TROPISETRON

89565-68-4
105826-92-4 (HCl)

Novartis (Originator)

Tropisetron (INN) is a serotonin 5-HT₃ receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia.^[1] The drug is available in a 5 mg oral preparation or in 2 mg intravenous form. It is marketed by Novartis in Europe, Australia, New Zealand, Japan, South Korea and the Philippines as Navoban, but is not available in the U.S. It is also available from Novell Pharmaceutical Laboratories and marketed in several Asian countries as Setrovel

Tropisetron is a 5-hydroxytryptamine receptor 3 (5-HT3) antagonist that was launched in 1992 by Novartis for the oral and injection treatment of chemotherapy-induced emesis. The drug has also been approved for the prophylaxis and treatment of post-operative nausea and vomiting, and is available in capsule and ampule formulations. In terms of clinical development, phase III trials were being carried out by the National Institute of Mental Health (NIHM) as an adjunct to risperidone therapy for the treatment of schizophrenia, but no recent development has been reported. Clinical trials for the treatment of fibromyalgia have also been conducted by Novartis, although recent progress reports on this indication have not been made available.

5-HT3 receptors are excitatory ligand-gated cation channel receptors that can be found in the presynaptic vagal afferents, the area postrema and the gastrointestinal tract. Stimulation of these receptors seems to be important in the emetic response and the gag reflex. It has also been shown that tropisetron shows agonistic effects on the 7 nicotinic acetylcholine receptor. This receptor is associated with auditory sensory gating, a neural mechanism believed to have important roles in information processing and cognition, both diminished in people with schizophrenia.

Tropisetron acts as both a selective 5-HT₃ receptor antagonist and α₇-nicotinic receptor agonist.^[2][3]

Tropisetron is a well-tolerated drug with few side effects. Headache, constipation, and dizziness are the most commonly reported side effects associated with its use. Hypotension, transient liver enzyme elevation, immune hypersensitivity syndromes and extrapyramidal side effects have also been associated with its use on at least one occasion.There have been no significant drug interactions reported with this drug’s use. It is broken down by the hepatic cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system.

As a biological stain and as trypanocide.

Tropisetron was originally developed by Novartis, and rights to the drug were subsequently acquired by Asta Medica (now, part of Meda). In December 1997, Novartis and Kyowa Hakko signed an agreement, pursuant to which the companies would copromote the product in Japan. Tropisetron is currently distributed in various countries worldwide, including Belgium, Germany, Italy, Japan, The Netherlands, Sweden and the U.K.

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• Official site
• Navoban data sheet

• Tropisetron hydrochloride (CAS 105826-92-4)

  Application: A potent SR-3 antagonist CAS Number: 105826-92-4 Purity: ≥99% Molecular Weight: 320.82 Molecular Formula: C17H20N2O2 HCl

• Navoban™ IS THE FORMULATION

Tropisetron hydrochloride is a potent SR (SR-3) antagonist. It is also a selective, partial agonist at AChR α 7 (α7 nicotinic receptors). Tropisetron hydrochloride is an inhibitor of HTR3.

1alphaH,5alphaH-Tropan-3alpha-yl Indole-3-carboxylate, could be produced through many synthetic methods.

Following is one of the synthesis routes: Indole 3-carbonyl chloride (I) is condensed with endo-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (II) in the presence of butyllithium in THF, or Na₂CO₃ in the same solvent to produce the final product of Tropisetron.

IMPORTANT REFERENCES

Drugs Fut 1986, 11(2): 106

US 4789673

CN 102532128

CN 102887893

WO 2013123426

WO 2007099069

WO 2009033305

WO 2003032897

WO 2004054552

WO 2005105089

WO 2000048597

WO 2000048581

CN101033225A	2 Apr 2007	12 Sep 2007	北京成宇化工有限公司	Process of preparing troipisetron
CN101787021A	5 Mar 2010	28 Jul 2010	王明	High-purified tropisetron hydrochloride compound
US4789673	10 Nov 1987	6 Dec 1988	Peter Donatsch	Heterocyclic carboxylic acid amides and esters

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5-HT₃ receptor antagonists are a class of compounds which block 5-HT₃receptors, and are also sometimes classified as serotonin M receptor antagonists. The 5-HT₃ receptor antagonists comprise a defined and recognised class of pharmaceutically active compounds well known in the art and characterised, as their name implies, by their pharmacological activity. Various 5-HT₃ receptor antagonist compounds are commercially available and clinically applied, e.g. in the treatment of emesis.

5-HT₃ receptor antagonists from various sources have been published for a wide variety of uses, for example for the treatment of visceral pain, migraine, vascular and cluster headache, trigeminal neuralgia, arrhythmia, serotonin-induced gastro-intestinal disorders, including emesis induced by anti-cancer agents, anxiety, stress-related psychiatric disorders, depression, cognitive disorders, social withdrawal, panic attacks, agoraphobia, lung embolism, rhinitis or serotonin-induced nasal disorders, fibromyalgia and local treatment of pain caused by various non-inflammatory or inflammatory conditions. Some have been commercially introduced for the treatment of emesis.

In accordance with the present invention it has now surprisingly been found that 5-HT₃ receptor antagonists are useful for the treatment of diseases caused or influenced by activation of thrombocytes.

Thrombocytes play a central role in blood coagulation (clotting) and are therefore also of high importance in the pathogenesis of cardiac infarction and stroke, furthermore also in thrombosis of the veins and inflammatory conditions in the development of atherosclerosis.

Activation of thrombocytes causing blood clotting is based on several mechanisms. It has ^■ now been demonstrated that 5-HT₃ receptors are present on platelets and that the number of these receptors at the platelet surface is increasing in a dose dependent fashion on addition of ADP (adenosine diphosphate) or TRAP (thrombin receptor activating peptide) known to stimulate thrombocyte activation. The increase of 5-HT₃ receptors on addition of compounds inducing aggregation such as ADP and TRAP is proof that such receptors play a role in thrombotic processes. Platelet activity is also important in inflammatory processes in atherosclerotic conditions. Thrombocytes activated by thrombin may, as is already known, induce the production of I L- 1 β , IL-8, MCP (monocyte chemoattractant protein) and other inflammation mediators These are impeded by 5-HT₃ receptor antagonists. This demonstrates that 5-HT₃ receptor antagonists not only influence blood coagulation but also processes playing a role in the development of atherosclerosis.

Hence, the present invention relates to the use of a 5-HT₃ receptor antagonist or of a pharmaceutically acceptable salt of such an antagonist for the manufacture of a pharmaceutical composition for the treatment of a disease caused or influenced by activation of thrombocytes, in particular myocardial infarction, stroke, thrombosis and atherosclerosis.

Any 5-HT₃ receptor antagonist can be used in accordance with the invention. Preferred 5-HT₃ receptor antagonists which may be employed in accordance with the present invention are ondansetron, 1 ,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1 H-imidazol-1-yl)- methyl]-4H-carbazol-4-one (cf. Merck Index, twelfth edition, item 6979), granisetron, ‘ endo-1-methyl-N-(9-methyl-9-aza-bicyclo[3.3.1]non-3-yl)-1 H-innidazole-3-carboxamide . (cf. loc. cit, item 4557), or dolasetron, 1 H-indole-3-carboxylic acid (2α,6α,8α,9αβ)- octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester, (cf. loc. cit., item 3471). ■•

Particular 5-HT₃ receptor antagonists which may be employed in accordance with the ■ present invention are those of the formula 1 as defined in European Patent Publication EP O 189 002 B1, in particular tropisetron, indol-S-yl-carboxylic acid-endo-δ-methyl-δ-aza- bicyclo[3,2,1]-oct-3-yl-ester, (cf. loc. cit., item 9914), ramosetron, 4,5,6,7-tetrahydro-5- [(1-methyl-indol-3-yl)carbonyl]benzimidazole (U.S. Pat. No. 5,344,927), fabesetron, (+)- 10-methyl-7-(5-methyl-1 H-imidazol-4-ylmethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (EP 0 361 317), lintopride, N-(1-ethyl-2-imidazolin-2-y-methyl)-2-methoxy-4-amino-5- chlorobenzamide (Chem. Abstr. No. 107429-63-0), alosetron, 2,3,4,5-tetrahydro-5-methyl- 2-[(5-methyl-1 H-imidazol-4-yl)methyl]-1 H-pyrido[4,3-b]indol-1-one (EP 0 306 323), cilansetron, (-)-(R)-5,6,9,10-tetrahydro-10-[(2-methylimidazol-1-yl)methyl]-4H-pyrido- (3,2,1-jk)carbazol-11(8H)-one, palonosetron, 2-(3S)-1-azabicyclo[2.2.2]oct-3-yl-2,3,3a(S), 4,5,6-hexahydro-1 H-benz(de)isoquinolin-1-one, azasetron, N-(1-azabicyclo[2.2.2]octan-8- yl)-6-chloro-4-methyl-3-oxo-1 ,4-benzoxazine-8-carboxamide, and zatosetron, 5-chloro- 2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-3H-1-benzofuran-7-carboxamide.

5-HT₃ receptor antagonists may be employed in accordance with the invention in free or in pharmaceutically acceptable salt form, e.g. as known in the art, for example, in the case of compounds mentioned above in pharmaceutically acceptable acid addition salt form, for example, in the case of ondansetron as the hydrochloride dihydrate, granisetron as the hydrochloride, dolasetron as the mesylate, tropisetron as the monohydrochloride, ramosetron, fabesetron, alosetron and cilansetron as the hydrochlorides, palonosetron as the monohydrochloride, azasetron as the hydrochloride, and zatosetron as the maleate.

References to 5-HT₃ receptor antagonists collectively or individually throughout the present specification and claims are accordingly to be understood as embracing both free compounds and such pharmaceutically acceptable salt forms, e.g. as clinically employed, and further also solvates, e.g. hydrates, or specific crystal forms of any of these compounds or salts.

For use in accordance with the present invention tropisetron (especially in the formulation called Navoban™) is most preferred.

tropisetron hydrochloride is a peripheral neurons and central nervous system 5 – hydroxytryptamine 3 (5-ΗΤ3) receptors potent, highly selective competitive antagonist, mainly by selectively blocking peripheral neurons presynaptic 5-ΗΤ3 receptors inhibit vomiting reflex. For the prevention and treatment of child and adult cancer chemotherapy, radiotherapy and post-operative nausea and vomiting caused.

About tropisetron hydrochloride preparation of patent literature, including (for example): US4797406, US 4789673, CN 101033225, CN 101838266, CN 101787021. Tropisetron hydrochloride preparation generally is this: the firstsynthesis of acid chloride intermediates, and then through esterification acidification, refining and other steps, resulting tropisetron hydrochloride.

The preparation method has, in U.S. Patent (US3980668, US4789673, US4797406, US4803199) described with indole-3 – carboxylic acid with oxalyl chloride, treatment with methylene chloride and n-hexane to give 3 – methyl indole chloride, then with tropenol activation in n-butyl lithium produced under tropenol lithium reaction was treated to obtain tropisetron, and the final hydrochloride salt obtained tropisetron hydrochloride

in which the U.S. patent literature US 4797406 and US 4789673 introduces the indole-3 – carboxylic acid with oxalyl chloride to give 3 – indole chloride then with tropenol activation in n-butyl lithium in the reaction system tray alkyl granisetron. This method uses expensive n-butyl lithium and polluting chloride compound, and the multi-step, only about 20% yield.

Chinese patent literature described in CN 101033225 is improved indolesynthesis _3_ chloro acid as raw material of 1,3 – dimethyl-2 – chloro-imidazoline as the condensing agent, an organic base directly under conditions esterified with tropenol obtain the target product. Although this method avoids the acylation step, a condensing agent in preparing dimethyl-2-chloro-1,3 _ – chloro-imidazoline must use highly toxic phosgene, so there is an obvious lack of this route.

In the literature [tropisetron hydrochloride synthesis improvements, Huaihai Institute of Technology, 2003; 12 (4): 4 wide 43; tropisetron hydrochloride Improved synthesis of Hunan Normal University (Medical Sciences), 2006; 3 (4): 29 ^ 30], respectively, 50%, 52.8% obtained in a yield tropisetron hydrochloride, but still use of expensive n-butyl lithium as a condensation reaction activator.

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CN102532128A

Example 2:

[0071] The indole-3 – carboxylic acid (20 g, 0. 124mol), benzenesulfonic acid (0. 791g, 0. 005mol), ethyl acetate (230ml), freshly activated 4A molecular sieves (0. 5-1 . Omm) (3 g) was added to a equipped with a thermometer, reflux condenser, 500ml three reaction flask, stir began to heat up, the temperature controlled at 75 ° C _77 ° C, and then began a slow drip Gato Decanter (19. 3 g, 0. 137mol), after the addition was complete the reaction refluxed for 11 hours.

[0072] The reaction was stopped, the organic layer was washed with IOOml a lmol / L of hydrochloric acid, extracting the product three times, the combined aqueous phase was then washed once with 50ml of ethyl acetate. Aqueous phase was 4mol / L sodium hydroxide aqueous solution was adjusted to pH = 9_10, precipitated yellow solid was suction filtered cake was washed with distilled water to neutral, dried under reduced pressure to obtain 33.1 Hector alkoxy granisetron crude. The crude product was dissolved at 60 ° C in 180ml of anhydrous ethanol was slowly added dropwise 12mol / L hydrochloric acid until the pH value 1_2, _5 ° C under crystallization 6 hours, filtered, the filter cake washed with ethanol to white . Drying get tropisetron hydrochloride concept .3 g, yield 71.1% (to indole-3 – carboxylic acid basis), as measured by liquid chromatography purity of 99.56%.

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CN102584815A

[0016] (3) tropisetron hydrochloride Preparation:

A solution of indole-3 – carbonyl chloride in THF was slowly added dropwise to sodium tropine THF solution, 35 ° C the reaction was stirred overnight, vacuum distillation recovery THF, and recrystallized from 95% ethanol to give a pale yellow solid adding 70mL ethanol, dissolved by heating, cooling pass into the HCl gas at room temperature, the reaction was stirred for 30min, filtered, tropisetron hydrochloride was crude. Recrystallization from absolute ethanol to give white crystalline product 21. 2g (Liquid chromatographic purity 99.91%), total yield of 53.29%, a melting point of view 3185, the product spectrum consistent with the literature.

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CN101787021B

Example 5 tropisetron hydrochloride refined

[0063] (a) The IOOg tropisetron hydrochloride was dissolved in 500ml water, then slowly adding 12% (g / ml) of sodium carbonate solution was stirred until the solution PH 8, resulting tropisetron sedimentation, filtration , 40 ° C under reduced pressure and dried to give tropisetron 84. lg.

[0064] (2) obtained in the above Step Tropisetron 84. Ig dissolved in 400ml ethanol, 5. 2g of activated charcoal, stirred at room temperature for 40 minutes, filtered decarbonization, collecting the filtrate.

[0065] (3) The use of the filtrate obtained in step purified by preparative chromatography separation tropisetron hydrochloride refined products, including the column using a mobile phase as the mobile phase volume accounted for 32% of total current volume of methylene chloride and with 68% aqueous hydrochloric acid to pH 1; stationary phase filler is silica; flow rate of 6. 2ml/min; column temperature: 25 ° C. The filtrate was collected, dried under reduced pressure, to obtain purified tropisetronhydrochloride 91. 7g, yield 91. 7%, HPLC purity of 99.9% method.

[0066] Elemental analysis = C17H21ClN2A

[0067] Theoretical value (%): C: 63. 65, H: 6. 60, N: 8. 73, Cl: 11. 05;

[0068] Found (%): C: 63. 62, H: 6. 64, N: 8. 74, Cl: 11. 06.

[0069] UV (MeOH) Amax: 214 (ε 38,222), 229 (ε 17,438), 282 (ε 13,405).

[0070] IR (KCl) CnT1: 3219,2496 (NH), 3103,748 (Ar CH), 2966,1428 (CH), 1692 (C = 0), 1580,1525 (Ar C = C), 1311, 1128 (CN), 1033 (CO).

[0071] 1HNMR (DMSO-D6) δ: 2. 10 (d, 2H, CH2), 2 · 32 (d, 4H, CH2), 2 · 52 (m, 2H, CH2), 2. 68 (s, 3H, CH3), 3. 88 (s, 2H,-CH), 5. 14 (s, H, CH), 8. 03 (m, H, CH), 8. 08 (d, H, CH), 10. 81 (s, H, HCl), 12. 10 (s, H, NH).

[0072] ESI-MS; EI m / z: 285 (M + H, 100%), 284 (M +, 21. 72%) ”

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CN102351857B

Example 1

[0048] equipped with stirrer, thermometer, condenser IOOOml reaction flask, add 80 grams of tropisetron hydrochloride (I Ci refined products) and 560ml of acetone-water (8:2) mixture, start stirring, heating heated to 60 ° C _65 ° C, until all dissolved clear, incubated for 30 minutes, filtered while hot. The filtrate was cooled to room temperature, and then incubated for 2 hours, crystalline precipitation, filtration, drying ie high purity tropisetron hydrochloride crystals, mp: 280.10C -281.1 ° C, purity 99.96% (HPLC normalization method), the solvent residue testing to meet the requirements.

[0049] Elementary analysis:

[0050] Found (calculated value), C: 63.64 (63.57), H: 6.60 (6.62), N: 8.73 (8.72),

[0051] Cl: 11.05 (11.01);

[0052] X-ray diffraction of the crystal shown in Figure 1. Instrument model and measurement conditions: Rigaku D / max 2500 type diffractometer; CuKa 40Kv 100mA; 2 Θ scan range: 0 – 50 °;

[0053] The infrared spectrum of this crystal is shown in Figure 2, as measured by KBr tablet.

 

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DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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