New Drug Approvals

Home » Uncategorized » RAMOSETRON

RAMOSETRON

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Recent Posts

Blog Stats

  • 3,262,384 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,585 other followers

add to any

Share

RAMOSETRON, Antiemetics

Ramosetron (INN),(1-methylindol-3-yl)-[(5R)-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl]methanone,  132036-88-5 cas no

  C17H17N3O 
  279.33 g/mol

(1-methyl-1H-indol-3-yl)[(5R)-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl]methanone

YM060

  • Nasea
  • Nor-YM 060
  • Ramosetron
  • UNII-7ZRO0SC54Y

…………………………………………………………………………………..

HYDROCHLORIDE SALT

2D image of a chemical structure

hyrochloride salt, cas no 132907-72-3

C17-H17-N3-O.Cl-H
315.8022
Yamanouchi (Originator)
GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, 5-HT3 Antagonists
Launched-1996 JAPAN

 (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride (yield 78.8%, 99.5% e.e.). FAB-MS (m/z): 280 [M+H+]

1H NMR (DMSO-d6, 30° C.): δ ppm (TMS internal standard): 1.82-1.95 (1H, m), 2.12-2.22 (1H, m), 2.66-2.94 (4H, m), 3.63-3.72 (1H, m), 3.88 (3H, s), 7.24 (1H, t, J=8.0 Hz), 7.30 (1H, t, J=8.0 Hz), 7.56 (1H, d, J=8.0 Hz), 8.22 (1H, d, J=8.0 Hz), 8.53 (1H, s), 8.90 (1H, s), 14.42 (1H, br)

…………………………………………………………………………………….

Ramosetron (INN) is a serotonin 5-HT3 receptor antagonist for the treatment of nausea and vomiting.[1] Ramosetron is also indicated for a treatment of “diarrhea-predominant irritable bowel syndrome in males”.[2] In India it is marketed under the brand name of“IBset”.
It is only licensed for use in Japan and selected Southeast Asian countries. In Japan it is sold under the tradename Iribo (イリボー). [3] Elsewhere it is commonly sold under the tradename Nasea and in India as Nozia (300 mcg/ml Inj. & 100 mcg Tab.) [4]

  1.  Fujii Y, Saitoh Y, Tanaka H, Toyooka H (February 2000). “Ramosetron for preventing postoperative nausea and vomiting in women undergoing gynecological surgery”.Anesth. Analg. 90 (2): 472–5. doi:10.1097/00000539-200002000-00043.PMID 10648342.
  2. http://www.astellas.com/en/corporate/news/detail/astellas-launches-irribow-for.html
  3.  Summary in Japanese. Retrieved on September 4, 2012.
  4.  Abridged prescribing information – Nasea (MIMS Philippines). Retrieved on June 13, 2008.
  5. Synthesis and 5-HT3 antagonistic activities of 4,5,6, 7-tetrahydrobenzimidazole derivatives
    200th ACS Natl Meet (August 26-31, Washington DC) 1990, Abst MEDI 39
1-27-2010
Process for producing ramosetron or its salt
11-20-1996
Intrabuccally dissolving compressed moldings and production process thereof
3-6-1996
5-substituted tetrahydrobenzimidazole compounds
11-15-1995
Intrabuccally disintegrating preparation and production thereof
9-7-1994
Tetrahydrobenzimidazole derivatives and pharmaceutical compositions containing same
6-24-1994
NEW USE OF 5-HT3 RECEPTOR ANTAGONISTS

AU 9048890; EP 0381422; JP 1991223278; US 5344927

CN1696128A Nov 2, 2004 Nov 16, 2005 天津康鸿医药科技发展有限公司 New method for synthesizing Ramosetron Hydrochloride
CN1765896A Oct 28, 2004 May 3, 2006 北京博尔达生物技术开发有限公司 Novel preparation method of ramosetron hydrochloride
US5496942 * 14 Feb 1994 5 Mar 1996 Yamanouchi Pharmaceutical Co., Ltd. 5-substituted tetrahydrobenzimidazole compounds
US5677326 * 30 Sep 1994 14 Oct 1997 Tokyo Tanabe Company Limited Indoline compound and 5-HT.sub.3 receptor antagonist containing the same as active ingredient
US7358270 28 Jan 2005 15 Apr 2008 Astellas Pharma Inc. Treating agent for irritable bowel syndrome
US7683090 18 Oct 2006 23 Mar 2010 Astellas Pharma Inc. Treating agent for irritable bowel syndrome
US7794748 27 Aug 2004 14 Sep 2010 Yamanouchi Pharmaceutical Co., Ltd. Stable oral solid drug composition

WO 2010024306

WO 2013005760

WO 2013100701

WO 2011001954

The chemical name of ramosetron is (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole, and it has the structure represented by the formula (II).

Figure US07652052-20100126-C00002

It is known that ramosetron or a salt thereof has a potent 5-HTreceptor antagonism (Patent Reference 1, Non-patent references 1 and 2), and it is on the market as a preventive or therapeutic agent for digestive symptoms (nausea, emesis) caused by administration of an anti-malignant tumor agent (cisplatin or the like). In addition, a possibility has been reported that ramosetron or a salt thereof may be useful as an agent for treating diarrheal-type irritable bowel syndrome or an agent for improving diarrheal symptoms of irritable bowel syndrome (Patent Reference 1), and its clinical trials are now in progress as an agent for treating diarrheal-type irritable bowel syndrome or an agent for improving diarrheal symptoms of irritable bowel syndrome.

As a process for producing ramosetron or a salt thereof, the following production methods are known.

Patent Reference 1 describes a production method shown by the following Production method A, namely a method for producing a tetrahydrobenzimidazole derivative (V) by allowing a heterocyclic compound (III) to react with a carboxylic acid represented by a formula (IV) or its reactive derivative.

(Production Method A)

Figure US07652052-20100126-C00003

(In the formula, Xis a single bond and binds to a carbon atom on the heterocyclic ring represented by Het.)

As an illustrative production method of ramosetron, Patent Reference 1 describes a production method (Production method A-1) in which racemic ramosetron are obtained by using 1-methyl-1H-indole as the compound (III), and N,N-diethyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide or N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine, which are acid amides, as the reactive derivative of compound (IV), and allowing them to undergo treatment with phosphorus oxychloride (Vilsmeyer reaction), and then their optical resolution is carried out by fractional crystallization using (+)-dibenzoyltartaric acid.

In addition, the Patent Reference 1 exemplifies an acid halide as one of the reactive derivatives of the compound (IV), and also describes another production method of the compound (V) (Production method A-2) in which the heterocyclic compound (III) is condensed with an acid halide of the compound (IV) by the Friedel-Crafts acylation reaction using a Lewis acid as the catalyst. However, illustrative production example of ramosetron by the Friedel-Crafts acylation reaction is not described therein.

Also, a method similar to the Production example A-1 is described in Non-patent References 1 and 2 as a production method of ramosetron.

In addition, Non-patent Reference 3 describes a method for producing ramosetron labeled with 11C, represented by a Production method B. However, it discloses only the methylation step, and does not disclose a production method of nor-YM060 as the starting material.

(Production Method B)

Figure US07652052-20100126-C00004

(In the formula, nor-YM060 means (R)-5-[(1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole which was provided by the present applicant, DMF means dimethylformamide.)

  • Non-patent Reference 1: Chemical Pharmaceutical Bulletin, 1996, vol. 44, no. 9, p. 1707-1716
  • Non-patent Reference 2: Drugs of the Future, 1992, vol. 17, no. 1, p. 28-29
  • Non-patent Reference 3: Applied Radiation and Isotopes, 1995, vol. 46, no. 9, p. 907-910
  • Patent Reference 1: JP-B-6-25153

LIU Qing-wen, XU Hao, TIAN Hua, ZHENG Liang-yu, ZHANG Suo-qin
Chemoenzymatic Synthesis of Ramosetron Hydrochloride

2012 Vol. 28 (1): 70-72 [Abstract] ( 1143 ) [HTML 1KB] [PDF 206KB] ( 1052 )
doi:http://www.cjcu.jlu.edu.cn/hxyj/EN/abstract/abstract13356.shtml

…………………………………………………………………………..

The Vilsmeier-type reaction of 1-methylindole (I) with 5 – (1-pyrrolidinocarbonyl) -4,5,6,7-1 H-tetrahydrobenzimidazole hydrochloride (II) and phosphorous oxychloride in 1,2-dichloroethane gives (-5? -. [(1-methyl-3-indolyl) carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazol e (III) Optical resolution of (III) with (+)-dibenzoyltartaric acid (DIBTA) in DMF -H2O, followed by exchange of the salt affords YM060.

………………………………………………….

Ondansetron: 1,2,3 ,9-Tetrahydro-9-methyl-3-[(2-methyl1-H-imidazole-1-yl)methyl]-4H-carbazol-4-one

Figure US06451808-20020917-C00005

Granisetron: Endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide

Figure US06451808-20020917-C00006

Tropisetron: Endo-1H-indole-3-carbocylic acid8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester

Figure US06451808-20020917-C00007

Dolasetron: 1H-Indole-3 -carboxylic acid (2a, 6a, 8a, 9up)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl Ester

Figure US06451808-20020917-C00008

Azasetron: (±)-N-Azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide

Figure US06451808-20020917-C00009

Alosetron: 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl- 1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one

Figure US06451808-20020917-C00010

Ramosetron

Figure US06451808-20020917-C00011
2D image of a chemical structure
Galdansetron hydrochloride [USAN]
156712-35-5

1 Comment

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,585 other followers

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

Personal Links

View Full Profile →

TWITTER

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: