibacterial (Antibiotics); Macrolides.

Azithromycin
Azithromycin structure.svg
Azithromycin 3d structure.png
Clinical data
Trade names Zithromax, Azithrocin, others[2]
Other names 9-deoxy-9α-aza-9α-methyl-9α-homoerythromycin A
AHFS/Drugs.com Monograph
MedlinePlus a697037
License data
Pregnancy
category
  • AU: B1 [1]
  • US: B (No risk in non-human studies) [1]
Routes of
administration
By mouth (capsule, tablet or suspension), intravenouseye drop
Drug class Macrolide antibiotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 38% for 250 mg capsules
Metabolism Liver
Elimination half-life 11–14 h (single dose) 68 h (multiple dosing)
Excretion Biliarykidney (4.5%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.126.551 Edit this at Wikidata
Chemical and physical data
Formula C38H72N2O12
Molar mass 748.984 g·mol−1 g·mol−1
3D model (JSmol)

/////////AZITHROMYCIN, Antibacterial, Antibiotics,  Macrolides, CORONA VIRUS, COVID 19, アジスロマイシン ,

Pretomanid, プレトマニド;


ChemSpider 2D Image | pretomanid | C14H12F3N3O5

Pretomanid.svg

Pretomanid

プレトマニド;

Formula
C14H12F3N3O5
CAS
187235-37-6
Mol weight
359.2574
(6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
187235-37-6 [RN]
2XOI31YC4N
5H-Imidazo(2,1-b)(1,3)oxazine, 6,7-dihydro-2-nitro-6-((4-(trifluoromethoxy)phenyl)methoxy)-, (6S)-
5H-Imidazo[2,1-b][1,3]oxazine, 6,7-dihydro-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-, (6S)-
9871
PA824
PA-824; Pretomanid
  • (S)-PA 824

2019/8/14 FDA 2109 APPROVED

Antibacterial (tuberculostatic),

MP 149-150 °C, Li, Xiaojin; Bioorganic & Medicinal Chemistry Letters 2008, Vol 18(7), Pg 2256-2262 and  Orita, Akihiro; Advanced Synthesis & Catalysis 2007, Vol 349(13), Pg 2136-2144 

150-151 °C Marsini, Maurice A.; Journal of Organic Chemistry 2010, Vol 75(21), Pg 7479-7482 

Pretomanid is an antibiotic used for the treatment of multi-drug-resistant tuberculosis affecting the lungs.[1] It is generally used together with bedaquiline and linezolid.[1] It is taken by mouth.[1]

The most common side effects include nerve damage, acne, vomiting, headache, low blood sugar, diarrhea, and liver inflammation.[1] It is in the nitroimidazole class of medications.[2]

Pretomanid was approved for medical use in the United States in 2019.[3][1] Pretomanid was developed by TB Alliance,[4] a not-for-profitproduct development partnership dedicated to the discovery and development of new, faster-acting and affordable medicines for tuberculosis (TB).[5]

Global Alliance for the treatment of tuberculosis (TB).

The compound was originally developed by PathoGenesis (acquired by Chiron in 2000). In 2002, a co-development agreement took place between Chiron (acquired by Novartis in 2005) and the TB Alliance for the development of the compound. The compound was licensed to Fosunpharma by TB Alliance in China.

History

Pretomanid is the generic, nonproprietary name for the novel anti-bacterial drug compound formerly called PA-824.[6] Pretomanid is referred to as “Pa” in regimen abbreviations, such as BPaL. The “preto” prefix of the compound’s name honors Pretoria, South Africa, the home of a TB Alliance clinical development office where much of the drug’s development took place. The “manid” suffix is used to group compounds with similar chemical structures. This class of drug is variously referred to as nitroimidazoles, nitroimidazooxazines or nitroimidazopyrans. Development of this compound was initiated because of the urgent need for new antibacterial drugs effective against resistant strains of tuberculosis. Also, current anti-TB drugs are mainly effective against replicating and metabolically active bacteria, creating a need for drugs effective against persisting or latent bacterial infections as often occur in patients with tuberculosis.[7]

Discovery and pre-clinical development

Pretomanid was first identified in a series of 100 nitroimidazopyran derivatives synthesized and tested for antitubercular activity. Importantly, pretomanid has activity against static M. tuberculosis isolates that survive under anaerobic conditions, with bactericidal activity comparable to that of the existing drug metronidazole. Pretomanid requires metabolic activation by Mycobacterium for antibacterial activity. Pretomanid was not the most potent compound in the series against cultures of M. tuberculosis, but it was the most active in infected mice after oral administration. Oral pretomanid was active against tuberculosis in mice and guinea pigs at safely tolerated dosages for up to 28 days.[7]

Image result for Pretomanid

Limited FDA approval

FDA approved pretomanid only in combination with bedaquiline and linezolid for treatment of a limited and specific population of adult patients with extensively drug resistant, treatment-intolerant or nonresponsive multidrug resistant pulmonary tuberculosis. Pretomanid was approved under the Limited Population Pathway (LPAD pathway) for antibacterial and antifungal drugs. The LPAD Pathway was established by Congress under the 21st Century Cures Act to expedite development and approval of antibacterial and antifungal drugs to treat serious or life-threatening infections in a limited population of patients with unmet need. Pretomanid is only the third tuberculosis drug to receive FDA approval in more than 40 years.[3][8]

PATENT

IN 201641030408

HETERO RESEARCH FOUNDATION

http://ipindiaservices.gov.in/PatentSearch/PatentSearch/ViewPDF

  • By Reddy, Bandi Parthasaradhi; Reddy, Kura Rathnakar; Reddy, Adulla Venkat Narsimha; Krishna, Bandi Vamsi
  • From Indian Pat. Appl. (2018), IN 201641030408

The nitroimidazooxazine Formula I (PA-824) is a new class of bioreductive drug for tuberculosis. The recent introduction of the nitroimidazooxazine Formula I (PA-824) to clinical trial by the Global Alliance for TB Drug Development is thus of potential significance, since this compound shows good in vitro and in vivo activity against Mycobacterium tuberculosis in both its active and persistent forms. Tuberculosis (TBa) remains a leading infectious cause of death worldwide, but very few new drugs have been approved for TB treatment ifi the past 35 years, the current drug therapy for TB is long and complex, involving multidrug combinations.

The mechanism of actiém of Pretomanid is thoughrto involve reduction of the nitro group, in a‘ process dependent on the Bacterial ‘ m E Nfilw‘fieéFPEOEPEa‘e fillyeifiaasnfi (F8189); $943“; 20mm; “q Mcyarecent Swiss on mutant strains showed that a 151-amino acid (17.37 kDa) protein of unknown function, Rv3547, also, appears to be critical for this activation. Equivalent genes are present in M. boVis and MaVium.

Pretomanid and its pharmace’utically acceptable salts Were generically disclosed in US 5,668,127 A and Specifically disclosed in US 6,087,358 A. US ‘358 patent discloses a process for the preparation of Pretomanid, which is as shown below in scheme 1:

CN 104177372 A discloses a process for the preparation of Pretomanid, which is as shown below in scheme II: 

Bioorganic & Medicinal Chemistry Letters 2008, Volume: 18, Issue: 7, Pages: 2256-2262 discloses a process for the preparation of Pretomanid, which is as shown below in scheme Ill: 

US 7,!15,736 B2-discloses_a process fdr the preparation of 3S-Hydroxy-6-nitrQ-2H-3, 4— dihydro-[2-1b]-imidazopyran which is a key intermediate of Pretomanid, which is as shown below in scheme IV:

Journal Medicinal Chemistry 2009, Volume: 52, Pages: 637 — 645 discloses a process for the preparation of ‘Pretomanid, which is as shown below in scheme V:

Joumal Organic Chemistry 2010; Volume: 75 (2]), Pages: 7479—82 discloses a process for. the preparation of Pretomanid, which is as shown below in scheme VI:

Example 3: Preparation of Pretomanid (S) 1- -(3 (tert- -Butyldomethylsilyloxy)- -2- -(-4 -(trifluoromethoxy)-71benzyloxy2‘- propyl)- 2- -methylP AT E N4Tnitro- fi-Eimigazole (Efgm Awlas (3315;501:1691 gin! %etra%1y7drofuraen (18(150 ml) at room temperature and stirred for 5 to 10 minutes then TBAF (9516 ml) was added to the reaction mixture and stirred for 2 hours, at room temperature, afler completion of the reaction removed solvent through vacuum to obtained residue, dissolved the residue in MDC (1800 ml) and water (1800 ml) stirred, separated the layers and the organic layer washed with 10% ‘ sodium bicarbonate the obtained organic solution was concentrated under atmospheric pressure to obtained residue added MeOH (1730 ml) at room temperature and the reaction mixture was cooled to 0°C to 5°C, added KOH (24.5 gm) at the same temperaturé then cooled to room temperature and stirred for 24 hours. After completion of reaction DM Water added drop wise over 30 minutes at 10°C to 15° C and stirred for 1 hour to 1 hour 30 minutes at room’lemperature, filtrated the compound and washed with DM wa‘er (133 ml) and dried under vacuum for 10 hours at 50° C. Yield: 53 gm , Chromatographic purity: 97.69% (by HPLC):

Example 4: Purification of Pretomanid Pretomanid (53 gm) was dissolved in MDC (795 ml) at room temperatur’e and stirred for 10 to 15 minutes, added charcoal (10 gm) and stirred for 30-35 minutes, remove the charcoal and concentrated to obtained residue: Dissolved the obtained residue in IPA (795 ml) and the reaction mixture was heated to 80°C maintained for 10-15 minutes, added cyclohexane (1600ml) for 30 minutes at 80° C, then cooled to room temperature and stirred the reaction mass for overnight, filtered the solid and washed with cyclohexane (265 ml), and dried under vacuum for 10 hours at 50° C. Yield: 48 gm (Percentage of Yield: 90%) Chromatographic purity: 99.97% by HPLC).

CLIP

https://www.researchgate.net/publication/278498983_Nitroimidazoles_Quinolones_and_Oxazolidinones_as_Fluorine_Bearing_Antitubercular_Clinical_Candidates/figures?lo=1

ReferencE

CN104177372A.

WO9701562A1.

IN 201641030408

IN 201621026053

CN 107915747

CN 106632393

CN 106565744

CN 104177372

WO 9701562

US 6087358

PAPER

Science (Washington, DC, United States) (2008), 322(5906), 1392-1395.

Paper

PAPER

Huagong Shikan (2010), 24(4), 32-34, 51.

Xiaojin; Bioorganic & Medicinal Chemistry Letters 2008, Vol 18(7), Pg 2256-2262

PAPER

Orita, Akihiro; Advanced Synthesis & Catalysis 2007, Vol 349(13), Pg 2136-2144 

https://onlinelibrary.wiley.com/doi/abs/10.1002/adsc.200700119

https://application.wiley-vch.de/contents/jc_2258/2007/f700119_s.pdf

PAPER

Marsini, Maurice A.; Journal of Organic Chemistry 2010, Vol 75(21), Pg 7479-7482 

Scheme 2. General Synthetic Strategy

Scheme 1

Scheme 1. Original Production Process for PA-824a

aDHP = 3,4-dihydropyran; p-TsOH = p-toluenesulfonic acid; MsOH = methanesulfonic acid.

Scheme 3

Scheme 3. Synthesis of a Functionalized Glycidol Derivativea

aCl3CCN = trichloroacetonitrile; TBME = tert-butylmethyl ether; TfOH = trifluoromethanesulfonic acid.

Scheme 4. Synthesis of PA-824
 The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. Chromatography (75% EtOAc/hexanes) followed by recrystallization (i-PrOH/hexanes) affords PA-824 (1) (2.41 g, 62%) as a crystalline solid. Mp 150−151 °C (lit.(11a) mp 149−150); Rf 0.2 (75% EtOAc/hexanes); ee >99.9% as determined by chiral SFC (see the Supporting Information);
 1H NMR (500 MHz, d6-DMSO) δ 8.09 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 4.81−4.62 (m, 3H), 4.51 (d, J = 11.9 Hz, 1H), 4.39−4.19 (m, 3H);
 13C NMR (126 MHz, d6-DMSO) δ 148.7, 148.1, 143.0, 138.3, 130.4, 122.0, 120.0, 119.8, 69.7, 68.8, 67.51, 47.73;
IR [CH2Cl2 solution] νmax (cm−1) 2877, 1580, 1543, 1509, 1475, 1404, 1380, 1342, 1281, 1221, 1162, 1116, 1053, 991, 904, 831, 740;
HRMS (ESI-TOF) calcd for C14H12F3N3O5 359.0729, found 359.0728.

PAPER

Journal of Medicinal Chemistry (2010), 53(1), 282-294.

Journal of Medicinal Chemistry (2009), 52(3), 637-645.

PATENT

References

Pretomanid
Pretomanid.svg
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
ChEMBL
CompTox Dashboard(EPA)
Chemical and physical data
Formula C14H12F3N3O5
Molar mass 359.261 g·mol−1
3D model (JSmol)

//////////////Pretomanid, FDA 2109, プレトマニド  , Antibacterial, tuberculostatic, PA-824, ANTI tuberculostatic

FDA approves new antibiotic Xenleta (lefamulin) to treat community-acquired bacterial pneumonia


FDA approves new antibiotic  Xenleta (lefamulin) to treat community-acquired bacterial pneumonia

The U.S. Food and Drug Administration today approved Xenleta (lefamulin) to treat adults with community-acquired bacterial pneumonia.

“This new drug provides another option for the treatment of patients with community-acquired bacterial pneumonia, a serious disease,” said Ed Cox, M.D., M.P.H., director of FDA’s Office of Antimicrobial Products. “For managing this serious disease, it is important for physicians and patients to have treatment options. This approval reinforces our ongoing commitment to address treatment of infectious diseases by facilitating the development of new antibiotics.”

Community-acquired pneumonia occurs when someone develops pneumonia in the community (not in a hospital). Pneumonia is a type of lung infection that can range in severity from mild to severe illness and can affect people of all ages. According to data from the Centers from Disease Control and Prevention, each year in the United States, about one million people are hospitalized with community-acquired pneumonia and 50,000 people die from the disease.

The safety and efficacy of Xenleta, taken either orally or intravenously, was evaluated in two clinical trials with a total of 1,289 patients with CABP. In these trials, treatment with Xenleta was compared to another antibiotic, moxifloxacin with or without linezolid. The trials showed that patients treated with Xenleta had similar rates of clinical success as those treated with moxifloxacin with or without linezolid.

The most common adverse reactions reported in patients taking Xenleta included diarrhea, nausea, reactions at the injection site, elevated liver enzymes and vomiting. Xenleta has the potential to cause a change on an ECG reading (prolonged QT interval). Patients with prolonged QT interval, patients with certain irregular heart rhythms (arrhythmias), patients receiving treatment for certain irregular heart rhythms (antiarrhythmic agents), and patients receiving other drugs that prolong the QT interval should avoid Xenleta. In addition, Xenleta should not be used in patients with known hypersensitivity to lefamulin or any other members of the pleuromutilin antibiotic class, or any of the components of Xenleta. Based on findings of fetal harm in animal studies, pregnant women and women who could become pregnant should be advised of the potential risks of Xenleta to a fetus. Women who could become pregnant should be advised to use effective contraception during treatment with Xenleta and for two days after the final dose.

Xenleta received FDA’s Qualified Infectious Disease Product (QIDP) designation. The QIDP designation is given to antibacterial and antifungal drug products intended to treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, Xenleta was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.

The FDA granted the approval of Xenleta to Nabriva Therapeutics.

A key global challenge the FDA faces as a public health agency is addressing the threat of antimicrobial-resistant infections. Among the FDA’s other efforts to address antimicrobial resistance, is the focus on facilitating the development of safe and effective new treatments to give patients more options to fight serious infections.

LINK

http://s2027422842.t.en25.com/e/er?utm_campaign=081919_PR_FDA%20approves%20new%20antibiotic%20to%20treat%20community-acquired%20bacterial%20pneumonia&utm_medium=email&utm_source=Eloqua&s=2027422842&lid=9299&elqTrackId=AC98B5F2F3FDA7EADC5780AB18C8861A&elq=a5d6c9e321e34425b20035738f0e4edf&elqaid=9185&elqat=1

//////////Xenleta,  Nabriva Therapeutics, Qualified Infectious Disease Product, QIDP, fda 2019, Generating Antibiotic Incentives Now, GAIN, lefamulin, community-acquired bacterial pneumonia, antibacterial, Priority Review

Novobiocin, ノボビオシン;


Novobiocin2DCSD.svg

ChemSpider 2D Image | novobiocin | C31H36N2O11

Novobiocin

ノボビオシン;

  • Molecular FormulaC31H36N2O11
  • Average mass612.624 Da
(3R,4S,5R,6R)-5-hydroxy-6-(4-hydroxy-3-(4-hydroxy-3-(3-methylbut-2-enyl)benzamido)-8-methyl-2-oxo-2H-chromen-7-yloxy)-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate
(3R,4S,5R,6R)-5-Hydroxy-6-[(4-hydroxy-3-{[4-hydroxy-3-(3-methyl-2-buten-1-yl)benzoyl]amino}-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (non-preferred name) [ACD/IUPAC Name]
(3R,4S,5R,6R)-5-Hydroxy-6-[(4-hydroxy-3-{[4-hydroxy-3-(3-methyl-2-buten-1-yl)benzoyl]amino}-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (non-preferred name)
(3R,4S,5R,6R)-5-Hydroxy-6-[(4-hydroxy-3-{[4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoyl]amino}-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (non-preferred name)
1476-53-5 [RN]
17EC19951N
216-023-6 [EINECS]
224-321-2 [EINECS]
575
Albamycin[Trade name]
Biotexin
CAS number303-81-1
WeightAverage: 612.6243
Monoisotopic: 612.231910004
Chemical FormulaC31H36N2O11
For the treatment of infections due to staphylococci and other susceptible organisms
Novobiocin
 Novobiocin
CAS Registry Number: 303-81-1
CAS Name: N-[7-[[3-O-(Aminocarbonyl)-6-deoxy-5-C-methyl-4-O-methyl-b-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl]-4-hydroxy-3-(3-methyl-2-butenyl)benzamide
Additional Names: crystallinic acid; streptonivicin
Manufacturers’ Codes: PA-93; U-6591
Molecular Formula: C31H36N2O11
Molecular Weight: 612.62
Percent Composition: C 60.78%, H 5.92%, N 4.57%, O 28.73%
Literature References: Antibiotic substance produced by Streptomyces spheroides: Kaczka et al., J. Am. Chem. Soc. 77, 6404 (1955); Wolf, US 3000873 (1961 to Merck & Co.); Stammer, Miller; Miller; Wallick, US 3049475US 3049476US 3049534 (all 1962 to Merck & Co.). By Streptomyces niveus: Hoeksema et al., J. Am. Chem. Soc. 77, 6710 (1955); Antibiot. Chemother. 6, 143 (1956); French, US 3068221 (1962 to Upjohn). Structure: Shunk et al., J. Am. Chem. Soc. 78, 1770 (1956); Hoeksema et al., ibid.2019; Walton et al., ibid. 82, 1489 (1960). Conformation: Golding, Richards, Chem. Ind. (London) 1963, 1081. Revised configuration: O. Achmatowicz et al., Tetrahedron 32, 1051 (1976). Synthesis: Stammer, US 2925411 (1960); Walton, Spencer, US2966484 (1960 to Merck & Co.); Vaterlaus et al., Helv. Chim. Acta 47, 390 (1964). Conversion of isonovobiocin to novobiocin: Caron et al., US 2983723 (1961 to Upjohn). Antiviral activity: Chang, Weinstein, Antimicrob. Agents Chemother. 1970, 165. Efficacy in canine respiratory infections: B. W. Maxey, Vet. Med. Small Anim. Clin. 75, 89 (1980). Mechanism of action studies: Smith, Davis, J. Bacteriol. 93, 71 (1967); H. T. Wright et al., Science 213, 455 (1981); I. W. Althaus et al., J. Antibiot. 41, 373 (1988). Review: Brock in Antibiotics vol. 1, R. Gottlieb, P. Shaw, Eds. (Springer-Verlag, New York, 1967) pp 651-665; M. J. Ryan, ibid. vol. 5(pt. 1), F. E. Hahn, Ed. (1979) pp 214-234.
Properties: Pale yellow orthorhombic crystals from ethanol. Sensitive to light. d 1.3448. Dec at 152-156° (a rarer modification dec 174-178°). Acid reaction: pKa1 4.3; pKa2 9.1. [a]D24 -63.0° (c = 1 in ethanol). uv max (0.1N NaOH; 0.1N methanolic HCl; pH 7 phosphate buffer): 307; 324; 390 nm (E1%1cm 600, 390, 350 resp.). Sol in aq soln above pH 7.5. Practically insol in more acidic solns. Sol in acetone, ethyl acetate, amyl acetate, lower alcohols, pyridine. Additional soly data: Weiss et al., Antibiot. Chemother.7, 374 (1957).
pKa: pKa1 4.3; pKa2 9.1
Optical Rotation: [a]D24 -63.0° (c = 1 in ethanol)
Absorption maximum: uv max (0.1N NaOH; 0.1N methanolic HCl; pH 7 phosphate buffer): 307; 324; 390 nm (E1%1cm 600, 390, 350 resp.)
Density: d 1.3448
Derivative Type: Monosodium salt
CAS Registry Number: 1476-53-5
Trademarks: Albamycin (Pharmacia & Upjohn)
Molecular Formula: C31H35N2NaO11
Molecular Weight: 634.61
Percent Composition: C 58.67%, H 5.56%, N 4.41%, Na 3.62%, O 27.73%
Properties: Minute crystals, dec 220°. [a]D24 -38° (c = 2.5 in 95% ethanol); [a]D24 -33° (c = 2.5 in water). Freely sol in water. A 100 mg/ml soln has a pH of 7.5 and a half-life of ~30 days at 25° and several months at 4°. Soly data: Weiss et al., loc. cit. Properties: Birlova, Traktenberg, Antibiotiki 13, 997 (1968).
Optical Rotation: [a]D24 -38° (c = 2.5 in 95% ethanol); [a]D24 -33° (c = 2.5 in water)
Therap-Cat: Antibacterial.
Therap-Cat-Vet: Antimicrobial.
INGREDIENT UNII CAS INCHI KEY
Novobiocin sodium Q9S9NQ5YIY 1476-53-5 WWPRGAYLRGSOSU-RNROJPEYSA-M

Reata Pharmaceuticals Inc

Abgentis is investigating a novobiocin analog, GYR-12 (discovery), as a re-engineered, previously-marketed-but-uncompetitive (undisclosed) antibacterial compound inhibiting ATPase activity of DNA supercoiling GyrB/ParE, for the potential broad-spectrum treatment of bacterial infections, including multi-drug resistant Gram-negative infections. In April 2017, development was underway [1924695].

Novobiocin, also known as albamycin or cathomycin, is an aminocoumarin antibiotic that is produced by the actinomycete Streptomyces niveus, which has recently been identified as a subjective synonym for S. spheroides[1] a member of the order Actinobacteria. Other aminocoumarin antibiotics include clorobiocin and coumermycin A1.[2] Novobiocin was first reported in the mid-1950s (then called streptonivicin).[3][4]

It is active against Staphylococcus epidermidis and may be used to differentiate it from the other coagulase-negative Staphylococcus saprophyticus, which is resistant to novobiocin, in culture.

Novobiocin was licensed for clinical use under the tradename Albamycin (Pharmacia And Upjohn) in the 1960s. Its efficacy has been demonstrated in preclinical and clinical trials.[5][6] The oral form of the drug has since been withdrawn from the market due to lack of efficacy.[7] Novobiocin is an effective antistaphylococcal agent used in the treatment of MRSA.[8]

Mechanism of action

The molecular basis of action of novobiocin, and other related drugs clorobiocin and coumermycin A1 has been examined.[2][9][10][11][12] Aminocoumarins are very potent inhibitors of bacterial DNA gyrase and work by targeting the GyrB subunit of the enzyme involved in energy transduction. Novobiocin as well as the other aminocoumarin antibiotics act as competitive inhibitors of the ATPase reaction catalysed by GyrB. The potency of novobiocin is considerably higher than that of the fluoroquinolones that also target DNA gyrase, but at a different site on the enzyme. The GyrA subunit is involved in the DNA nicking and ligation activity.

Novobiocin has been shown to weakly inhibit the C-terminus of the eukaryotic Hsp90 protein (high micromolar IC50). Modification of the novobiocin scaffold has led to more selective Hsp90 inhibitors.[13] Novobiocin has also been shown to bind and activate the Gram-negative lipopolysaccharide transporter LptBFGC.[14][15]

Structure

Novobiocin is an aminocoumarin. Novobiocin may be divided up into three entities; a benzoic acid derivative, a coumarin residue, and the sugar novobiose.[9] X-ray crystallographic studies have found that the drug-receptor complex of Novobiocin and DNA Gyrase shows that ATP and Novobiocin have overlapping binding sites on the gyrase molecule.[16] The overlap of the coumarin and ATP-binding sites is consistent with aminocoumarins being competitive inhibitors of the ATPase activity.[17]

Structure–activity relationship

In structure activity relationship experiments it was found that removal of the carbamoyl group located on the novobiose sugar lead to a dramatic decrease in inhibitory activity of novobiocin.[17]

Biosynthesis

This aminocoumarin antibiotic consists of three major substituents. The 3-dimethylallyl-4-hydroxybenzoic acid moiety, known as ring A, is derived from prephenate and dimethylallyl pyrophosphate. The aminocoumarin moiety, known as ring B, is derived from L-tyrosine. The final component of novobiocin is the sugar derivative L-noviose, known as ring C, which is derived from glucose-1-phosphate. The biosynthetic gene cluster for novobiocin was identified by Heide and coworkers in 1999 (published 2000) from Streptomyces spheroidesNCIB 11891.[18] They identified 23 putative open reading frames (ORFs) and more than 11 other ORFs that may play a role in novobiocin biosynthesis.

The biosynthesis of ring A (see Fig. 1) begins with prephenate which is a derived from the shikimic acid biosynthetic pathway. The enzyme NovF catalyzes the decarboxylation of prephenate while simultaneously reducing nicotinamide adenine dinucleotide phosphate (NADP+) to produce NADPH. Following this NovQ catalyzes the electrophilic substitution of the phenyl ring with dimethylallyl pyrophosphate (DMAPP) otherwise known as prenylation.[19] DMAPP can come from either the mevalonic acid pathway or the deoxyxylulose biosynthetic pathway. Next the 3-dimethylallyl-4-hydroxybenzoate molecule is subjected to two oxidative decarboxylations by NovR and molecular oxygen.[20] NovR is a non-heme iron oxygenase with a unique bifunctional catalysis. In the first stage both oxygens are incorporated from the molecular oxygen while in the second step only one is incorporated as determined by isotope labeling studies. This completes the formation of ring A.

Figure 1. Biosynthetic scheme of benzamide portion of novobiocin (4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoic acid)

The biosynthesis of ring B (see Fig. 2) begins with the natural amino acid L-tyrosine. This is then adenylated and thioesterified onto the peptidyl carrier protein (PCP) of NovH by ATPand NovH itself.[21] NovI then further modifies this PCP bound molecule by oxidizing the β-position using NADPH and molecular oxygen. NovJ and NovK form a heterodimer of J2K2 which is the active form of this benzylic oxygenase.[22] This process uses NADP+ as a hydride acceptor in the oxidation of the β-alcohol. This ketone will prefer to exist in its enol tautomer in solution. Next a still unidentified protein catalyzes the selective oxidation of the benzene (as shown in Fig. 2). Upon oxidation this intermediate will spontaneously lactonize to form the aromatic ring B and lose NovH in the process.

Figure 2. Biosynthesis of 3-amino-4,7-dihydroxy-2H-chromen-2-one component of novobiocin (ring B)

The biosynthesis of L-noviose (ring C) is shown in Fig. 3. This process starts from glucose-1-phosphate where NovV takes dTTP and replaces the phosphate group with a dTDP group. NovT then oxidizes the 4-hydroxy group using NAD+. NovT also accomplishes a dehydroxylation of the 6 position of the sugar. NovW then epimerizes the 3 position of the sugar.[23] The methylation of the 5 position is accomplished by NovU and S-adenosyl methionine (SAM). Finally NovS reduces the 4 position again to achieve epimerization of that position from the starting glucose-1-phosphate using NADH.

Figure 3. Biosynthesis of L-noviose component of novobiocin (ring C)

Rings A, B, and C are coupled together and modified to give the finished novobiocin molecule. Rings A and B are coupled together by the enzyme NovL using ATP to diphosphorylate the carboxylate group of ring A so that the carbonyl can be attacked by the amine group on ring B. The resulting compound is methylated by NovO and SAM prior to glycosylation.[24] NovM adds ring C (L-noviose) to the hydroxyl group derived from tyrosine with the loss of dTDP. Another methylation is accomplished by NovP and SAM at the 4 position of the L-noviose sugar.[25] This methylation allows NovN to carbamylate the 3 position of the sugar as shown in Fig. 4 completing the biosynthesis of novobiocin.

Figure 4. Completed biosynthesis of novobiocin from ring systems AB, and C.
CLIP

CLIP

CLIP

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str1-1

PATENT

US-20190241599

Novel co-crystal forms of novobiocin and its analogs and proline, processes for their preparation and compositions comprising them are claimed. Also claims are methods for inhibiting heat shock protein 90 and treating or preventing neurodegenerative disorders, such as diabetic peripheral neuropathy.

References

  1. ^ Lanoot B, Vancanneyt M, Cleenwerck I, Wang L, Li W, Liu Z, Swings J (May 2002). “The search for synonyms among streptomycetes by using SDS-PAGE of whole-cell proteins. Emendation of the species Streptomyces aurantiacus, Streptomyces cacaoi subsp. cacaoi, Streptomyces caeruleus and Streptomyces violaceus”. International Journal of Systematic and Evolutionary Microbiology52 (Pt 3): 823–9. doi:10.1099/ijs.0.02008-0PMID 12054245.
  2. Jump up to:a b Alessandra da Silva Eustáquio (2004) Biosynthesis of aminocoumarin antibiotics in Streptomyces: Generation of structural analogues by genetic engineering and insights into the regulation of antibiotic production. DISSERTATION
  3. ^ Hoeksema H.; Johnson J. L.; Hinman J. W. (1955). “Structural studies on streptonivicin, a new antibiotic”. J Am Chem Soc77 (24): 6710–6711. doi:10.1021/ja01629a129.
  4. ^ Smith C. G.; Dietz A.; Sokolski W. T.; Savage G. M. (1956). “Streptonivicin, a new antibiotic. I. Discovery and biologic studies”. Antibiotics & Chemotherapy6: 135–142.
  5. ^ Raad I, Darouiche R, Hachem R, Sacilowski M, Bodey GP (November 1995). “Antibiotics and prevention of microbial colonization of catheters”Antimicrobial Agents and Chemotherapy39 (11): 2397–400. doi:10.1128/aac.39.11.2397PMC 162954PMID 8585715.
  6. ^ Raad II, Hachem RY, Abi-Said D, Rolston KV, Whimbey E, Buzaid AC, Legha S (January 1998). “A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2”. Cancer82 (2): 403–11. doi:10.1002/(SICI)1097-0142(19980115)82:2<412::AID-CNCR22>3.0.CO;2-0PMID 9445199.
  7. ^ “Determination That ALBAMYCIN (Novobiocin Sodium) Capsule, 250 Milligrams, Was Withdrawn From Sale for Reasons of Safety or Effectiveness”The Federal Register. 19 January 2011.
  8. ^ Walsh TJ, Standiford HC, Reboli AC, John JF, Mulligan ME, Ribner BS, Montgomerie JZ, Goetz MB, Mayhall CG, Rimland D (June 1993). “Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome”Antimicrobial Agents and Chemotherapy37 (6): 1334–42. doi:10.1128/aac.37.6.1334PMC 187962PMID 8328783.
  9. Jump up to:a b Maxwell A (August 1993). “The interaction between coumarin drugs and DNA gyrase”. Molecular Microbiology9 (4): 681–6. doi:10.1111/j.1365-2958.1993.tb01728.xPMID 8231802.
  10. ^ Maxwell A (February 1999). “DNA gyrase as a drug target”. Biochemical Society Transactions27 (2): 48–53. doi:10.1042/bst0270048PMID 10093705.
  11. ^ Lewis RJ, Tsai FT, Wigley DB (August 1996). “Molecular mechanisms of drug inhibition of DNA gyrase”. BioEssays18 (8): 661–71. doi:10.1002/bies.950180810PMID 8760340.
  12. ^ Maxwell A, Lawson DM (2003). “The ATP-binding site of type II topoisomerases as a target for antibacterial drugs”. Current Topics in Medicinal Chemistry3 (3): 283–303. doi:10.2174/1568026033452500PMID 12570764.
  13. ^ Yu XM, Shen G, Neckers L, Blake H, Holzbeierlein J, Cronk B, Blagg BS (September 2005). “Hsp90 inhibitors identified from a library of novobiocin analogues”. Journal of the American Chemical Society127 (37): 12778–9. doi:10.1021/ja0535864PMID 16159253.
  14. ^ Mandler MD, Baidin V, Lee J, Pahil KS, Owens TW, Kahne D (June 2018). “Novobiocin Enhances Polymyxin Activity by Stimulating Lipopolysaccharide Transport”Journal of the American Chemical Society140 (22): 6749–6753. doi:10.1021/jacs.8b02283PMC 5990483PMID 29746111.
  15. ^ May JM, Owens TW, Mandler MD, Simpson BW, Lazarus MB, Sherman DJ, Davis RM, Okuda S, Massefski W, Ruiz N, Kahne D (December 2017). “The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport”Journal of the American Chemical Society139 (48): 17221–17224. doi:10.1021/jacs.7b07736PMC 5735422PMID 29135241.
  16. ^ Tsai FT, Singh OM, Skarzynski T, Wonacott AJ, Weston S, Tucker A, Pauptit RA, Breeze AL, Poyser JP, O’Brien R, Ladbury JE, Wigley DB (May 1997). “The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin”. Proteins28 (1): 41–52. doi:10.1002/(sici)1097-0134(199705)28:1<41::aid-prot4>3.3.co;2-bPMID 9144789.
  17. Jump up to:a b Flatman RH, Eustaquio A, Li SM, Heide L, Maxwell A (April 2006). “Structure-activity relationships of aminocoumarin-type gyrase and topoisomerase IV inhibitors obtained by combinatorial biosynthesis”Antimicrobial Agents and Chemotherapy50 (4): 1136–42. doi:10.1128/AAC.50.4.1136-1142.2006PMC 1426943PMID 16569821.
  18. ^ Steffensky M, Mühlenweg A, Wang ZX, Li SM, Heide L (May 2000). “Identification of the novobiocin biosynthetic gene cluster of Streptomyces spheroides NCIB 11891”Antimicrobial Agents and Chemotherapy44 (5): 1214–22. doi:10.1128/AAC.44.5.1214-1222.2000PMC 89847PMID 10770754.
  19. ^ Pojer F, Wemakor E, Kammerer B, Chen H, Walsh CT, Li SM, Heide L (March 2003). “CloQ, a prenyltransferase involved in clorobiocin biosynthesis”Proceedings of the National Academy of Sciences of the United States of America100 (5): 2316–21. Bibcode:2003PNAS..100.2316Pdoi:10.1073/pnas.0337708100PMC 151338PMID 12618544.
  20. ^ Pojer F, Kahlich R, Kammerer B, Li SM, Heide L (August 2003). “CloR, a bifunctional non-heme iron oxygenase involved in clorobiocin biosynthesis”. The Journal of Biological Chemistry278 (33): 30661–8. doi:10.1074/jbc.M303190200PMID 12777382.
  21. ^ Chen H, Walsh CT (April 2001). “Coumarin formation in novobiocin biosynthesis: beta-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI”. Chemistry & Biology8 (4): 301–12. doi:10.1016/S1074-5521(01)00009-6PMID 11325587.
  22. ^ Pacholec M, Hillson NJ, Walsh CT (September 2005). “NovJ/NovK catalyze benzylic oxidation of a beta-hydroxyl tyrosyl-S-pantetheinyl enzyme during aminocoumarin ring formation in novobiocin biosynthesis”. Biochemistry44 (38): 12819–26. CiteSeerX 10.1.1.569.1481doi:10.1021/bi051297mPMID 16171397.
  23. ^ Thuy TT, Lee HC, Kim CG, Heide L, Sohng JK (April 2005). “Functional characterizations of novWUS involved in novobiocin biosynthesis from Streptomyces spheroides”. Archives of Biochemistry and Biophysics436 (1): 161–7. doi:10.1016/j.abb.2005.01.012PMID 15752721.
  24. ^ Pacholec M, Tao J, Walsh CT (November 2005). “CouO and NovO: C-methyltransferases for tailoring the aminocoumarin scaffold in coumermycin and novobiocin antibiotic biosynthesis”. Biochemistry44 (45): 14969–76. doi:10.1021/bi051599oPMID 16274243.
  25. ^ Freel Meyers CL, Oberthür M, Xu H, Heide L, Kahne D, Walsh CT (January 2004). “Characterization of NovP and NovN: completion of novobiocin biosynthesis by sequential tailoring of the noviosyl ring”. Angewandte Chemie43 (1): 67–70. doi:10.1002/anie.200352626PMID 14694473.

External links

Novobiocin
Novobiocin2DCSD.svg
Space-filling model of the novobiocin molecule
Clinical data
AHFS/Drugs.com International Drug Names
Routes of
administration
intravenous
ATCvet code
Pharmacokinetic data
Bioavailability negligible oral bioavailability
Metabolism excreted unchanged
Elimination half-life 6 hours
Excretion renal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard 100.005.589 Edit this at Wikidata
Chemical and physical data
Formula C31H36N2O11
Molar mass 612.624 g·mol−1
3D model (JSmol)

Novobiocin calcium.png

4309-70-0  CAS

calcium;7-[(2R,3R,4S,5R)-4-carbamoyloxy-3-hydroxy-5-methoxy-6,6-dimethyloxan-2-yl]oxy-3-[[4-hydroxy-3-(3-methylbut-2-enyl)benzoyl]amino]-8-methyl-2-oxochromen-4-olate

///////// Novobiocin, ノボビオシン  , Antibacterial, Antimicrobial,  crystallinic acid, streptonivicin,

Manufacturers’ Codes: PA-93; U-6591

History

Novobiocin is a coumarin antibiotic obtained from Streptomyces niveus and other Streptomyces species. Novobiocin is useful primarily in infections involving staphylococci, and other gram-positive organisms. It acts by inhibiting the initiation of DNA replication in bacterial and mammanlian cells. Evidences indicated that Novobiocin blocks prokaryotic DNA gyrase and eukaryotic II topoisomerase, enzymes that relax super-coiled DNA and are crucial for DNA replication.1

Novobiocin

UIPAC Name 4-Hydroxy-3-4-hydroxy-3-(3-methylbut-2-enyl)benzamido-8-methylcoumarin-7-yl 3-O-carbamoyl-5,5-di-C-methyl-α-l-lyxofuranoside
CAS Number 303-81-1
Molecular Mass 612.624 g / mol
Chemical Formular C31H36N2O11

Biosynthesis

The substituted coumarin (ring B, red) and the 4-OH benzoyl moiety (ring A, aqua) in novobiocin were derived from Image-Tyr based on earlier labeling studies. β-OH-Tyr is proposed to be a common intermediate in these two biosynthetic pathways.2

NovH is a Image-Tyr specific didomain NRPS that generates the Image-tyrosyl-S-NovH intermediate. NovH, isolated from E. coli is primed by a PPTase with CoA. The A domain activates Image-Tyr as Image-tyrosyl-AMP and then transfers the Image-tyrosyl group to the HS-pant-PCP domain of NovH through thioester formation.3

Image-tyrosyl-S-NovH is then function as a cytochrome P450 monooxygenase that hydroxylates the β-carbon of the tethered Image-tyrosyl group on NovH. While the substrate Image-tyrosyl-S-NovH provides two electrons for a single round of the hydroxylation reaction, the other two electrons needed to reduce the oxygen atom are provided by NADPH via two-electron transfer effected by electron transfer proteins ferrodoxin (Fd) and ferrodoxin reductase (Fd Red).3 The electron transfer route is from NADPH→FAD in Fd Red→Fe–S center in Fd→Heme in NovI→oxygen.

Both NovJ and NovK are similar to 3-keto-ACP reductase and they may form a heterodimer and operate in the reverse direction to oxidize 3-OH to 3-keto. NovO is similar to some quinone C-methyltransferases 3 but the timing of methylation is not clear. NovC resembles flavin-dependent monooxygenases (35 and 32% similarity to dimethylaniline and cyclohexanone monooxygenases, respectively) 3 and is proposed to hydroxylate the ortho position of the phenyl ring. The nucleophilic attack of the ortho hydroxyl group on the thioester carbonyl center would release the coumarin ring and regenerate NovH. Ring B is then synthesized.

Synthesis

Mechanism of action

E.Coli DNA gyrase utilizes ATP to catalyze the negative supercoiling, or under-twisting, of duplex DNA. The energy coupling components of the supercoiling reaction includes 1) the DNA-dependent hydrolysis that converts ATP to ADP and Pi, and 2) the gyrase cleavage reaction that targets the specified DNA site. The two activities are induced by treating the stable gyrase-DNA complex trapped by the inihibitor oxolinic acid with sodium dodecyl sulfate (SDS or Sulphate). 4 Novobiocin competes with ATP in the ATPase and supercoiling assays, hence Novobiocin prevents the ATP from shifting the primary cleavage site on ColE1 DNA by places the site of action of the antibiotics at a reaction step prior to ATP hydrolysis and blocks the binding of ATP. 4 Such a simple mechanism of action represents for all effects of the drugs on DNA gyrase.

Clinical Use

Due to factors as low solubility, poor pharmacokinetics, and limited activity agasinst Gram-negative bacteria, the clinical usage of Novobiocin is not achieved. 5 Therefore, it is of interest to study the novobiocin biosynthetic pathway in order to generate analogs with enhanced solubility and pharmacokinetic properties while maintaining the gyrase inhibitory properties.

References

1 J.C. D’Halluin, M. Milleville, and P. Boulanger. “Effect of Novobiocin on adenovirus DNA synthesis and encapsidation”. Nucleic Acids Research 1980; 8: 1625-1641

2 M. Steffensky, S.M. Li and L. Heide, “Cloning, overexpression, and purification of novobiocic acid synthetase from Streptomyces spheroides ” NCIB 11891. J. Biol. Chem. 275 (2000), pp. 21754–21760.

3 Huawei Chen and Christopher T. Walsh, “Coumarin formation in novobiocin biosynthesis: β-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI” Chemistry and Biology; 2001; 8: 301-312

4 K. Scheirer and N. P. Higgins. “The DAN Cleavage Reaction of DNA Gyrase ” The Journal of Biological Chemistry; 1997; 272 (43): 27202-27209

5 N Pi, C. L. F. Meyers, M. Pacholec, C. T. Walsh, and J. A. Leary. “Mass spectrometric characterization of a three-enzyme tandem reacton for assembly and modification of the novobiocin skeleton” PNAS 2004;101;10036-10041

New Antibacterial oxazolidinones in pipeline by Wockhardt


WCK ?

(5S)-N-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

(5S)-N- {3-[3,5-difluoro-4-(4-hydroxy-(4-methoxymethyl)-piperidin- lyl)phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

MF C19 H25 F2 N3 O5, MW 413.42

Acetamide, N-​[[(5S)​-​3-​[3,​5-​difluoro-​4-​[4-​hydroxy-​4-​(methoxymethyl)​-​1-​piperidinyl]​phenyl]​-​2-​oxo-​5-​oxazolidinyl]​methyl]​-

CAS 957796-51-9

Antibacterial oxazolidinones

Wockhardt Ltd,  Innovator

Wockhardt Research Center,

THIS MAY BE WCK 4086?????….WATCHOUT THIS POST FOR UPDATION

PATENTS

WO 2015173664, US8217058, WO 2012059823, IN 2011MU03726 

 

s1

Oxazolidinone represent a novel chemical class of synthetic antimicrobial agents. Linezolid represents the first member of this class to be used clinically. Oxazolidinones display activity against important Gram-positive human and veterinary pathogens including Methicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin Resistant Enterococci (VRE) and β-lactam Resistant Streptococcus pneumoniae (PRSP). The oxazolidinones also show activity against Gram-negative aerobic bacteria, Gram-positive and Gram-negative anaerobes. (Diekema D J et al., Lancet 2001 ; 358: 1975-82).

Various oxazolidinones and their methods of preparation are disclosed in the literature. International Publication No. WO 1995/25106 discloses substituted piperidino phenyloxazolidinones and International Publication No. WO 1996/13502 discloses phenyloxazolidinones having a multisubstituted azetidinyl or pyrrolidinyl moiety. US Patent Publication No. 2004/0063954, International Publication Nos. WO 2004/007489 and WO 2004/007488 disclose piperidinyl phenyl oxazolidinones for antimicrobial use.

Pyrrolidinyl/piperidinyl phenyl oxazohdinone antibacterial agents are also described in Kim H Y et al., Bioorg. & Med. Chem. Lett., (2003), 13:2227-2230. International Publication No. WO 1996/35691 discloses spirocyclic and bicyclic diazinyl and carbazinyl oxazolidinone derivatives. Diazepeno phenyloxazolidinone derivatives are disclosed in the International Publication No. WO 1999/24428. International Publication No. WO 2002/06278 discloses substituted aminopiperidino phenyloxazolidinone derivatives.

Various other methods of preparation of oxazolidinones are reported in US Patent No. 7087784, US Patent No. 6740754, US Patent No. 4948801 , US Patent No. 3654298, US Patent No. 5837870, Canadian Patent No. 681830, J. Med. Chem., 32, 1673 (1989), Tetrahedron, 45, 1323 (1989), J. Med. Chem., 33, 2569 (1990), Tetrahedron Letters, 37, 7937-40 (1996) and Organic Process Research and Development, 11 , 739-741(2007).

Indian Patent Application No. 2534/MUM/2007 discloses a process for the preparation of substituted piperidino phenyloxazolidinones. International Publication No. WO2012/059823 further discloses the process for the preparation of phosphoric acid mono-(L-{4-[(5)-5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}4-methoxymethyl piperidine-4-yl)ester.

US Patent No. 8217058 discloses (5S)-N-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide as an antibacterial agent and its process for preparation.

PATENT

WO2015173664

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015173664&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

 

In some embodiments, there is provided a process for preparation of a compound of Formula (I) as shown in Scheme 1

(I I) (I N)

Scheme 1

 

 

Example 1

Preparation of (55)-iV-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (I)

To a stirred solution of lithium teri-butoxide (59.1 g, 0.74 mol) in tetrahydrofuran (500 ml) was added a solution of [3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)-phenyl]-carbamic acid benzyl ester (II) (100 g, 0.25 mol) in 500 ml of tetrahydrofuran slowly at room temperature. The resulting mixture was stirred for 3 hours at room temperature (formation of lumps observed). The reaction mixture was cooled to temperature of 10°C to 15°C and acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III) (95.2 g, 0.49 mol) was added in one lot, after 5 minutes methanol (2.36 g, 0.075 mol) was added in one portion. The resulting mixture was stirred further at temperature of 10°C to 15°C. After 5 hours the reaction mixture was allowed to warm to room temperature and stirring continued further for 16 hours. An aqueous solution of saturated ammonium chloride (100 ml) was added to the reaction mixture, the resulting mixture was stirred well and the solvent evaporated under reduced pressure (35°C, 150 mm Hg). The residual mixture was diluted with water (1 L stirred well and filtered under suction, the residual solid was washed with additional fresh water (100 ml). The residual mass was suspended in acetone (500 ml), stirred well and the mixture diluted with hexane (1 L), slowly. The mixture was stirred further for 1 hour and filtered under suction. The residual solid was washed with a 2:1 mixture of acetone and water (100 ml). The residual solid was dried at 45°C, for 3.5 hour at 4 mm Hg, to obtain the 78 g of (55)-N-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l -yl)-phenyl]-2-oxo-oxazolidin-5-ylmethylj -acetamide (I) as white solid, in 77% yield.

Analysis:

Mass: 414 (M+l ); for Molecular Weight: 413 and Molecular Formula:

Melting Point: 178-179°C;

1H NMR (400 MHz, DMSO): δ 8.18-8.21 (m, 1H), 7.19-7.25 (d, 2H), 4.07-4.71 (m, 1H), 4.32 (s, 1H), 4.02-4.07 (t, 1H), 3.64-3.68 (t, 1H), 3.14 (s, 2H), 2.81-2.83 (d, 2H), 1.81 (s, 3H), 1.63-1.69 (t, 2H), 1.42-1.45 (d, 2H);

Purity as determined by HPLC: 97.65%.

Example 2

Preparation of acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III)

Step-I: Preparation of l-amino-3-chloro-propan-2-ol hydrochloride (VI)

Benzaldehyde (118.67 g, 1.03 mol) was dissolved in ethanol (297 ml) under stirring and the solution was cooled to 18-19°C. To this solution aqueous ammonia solution (25%) (101.58 ml) was added slowly, followed by slow addition of S-epichlorohydrin (100 g, 1 mol). The resulting mixture was warmed to 40°C and stirred for 7 hours. The mixture was allowed to cool to room temperature and stirred further. After 16 hours, the reaction mixture was concentrated to 50% volume under reduced pressure. Toluene (228 ml) was added to the reaction mixture followed by addition of aqueous hydrochloric acid (162 ml of concentrated hydrochloric acid diluted with 152 ml of water). The mixture thus obtained for 3 hours at 45°C, the resulting mixture was allowed to cool to room temperature and the toluene layer separated. The toluene layer was further extracted with water (56 ml). The combined aqueous layer was diluted with ethanol (56 ml) and the mixture evaporated under reduced pressure. This process was repeated again. To the final concentrate was added ethanol (180 ml), stirred for 10 minutes and the mixture cooled to -28°C to -30°C and maintained at this temperature for 2 hours. The separated solid was filtered under suction and the residue washed with cold (-30°C) ethanol (50 ml). The residue was dried at 45°C, under reduced pressure (4 mm Hg) for 3 hours, to obtain 96 g of l-amino-3-chloro-propan-2-ol hydrochloride (VI) as white solid in 61% yield.

Analysis:

Mass: 110 (M+l) as free base; for Molecular Weight: 145.5 and Molecular Formula:

1H NMR (400 MHz, D20): δ 4.02-4.08 (m, 1H), 3.51-3.61 (m, 2H), 3.12-3.16 (dd, 1H), 2.93 -2.99 (dd, 1H).

Step-II: Preparation of acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III).

A stirred solution of dichloromethane (220.8 ml) containing the step-I salt (96 g, 0.66 mol) was cooled to 18-20°C. Acetic anhydride (154.78 g, 1.5175 mol) was added slowly (slight exothermic). Pyridine (67.76 g, 0.8577 mol) was added slowly (exothermic) while maintaining the temperature at 18-20°C. The resulting mixture was heated to 40°C for 5 hours. The reaction mixture was allowed to cool to room temperature and stirring continued for further 16 hours. The reaction mass was cooled to 3-6°C and diluted with 170 ml of fresh water. To this was added an aqueous solution of potassium carbonate (191.2 g of K2CO3 in 382 ml water). The reaction mixture was further diluted with additional dichloromethane (170 ml) and water (425 ml). The reaction mass was stirred well and the dichloromethane layer separated. The aqueous layer was further extracted with 2×170 ml dichloromethane. The combined dichloromethane layer was washed with aqueous sodium chloride solution (13.6 g of sodium chloride in 493 ml water). The solvent was evaporated till a volume of 170 ml and the residual layer was diluted with toluene (340 ml), stirred well and the solvent was evaporated completely at 40°C under reduced pressure (4 mm Hg). To the residue ethyl acetate (170 ml) and hexane (187 ml) were added and the mixture stirred for 30 minute. The separated solid was filtered under suction and the residue washed with 50 ml of a 1 :1 mixture of ethyl acetate and hexane. The solid obtained was dried under reduced pressure (4 mm Hg) at 45°C for 3.5 hours, to obtain 96 g of acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III) as a white solid, in 75% yield.

Analysis:

Mass: 194 (M+l); for Molecular Weight: 193 and Molecular Formula: C7Hi2ClN03; 1H NMR (400 MHz, CDC13): 5 5.69 (s, 1H), 5.0-5.1 (m, 1H), 3.4-3.7 (m, 4H), 2.1 (s, 3H), 1.9 (s, 3H).

PATENT

http://www.google.st/patents/WO2007132314A2?cl=en

 

Figure imgf000004_0001

Wockhardt Ltd,

Figure imgf000006_0001
Figure imgf000006_0002

(3) (4)

Scheme -1

Figure imgf000008_0001

(6) Formula π Scheme-2

Figure imgf000010_0001

Formula II Formula in

Figure imgf000010_0002

Formula I(a) Scheme-4

Example -11 : (5S)-N- {3-[3,5-difluoro-4-(4-hydroxy-(4-methoxymethyl)-piperidin- lyl)phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

The example- 10 (54.86 g, 0.144 mol) was suspended in methanol (1100 ml) under stirring at RT. Sodium metal (4 g, 0.174 mol) was added in small lots in 2 min to the above suspension under stirring. The reaction mixture was warmed to 40-420C and was stirred at this temperature for about 40 hrs. After completion of the reaction (TLC), the solvent was evaporated under reduced pressure to obtain a thick slurry. The thick slurry thus obtained was gradually added to water (1100 ml) under stirring. After the complete addition, the pH of the aqueous suspension was adjusted to 7 by adding sufficient quantity of glacial acetic acid. The separated solid was filtered and the residue was washed with water. The obtained solid was further purified by column chromatography over silica gel to obtain the product as a white solid, 32.7 g, 55 % yield.

M.P.: 173-1740C;

MS : M+l= 414(MH+, 100%); for M.F.: Ci9H25F2N3O5

1H-NMR (400 MHz, CDCl3): δ 7.0-7.1 (m, 2H5Ar-H), 6.0 (t, IH, NH), 4.70-4.80 (m, IH), 4.00 (t,lH), 3.70-3.75 (m, 2H), 3.5-3.7 (m, IH), 3.43 (s, 3H, OCH3), 3.37-3.42 (m, 2H), 3.30 (s, 2H, -OCH2), 3.0-3.05 (m, 2H), 2.22(bs,lH ,-OH),2.04 (s, 3H, COCH3), 1.70-1.75 (m, 4H).

 

Patent

INDIAN 3049/MUM/2010

Phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxy methyl-piperidin-4-yl) ester

Figure imgf000022_0001

Specific intermediate compounds of the invention include:
6-(2,6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]octane;
1-(2,6-Difluoro-4-nitro-phenyl)-4-methoxymethyl-piperidin-4-ol;
[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-carbamic acid benzyl ester;
(5R)-3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-hydroxymethyl-oxazolidin-2-one;
(5R)-Methanesulfonic acid 3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl ester;
(5R)-3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-azidomethyl-oxazolidin-2-one; and
(5S)- N-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide.

 

Examples

Preparation of Intermediate-1: 1-(2,6-Difluoro-4-nitrophenyl)-piperidin-4-one
Chloroform (9.3 L) was charged in a 20 L reaction assembly and 4-piperidone hydrochloride (1.17 Kg, 7.62 mol) was added under stirring followed by triethylamine (2.14 Kg, 2.95 L, 21.1 mol). After 30 minutes of stirring, 3,4,5-trifluoronitrobenzene (1.5 Kg, 8.47 mol) was added to the mixture in one lot and the contents were heated to 65-70ºC for 8 h. After completion of the reaction, chloroform was removed under vacuum to obtain a syrupy mass. At this stage, water (10 L) was added to the mass and the chloroform recovery was continued under vacuum below 65oC till the chloroform was removed completely. The slurry was cooled to RT and filtered. The solid product was washed with water (3 L) followed by hexanes (2 L). The product was dried in a vacuum oven below 70oC to obtain the product as a yellow solid, 1.88 Kg ; Yield 97%.
M.P.: 130-132oC; MS: 257(M+1); M.F.: C11H10F2N2O3.

 

Preparation of Intermediate 3: 1-(2,6-Difluoro-4-nitro-phenyl)-4-methoxymethyl-piperidin-4-ol

Method A:
Preparation of Intermediate–2: (Stage-I): 6-(2,6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]octane
A solution of trimethylsulfoxonium iodide (1.504kg, 6.836mol) in acetonitrile (7L) was cooled to 0 to 5oC. , under argon atmosphere. Potassium tert-butoxide (0.736kg, 6.552 mol) was added in small lots over 0.5h. The resulting solution was stirred for 2h at the same temperature. To this solution was added 1-(2,6-Difluoro-4-nitrophenyl)-piperidin-4-one ( 1.4kg, 5.46mol) in small lots over a period of 1h, while maintaining the temp. between 5-10oC. The resulting mixture was stirred for 1h. The solvent was evaporated to a minimum amount possible, under reduced pressure while maintaining the temperature below 10oC. The residue was poured in water( 18L) and the pH adjusted to neutral with dilute acetic acid. The resulting slurry was stirred well and the separated solid filtered under suction. The solid was washed with fresh water till the filtrate was free of acetic acid. The solid was dried at 80oC, for 6h, under reduced pressure to obtain the product as pale yellow solid, 1.264kgs, yield 85%.
M.P.: 96-97oC; MS: M+1: 271; M.F.: C12H12F2N2O3,.
Preparation of Intermediate-3: (Stage-II): 1-(2,6-Difluoro-4-nitro-phenyl)-4-methoxymethyl-piperidin-4-ol
To a solution of sodium methoxide (236g, 4.35mol) in methanol (3L), at RT, was added 6-(2,6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro [2.5]octane (964g, 3.57mol) in small portions and the reaction mixture was stirred for 26h at RT. Acetic acid (265g, 4.44mol) was added slowly to neutralize the pH of the solution. The resulting mixture was poured into chilled water(18L) and stirred for 1h. The separated solid was filtered under suction. The solid was washed with additional water till the filtrate was free of acetic acid. The solid was dried for 10hat RT under reduced pressure, to obtain the product as a pale yellow solid, 973g, yield, 90%
M.P.: 84-86oC; MS: 303 (M+1); M.F.: C13H16F2N2O4

Method B:
Dimethylsulfoxide (DMSO, 100 ml) and methanol (500 ml) were charged in a 1 L glass reaction assembly. Potassium hydroxide (59.2g, 0.898 mol) was charged in the assembly followed by trimethylsulfoxonium iodide (94.5 g, 0.43 mol) and the contents were stirred for 30 minutes and then cooled to 10oC-15oC. To the cooled contents was added 1-(2,6-difluoro-4-nitrophenyl)-piperidin-4-one (100 g, 0.39 mol) in small lots. After the addition, the temperature was allowed to raise to RT and the contents were further stirred for 24 h (ring opening of the epoxide intermediate viz. 6-(2,6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]octane takes place).
[Physical data of the intermediate: M.P.: 96-970C, MS: 271(M+1); M.F.: C12H12F2N2O3, .
After completion of the reaction the contents were poured slowly in ice-water (600g crushed ice in 600 ml water). The precipitated solid product was filtered and was washed with water:methanol, 2:1 (100 ml X 2). The wet product was used in the next step.
M.P.: 84-86oC; MS: 303 (M+1);.M.F.: C13H16F2N2O4,:

Preparation of Intermediate -5: [3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-carbamic acid benzyl ester

Method A: Preparation of Intermediate 4: ( Stage-I)
Water (1.19 L) and methanol (595 ml) were charged in a 3 L glass reaction assembly, followed by 1-(2,6-difluoro-4-nitro-phenyl)-4-methoxymethyl-piperidin-4-ol (85 g, 0.281 mol) and the contents were stirred. Sodium dithionite (288 g, 1.407 mol) was added in one lot and the reaction mixture was heated to 80oC for 8 h. After completion of the reaction (TLC), methanol was recovered under vacuum below 65oC. After the recovery, the aqueous residue was extracted with chloroform (400 ml X 3). The combined chloroform extract (containing the intermediate 1-(4-amino-2,6-difluoro-phenyl)-4-methoxymethyl-piperidin-4-ol) was dried over anhydrous Sodium sulfate and used in the next step (carbamate formation).

Preparation of Intermediate -5: (Stage-II):
The above chloroform extract was charged in a 3 L glass reaction assembly. Sodium bicarbonate (70 g, 0.843 mol) was added to the extract and the contents were cooled to 15oC-20oC. Benzylchloroformate solution (50% in toluene, 48 g, 96 ml, 0.281 mol) was added slowly to the above mixture under stirring. After completion of the addition, the reaction mixture was stirred at RT for 2 h. After completion of the reaction (TLC), the contents were filtered on a Buchner assembly and the solid cake was washed with chloroform (85 ml X 2). The combined filtrate was evaporated under vacuum below 50oC to obtain yellowish oily mass, which was poured slowly in hexanes (850 ml) under stirring to obtain a precipitate. The precipitated product was filtered and washed with hexanes (100 ml X 2). The product was dried in a vacuum oven below 65oC to obtain 60.2 g brownish product (Yield = 38% on the basis of step-I input).
M.P.: 138-140oC; MS: 407(M+1); M.F.: C21H24F2N2O4.:.

Method B: : Preparation of Intermediate 4: ( Stage-I): To a solution of 1-(2,6-difluoro-4-nitro-phenyl)-4-methoxymethyl-piperidin-4-ol (973g, 3.22 mol) in ethyl acetae (10L) was added 10% Pd-C, (250g, 50% wet) and the resulting miture was hydrogenated in a pressure at 30 PSI, 45-55oC, for 3h. The catakyst was filtered and the residue was washed with additional ethyl acetate( 200ml). The combined filtrates were used as such for the next reaction (carbamate formation)

Preparation of Intermediate -5: (Stage-II):
To the above filtrate was added sodium bicarbonate(406g, 4.83 mol) and the mixture warmed to 40-45oC. To this mixture was added a 50% solution of Benzyl chloroformate in toluene(1.373L, 4.025 mol), drop-wise, over a period of 1h. Stir the resulting mixture for 1h and filter the insoluble material. The residue was washed with 300ml of ethyl acetate. The filtrates were combined and the solvent evaporated under reduced pressure, below 55oC.. Cool the residue and dilute it with hexane(10L). The resulting slurry was stirred well and the separated solid was filtered under suction. The residue was washed with additional hexane ( 2L). The solid was dried for 10h at RT, to obtain the product as dark brown solid, 1200g, yield, 96%.
M.P.: 138-140oC; MS: 407( M+1); M.F.: C21H24F2N2O.

Preparation of Intermediate -6:

(5R)-3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-hydroxymethyl-oxazolidin-2-one

To a mixture of [3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-carbamic acid benzyl ester (100g, 0.237 mol) in dry tetrahydrofuran (THF) (2 L) at 40ºC was added drop-wise n-BuLi in hexane (1.6M, 45.5 g, 455 ml, 0.711 mol) under nitrogen atmosphere. The contents were stirred for 1 h at 40ºC and R-(-)-glycidyl butyrate (68.25 g, 0.474 mol) was added gradually. After the addition of R-(-)-glycidyl butyrate, the reaction mixture was stirred for 5-6 h at 40oC till completion of the reaction (TLC). After completion of the reaction, a solution of sodium methoxide (2 g) in methanol (66 ml) was added to the contents followed by water (8 ml) and the contents were stirred for an additional 0.5 h. Water (1 L) was added to the solution and the contents were extracted with ethyl acetate (1 L). The aqueous layer was further extracted with ethyl acetate (3 X 500 ml). The combined organic layer was evaporated under vacuum to obtain a thick residue. tert-Butyl methyl ether (1 L) was added to the residue and the contents were stirred for about 1 h to obtain a solid product, which was filtered and washed with tert-butyl methyl ether (2 X 100 ml). The product was dried under vacuum below 60ºC to obtain the product as a 46.5 g dark brown compound, 46.5g ,yield 51%.
M.P.: 117-119oC; MS: 373(M+1); M.F.: C17H22F2N2O5..

Preparation of Intermediate -7: (5R)-Methanesulfonic acid 3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl ester

To a mixture of (5R)-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-hydroxymethyl-oxazolidin-2-one (45 g, 0.121 mol) in dichloromethane (0.3 L), was added triethylamine (24.5 g, 34 ml, 0.242 mol) while stirring. Methanesulfonyl chloride (18 g, 12.2 ml, 0.157 mol) was added to the above solution over a period of 1 h at 10oC -20oC and the reaction mixture was stirred for additional 2 h at RT. After completion of the reaction (TLC), the contents were evaporated under vacuum at 40oC to obtain an oily residue. Water (450 ml) was added to the residue and the traces of dichloromethane were removed under vacuum. The solid product thus obtained was filtered, washed with water (2 X 50 ml) and dried under vacuum at 70oC to obtain 50.6 g brownish compound. Yield = 93%; M.P.:106-108oC; MS: 451(M+1); M.F.: C18H24F2N2O7S.

Preparation of Intermediate 8a: (5R)-3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-azidomethyl-oxazolidin-2-one

Method A:
To a solution of (R)-3-(3,5-difluoro-4-(4-hydroxy-4-(methoxymethyl)piperidin-1-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one (2g, 5.3 mmol),in tetrahydrofuran (20 mL), under argon , was added diphenylphosphoryl azide (1.63mL, 5.9 mmol). The solution was cooled to 0oC in an ice-bath. 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.76mL, 4.9mmol) was added drop-wise over 15min..The reaction was stirred at same temperature for 1 hr, and then warmed to room temperature and stirred under for 16 hr. The reaction mixture was diluted with ethyl acetate (20 mL), and water (20mL). After separation of water layer, the organic layer was washed with water and 0.5M citric acid monohydrate (10 mL). The organic layer was dried over sodium sulfate and the solvent evaporated under reduced pressure.The residue was triturated with ether to obtain the product as a buff colored solid, 1.32g (62%).
M.P.: 106-108oC; M.S.- 398(M+1); M.F.- C17H21F2N5O4,

Method B:
To a solution of (5R)-methanesulfonic acid 3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl ester (20 g, 0.044 mol, wet) in N,N-dimethylformamide (30 ml), was added sodium azide (8.6 g, 0.133 mol) in a single lot. The reaction mixture was gradually heated and the temperature was maintained at 70ºC for 8 h. After completion of the reaction (TLC), the contents were cooled to 20-25ºC and poured slowly into chilled water (300 ml). The solid product thus obtained was filtered and washed with water (2 x 50 ml). The wet product was air dried to obtain 16.5g dark brown compound (being an azide, it was NOT exposed to heat during drying) Yield ~ 93%.
M.P.: 106-108oC; MS : 398(M+1); M.F.: C17H21F2N5O4;:

Preparation of Intermediate 8b: (5S)-N-2-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-phthalimide

Method A:
A mixture of (5R)-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-methanesulfonate(10g, 0.022 mol), Potassium phthalimide (12.2g, 0.066 mol) and DMF (50ml) was heated, with stirring, at 90oC for 4h. The resulting mixture was cooled to RT and poured over ice-water mixture. The separated solid was filtered, washed with water and dried under suction to obtain the product as a white solid, 9.46g, in 85% yield.
M.P.: 154-156 oC; MS: 502 (M+1); M.F. C25H25F2N3O6.

Method B:
To tetrahydrofuran (30 ml) were added triphenylphosphine (2.11g, 8 mmol)) and diethyldiazocarboxylate (1.62g, 8 mmol)), and the solution stirred at room temperature. After 10 minute phthalimide (1.18g, 8 mmol)) was added and after a further stirring for 10 minute, (R)-3-(3,5-difluoro-4-(4-hydroxy-4-(methoxymethyl)piperidin-1-yl)phenyl)-5-(hydroxymethyl) oxazolidin-2-one (2g, 5.3 mmol) was added and stirring continued further at room temperature. After 8 hrs ice-cold water (4 ml) was added to the reaction mixture and the resulting mixture was extracted by ethyl acetate (2 x 20ml). The ethyl acetate extract was dried (over sodium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel to obtain the product as an off-white solid, 1.56g, yield 58%.
M.P.: 154-156 oC; MS : 502 (M+1); M.F. C25H25F2N3O6.

Preparation of Intermediate 10: (5S)- N-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide
via
Intermediate 9: 5-aminomethyl-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-oxazolidin-2-one

Method A:
To a solution of (5R)-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-azidomethyl-oxazolidin-2-one (10 g, 0.025 mol) in methanol (100 ml), were charged cobalt chloride (0.6 g, 0.0025 mol) followed by sodium borohydride (0.95 g, 0.025 mol) in small lots over a period of 30 minutes. The reaction mixture was stirred at RT for additional 2 h. After completion of the reaction , the contents were evaporated under vacuum below 40oC to obtain a sticky mass. The contents were suspended in a mixture of water (100 ml) and ethyl acetate (50 ml) and stirred for 15 minutes. The contents were filtered through a filter-aid bed and the bed was washed with ethyl acetate (2 X 25 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate (4 X 50 ml). The combined organic layer was washed with 1% HCl solution (100 ml). The aqueous layer was separated and washed with dichloromethane (4 X 50 ml). The pH of the aqueous layer was adjusted to 8 by adding saturated sodium bicarbonate solution. The contents were extracted with ethyl acetate (6 X 50 ml) till no amine spot was seen in the final organic extract. The combined organic layer (containing the intermediate 5-aminomethyl-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-oxazolidin-2-one) was dried over anhydrous sodium sulfate.

Triethylamine (3.3 g, 4.5 ml, 0.0327 mol) was added to the above organic layer and acetyl chloride (2.17 g, 2 ml, 0.0277 mol) was added gradually over a period of 1 h at RT. The reaction mixture was stirred for 2 h and after completion of the reaction (TLC), the contents were washed with water (50 ml) and the layers separated. Activated carbon (1 g) was added to the organic layer and the contents were stirred for 15 minutes. The contents were filtered on a celite bed and the carbon-celite bed was washed with ethyl acetate (2 X 10 ml). The combined filtrate was evaporated under vacuum to obtain a slurry, which was filtered on a Buchner assembly and the product was washed with ethyl acetate (2 X 10 ml). The product was dried under vacuum at 70oC to obtain 5 g off-white solid. Yield = 48% (on the basis of azide). HPLC Purity ~ 98%.
M.P.: 178-179oC; MS : 414 (M+1); M.F.: C19H25F2N3O5.

Method B:
A solution of (5R)-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-azidomethyl-oxazolidin-2-one (50 g, 0.125 mol) in ethyl acetatel (1L ml), were charged with 5g of 10% of Pd-C catalyst(50% wet) and the resulting mixture was hydrogenated at 30psi for 3h at 50oC.. The resulting mixture was cooled and filtered under suction over celite bed. The residue was washed with additional ethyl acetate (200ml). The combined filtrates were concentrated to 500ml volume.

To the above ethyl acetate solution was added Triethyl amine (19.1g, 0.189 mol), and acetic anhydride (16.1g, 1.58mol) in a single lot in few minutes). The reaction mixture was stirred for 16h at R.T. .The resulting mixture was cooled to 0-5oC, stirred for 0.5h and filtered under suction. The residue was washed with cold ethyl acetate(100ml) and dried at 70oC under reduced pressure to obtain the product as a a off-white solid, 43.5g, in 84% yield over two steps.
HPLC Purity ~ 98%
M.P.: 178-179oC; MS : 414 (M+1); M.F.: C19H25F2N3O5.

Method C:
To a solution of (S)-N-2-{3-[3,5-Difluoro-4-(4-methoxymethyl-4-hydroxypiperidine-1yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-phthalimide (2.77g, 0.0055mol) in ethanol (20ml) was added hydrazine hydrate ( 0.554g, 0.011mol) and the resulting solution stirred at RT for 6h. The solvent was evaporated under reduced pressure, the residue suspended in 3% sodium carbonate solution and extracted in dichloromethane (40ml). The dichloromethane layer was dried and to this solution was added triethylamine(1.11g, 0.011mol) and acetic anhydride (0.67g, 0.007mol) and the solution stirred for 6h at RT. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography to obtain the product as white solid, 1.94g, in 85% yield.
M.P.: 178-179oC; MS: 414 (M+1); M.F.: C19H25F2N3O5.

Method D:
A mixture of (5R)-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-methanesulfonate (1gm, 4.4mmol) and sodium diformylamide (2gms, 22mmol) in DMF (5ml) was stirred at 95 ºC. for 15hrs. Then a mixture of conc. HCl (0.6ml) and water (0.6ml) and ethanol (8ml) were added. The solution was stirred at 75ºC for 5hrs. The mixture was concentrated under reduced pressure at 60-75 ºC. Water (1ml), ammonia solution (0.5ml) and acetic anhydride (1ml) was added to the residue and the mixture stirred at 70-75 ºC for 4-5 hrs. The solution was cooled to room temperature, diluted with water (5ml) and the separated solid filtered. The residue was washed with water (4ml.) and dried in a vacuum oven at 50ºC to obtain the product as an off-white solid, 0.37g, in 41% yield.
M.P.: 178-179oC; MS : 414 (M+1); M.F.: C19H25F2N3O5.

Method E:

To tetrahydrofuran (30 ml) were added triphenylphosphine (2.11g, 8 mmol)) and diethyldiazocarboxylate (1.62g, 8 mmol)), and the solution stirred at room temperature. After 10 min acetamide (0.475g, 8 mmol)) was added and after a further stirring for 10 min, (R)-3-(3,5-difluoro-4-(4-hydroxy-4-(methoxymethyl)piperidin-1-yl)phenyl)-5-(hydroxymethyl) oxazolidin-2-one (2g, 5.3 mmol) was added and stirring continued further at room temperature. After 16 hrs ice-cold water (4ml) was added to the reaction mixture and the resulting mixture was extracted by ethyl acetate (2 x 20ml). The ethyl acetate extract was dried (over sodium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel to obtain the product as an off-white solid, 0.50g, yield 22%.
M.P.: 178-179oC; MS: 414 (M+1); M.F.: C19H25F2N3O5.
Preparation of Intermediate -11: (S)-N-{3-[3,5-Difluoro-4-(4-methoxymethyl-4-di-O-benzylphosphoryloxy-piperi din-1yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

To a solution of (S)-N-{3-[3,5-difluoro-4-(4-methoxymethyl-4-hydroxypiperidine-1yl)-phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (0.2 mmol) and tetrazole (0.6 mmol) in dichloromethane (5 ml) was added dibenzyl N,N,diisopropylphosphoramidite (0.4 mmol) and the resulting mixture was stirred for 4h. The resulting solution was cooled to 0 oC and 0.6 ml of 0.5M m-chloroperbenzoic acid solution in dichloromethane was added. After 4h, the solvent was evaporated under residue pressure and the residue chromatographed on a column of silica gel to obtain the product as a off-white solid in 75% yield,
MS: 674 (M+1); M.F. C33H38F2N3O8P;

Example A: Phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl) ester

To a suspension of (S)-N-{3-[3,5-difluoro-4-(4-methoxymethyl-4-di-O-benzylphosphoryl- oxypiperidine-1yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (0.15 mmol) and 20 % palladium hydroxide (20 mg) in 20 ml of a mixture of dichloromethane /aqueous methanol was stirred at room temperature for 6h. The catalyst was filtered and the residue evaporated under reduced pressure. The residue obtained was triturated with acetone to obtain a white solid as product in 70% yield.
MP. >140 °C; MS : 494(M+1) M.F.: C19H26F2N3O8P.

 

PATENT

WO 2012059823

http://www.google.co.in/patents/WO2012059823A1?cl=en

Phosphoric acid mono-(l-{4-[(S)-5-(acetylamino- methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl) ester of Formula (A),
Figure imgf000022_0001
the process comprising the steps of:
a) Converting intermediate of Formula (1) into intermediate of Formula (3)
Figure imgf000022_0002
b) Converting intermediate of Formula (3) into intermediate of Formula (5)
Figure imgf000022_0003

c) Converting intermediate of Formula (5) into intermediate of structure (6)

Figure imgf000022_0004
(5) <6> d) Converting intermediate of Formula (6) into intermediate of Formula (10)
Figure imgf000023_0001
e) Converting intermediate of Formula (10) into intermediate of Formula (11),
Figure imgf000023_0002

f) Converting intermediate of Formula (11) into compound of Formula (A) or Pharmaceutically acceptable salts thereof

Figure imgf000023_0003

 

 

Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0003

ormu a-

Scheme-1

Preparation of Intermediate 10: (5S)- N-{ 3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl- piperidin- 1 -yl)-phenyl] -2-oxo-oxazolidin-5-ylmethyl } -acetamide

via

Intermediate 9: 5-aminomethyl-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l- yl)-phenyl] -oxazolidin-2-one

Method A:

To a solution of (5R)-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)- phenyl]-5-azidomethyl-oxazolidin-2-one (10 g, 0.025 mol) in methanol (100 ml), were charged cobalt chloride (0.6 g, 0.0025 mol) followed by sodium borohydride (0.95 g, 0.025 mol) in small lots over a period of 30 minutes. The reaction mixture was stirred at RT for additional 2 h. After completion of the reaction , the contents were evaporated under vacuum below 40°C to obtain a sticky mass. The contents were suspended in a mixture of water (100 ml) and ethyl acetate (50 ml) and stirred for 15 minutes. The contents were filtered through a filter-aid bed and the bed was washed with ethyl acetate (2 X 25 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate (4 X 50 ml). The combined organic layer was washed with 1% HC1 solution (100 ml). The aqueous layer was separated and washed with dichloromethane (4 X 50 ml). The pH of the aqueous layer was adjusted to 8 by adding saturated sodium bicarbonate solution. The contents were extracted with ethyl acetate (6 X 50 ml) till no amine spot was seen in the final organic extract. The combined organic layer (containing the intermediate 5-aminomethyl-3-[3,5-difluoro-4-(4- hydroxy-4-methoxymethyl-piperidin-l-yl)-phenyl]-oxazolidin-2-one) was dried over anhydrous sodium sulfate.

Triethylamine (3.3 g, 4.5 ml, 0.0327 mol) was added to the above organic layer and acetyl chloride (2.17 g, 2 ml, 0.0277 mol) was added gradually over a period of 1 h at RT. The reaction mixture was stirred for 2 h and after completion of the reaction (TLC), the contents were washed with water (50 ml) and the layers separated. Activated carbon (1 g) was added to the organic layer and the contents were stirred for 15 minutes. The contents were filtered on a celite bed and the carbon-celite bed was washed with ethyl acetate (2 X 10 ml). The combined filtrate was evaporated under vacuum to obtain a slurry, which was filtered on a Buchner assembly and the product was washed with ethyl acetate (2 X 10 ml). The product was dried under vacuum at 70°C to obtain 5 g off-white solid. Yield = 48% (on the basis of azide). HPLC Purity ~ 98%.

M.P.: 178-179°C; MS : 414 (M+l); M.F.: C19H25F2N3O5. Method B:

A solution of (5R)-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)-phenyl]-5- azidomethyl-oxazolidin-2-one (50 g, 0.125 mol) in ethyl acetatel (1L ml), were charged with 5g of 10% of Pd-C catalyst(50% wet) and the resulting mixture was hydrogenated at 30psi for 3h at 50°C. The resulting mixture was cooled and filtered under suction over celite bed. The residue was washed with additional ethyl acetate (200ml). The combined filtrates were concentrated to 500ml volume. To the above ethyl acetate solution was added Triethyl amine (19. lg, 0.189 mol), and acetic anhydride (16. lg, 1.58mol) in a single lot in few minutes). The reaction mixture was stirred for 16h at R.T. .The resulting mixture was cooled to 0-5°C, stirred for 0.5h and filtered under suction. The residue was washed with cold ethyl acetate( 100ml) and dried at 70°C under reduced pressure to obtain the product as a a off-white solid, 43.5g, in 84% yield over two steps.

HPLC Purity ~ 98%

M.P.: 178-179°C; MS : 414 (M+l); M.F.: C19H25F2N3O5. Method C:

To a solution of (S)-N-2-{3-[3,5-Difluoro-4-(4-methoxymethyl-4-hydroxypiperidine- lyl)phenyl]-2-oxo-oxazolidin-5-yl methyl }-phthalimide (2.77g, 0.0055mol) in ethanol (20ml) was added hydrazine hydrate ( 0.554g, 0.01 lmol) and the resulting solution stirred at RT for 6h. The solvent was evaporated under reduced pressure, the residue suspended in 3% sodium carbonate solution and extracted in dichloromethane (40ml). The dichloromethane layer was dried and to this solution was added triethylamine(l.l lg, 0.01 lmol) and acetic anhydride (0.67g, 0.007mol) and the solution stirred for 6h at RT. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography to obtain the product as white solid, 1.94g, in 85% yield.

M.P.: 178-179°C; MS: 414 (M+l); M.F.: C19H25F2N3O5. Method D:

A mixture of (5R)-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)phenyl]- 2-oxo-oxazolidin-5-yl methyl }-methanesulfonate (lgm, 4.4mmol) and sodium diformylamide (2gms, 22mmol) in DMF (5ml) was stirred at 95 °C. for 15hrs. Then a mixture of cone. HC1 (0.6ml) and water (0.6ml) and ethanol (8ml) were added. The solution was stirred at 75°C for 5hrs. The mixture was concentrated under reduced pressure at 60-75 °C. Water (1ml), ammonia solution (0.5ml) and acetic anhydride (1ml) was added to the residue and the mixture stirred at 70-75 °C for 4-5 hrs. The solution was cooled to room temperature, diluted with water (5ml) and the separated solid filtered. The residue was washed with water (4ml.) and dried in a vacuum oven at 50°C to obtain the product as an off-white solid, 0.37g, in 41% yield.

M.P.: 178-179°C; MS : 414 (M+l); M.F.: C19H25F2N3O5. Method E:

To tetrahydrofuran (30 ml) were added triphenylphosphine (2.1 lg, 8 mmol)) and diethyldiazocarboxylate (1.62g, 8 mmol)), and the solution stirred at room temperature. After 10 min acetamide (0.475g, 8 mmol)) was added and after a further stirring for 10 min, (R)-3- (3,5-difluoro-4-(4-hydroxy-4-(methoxymethyl)piperidin-l-yl)phenyl)-5-(hydroxymethyl) oxazolidin-2-one (2g, 5.3 mmol) was added and stirring continued further at room temperature. After 16 hrs ice-cold water (4ml) was added to the reaction mixture and the resulting mixture was extracted by ethyl acetate (2 x 20ml). The ethyl acetate extract was dried (over sodium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel to obtain the product as an off-white solid, 0.50g, yield 22%.

M.P.: 178-179°C; MS: 414 (M+l); M.F.: C19H25F2N3O5.

 

PATENT

http://www.google.co.in/patents/WO2008038092A2?cl=en

Wockhardt Research Center,

Figure imgf000010_0001

IV

Figure imgf000010_0002

V

‘ Scheme-1 ‘

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SEE FULL ZOLID SERIES…………http://drugsynthesisint.blogspot.in/p/zolid.html

Dalfopristin


Dalfopristin.png

Dalfopristin

Dalfopristin;Dalfopristin Mesylate;(3R,4R,5E,10E,12E,14S,26R,26aS)-26-[[2-(DiethylaMino)ethyl]sulfonyl]-8,9,14,15,24,25,26,26a-octahydro-14-hydroxy-4,12-diMethyl-3-(1-Methylethyl)-3H-21,18-nitrilo-1H,22H-pyrrolo[2,1-c][1,8,4,19]dioxadiazacyclotetracosine-1,7,16,22(4H,17H)-tetr

Preparation: J.C. Barriere et al., EP 191662; eidem, US 4668669 (1986, 1987 both to Rhone-Poulenc)

Rhone-Poulenc Sante …..LINK

  • Dalfopristin
  • Dalfopristina
  • Dalfopristina [INN-Spanish]
  • Dalfopristine
  • Dalfopristine [INN-French]
  • Dalfopristinum
  • Dalfopristinum [INN-Latin]
  • RP 54476
  • UNII-R9M4FJE48E

Usage
A Viiginiamycin M1 (V672810) derivative. A streptogramin antibiotic used to treat infections by staphylococci and by vancomycin-resistant Enterococcus faecium.
Usage
Dalfopristin is a semi-synthetic analogue of ostreogyrcin A (virginiamycin M, pristinamycin IIA, streptogramin A) formed by addition of diethylaminoethylthiol to the 2-pyrroline group of ostreogyrcin, followed by oxidation to the sulphone. The structural changes provide a more hydrophobic compound with a readily ionisable group for generating a salt. Dalfopristin is used commercially in synergistic combination with quinupristin (70:30). There is little published data on the synthesis, biological or antibiotic activity of dalfopristin alone, however the combination product is highly effective, including activity against antibiotic resistant strains.
Brief background information
Salt ATC Formula MM CAS
J01FG02 C 34 H 50 N 4 O 9 S 690.86 g / mol 112362-50-2

Application

  • antibiotic (used for bacteremia caused by the vancomycin-resistant Enterococcus faecium )

Dalfopristin
Dalfopristin.png
Systematic (IUPAC) name
(3R,4R,5E,10E,12E,14S,26R,26aS)-26-[[2-(diethylamino)ethyl]sulfonyl]-8,9,14,15,24,25,26,26a- octahydro-14-hydroxy-3-isopropyl-4,12-dimethyl-3H-21,18-nitrilo-1H,22H-pyrrolo[2,1-c][1,8,4,19]-dioxadiazacyclotetracosine-1,7,16,22(4H,17H)-tetrone
Clinical data
AHFS/Drugs.com International Drug Names
MedlinePlus a603007
Legal status
Pharmacokinetic data
Half-life 1 hour
Identifiers
CAS number 112362-50-2 Yes
ATC code None
PubChem CID 6435782
DrugBank DB01764
Chemical data
Formula C34H50N4O9S 
Mol. mass 690.85 g/mol

Dalfopristin is a semi-synthetic streptogramin antibiotic analogue of ostreogyrcin A (virginiamycin M, pristinamycin IIA, streptogramin A).[1] The combination quinupristin/dalfopristin (marketed under the trade name Synercid) was brought to the market by Rhone-Poulenc Rorer Pharmaceuticals in 1999.[2] Synercid (weight-to-weight ratio of 30% quinupristin to 70% dalfopristin) is used to treatinfections by staphylococci and by vancomycin-resistant Enterococcus faecium.[3]

Synthesis

Through the addition of diethylaminoethylthiol to the 2-pyrroline group and oxidation of the sulfate of ostreogrycin A, a structurally more hydrophobic compound is formed. This hydrophobic compound contains a readily ionizable group that is available for salt formation.[1]

Large Scale Preparation

Dalfopristin is synthesized from pristinamycine IIa through achieving a stereoselective Michael-type addition of 2-diethylaminoethanethiol on the conjugated double bond of the dehydroproline ring [4] . The first method found was using sodium periodate associated with ruthenium dioxide to directly oxidize the sulfur derivative into a sulfone. However, using hydrogen peroxidewith sodium tungstate in a 2-phase medium produces an improved yield, and is therefore the method of choice for large scale production.

The production of the dalfopristin portion of quinupristin/dalfopristin is achieved through purifying cocrystallization of the quinupristin and dalfopristin from acetone solutions.[4]

Physical Characteristics (as mesylate salt)

Appearance White to yellow solid
Physical State Solid
Solubility Soluble in ethanol, methanol, DMSO, DMF, and water (0.072 mg/ml)
Storage -20°C
Boiling Point 940.5°C at 760 mmHg
Melting Point 150°C
Density 1.27 g/cm^3
Refractive Index n20D 1.58
pK Values pKa: 13.18 (Predicted), pKb: 8.97 (Predicted)

Antimicrobial Activity

Alone, both dalfopristin and quinupristin have modest in vitro bacteriostatic activity. However, 8-16 times higher in vitro bactericidal activity is seen against many gram-positive bacteria when the two streptogramins are combined [5] . While quinupristin/dalfopristin is effective against staphylococci and vancomycin-resistant Enterococcus faecium, in vitro studies have not demonstrated bactericidal activity against all strains and species of common gram-positive bacteria.

Mechanism of Action

Both dalfopristin and quinupristin bind to sites located on the 50S subunit of the ribosome. Initial dalfopristin binding results in a conformational change of the ribosome, allowing for increased binding by quinupristin.[5] A stable drug-ribosome complex is created when the two drugs are used together. This complex inhibits protein synthesis through prevention of peptide-chain formation and blocking the extrusion of newly formed peptide chains. In many cases, this leads to bacterial cell death.

Mechanism of Resistance

Streptogramin resistance is mediated through enzymatic drug inactivation, efflux or active transport of drug out of the cell, and most commonly, conformational alterations in ribosomal target binding sites.[5] Enzymatic drug inactivation may occur in staphylococcal and enterococcal species through production of dalfopristin-inactivating acetyltransferase or quinupristin-inactivating hydrolase. Efflux or active transport of the drug may occur in coagulase-negative staphylococci and Enterococcus faecium. Constitutive ribosome modification has been seen in staphylococci with resistance seen in quinupristin only.

While resistance to dalfopristin may be conferred via a single point of mutation, quinupristin/dalfopristin offers the benefit of requiring multiple points of mutation targeting both dalfopristin and quinupristin components to confer drug resistance.[5] Comparatively, only 2-5% of staphylococcal isolates collected in France show resistance to a related streptogramin, pristinamycin, in over 35 years of use.

Drug Interactions

Both dalfopristin and quinupristin are extensively hepatically metabolized, excreted from the feces, and serve as an inhibitor of cytochrome P450 (CYP) 3A4 enzyme pathway.[5]Caution should be taken with concommitent use with drugs metabolized by the CYP3A4 pathway. Concomitant use of quinupristin/dalfopristin with cyclosporine for 2–5 days has shown to result in a two-fold increase in cyclosporine levels.

No adverse effects have been seen in patients with hepatic impairment and no recommendations by the manufacturer have been made for dose reduction ofquinupristin/dalfopristin in this patient population.

Commercialization

While little information is available regarding the regulatory and commercialization history of Dalfopristin alone, Synercid (quinupristin/dalfopristin), made by Rhone-Poulenc Rorer Pharmaceuticals, was approved in 1999 as an IV injectable for the treatment of vancomycin resistant Enterococcus faecium and complicated skin and skin structure infections.[2]Dalfopristin can be purchased alone on the internet from various chemical manufacturers as a mesylate salt.

Synthesis pathway

Synthesis a)

US 4668669

OR

http://www.google.com/patents/EP0191662A1

    EXAMPLE 4

  • By proceeding in a similar manner to that described in subs. Ple 1, but starting from 5.5 g of (2-dimethylamino ethyl) thio-26 pristinaffycine II B, of 0.67 cm3 trifluoroacetic acid 1.8 g of meta-chloroperbenzoic acid and after purification by “flash” chromatography [eluent: chloroform-methanol (90:10 by volume)], collecting fractions of 30 cm3 and concentration to dryness fractions 23-40 under reduced pressure (2.7 kPa) at 30 ° C, 0.4 g of (2-dimethylamino ethyl) sulfinyl-26 pristinamycin II B (isomer A 2 70% 1 15% A isomer, isomer B 1 7%, isomer B 28%) as a yellow powder melting at 150 ° C.
  • NMR spectrum (isomer 2):

    • 1.77 (s,-CH 3 at 33)
    • 2.41 (s, – N (CH 3) 2)
    • 2.70 to 3.20 (mt,
      Figure imgb0032

      > CH 2-15 and H 4)

    • 3.82 (s,> CH 2 at 17)
    • 4.84 (m, – H 3 and H-27)
    • 5.52 (d,H13)
    • 6.19 (d, H-11)
    • 6.42 (m,> NH at 8)
    • 8.14 (s, – H 20)
  • The (2-dimethylamino ethyl) thio pristinamycin II B-26 can be prepared as follows:

    • By proceeding in a similar manner to that described in Example 3, but using 2.7 g of pristinamycin II A and 0.58 g of dimethylamino-ethanethiol and 2 after purification by “flash” chromatography [eluent: chloroform -methanol (90:10 by volume)] and concentration to dryness fractions 11-17 under reduced pressure (2.7 kPa) at 30 ° C, 1.1 g of (2-dimethylamino ethyl) thio-26 pristinamycin II B as a yellow powder melting at 100 ° C.
  • NMR spectrum:

    • 2.35 (s, 6H:-N (CH 3) 2)
    • 2.80 (m, 4H:-S-CH 2 CH 2 – <N)
    • 3 40 (ddd, 1H: – H 26)
    • 4.75 (d, 1 H, H-27)
    • 8.10 (s, 1 HH 20)

Trade Names

Country Trade name Manufacturer
Germany Sinertsid Aventis Pharma
United Kingdom – “- Aventis
Italy – “- Aventis
USA – “- Aventis
Ukraine No No

Formulations

  • injection of 180 mg / vial, 420 mg / vial

Links

  • US 4,668,669 (Rhône-Poulenc Sante; 26.5.1987; F-prior. 11.1.1985).
  • US 4,798,827 (Rhône-Poulenc Sante; 17.1.1989; F-prior. 22.5.1986).
  • GB 2206879 (Rhône-Poulenc Rorer; appl. 7/7/1987; GB -prior. 18/1/1989).

Chemical structure for DALFOPRISTIN

References

  1.  Dalfopristin (as mesylate) (CAS 112362-50-2)
  2.  http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/50747_Synercid.cfm
  3.  Allington DR, Rivey MP (2001). “Quinupristin/dalfopristin: a therapeutic review”. Clin Ther 23 (1): 24–44. doi:10.1016/S0149-2918(01)80028-X. PMID 11219478.
  4.  Barriere, J.C.; Berthaud, N.; Beyer, D.; Dutka-Malen, S.; Paris, J.M.; Desnottes, J.F. (April 1998). “Recent Developments in Streptogramin Research”. Current Pharmaceutical Design 4 (2): 155–190. PMID 10197038. Retrieved 24 November 2013.
  5. Allington, Douglas R.; Rivey, Michael P. (January 2001). “Quinupristin/Dalfopristin: A Therapeutic Review”. Clinical Therapeutics 23 (1): 1–21. doi:10.1016/S0149-2918(01)80028-X. PMID 11219478.

Dalfopristin

Title: Dalfopristin
CAS Registry Number: 112362-50-2
CAS Name: (26R,27S)-26-[[2-(Diethylamino)ethyl]sulfonyl]-26,27-dihydrovirginiamycin M1
Additional Names: 26-(2-diethylaminoethyl)sulfonylpristinamycin IIB
Manufacturers’ Codes: RP-54476
Molecular Formula: C34H50N4O9S
Molecular Weight: 690.85
Percent Composition: C 59.11%, H 7.29%, N 8.11%, O 20.84%, S 4.64%
Literature References: Semisynthetic polyunsaturated macrolactone type II streptogramin, q.v. Prepn: J.-C. Barriere et al., EP191662; eidem, US 4668669 (1986, 1987 both to Rhone-Poulenc). In vitro activity: H. C. Neu et al., J. Antimicrob. Chemother. 30,Suppl. A, 83 (1992). HPLC determn in plasma: A. Le Liboux et al., J. Chromatogr. B 708, 161 (1998)
Properties: White solid, mp ~150°.
Melting point: mp ~150°
Derivative Type: Mixture with quinupristin
CAS Registry Number: 126602-89-9
Manufacturers’ Codes: RP-59500
Trademarks: Synercid (Rh>e-Poulenc)
Literature References: Semisynthetic streptogramin comprised of two synergistic components in a defined 70:30 percent w/w mixture of dalfopristin and quinupristin, q.v., mesylate salts. HPLC determn for quality control: B. Vasselle et al., J. Pharm. Biomed. Anal. 19, 641 (1999). In vitro activity in comparison with pristinamycin, q.v.: A. Lozniewski et al., Pathol. Biol. 48, 463 (2000). Clinical trial in vancomycin resistant Enterococcus faecium (VREF) infection: R. C. Moellering et al., J. Antimicrob. Chemother. 44, 251 (1999); in skin infections: R. L. Nichols et al., ibid. 263. Review: B. Pavan, Curr. Opin. Invest. Drugs 1, 173-180 (2000).
Therap-Cat: Antibacterial.
Keywords: Antibacterial (Antibiotics).
EP0252720A2 * Jul 7, 1987 Jan 13, 1988 MAY &amp; BAKER LIMITED Pristinamycin process
EP0298177A1 * Jul 7, 1987 Jan 11, 1989 Rhone-Poulenc Sante Process for preparing pristinamycine IIB derivatives
US4866172 * Apr 12, 1988 Sep 12, 1989 May & Baker Limited Pristinamycin process
WO1992001693A1 * Jul 15, 1991 Jan 17, 1992 Rhone Poulenc Rorer Sa Method for the preparation of sulphinyl pristinamycin ii¿b?
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