All About Drugs

Share:

ALOSETRON

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

132414-02-9, Hydrochloride
122852-42-0 (free base)

122852-69-1 CHECK…..

GR-68755C

• Alosetron HCl
• Alosetron hydrochloride
• GR 68755c
• HSDB 7055
• Lotronex
• UNII-2F5R1A46YW

GSK

LAUNCHED 2002

Alosetron is a 5-HT3 antagonist used only for the management of severe diarrhoea-predominant irritable bowel syndrome (IBS) in women. Alosetron has an antagonist action on the 5-HT3 receptors and thus may modulate serotonin-sensitive gastrointestinal (GI) processes. Alosetron was voluntarily withdrawn from the US market in November 2000 by the manufacturer due to numerous reports of severe adverse effects including ischemic colitis, severely obstructed or ruptured bowel, and death. In June 2002, the FDA approved a supplemental new drug application allowing the remarketing of the drug under restricted conditions of use.

Alosetron hydrochloride (initial brand name: Lotronex; originator: GSK) is a 5-HT₃ antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women only. It is currently marketed by Prometheus Laboratories Inc. (San Diego), also under the trade name Lotronex. Alosetron was withdrawn from the market in 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, but was reintroduced in 2002 with availability and use restricted.

Alosetron hydrochloride is a potent and selective 5-HT3 antagonist marketed by GlaxoSmithKline for the oral treatment of irritable bowel syndrome (IBS) in female patients whose predominant bowel symptom is diarrhea. It is currently marketed in a tablet formulation. In 2000, the drug was withdrawn from several markets based on adverse reactions, however, was reintroduced on the U.S. market in 2002 following a recommendation of a joint FDA advisory panel comprising members of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Pharmaceutical Science Committee which stipulated reintroduction of the drug in conjunction with a risk management plan.

Alosetron was originally approved by the U.S. Food and Drug Administration (FDA) on February 9, 2000,^[1] after a seven month review.^[2] At the time of the initial approval U.S. Food and Drug Administration (FDA) reviewers found that alosetron improved symptoms in 10% to 20% of patients.^[3]

Shipment to pharmacies started in March, 2000. On July 17, a health professional filed a report with the FDA on the death of a 50-year-old woman who suffered mesenteric ischemia. The report identified alosetron as the “primary suspect” in the death.^[4]

Alosetron was withdrawn from the market voluntarily by GlaxoWellcome on November 28, 2000 owing to the occurrence of serious life-threateninggastrointestinal adverse effects, including 5 deaths and additional bowel surgeries.^[2] The FDA said it had reports of 49 cases of ischemic colitis and 21 cases of “severe constipation” and that ten of the 70 patients underwent surgeries and 34 others were examined at hospitals and released without surgery. Through November 17, 2000, pharmacists had filled 474,115 prescriptions for Alosetron.^[2] Severe adverse events continued to be reported, with a final total of 84 instances of ischaemic colitis, 113 of severe constipation, 143 admissions to hospital, and 7 deaths.^[5]

Patient advocacy groups, most notably the Lotronex Action Group and the International Foundation for Functional Gastrointestinal Disorders (IFFGD) lobbied for the drug’s return. Public Citizen Health Research Group, another patient advocacy group, opposed the reintroduction.^[6][7]

On June 7, 2002, the FDA announced the approval of a supplemental New Drug Application (sNDA) that allows restricted marketing of Lotronex (alosetron hydrochloride), to treat only women with severe diarrhea-predominant irritable bowel syndrome (IBS).^[8] It was the first drug ever returned to the U.S. market after withdrawal for safety concerns.^[9][10]

It is not known whether alosetron has been filed for registration in the EU.

GSK sold Lotronex to the Californian corporation Prometheus in late 2007.^[11]

Alosetron hydrochloride works through antagonism of the serotonin 5-HT3 receptor, distributed extensively on visceral neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of 5-HT3 channels results in neuronal depolarization and affects the regulation of visceral pain, colonic transit and gastrointestinal secretions. Alosetron inhibits activation of non-selective cation channels and modulates the enteric nervous system. In previous clinical trials, the drug increased colonic transit time without affecting orocecal transit time, increased basal jejunal water and sodium absorption and significantly increased colonic compliance. In 2007, the compound was licensed to Prometheus Laboratories by GlaxoSmithKline in the U.S. for the treatment of IBS in patients whose predominant bowel symptom is diarrhea.

Criticism of the FDA

In 2001, the editor of the renowned medical journal The Lancet, Richard Horton, criticized the FDA’s handling of alosetron in an unusually sharp language.^[12] Horton argued that the treatment of a non-fatal condition did not justify the use of a drug with potentially lethal side effects, and that the FDA should have revoked the approval for alosetron sooner when postmarketing surveillance revealed that many patients had suffered constipation necessitating surgical intervention and ischaemic colitis. He asserted that FDA officials were improperly motivated to maintain and reinstate the approval for alosetron because of the extent to which the FDA’s Center for Drug Evaluation and Research is funded by user fees paid by pharmaceutical manufacturers, and that the reinstatement of alosetron was negotiated in confidential meetings with representatives ofGlaxoSmithKline.

An article published in the British Medical Journal (BMJ) noted: “By allowing the marketing of alosetron, a drug that poses a serious and significant public health concern according to its own terms, the FDA failed in its mission.”^[13] Others have argued that the approval process of Lotronex was an example of regulatory capture.^[7]

Alosetron has an antagonist action on the 5-HT₃ receptors of the enteric nervous system of the gastrointestinal tract. While being a 5-HT₃ antagonist like ondansetron, it is not classified or approved as an antiemetic. Since stimulation of 5-HT₃ receptors is positively correlated with gastrointestinal motility, alosetron’s 5-HT₃ antagonism slows the movement of fecal matter through the large intestine, increasing the extent to which water is absorbed, and decreasing the moisture and volume of the remaining waste products.^[14]

IMPORTANT REF

Drugs Fut 1992, 17(8): 660

US 2012178937

JP 2012140415

WO 2010121038

US 200815392

WO 2006119329

JP 2005225844

WO 1999017755

WO 2001087305

WO 2001045685

US 5229407

US 5008272

The Alosetron hydrochloride is a potent and selective antagonist of the serotonin 5-HT3 receptor type. Chemically, Alosetron is designated as 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one, monohydrochloride. This is marketed in United States under trade name of LOTRONEX®

U.S. Pat. No. 5,360,800 discloses a preparation of Alosetron by condensing 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one with 4-chloromethyl-5-methylimidazole in presence of strong base such as sodium hydride. The sodium hydride was corrosive and highly flammable. This type of reaction required extra care, special type of equipments and it is commercially not feasible. This process also provides low yield.

U.S. Pat. No. 6,175,014 patent describes a process for the process Alosetron by reacting of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one of formula (II) with 4-hydroxymethyl-5-methylimidazole of formula (IIIa) or its salt in presence of mineral acid like hydrochloric acid or sulfonic acids such as p-toluene sulfonic acid or methane sulfonic acid. The process requires purification to get pure Alosetron.

Hence there is a need for a simple and commercially viable process for the preparation of Alosetron which avoids hazardous base such as sodium hydride.

The present inventors identified a new process for the preparation of Alosetron by reaction of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one of formula (II) with 4-hydroxymethyl-5-methylimidazole of formula (III) or its protected derivative. This process is simple to carryout for large scale preparation and industrially viable

medical use for compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT₃ receptors.

5-HT₃ receptor antagonists may be identified by methods well known in the art, for example by their ability to inhibit 3-(5-methyl-1H-imidazole-4-yl)-1-[1-[³H]- methyl-1 H-indol-3-yl]-1-propanone binding in rat entorhinal cortex homogenates (following the general procedure described by G Kilpatrick et al, Nature, 1987, 330, 746-748), and/or by their effect on the 5-HT-induced Bezold-Jarisch (B-J) reflex in the cat (following the general method described by A Butler et al, Br. J. Pharmacol., 94, 397-412 (1988)).

A number of different 5-HT₃ receptor antagonists have been disclosed, for example those of group A: indisetron, Ro-93777, YM-114, granisetron, talipexole, azasetron, tropisetron, mirtazapine, ramosetron, ondansetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620, lintopride, KAE- 393, itasetron, mosapride and dolasetron.

In UK Patent No. 2209335, incorporated herein by reference, there is disclosed, inter alia, the compound 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4- yl)methyl]-1H-pyrido[4,3-b]indol-1-one, now known as alosetron, which may be represented by the formula (I):

and pharmaceutically acceptable salts, solvates and pharmaceutically acceptable equivalents thereof, in particular its hydrochloride salt.

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

US20120178937

EXAMPLE 1 Process for the Preparation of Alosetron

To a mixture of acetic acid and dimethylformamide, 3N-BOC-(-hydroxymethyl-5-methyl imidazole (95.4 g), 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (50 g), trifluoroacetic acid were added and heated to 100-115° C. After completion of the reaction, the reaction mass was cooled to room temperature. To the reaction mass, carbon was added, stirred and filtered though hyflo bed. The bed was washed with dimethylformamide. The filtrate was distilled under vacuum. To the residue, water was added and washed the reaction mass with toluene followed by isopropyl ether. The pH of the reaction mass was adjusted to 6.8-7 using potassium carbonate solution, stirred, cooled and the obtained solid was dried.

EXAMPLE 2 Process for the Preparation of Alosetron

To trifluoroacetic acid, 3N-BOC-4-hydroxymethyl-5-methylimidazole (95.4 g), dimethylformamide (480 mL) and 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (58 g) were added and heated to 100-115° C. After completion of the reaction, the reaction mass was cooled to room temperature. To the reaction mass, carbon was added and filtered though hyflo bed. The bed was washed with dimethylformamide and the filtrate was distilled under vacuum. To the residue, water was added and washed the aqueous layer with toluene followed by isopropyl ether. The pH of the reaction mass was adjusted to 6.8-7 using potassium carbonate solution, cooled and the obtained solid was dried.

The above table clearly indicates that the use trifluoroacetic acid (TFA) enhances the reaction progress and also increases the yield of the product.

EXAMPLE 3 Purification of Alosetron

To acetic acid, crude Alosetron containing >0.2% of compound of formula (IV) was added and heated to 60-65° C., the reaction mass maintained at same temperature and cooled to 40-45° C. To the reaction mass acetone was added and refluxed. The reaction mass was cooled to 0-5° C., the solid obtained was filtered, washed with acetone (slurry) and dried to yield pure Alosetron having less than 0.02% of Impurity of formula (IV) by HPLC. Yield: 53-50 g

Reference Example 1 Preparation of Alosetron Hydrochloride

To a methanol (50 mL), Alosetron (10 g) and of IPA.HCl (8.5 mL) were added and heated to 40-45° C. The reaction mass was cooled, stirred and filtered and washed with methanol. The reaction mass was dissolved in methanol, treated with carbon, filtered and washed with methanol. The reaction mass was distilled and isopropyl ether was added to the residue and stirred at room temperature. The reaction mass was cooled, stirred. The solid obtained was filtered and washed with chilled methanol and dried.

Yield: 7.8 g Reference Example-2 Process for the preparation of 3N-BOC-(4-hydroxymethyl)-5-methylimidazole

4-Hydroxymethyl-5-methylimidazole (100 g) was dissolved in water, to the solution was added sodium carbonate (107 g) and stirred. To the reaction mass acetonitrile (400 mL) was added and cooled to 10-15° C. followed by addition of solution of DIBOC (di-tert-butyl dicarbonate) in acetonitrile. After completion of the reaction, water was added to the reaction mass and filtered. The filtrate was washed with 1:1 acetonitrile and water and than washed with hexane. The mass was extracted with toluene and the organic layer was washed with water followed by brine. The organic layer was distilled under vacuum to get oily mass of the title compound.

……………………………………..