GRANISETRON

GRANISETRON

1-methyl-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-indazole-3-carboxamide

Nausea and Vomiting, Treatment of, Neurologic Drugs, 5-HT3 Antagonists

107007-99-8 hydrochloride
109889-09-0 (free base)

AB-1001
ALM-101
BRL-43694
Inno-P08002
SP-01
SyB D-0701
SyB L-0701
SyB-0701
TRG

Chugai (Proprietary), Roche (Proprietary), GlaxoSmithKline (Originator)

Granisetron is a serotonin 5-HT₃ receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect on vomiting due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

Granisetron hydrochloride is an anti-emetic drug, used for treatment or prophylaxis of emesis and post operative nausea and vomiting. Granisetron hydrochloride is marketed under the trade name Kytril as solution for injection as well as tablets. The chemical name of granisetron is N-(endo-9-methyl-9- azabicyclo[3.3.2]non-3-yl)-l-methylindazole-3-carboxamide and it is represented by the following structural formula :

Granisetron is usually administered as the hydrochloride salt for relieving the symptoms of vomiting and nausea in cancer patients. Recently the U.S. Food and Drug Administration (FDA) has accepted an investigational New Drug (IND) application for transdermal granisetron patch, Sancuso™, for the prevention of chemotherapy-induced nausea and vomiting (CINV). The Sancuso™ Phase I I Istudy is now underway in Europe and in the U.S. Typically, a non-oral form such as transdermal patch uses granisetron base as the active ingredient.  The preparation of granisetron base is described in U.S. Patent No. 6,268,498 without referring to the solid state characteristics of granisetron. The preparation of granisetron base is further described in example 3 of U.S. Patent No. 7,071,209 (hereinafter the ‘209 patent), having a melting point of 121-122⁰C. The ‘209 patent is silent with regard to the solid state of granisetron base as well as to the solid state of the hydrochloride salt,

Granisetron was developed by chemists working at the British drug company Beecham around 1988 and is available as a generic. It is produced byRoche Laboratories under the trade name Kytril. The drug was approved in the United Kingdom in 1991 and in United States in 1994 by the FDA.

A granisetron transdermal patch with the trade name Sancuso was approved by the US FDA on September 12, 2008.^[1] Sancuso is manufactured by ProStrakan, Inc., a pharmaceutical company headquartered in Bedminster, NJ, with global headquarters in Scotland.

Granisetron is metabolized slowly by the liver, giving it a longer than average half-life. One dose usually lasts 4 to 9 hours and is usually administered once or twice daily. This drug is removed from the body by the liver and kidneys.

Granisetron hydrochloride is a 5-HT3 antagonist that was launched in 1991 at Roche for the oral treatment of nausea. Preclinical studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In 2008, FDA approval of a transdermal patch was obtained by ProStrakan for the prophylaxis of chemotherapy-induced nausea/vomiting. Commercial launch took place the same year. This formulation has been filed for approval in the E.U. for the prevention of chemotherapy-induced nausea and vomiting. E.U. approval was obtained in 2012. In 2013, launch took place in United Kingdom. In 2011, Chugai Pharmaceutical received approval in Japan for the prevention of nausea and vomiting associated with antineoplastic agent administration and radiotherapy. Translational Research has developed an intranasal formulation that is in the preclinical phase of development. Acrux has also studied a proprietary metered-dose transdermal system, but progress reports on this formulation are not presently available. Currently marketed formulations include an oral solution, film-coated tablets, injections and sachets. BioDelivery Sciences is developing a formulation of granisetron hydrochloride using its film technology (BioErodable MucoAdhesive) BEMA technology. Almac is developing the compound in phase I clinical studies for the prevention of chemotherapy-induced nausea/vomiting.

It may be used for chemotherapy-induced nausea and vomiting and appears to work about the same as ondansetron.^[2]

A number of medications including granisetron appear to be effective in controlling post-operative nausea and vomiting (PONV).^[3] It is unclear if it is better than or worse than other agents like droperidol, metoclopramide, ondansetron or cyclizine.^[3]

Its efficacy has also been questioned with a research Dr. Yoshitaka Fujii having 12 published papers on this topic in Canadian Journal of Anesthesia retracted. A further five papers in the same journal on the same drug by Dr Fujii are considered indeterminate.

• Is a possible therapy for nausea and vomiting due to acute or chronic medical illness or acute gastroenteritis
• Treatment of cyclic vomiting syndrome although there are no formal trials to confirm efficacy.

Granisetron is a well-tolerated drug with few side effects. Headache, dizziness, and constipation are the most commonly reported side effects associated with its use. There have been no significant drug interactions reported with this drug’s use. It is broken down by the liver‘s cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system.

APF530

A New Drug Application (NDA) for APF530, a sustained-delivery form of Granisetron, was accepted in October 2012.^[4] APF530 will be targeted as anantiemetic, towards patients undergoing radiation therapy and chemotherapy. APF530 contains the 5-HT3 antagonist, granisetron, formulated in the Company’s proprietary Biochronomer™ drug delivery system, which allows therapeutic drug levels to be maintained for five days with a single subcutaneous injection.

Originally developed at GlaxoSmithKline, granisetron hydrochloride was divested in September 2000 giving Roche global rights to the drug. Currently, granisetron is being distributed by Roche in France, Italy, South Africa, the U.K. and the U.S. and in Japan by Roche’s subsidiary Chugai. In 2007, a license agreement was signed between LG Life Sciences and ProStrakan in Korea. In 2008, the product was licensed to JapanBridge by ProStrakan for development and marketing in Asia for the prophylaxis of chemotherapy-induced nausea and vomiting. An additional license agreement was made in 2008 granting Paladin rights to granisetron transdermal patches for the treatment of nausea. In 2010, granisetron hydrochloride extended-release transdermal patches were licensed to Kyowa Hakko Kirin by Solasia Pharma in Taiwan, Hong Kong, Singapore and Malaysia for the prevention of chemotherapy-induced nausea and vomiting. Solasia retains full rights in Japan and China.

• Kytril Web site
• Sancuso Web siteKYTRIL Tablets and KYTRIL Oral Solution contain granisetron hydrochloride, an antinauseant and antiemetic agent. Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its empirical formula is C18H24N4O•HCl, while its chemical structure is:
  

  granisetron hydrochloride

  Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal saline at 20°C.

1.  PRNewswire. FDA Approves Sancuso, the First and Only Patch for Preventing Nausea and Vomiting in Cancer Patients Undergoing Chemotherapy. September 12, 2008.
2.  Billio, A; Morello, E; Clarke, MJ (2010 Jan 20). “Serotonin receptor antagonists for highly emetogenic chemotherapy in adults.”. The Cochrane database of systematic reviews (1): CD006272.PMID 20091591.
3.  Carlisle, JB; Stevenson, CA (2006 Jul 19). “Drugs for preventing postoperative nausea and vomiting.”. The Cochrane database of systematic reviews (3): CD004125. PMID 16856030.
4.  Drugs.com A.P. Pharma Announces PDUFA Action Date for APF530 New Drug Application Resubmission. October 16, 2012.

• Katzung, Bertram G. Basic and Clinical Pharmacology, 9th ed. (2004). ISBN 0-07-141092-9
• Aapro, M. (2004). “Granisetron: an update on its clinical use in the management of nausea and vomiting”. The oncologist 9 (6): 673–686. doi:10.1634/theoncologist.9-6-673. ISSN 1083-7159. PMID 15561811. edit

EP0200444A2 *	Apr 21, 1986	Nov 5, 1986	Beecham Group Plc	Azabicyclononyl-indazole-carboxamide having 5-HT antagonist activity
EP1484321A1 *	May 27, 2004	Dec 8, 2004	Chemagis Ltd.	Process for preparing 1-methylindazole-3-carboxylic acid

WO1995023799A1 *	Feb 28, 1995	Sep 8, 1995	Victor Witold Jacewicz	Process for the preparation of an indazole-3-carboxamide derivative
WO1997030049A1 *	Feb 11, 1997	Aug 21, 1997	Victor Witold Jacewicz	Process for the preparation of granisetron
EP0200444A2 *	Apr 21, 1986	Nov 5, 1986	Beecham Group Plc	Azabicyclononyl-indazole-carboxamide having 5-HT antagonist activity
ES2129349A *				Title not available

1	*	BERMUDEZ J. ET AL.: ‘5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivatives‘ J. MED. CHEM. vol. 33, no. 7, 1990, pages 1924 – 1929

Patent	Filing date	Publication date	Applicant	Title
WO2008117282A1 *	Mar 24, 2008	Oct 2, 2008	Itai Adin	Polymorph of granisetron base and production process therefor
EP2323654A1 *	Aug 18, 2009	May 25, 2011	ScinoPharm Taiwan, Ltd.	Polymorphic form of granisetron hydrochloride and methods of making the same

WO2003080606A1 *	Mar 21, 2003	Oct 2, 2003	Barjoan Pere Dalmases	Process for preparing a pharmaceutically active compound (granisetron)
WO2007054784A1 *	Nov 8, 2006	May 18, 2007	Shanmuga Sundaram Bharan Kumar	An improved process for the preparation of granisetron hydrochloride
WO2007088557A1 *	Jan 18, 2007	Aug 9, 2007	Prasad Ramanadham Jyothi	Process for highly pure crystalline granisetron base
ES2124162A1 *				Title not available

WO2007007886A1 *	Jul 10, 2006	Jan 18, 2007	Tanabe Seiyaku Co	An oxime derivative and preparations thereof
WO2007088557A1 *	Jan 18, 2007	Aug 9, 2007	Prasad Ramanadham Jyothi	Process for highly pure crystalline granisetron base
WO2008117282A1 *	Mar 24, 2008	Oct 2, 2008	Itai Adin	Polymorph of granisetron base and production process therefor
WO2008151677A1	Dec 20, 2007	Dec 18, 2008	Inke Sa	Polymorphic form of granisetron base, methods for obtaining it and formulation containing it
EP2164848A1 *	Dec 20, 2007	Mar 24, 2010	Inke, S.A.	Polymorphic form of granisetron base, methods for obtaining it and formulation containing it
EP2323654A1 *	Aug 18, 2009	May 25, 2011	ScinoPharm Taiwan, Ltd.	Polymorphic form of granisetron hydrochloride and methods of making the same

US8193217 *	Aug 18, 2009	Jun 5, 2012	Scinopharm Taiwan Ltd.	Polymorphic form of granisetron hydrochloride and methods of making the same
US20100048613 *	Aug 18, 2009	Feb 25, 2010	Scinopharm Taiwan Ltd.	Polymorphic form of granisetron hydrochloride and methods of making the same

WO2007088557A1 *	Jan 18, 2007	Aug 9, 2007	Prasad Ramanadham Jyothi	Process for highly pure crystalline granisetron base
WO2008117282A1 *	Mar 24, 2008	Oct 2, 2008	Itai Adin	Polymorph of granisetron base and production process therefor
WO2008151677A1	Dec 20, 2007	Dec 18, 2008	Inke Sa	Polymorphic form of granisetron base, methods for obtaining it and formulation containing it
EP2164848A1 *	Dec 20, 2007	Mar 24, 2010	Inke, S.A.	Polymorphic form of granisetron base, methods for obtaining it and formulation containing it
EP2323654A1 *	Aug 18, 2009	May 25, 2011	ScinoPharm Taiwan, Ltd.	Polymorphic form of granisetron hydrochloride and methods of making the same

Drugs Fut 1989, 14(9): 875

5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivatives
J Med Chem 1990, 33(7): 1924

WO 2007054784

US 4886808
US 5034398

IN 200901669

……………………………………………………………………………………………………………………………………

Granisetron hydrochloride of formula (I). More particularly this invention relates to the preparation of Granisetron hydrochloride using methyl isobutyl ketone (MIBK) as a single solvent in presence of an organic base such as triethylamine.

(I)

Granisetron hydrochloride which is chemically known as endo-l-methyl-N-(9- methyl-9-azabicyclo[3.3.1]non-3-yl)-lH-indazole-3-carboxamide monohydrochloride is a 5-HT (5 -hydroxy triptamine) antagonist, and has the following structural formula:

(I)

Granisetron hydrochloride is useful as an anti-emetic and marketed as Kytril by Roche.

EP-A-0200444 provides certain 5-HT (5-hydroxytryptamine) antagonists, which are described as possessing a number of therapeutic utilities, inter alia, the prevention of vomiting following the administration of cytotoxic agents. The compound described in Example 6 is endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)- l-methylindazole-3-carboxamide, and this compound has been assigned the INN Granisetron. EP-A-0200444 also discloses that Granisetron can be prepared by reacting l-methylindazole-3-carboxylic acid chloride with endo-3-amino-9-methyl-9-azabicyclo [3.3.1] nonane.

EP 748321 claims a process for preparing Granisetron or a pharmaceutical acceptable salt thereof. The process comprises the condensation of compound of formula (3) and (4) followed by de-protecting the intermediate compound of structure (2) to get the granisetron or optionally forming a pharmaceutically accepted salt of Granisetron. The scheme is presented below in which Q is a leaving group displaceable by a secondary amine wherein R may be represented as benzyl, benzyl substituted with one or more chloro, alkyl or alkoxy group, t-butyl, allyl or a t-butyldimethylsilylgroup.

GRANISETRON

US Pat. No. 6,268,498 discloses an alternative process for preparing

Granisetron, by cyclisation of a previously methylated compound of formula (C), which is shown below. It should be noted that the methylation prior to cyclisation is carried out with sodium hydride and methyl iodide as disclosed in example 1 (b) of said patent. However, the cyclisation conditions applied to that compound of formula (C) may facilitate demethylation of the indazole of the Granisetron so obtained. Thus, for example, in examples 2 and 3 of said patent described the cyclisation reaction, but although in example 2 the reaction leads to Granisetron, in example 3, when the reaction time is increased under the same conditions, quantitatively demethylated Granisetron is provided. The reaction time therefore has a consideration influence on the yield values in the second step of the process that is in the cyclisation, since the Granisetron provided by this process contains as an impurity significant amounts of demethylated Granisetron, which will have to be re-methylated in an additional step.

(C) ES 2,124,162 patent discloses a procedure for the preparation of Granisetron or its pharmaceutically acceptable salts consisting of reaction of l-methylindazole-3- carboxamide of formula (A) with 9-methyl-9-azabicyclononane of formula (B) (L = halogen, OMs, OTs; halogen = esp. Cl, Br; Ms = SO₂Me; Ts = SO₂C₆H₄Me₄). Thus, l-methylindazole-3-carboxamide in tetrahydrofuran (THF) containing tetramethylethylenediamine is treated with BuLi in hexane followed by addition of endo-3-(mesyloxy)-9-methyl-9-azabicyclo [3.3.1] nonane hydrochloride (L = OMs) to give the title compound i.e. Granisetron The scheme is represented below:

(A) (B) GRANISETRON

As discussed above none of the prior art references disclosed or claimed the use of methyl isobutyl ketone (MIBK) as a single solvent in presence of an organic _Λ

4

base such as triethylamine for the preparation of compound of formula (I), hence we focused our research to develop an improved and efficient process for the preparation of the compound of formula (I) in substantial good yield and high purity.

,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

 

 

The synthesis of granisetron has been reported: The reaction of 1-methylindazole-3-carboxylic acid (I) with oxalyl chloride and DMF in dichloromethane gives 1-methylindazole-3-carbonyl chloride (II), which is then condensed with endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (III) by means of triethylamine in dichloromethane.

AU 8656579; EP 0200444; EP 0223385; EP 0498466; ES 8707948; JP 1986275276; JP 1993194508; US 4886808; US 5034398

 

…………………………………………………………………………………………………….

WO2007054784A1

Example (1) Preparation of Granisetron hydrochloride

10OmL of methyl isobutyl ketone (MIBK), 8.6g of triethylamine and 1Og of 1- methyl indazole-3-carboxylic acid were placed in a 25OmL RBF. The reaction mass was stirred and treated with 7.4g of ethyl chloro formate at O⁰C to (-) 5⁰C to get a mixed anhydride and then condensed with 8.75g of endo-9-methyl-9-azabicycolo [3.3.1] nonan-3-amine and stirred the reaction mass till the completion of reaction. To the reaction mixture 100 mL of water was added, organic layer separated and distilled to 8 volumes of MIBK, cooled the reaction mass and treated with 10.3g of IPA/HC1 (~ 20%) to get 1Og of Granisetron hydrochloride. Example (2) Preparation of Granisetron base

75OmL of methyl isobutyl ketone, 4Og of triethylamine and 5Og of 1-methyl indazole-3-carboxylic acid were placed in a 2L RBF. The reaction mass was stirred and treated with 34g of ethyl chloro formate at 20°C to 25°C to get a mixed anhydride and then condensed with 48g of endo-9-methyl-9-azabicycolo [3.3.1] nonan-3-amine and stirred the reaction mass till the completion of reaction. To the reaction mixture 500 mL of water was added and the organic layer separated, washed with 5% sodium carbonate

(50OmL) solution and distilled the organic layer to obtain Granisetron freebase with HPLC purity 99.91%.

Example (2 – a ) Preparation of Granisetron hydrochloride

1Og of Granisetron freebase, 10OmL of methanol were placed in 250 mL RBF and heated the reaction mass to 40⁰C to 55⁰C to get a clear solution. The clear solution was filtered and treated with 3.5g of concentrated hydrochloric acid (36%) and diluted the reaction mass with 20OmL of MIBK, heated the reaction mass to 60⁰C to 65°C and distilled the reaction mass up to 10 to 12 Volumes. The reaction mass was cooled and isolated 1Og of Granisetron hydrochloride with HPLC purity 99.91%.

………………………………………………………………………………………………………………………….

http://www.google.com/patents/WO1997030049A1?cl=en

Example 3 Preparation of endo-N-(9-methyl-9-azabicyclo[3.3. l]non-3-yl)-indazole-3- carboxamide.

A solution of 2-(N-methylbenzylidenehydrazino)-α-oxophenyl-[endo-N-(9- methyl-9-azabicyclo[3.3.1]non-3-yl)] carboxamide(0.536 g) in methanol (8 ml) was treated with 2N hydrochloric acid (0.4 ml) at room temperature. A rapid colour change from orange to green was observed. The solution was stirred for 24 hours then evaporated to the give the crude endo-N-(9-methyl-9-azabicyclo[3.3.1] non-3-yl)-indazole-3-carboxamide (0.630g).

Example 4 Preparation of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-l-methylindazole- 3-cjχboxamide (granisetron).

Sodium hydride (72 mg, 60% dispersion in oil) was added to a solution of endo- N-(9-methyl-9-azabicyclo[3.3. l]non-3-yl)-indazole-3-carboxamide (0.130g) in dry tetrahydrofuran (3.0 ml) under nitrogen at -50°C. The resultant solution was warmed to room temperature over 20 minutes then cooled to -40°C and treated with methyl iodide (0.015 ml). After 3 hours at room temperature HPLC analysis showed complete conversion to endo-N-(9-methyl-9-azabicyclo[3.3.1] non-3-yl)- l-methy-indazole-3-carboxamide. Water (10 ml) was added and the mixture extracted with ethyl acetate (2x 20 ml). The extracts were dried (MgSO4) ^ evaporated to give endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-l- methylindazole-3-carboxamide 50 mg (41%). MS 313 (M+H)⁺.