Use of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide for the manufacture of a medicament having anti-emetic activity.

Abstract: 2-Alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl) benzamides and thiobenzamides having the formula wherein X is oxygen or sulphur; R₁ is loweralkyl; and R₂ is hydrogen, halo, 4,5-benzo, alkoxy or Am wherein Am is amino, methylamino or dimethylamino, and n is 1 or 2, and the pharmaceutically acceptable acid addition salts thereof have gastrokinetic and anti-emetic activity.

Description: The present invention relates to a N-(3-quinuclidinyl) benzamide namely the 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxy benzamide and the pharmaceutically acceptable acid addition salts thereof, which have been observed to exhibit antiemetic properties in warm blooded animals with minimal neuropharmacological side effects. The invention is also concerned with a method of and compositions for alleviating emesis, particularly emesis due to administration of platinum anticancer drugs such as cisplatin. Quinuclidine analogues of sulpiride were prepared and studied by Mikhlina, E. E. et al as reported in Khim-Farmatsevt. Zh. 10 , No. 11, 56-60 (1976); C.A. 86 : 155489r exemplified by the compound: 5-aminosulphonyl-N-(1-azabicyclo [2.2.2]oct-3-yl)-2-methoxybenzamide. This compound and others in the series were reported by the authors not to have antiemetic activity. The above named compound was reported in USSR Patent SU-414-261 to have neuroleptic activity. In comparison, the compounds of the present invention show strong antiemetic activity without neuroleptic activity (blockade of d-amphetamine lethality in mice). Syntheses of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl) benzamide and N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide were reported by Mikhlina, E. E. et al in Khim - Farmatsevt. Zh. 7 , 20-24 (1974); C.A. 79 , 146358a and the latter in Khim . Geterosikl. Soedin., Akad. Nauk. Latv. SSR 243-9 (1966); C.A. 65 : 2220b. These compounds were reported to exhibit hypotensive, narcotic and ganglionic stimulation and blocking activities, properties not seen in the compounds of the present invention. Synthesis of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-chloro-5-trifluoromethylbenzamide was reported in DE-A- 2,548,968; C.A. 87 , 68001c and in equivalently related U. S. 4,093,734 from 4-amino-3-chloro-5-trifluoro-methyl benzoic acid chloride and 3-aminoquinuclidine. The compound is in a class among pyrrolidinyl and piperidinyl benzamides which are said to be useful as anxiolytics, anticonvulsives, antiemetics and antiulcerogenics. None of the compounds have orthoalkoxy substitution on benzamide as do the compounds of the present invention. It is widely recognized that substituted benzamides are a class of drugs known to be effective in psychiatry and gastroenterology (Sulpiride and other Benzamides; International Workshop on Sulpiride and other benzamides, Florence, Feb. 17-18 (1978), Raven Press]. However, the compounds of this invention exhibit an anti-emetic activity and do not show neuropharmacological activity. This is in marked contrast to the compounds described in the prior art which show a range of pharmacological activities that include both neuropharmacological and gastrointestinal effects. Aspects of the invention include : (a) The use of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxyhensamide or a pharmaceutically acceptable acid addition salt thereof, in the manufacture of medicaments having antiemetic activity ; (b) A method of reducing the emetic property of a pharmaceutical agent comprising a platinum anti-cancer drug, the method comprising admixing with the agent the compound or salt as defined under (a); (c) A pharmaceutical composition comprising a platinum anti-cancer drug and the compound or salt as defined under (a); (d) A product containing a platinum anti-cancer drug and an antiemetic effective amount of the compound or salt as defined under, (a) for use as a combined preparation for simultaneous, separate or sequential use in cancer therapy. "Pharmaceutically acceptable acid addition salts" include the acid addition salts, hydrates, alcoholates and salts of the compound, which salts are pysiologically compatible in warm blooded animals. The acid addition salts may be formed by either strong or weak acids. Representative of strong acids are hydrochloric, sulphuric and phosphoric acids. Representative of weak acids are fumaric, maleic, succinic, oxalic, citric, tartaric, cyclohexamic and the like. Anti-emetic properties in the control of emesis due to administration of platinum anti-cancer drugs were determined by a modification of the method described by Gylys, J. A., in Res. Commun. Chem. Pathol. Pharmacol. 23, No. 1, Jan. 1979, pp 61-68 as follows: cisplatin (cis-diammine-dichloro-platinum) is administered at a dose of 3 mg/kg intravenously to non-fasted dogs (both sexes). Ninety minutes after cisplatin administration, the test drug in saline at a dose volume of 2 ml/kg is administered intravenously. A control group of dogs are given the cisplatin followed by saline at 90 min without test drug. The dogs are observed continuously for a period of 5 hr counting the number of emetic episodes compared to emetic episodes observed for the controls. Utilizing this procedure, the compound of Example 1, administered in a single dose of 1 mg/kg gave 68% reduction in the number of emetic episodes. The free base of the invention compound from its acid addition salt may be regenerated by usual procedures of partitioning between dilute aqueous base and a suitable solvent, separating the solvent layer, drying and evaporating. The invention compounds are highly potent as anti-emetics in conjunction with cisplatin cancer treatment, being more potent than metoclopramide and devoid of undesirable neuroleptic side effects even at much higher doses than required for their antiemetic effects. The following examples are provided merely by way of illustrating the methods of preparation of the compounds of the invention and salts thereof and are not to be construed as being limiting in nature. Example 1 4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, fumarate [1:1]. In a closed system equipped with an oil bubbler, 30 ml of tetrahydrofuran was added to a mixture of 4-amino-5-chloro-2-methoxybenzoic acid, 2.02 g, (0.010 mole) and 1,1'-carbonyldiimidazole, 1.62 g (0.010 mole) with stirring. When evolution of carbon dioxide ceased, nitrogen was bubbled through the reaction mixture for 1 hr. A solution of 3-aminoquinuclidine, 1.26 g, (0.010 mole) in 10 ml tetrahydrofuran was added dropwise to the stirred reaction mixture and stirring at room temperature continued for 3 hrs. TLC analysis (3% conc. ammonium hydroxide solution in methanol) showed some product formation. The mixture was heated at reflux temperature for 18 hours and then concentraded to an oil. TLC analysis showed the presence of the product, imidazole, and 3-aminoquinuclidine. The oil was dissolved in methylene chloride (75 ml) and washed twice with 50 ml portions of aqueous sodium bicarbonate solution. The methylene chloride layer was dried over anhydrous magnesium sulphate and concentrated to yield 2.0 g (67%) of a glassy amorphous solid, the free base of the title compound. In another reaction on a 0.020 mole scale, 5.18 g (83.8%) of the product as the free base was obtained. The products were combined, dissolved in methanol (20 ml)and the solution and treated with a solution of fumaric acid (2.73 g) in methanol (50 ml). Absolute ether was added to precipitate the salt which was collected by filtration and recrystallized from methanol-water (200:20) with isopropyl ether added to the point of incipient cloudiness. The recrystallized salt (5.38 g) melted at 223-225°C. Analysis: Calculated for C₁₉H₂₄N₃O₆Cl C,53.59; H,5.68; N,9.89 Found C,53.35; H,5.72; N,9.95 Example 2 4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, hydrochloride, hydrate (1:1:1). To an isopropyl alcohol solution of the free base of the title compound such as was obtained by the procedure of Example 1 is added an equal molar amount of 37% (conc.) hydrochloric acid. The crude salt is separated by filtration and recrystallized from acetone-water to give the title compound, m.p. 158-160°C. Pharmaceutical Methods and Compositions Generally, the method of controlling emesis in accordance with this invention comprises administering internally to warm blooded animals including human beings 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, or a non-toxic organic or inorganic acid addition salt thereof in a wide variety of pharmaceutical forms well known in the art, preferably with a non-toxic pharmaceutical carrier such as is described below in an amount to control emesis. The active agent is administered orally, subcutaneously, intravenously or intramuscularly or parenterally and, if necessary, in repeated doses until satisfactory response is obtained. The daily dosage is from about 5 to about 300 mg of active agent, advantageously from about 5 mg to 50 mg. Co-administration of the invention compounds and the platinum drug is within the purview of the method of this invention. In the particular method of controlling emesis due to administration of platinum drugs in cancer treatment, it may at times be desirable to administer a mixture composed of the invention compounds and the platinum drug to the animal, including humans, the daily dosage being within the range cited above. The pharmaceutical compositions for general use as antiemetics of this invention comprise at least one of the invention compounds, as active ingredients in an amount to provide effective antiemetic action. The compositions contain 0.05 to 100 mg active agent per unit dose. Preferably, the compositions contain from about 5 mg to 100 mg of active agent, advantageously from about 5 mg to about 50 mg per unit dose. The compounds are thus presented in a therapeutic composition suitable for oral, parenteral, subcutaneous, intramuscular, intraperitoneal or intravenous administration. Thus, for example, compositions for oral administration can take the form of elixirs, capsules, tablets or coated tablets containing carriers conveniently used in the pharmaceutical art. Exemplary of solid carriers including tableting and capsulating excipients are lactose, sucrose, potato and maize starches, talc, gelatin, agar, pectin or acacia, stearic and silicic acids, magnesium stearate, terra alba and polyvinyl pyrrolidone. For parenteral administration, the carrier or excipient can be composed of a sterile parenterally acceptable liquid; e.g., water or arachis oil contained in ampoules. The pharmaceutical compositions for use in conjunction with administration of platinum drugs in cancer treatment will be formulated to contain from about 0.1 mg/kg to about 3.0 mg/kg body weight, preferably 1.0 mg/kg body weight or less. As stated above, co-formulation of platinum anticancer drug and invention compounds are within the scope of this invention and it is only necessary that the active ingredient constitutes an effective amount. In all of the above, it is only necessary that a suitable effective dosage will be consistent with the dosage form employed. The exact individual dosages, as well as daily dosages, will of course be determined according to standard medical principles under the direction of a physician or veterinarian. Generally, the pharmacology tests on rats in comparison to metoclopramide suggests that much less of the active agent selected from the invention compounds would be required for a given antiemetic effect than would be required for metoclopramide and dosages can thereby be estimated to some extent.

Claims: The use of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, or a pharmaceutically acceptable acid addition salt thereof, in the manufacture of a medicament having antiemetic activity. A method of reducing the emetic property of pharmaceutical agent comprising a platinum anti-cancer drug, the method comprising admixing the agent with 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a platinum anti-cancer drug and 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide or a pharmaceutically acceptable salt thereof. A product containing a platinum anti-cancer drug and 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide or a pharmaceutically acceptable acid addition salt thereof, for use as a combined preparation for simultaneous, separate or sequential use in cancer therapy.

Inventors: BOSWELL ROBERT FREDERICK JR, MUNSON HARRY RANDALL JR, BOSWELL, ROBERT FREDERICK, JR., MUNSON, HARRY RANDALL, JR.
Applicants: SYNTHELABO
Application year: 1985
Main classification: C07D453
IPC codes: A61P1, A61K31, C07D453