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Rebamipide, ребамипид , ريباميبيد ,瑞巴派特 ,

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ChemSpider 2D Image | Rebamipide | C19H15ClN2O4DB11656.pngRebamipide.svg

Rebamipide

  • Molecular FormulaC19H15ClN2O4
  • Average mass370.786 Da
  • Monoisotopic mass370.072021 Da

OPC-12759
OPC-12759E
OPC-759

(±)-a-(p-Chlorobenzamido)-1,2-dihydro-2-oxo-4-quinolinepropionic acid
2-(4-Chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid
4-Quinolinepropanoic acid, α-[(4-chlorobenzoyl)amino]-1,2-dihydro-2-oxo- [ACD/Index Name]
4-quinolinepropanoic acid, α-[(4-chlorobenzoyl)amino]-2-hydroxy-
6454
CAS 90098-04-7 [RN]
a-[(4-Chlorobenzoyl)amino]-1,2-dihydro-2-oxo-4-quinolinepropanoic acid
LR583V32ZR
UNII:LR583V32ZR
ребамипид [Russian] [INN]
ريباميبيد [Arabic] [INN]
瑞巴派特 [Chinese] [INN]
(±)-2-(4-CHLOROBENZOYLAMINO)-3-(2(1H)-QUINOLINON-4-YL)-PROPIONIC ACID
obtain the white powder from dimethylformamide-water with its hemihydrate m.p. being 288-290°C (decomposition).
(-)-Configuration: from dimethylformamide to give colorless needles, mp 305~306 °C (decomposition). [α] D20-116.7 ° (C = 1.0, dimethylformamide).
(+)-Configuration: from dimethylformamide to give colorless needles, mp 305~306 °C (decomposition). [α] D20 + 116.9 ° (C = 1.0, dimethylformamide).
Rebamipide is a quinolone derivative that was launched in 1990 by Otsuka in Japan for the oral treatment of Helicobacter pylori-induced gastric inflammation after eradication therapy and peptic ulcer
Title: Rebamipide
CAS Registry Number: 90098-04-7
CAS Name: a-[(4-Chlorobenzoyl)amino]-1,2-dihydro-2-oxo-4-quinolinepropanoic acid
Additional Names: (±)-a-(p-chlorobenzamido)-1,2-dihydro-2-oxo-4-quinolinepropionic acid; 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid; proamipide
Manufacturers’ Codes: OPC-12759
Trademarks: Mucosta (Otsuka)
Molecular Formula: C19H15ClN2O4
Molecular Weight: 370.79
Percent Composition: C 61.55%, H 4.08%, Cl 9.56%, N 7.56%, O 17.26%
Literature References: Gastric cytoprotectant. Prepn: M. Uchida et al., DE 3324034eidem, US 4578381; (1984, 1986 both to Otsuka). Synthesis and pharmacology: M. Uchida et al., Chem. Pharm. Bull. 33, 3775 (1985); of enantiomers: eidem, ibid. 35, 853 (1987). Antiulcer activity in rats: K. Yamasaki et al., Eur. J. Pharmacol. 142, 23 (1987); K. Yamasaki et al., Jpn. J. Pharmacol. 49,441 (1989). HPLC determn in plasma and urine: Y. Shioya, T. Shimizu, J. Chromatogr. 434, 283 (1988).
Properties: White powder from DMF-water, mp 288-290° (dec) as hemihydrate.
Melting point: mp 288-290° (dec) as hemihydrate
Derivative Type: (-)-Form
Properties: Colorless needles from DMF, mp 305-306° (dec). [a]D20 -116.7° (c = 1.0 in DMF).
Melting point: mp 305-306° (dec)
Optical Rotation: [a]D20 -116.7° (c = 1.0 in DMF)
Derivative Type: (+)-Form
Properties: Colorless needles from DMF, mp 305-306° (dec). [a]D20 +116.9° (c = 1.0 in DMF).
Melting point: mp 305-306° (dec)
Optical Rotation: [a]D20 +116.9° (c = 1.0 in DMF)
Therap-Cat: Antiulcerative.
Keywords: Antiulcerative; Cytoprotectant (Gastric).
Rebamipide has been investigated for the treatment of Stomach Ulcer, Keratoconjunctivitis Sicca, and Gastric Adenoma and Early Gastric Cancer.
Rebamipide is a quinolinone derivative that stimulates endogenous PGE2 generation in gastric mucosa, enhancing gastric mucosal defense in a COX-2-dependent manner.
Rebamipide has been shown to inhibit the production of reactive oxygen species and to decrease cytokine release induced by H. pylori infection.
A daily oral dose of 100 mg/kg was found to be protective against the development of pyloric channel ulcers in Mongolian gerbils infected with H. pylori.
In addition to the stomach, rebamipide can also enhance secretion of mucin covering the conjunctiva and cornea, which is important for tear film adhesion.
Rebamipide, a gastroprotective drug, was developed in Japan and was proven to be superior to cetraxate, the former most prescribed drug of the same category, in 1989 in the treatment for gastric ulcers. The initially discovered basic mechanisms of action of rebamipide included its action as a prostaglandin inducer and oxygen free-radical scavenger. In the last 5 years, several basic and clinical studies have been performed for functional dyspepsia, chronic gastritis, NSAID-induced gastrointestinal injuries, gastric ulcer following eradication therapy for Helicobacter pylori, gastric ulcer after endoscopic surgery and ulcerative colitis. In addition, several molecules have been identified as therapeutic targets of rebamipide to explain its pleiotropic pharmacological actions.

Rebamipide, an amino acid derivative of 2-(1H)-quinolinone, is used for mucosal protection, healing of gastroduodenal ulcers, and treatment of gastritis. It works by enhancing mucosal defense, scavenging free radicals, and temporarily activating genes encoding cyclooxygenase-2.

Rebamipide is used in a number of Asian countries including Japan (marketed as Mucosta), South KoreaChina[1] and India (where it is marketed under the trade name Rebagen). It is also approved in Russia under the brand name Rebagit.[2] It is not approved by the Food and Drug Administration for use in the United States.

Studies have shown that rebamipide can fight the damaging effects of NSAIDs on the GIT mucosa, and more recently, the small intestine.[citation needed] It has also been studied for the treatment of Behçet’s disease.[3] It was shown to successfully treat pouchitis in a single-N study after first-line therapies for the condition were unsuccessful.[4] Some studies have shown effectiveness in presbyacusis(age-related hearing loss).[citation needed]

It has also been shown to alleviate signs and symptoms of dry eyes in a randomised controlled trial although this is not yet widely available clinically.[5]

SYN

Rebamipide (CAS NO.: 111911-87-6), with its systematic name of 4-Quinolinepropanic acid, alpha-((4-chlorobenzoyl)amino)-1,2-dihydro-2-oxo-, (+-)-, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Rebamipide

4-(Bromomethyl)quinolin-2(1H)-one (I) could react with hot phosphorus oxychloride to produce a mixture of 4-(bromomethyl)-2-chloroquinoline (II) and 2-chloro-4-(chloromethyl)quinoline (III), and then the mixture without separation is  ondensed with 2(S)-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (IVs) in the presence of butyllithium in hexane, affording (-)-2-chloro-4-[6(S)-isopropyl-2,5-dimethoxy-3,6-dihydropyrazin-3(R)-yl methyl]quinoline (Vr). The hydrolysis of (Vr) with HCl produces 3-(2-chloroquinolin-4-yl)-(R)-alanine methyl ester (VIr), which is treated with HCl and propylene oxide to afford 3-(2-oxo-2,3-dihydroquinolin-4-yl)-(R)-alanine (VIIr). At last, this compound is acylated with 4-chlorobenzoyl chloride (VIII) by means of K2CO3in acetone, affording (R)-OPC-12759.

The synthetic route of Rebamipide
Figure 2 The synthetic route of Rebamipide.

DE 3324034; US 4578381 ABOVE

The condensation of 4-(bromomethyl)quinolin-2(1H)-one (I) with diethyl acetamidomalonate (II) by means of sodium ethoxide in refluxing ethanol gives ethyl 2-acetamido-2-(ethoxycarbonyl)-3-(2-oxo-1,2-dihydroquinolin-4yl)propionate (III), which is submitted to a decarboxylative hydrolysis with refluxing 20% HCl yielding 3-(2-oxo-1,2-dihydroquinolin-4yl)alanine (IV). Finaily this compound is acylated with 4-chlorobenzoyl chloride by means of K2CO3 in acetone water.

SYN

Chem Pharm Bull 1991,39(11),2906 ABOVE

The synthesis of (R)- and (S)-isomers of OPC-12759 has been described: These optical isomers can be obtained in three different ways: 1) The reaction of 4-(bromomethyl)quinolin-2(1H)-one (I) with hot phosphorus oxychloride gives a mixture of 4-(bromomethyl)-2-chloroquinoline (II) and 2-chloro-4-(chloromethyl)quinoline (III), which, without separation, is condensed with 2(S)-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (IVs) by means of butyllithium in hexane, yielding (-)-2-chloro-4-[6(S)-isopropyl-2,5-dimethoxy-3,6-dihydropyrazin-3(R)-yl methyl]quinoline (Vr). The hydrolysis of (Vr) with HCl affords 3-(2-chloroquinolin-4-yl)-(R)-alanine methyl ester (VIr), which is treated with HCl and propylene oxide to give 3-(2-oxo-2,3-dihydroquinolin-4-yl)-(R)-alanine (VIIr). Finally, this compound is acylated with 4-chlorobenzoyl chloride (VIII) by means of K2CO3 in acetone, affording (R)-OPC-12759.

SYN

3) The methylation of 3-(2-oxo-1,2-dihydroquinolin-4-yl)-(R,S)-alanine (IX) with SOCl2 and methanol yields the corresponding methyl ester (X), which is submitted to optical resolution with D-(-)-mandelic acid, affording adducts (XII) and (XIII). The hydrolytic treatment of (XII) and (XIII) with HCl and propylene oxide finally yields isomers (VIIr) and (VIIs), already obtained. Racemic OPC-12759 can also be resolved into its optical isomers by treatment with brucine and fractionated crystallization.

Rebamipide

    • Synonyms:Proamipide
    • ATC:A02BX
  • Use:ulcer therapeutic
  • Chemical name:α-[(4-chlorobenzoyl)amino]-1,2-dihydro-2-oxo-4-quinolinepropanoic acid
  • Formula:C19H15ClN2O4
  • MW:370.79 g/mol
  • CAS-RN:90098-04-7
  • LD50:572 mg/kg (M, i.v.);
    700 mg/kg (R, i.v.);
    >2 g/kg (dog, p.o.)

Substance Classes

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RN Formula Chemical Name CAS Index Name
39098-85-6 C4H5ClO2 acetoacetyl chloride Butanoyl chloride, 3-oxo-
62-53-3 C6H7N aniline Benzenamine
4876-10-2 C10H8BrNO 4-(bromomethyl)-2(1H)-quinolinone 2(1H)-Quinolinone, 4-(bromomethyl)-
128-08-5 C4H4BrNO2 N-bromosuccinimide 2,5-Pyrrolidinedione, 1-bromo-
122-01-0 C7H4Cl2O 4-chlorobenzoyl chloride Benzoyl chloride, 4-chloro-
1068-90-2 C9H15NO5 diethyl acetamidomalonate Propanedioic acid, (acetylamino)-, diethyl ester
4900-38-3 C19H22N2O6 ethyl 2-acetamido-2-(ethoxycarbonyl)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate Propanedioic acid, (acetylamino)[(1,2-dihydro-2-oxo-4-quinolinyl)methyl]-, diethyl ester
5162-90-3 C12H12N2O3 3-(2-oxo-1,2-dihydroquinolin-4-yl)alanine 4-Quinolinepropanoic acid, α-amino-1,2-dihydro-2-oxo-
102-01-2 C10H11NO2 3-oxo-N-phenylbutanamide Butanamide, 3-oxo-N-phenyl-

Trade Names

Country Trade Name Vendor Annotation
J Mucosta Otsuka

Formulations

  • tabl. 100 mg

References

    • Uchida, M. et al.: Chem. Pharm. Bull. (CPBTAL) 33, 3775 (1985).
    • DOS 3 324 034 (Otsuka; appl. 7.4.1983; J-prior. 7.5.1982).
    • GB 2 123 825 (Otsuka; appl. 7.5.1983; J-prior. 7.5.1982).
  • oral and parenteral formulations:

    • JP 60 019 767 (Otsuka; appl. 7.11.1983).

PAPER

Magic Bullet! Rebamipide, a Superior Anti-ulcer and Ophthalmic Drug and Its Large-Scale Synthesis in a Single Organic Solvent via Process Intensification Using Krapcho Decarboxylation

https://pubs.acs.org/doi/10.1021/acs.oprd.7b00382#

Chemical Research Division, API R&D CentreMicro Labs Ltd.Plot No.43-45, KIADB Industrial Area, fourth phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore 560 105, Karnataka, India
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00382
Publication Date (Web): May 31, 2018
Copyright © 2018 American Chemical Society
Abstract Image

Rebamipide (1) is a superior drug compared to existing drugs for use in healing of peptic ulcers, gastrointestinal bleeding, and dyspepsia. It is also useful as an ophthalmic drug for the treatment of dry eye syndrome. Process intensification for its synthesis was achieved by (i) averting uncontrollable frothing using Krapcho decarboxylation instead of conventional acid hydrolysis, where uncontrollable frothing became chaotic, (ii) minimizing organic waste generation by using a single organic solvent, and (iii) avoiding anti-foaming agents (n-octanol, acetophenone) and acetic acid. With these trifling modifications, the overall yield of active pharmaceutical ingredient (API) was ≥83% with excellent purity (≥99.89%), and the process meets the metrics of “green” chemistry with an E-factor = 11.5. The developed hassle-free commercial process is viable for multi-kilogram synthesis of Rebamipide (1) as the key step, Krapcho decarboxylation is safe to run at 130–140 °C in DMSO, and it was proved to be effective by differential scanning calorimetry thermal screening studies. The characterization data of intermediates, process-related impurities, and API are reported. The carryover and process-related impurities were controlled efficiently. The present work can enhance the scope and worldwide adoptability of Rebamipide (1), which is currently limited to Asian countries.

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00382/suppl_file/op7b00382_si_001.pdf

STR1 STR2 str3 str4 str5

Articles

  • Arakawa T, Watanabe T, Fukuda T, Yamasaki K, Kobayashi K (1995). “Rebamipide, novel prostaglandin-inducer accelerates healing and reduces relapse of acetic acid-induced rat gastric ulcer. Comparison with cimetidine”. Dig Dis Sci40 (11): 2469–72. doi:10.1007/BF02063257PMID 7587834.
  • Arakawa T, Kobayashi K, Yoshikawa T, Tarnawski A (1998). “Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing”. Dig Dis Sci43 (9 Suppl): 5S–13S. PMID 9753220.
  • Tarnawski AS, Chai J, Pai R, Chiou SK (2004). “Rebamipide activates genes encoding angiogenic growth factors and Cox2 and stimulates angiogenesis: a key to its ulcer healing action?”. Dig Dis Sci49 (2): 202–9. doi:10.1023/B:DDAS.0000017439.60943.5cPMID 15104358.
  • Takumida M, Anniko M (2009). “Radical scavengers for elderly patients with age-related hearing loss”. Acta Otolaryngol129 (1): 36–44. doi:10.1080/00016480802008215PMID 18607930.

References

  1. Jump up^ drugs.com
  2. Jump up^ “Russian State Register of Medicines. Registration Sertificate: Rebagit (rebamipide) Film-Coated Tablets” (in Russian). Retrieved 10 June 2017.
  3. Jump up^ Matsuda T, Ohno S, Hirohata S, Miyanaga Y, Ujihara H, Inaba G, Nakamura S, Tanaka S, Kogure M, Mizushima Y (2003). “Efficacy of rebamipide as adjunctive therapy in the treatment of recurrent oral aphthous ulcers in patients with Behcet’s disease: a randomised, double-blind, placebo-controlled study”. Drugs R D4 (1): 19–28. doi:10.2165/00126839-200304010-00002PMID 12568631.
  4. Jump up^ http://www.wjgnet.com/1007-9327/12/656.pdf Archived October 20, 2013, at the Wayback Machine.
  5. Jump up^ Kinoshita, S.; K. Oshiden; S. Awamura; H. Suzuki; N. Nakamichi (2013). “A randomized, multicenter phase 3 study comparing 2% rebamipide (OPC-12759) with 0.1% sodium hyaluronate in the treatment of dry eye”. Ophthalmology120 (6): 1158–65. doi:10.1016/j.ophtha.2012.12.022PMID 23490326.
Rebamipide
Rebamipide.svg
Clinical data
Trade names Mucosta (JP), Rebagen (KR,CNIN), Rebagit (RU)
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral (tablets)
ATC code
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C19H15ClN2O4
Molar mass 370.786 g/mol
3D model (JSmol)

/////////Rebamipide, UNII:LR583V32ZR, ребамипид ريباميبيد ,瑞巴派特 , OPC-12759  , OPC-12759E  , OPC-759 , OPC 12759  , OPC 12759E  , OPC 759 , OTSUKA, JAPAN 1990

OC(=O)C(CC1=CC(O)=NC2=CC=CC=C12)NC(=O)C1=CC=C(Cl)C=C1

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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