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)

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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

US7652052	1-27-2010	Process for producing ramosetron or its salt
US5576014	11-20-1996	Intrabuccally dissolving compressed moldings and production process thereof
US5496942	3-6-1996	5-substituted tetrahydrobenzimidazole compounds
US5466464	11-15-1995	Intrabuccally disintegrating preparation and production thereof
US5344927	9-7-1994	Tetrahydrobenzimidazole derivatives and pharmaceutical compositions containing same
WO9413284	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).

It is known that ramosetron or a salt thereof has a potent 5-HT₃ receptor 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)

(In the formula, X² is 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)

(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

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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.

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

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

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

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

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

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

Ramosetron