FR2496463A1 - Gastric secretion redn. in mammals - by admin. of 1-aminoalkyl-2-phenyl-1,4,5,6-tetra: cyclo-penta-(b)-pyrrole or analogue - Google Patents

Abstract

Redn. of gastric secretion in a mammal involves admin. of a 1-aminoalkyl-2-phenyl-1,4,5,6- tetracyclopenta (b)pyrrole or analogue of formula (I) or its acid-addn. salt. In (I) Z is opt. branched, satd. or olefinically unsatd. hydrocarbyl chain of 2-5C, R1 is H or 1-3C alkyl, R2 is 1-3C alkyl or Ph, or NR1R2 is pyrrolidino, piperidino, piperazino, imidazolidonyl or morpholino, R3 is H, or Ph opt. substd. R4 is 1-6C alkyl, 1-4C alkoxy, halogen, CF3, OH, NO2, CN, NH2, MeCONH or Ph opt. substd., n is 0-3, X is 3-7C alkylene, and R5 is H, 1-5C alkyl, MeO or EtO. Cpds. (I) are gastric antisecretory and antiulcer agents. They are known antiarrhythmic, CNS depressant, anti-inflammatory and antihypertensive agents described in US3997557. Dose is 10-200 mg/kg daily orally.

Description

 The present invention relates to a composition for reducing gastric secretion or the formation of ulcers and, more particularly, for reducing gastric secretion or the formation of ulcers in bacteria, including in humans, with a substituted N-aminoalkylpyrrole.

 It is known that indole-lower alkane-carboxamides substituted in position 2 have anti-secretion or anti-ulcer activity (US Pat. No. 4,021,448 and 4,069,337). US Patent 3,997,557 describes substituted N-aminoalkylpyrroles as having antiarrhythmic activity, as being depressants of the central nervous system and as having anti-inflammatory and anti-hypertensive activities. No document describes or suggests the use of substituted N-aminoalkylpyrroles as anti-secretion agents or anti-ulcers.

 The subject of the invention is a composition for reducing gastric secretion or the formation of ulcers and, more particularly, for reducing gastric secretion or the formation of ulcers in mammals, using a substituted N-aminoalkylpyrrole.

dans laquelle Z est une chatne hydrocarbonée droite ou ramifiée, saturée ouàinsaturation oléfinique ayant de 2 à 5 atomes de carbone; R1 est un atome d'hydrogène ou un groupe alkyle de 1 à 3 atomes de carbone, R2 est un groupe alkyle de 1 à 3 atomes de carbone ou un groupe phényle; ou R1 et R2 ensemble avec l'atome d'azote sur lequel ils sont fixés forment un hétérocycle choisi parmi les radicaux pyrrolidinyle, pipéridino, pipérazinyle, imidazolidonyle et morpholino; R3 est un atome dthydro- gène ou un groupe phényle ou un groupe phényle substitué;Ra est un groupe alkyle ayant ce 1 à 6 atomes de carbone, un groupe alcoxy ayant de 1 à 4 atomes de carbone, un atome d'halogène, un groupe trifluorométhyle, hydroxy, nitro, cyano, amino, acétamide, phényle ou phényle substitué; n est un entier de O à 3 inclus; X est un radical alkylène ayant de 3 à 7 atomes de carbone; et R5 est un atome d'hydrogène, un groupe alkyle de 1 à 5 atomes de carbone, un groupe alcoxy ayant 1 ou 2 atomes de carbone ou un atome dthalogène, ou l'5un de ses sels d'addition avec des acides physiologiquement acceptables.The composition comprises an effective amount, for opposing gastric secretion or the formation of ulcers, of a substituted N-aminoalkylpyrrole of formula

in which Z is a straight or branched, saturated or olefinically unsaturated hydrocarbon chain having from 2 to 5 carbon atoms; R1 is a hydrogen atom or an alkyl group of 1 to 3 carbon atoms, R2 is an alkyl group of 1 to 3 carbon atoms or a phenyl group; or R1 and R2 together with the nitrogen atom to which they are attached form a heterocycle chosen from the pyrrolidinyl, piperidino, piperazinyl, imidazolidonyl and morpholino radicals; R3 is a hydrogen atom or a phenyl group or a substituted phenyl group; Ra is an alkyl group having this 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, a trifluoromethyl, hydroxy, nitro, cyano, amino, acetamide, phenyl or substituted phenyl group; n is an integer from 0 to 3 inclusive; X is an alkylene radical having 3 to 7 carbon atoms; and R5 is a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an alkoxy group having 1 or 2 carbon atoms or a halogen atom, or one of its addition salts with physiologically acceptable acids .

dans laquelle Z représente une chaîne hydrocarbonée droite ou ramifiée, saturée ou à insaturation oléfinique ayant de 2 à 5 atomes de carbone; R1 représente un atome d'hydrogène ou un radical alkyle ayant de 1 à 3 atomes de carbone;R2 représente un groupe alkyle ayant de 1 à 3 atomes de carbone ou un groupe phényle;
ou R1 et R2 ensemble avec l'atome d'azote sur lequel ils sont fixés forment un hétérocycle choisi parmi des radicaux pyrrolidinyle, pipéridino, pipérazinyle, imidazolidonyle et morpholino; R3 représente un atome d'hydro- gene ou un groupe phényle ou phényle substitué; R4 peut être en position méta, ortho ou para et représente un groupe alkyle ayant de 1 à 6 atomes de carbone, un groupe alcoxy ayant de 1 à 4 atomes de carbone, un atome d'halogène, un groupe trifluorométhyle, hydroxy, nitre, amino, cyano, acétamido, phényle ou phényle substitué5 n est un entier égal à 0, 1, 2 ou 3; et X est un radical alkylène ayant de 3 à 7 atomes de carbone, un groupe

et R5 est un atome d'hydrogène, un groupe alkyle ayant de 1 à 5 atomes de carbone, un groupe alcoxy ayant 1 ou 2 atomes de carbone ou un atome d'halogène ou l'un de ses sels d'addition avec des acides physiologiquement acceptables.The present invention more specifically relates to a composition having an anti-gastric secretion and anti-ulcer activity which comprises, as active principle, a substituted N-aminoalkylpyrrole of formula

wherein Z represents a straight or branched, saturated or olefinically unsaturated hydrocarbon chain having from 2 to 5 carbon atoms; R1 represents a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms; R2 represents an alkyl group having from 1 to 3 carbon atoms or a phenyl group;
or R1 and R2 together with the nitrogen atom to which they are attached form a heterocycle chosen from pyrrolidinyl, piperidino, piperazinyl, imidazolidonyl and morpholino radicals; R3 represents a hydrogen atom or a phenyl or substituted phenyl group; R4 can be in meta, ortho or para position and represents an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a halogen atom, a trifluoromethyl, hydroxy, nitre group, amino, cyano, acetamido, phenyl or substituted phenyl5 n is an integer of 0, 1, 2 or 3; and X is an alkylene radical having from 3 to 7 carbon atoms, a group

and R5 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 or 2 carbon atoms or a halogen atom or one of its addition salts with acids physiologically acceptable.

These compounds and their preparation are described in US Patent 3,997,557. Typical compounds are 1- (2-dimethylaminoethyl) -2-phenyl-4,5,6,7-'etra-hydroindole; 1- / 2- (1-imidazolidonylethylg7-2-phenyl-h, 5ss6,7-tetrahydroindole;
1- (2-dimethylaminoethyl) -2- (p-methoxyphenyl) -4,5,6,7-tetrahydroindole; 1- (3-dimethylaminopropyl) -2- (p-methoxyphenyl) -4J5, 6,7-tetrahydroindole; 2- (p-eromophenyl) -1- (3-dimethylaminopropyl) -415,6,7-tetrahydroindole; 2- (p-bromophenyl) -1- [2- (1-morphloinoethyl)] 4,5,6,7 tetrahydroindole; 1- (2-methylaminoethyl) -2- (m-trifluoroethylphenyl) -4,5,6,7-tetrahydroindole; 1- (3-di-imethylaminopropyl) -2- (p-chlorophenyl) -4,5,6,7-tetrahydroindole; 1- (2-isopropylaminopropyl) -2- (p-chlorophenyl) -4,5,6,7-tetrahydroindole; 2- (p-hydroxyphenyl-1- (2-isopropylaminoethyl) -4,5,6,7-tetrahydroindole; 1- (2-diisopropylaminoethyl) -2-p-hydroxyphenyl) -4,5,6X7-tetrahydroindole; 1- (2-diethylaminoethyl) -2-phenyl-5-methyl-4,5,6,7tetrahydroindole; 1- (2-diethylaminoethyl) -2-phenyl-5- (t-butyl) -4,5,6,7-tetrahydroindole; 1- (2-diethylamiffoethyl) -2-phenyl-5-methoxy-h, 5,6,7-tetrahydroindole; 1- (2-isopropylaminoethyl) -2-s (3,4-dichlorophenyl) -4,5,6,7-tetrahydroindole; 1- (3-dimethylaminopropyl) -2,3-diphenyl-4,5,6,7-tetrahydroindole; l- / 3- (1-pyrrolidinopropylg -2- (p-fluorophenyl) -4,5,6,7-tetrahydroindole; 1- (3-dimethylaminopropyl) -c-phenyl-4,5-dthydrobenz [g] -indole; 1 (3-dimethylamincpropyl) -2-phenyl-4,5-dShydrobenzZev indole; 1- (3 diethylaminopropyl) -4,5-dihydro-2-phenylbenzXe indole; 1- (3-methylaminopropyl) - 2-phenyl-7-chloro-4,5-dthydro-benz [e] indole; 1- (3-methylaminopropyl) -2-phenyl-l, X, 5,6-tetrahydro-cyclopenta / o7pyrrole; 1- (2-methylaminoethyl) -2- (m-trifluoromethylphenyl) 1,4,5,6,7, 3-hexahydrocyclohepta [b] pyrrole; 1- (3-dimethylaminopropyl) -2- (p-methoxyphenyl) -1, 4,5,6,7,8-hexahydrocylclohepta [be] pyrrole; 1- (3-methylaminopropyl) -2- (p-methoxyphenyl) -1,4,5,6,7,8-hexahydrocyclohepta [be] pyrole ; 1- (3-dimethylaminopropyl) -2- (p-bromophenyl) -1,4,5,6,7,8-hexahydrocyclohepta / pyrrole; 1- (3-dimethylaminopropyl) -2- (p-cyanophenyl) -1,4,5,6,7,8-hexahydrocyclohepta [b] pyrole; 1- (3-dimethylaminopropyl) -2- (p-nitrophenyl) -1,4,5,6,7,8-hexahydrocyclohepta [ b] pyrole; 1- (3-dimethylaminopropy l) -2- (p-aminophenyl) -1,4,5,6,7,8-hexahydrocyclohepta [b] pyrrole; 1- (3-dimethylaminopropyl) -2- (3,4,5-trimethoxyphenyl) - 1,4,5,6,7,8-hexahydrocyclohepta [b] pyrrole; 1- (3-dimethylaminopropyl) -2- (p-fluorophenyl) -1,4,5,6,7,8-hexahydrocyclohepta [b] pyrrole; 1- (3-dimethylaminopropyl) -2-phenyl-4,5,6,7,8,9-hexa hydrocycloocta / b? pyrrole; 1- (2-ethylaminoethyl) -2-phenyl-4,5,6,7,8,9-hexahydro cycloocta / pyrrole; 1- (3-dimethylaminopropyl) -2- (p-nitrophenyl) -4,5,6,7,8,9-hexahydrocycloocta [b] pyrrole; 1- (3-dimethylaminopropyl) -2- (p-aminophenyl) -4,526,7,8,9-hexahydrocycloocta [b] pyrrole; 1- (3-dimethylaminopropyl) -2- (p-fluorophenyl) -4,5,6,7,8,9-hexahydrocycloocta [b] pyrrole; 1- (3-dimethylaminopropyl) -2- (p-methoxyphenyl) -4s5,6,7,8,9-hexahydrooctaZbJpyrrole; 1- (3-methylaminopropyl) -2-phenyl-4,5,6,7-tetrahydro-dinol; 2- (p-bromophenyl) -1- (3-dimethylaminopropyl) -1,4,5,6,7,8-hexahydrocyclohepta [b] pyrrole; 2- (p-cyanophenyl) -1- (3-dimethylaminopropyl) -1,4,5,6,7,8-hexahydrocyclohepta [b] pyrrole; 1- (3-methylaminopropyl) -2-phenyl-7-chloro-4,5-di hydrobenz / e7indole; 1- (X-diethylaminopropyl) -2- (p-methoxyphenyl) -4,5,6,7,7,9-hexahydrocyclooctaib7pyrrole; 1- (4-diethylamino-2-butenyl) -2-phenyl-4,5,5,7-tetra-hydroindole hydrochloride; 1- (3-dimethylaminopropyl) -2-phenyl-1,4,5,6-terahydro cyclopenta'bjpyrrole; 1- (2-methylaminoethyl) -2-phenyl-1,4,5,6,7,8-hexahydrocyclohepta [b] pyrrole; 1- (3-diethylaminopropyl) -2-phenyl-1,4,5,6,7,8-hexa hydrocyclohepta / 7pyrrole; 1- (3-diethylaminopropyl) -2-phenyl-1,4,5,6,7,8-hexahydrocyclohepta [b] pyrole; and 1- (1-methyl-2-dimethylaminoethyl) -2-phenyl-1,4,5,6,7,8-hexa hydrocyclohepta / bJpyrrole; and physiologically acceptable salts of these compounds.

dans lequel X, Z, n, R1, R2 et R4 sont tels que définis précédemment. Dans un mode de mise en oeuvre, on laisse réagir la γ-dicétone et l'aminoalkylamine avec ou sans solvant tel que de l'acide acétique ou de l'éthanol à une température de 50 à 1200C pendant une période allant de quelques minutes à 24 heures en présence ou en l'absence d'un catalyseur acide tel que l'acide chlorhydrique.These compounds are prepared as described in US Pat. 3,997,557. More advantageously, the compounds used in the present invention are prepared by condensation of a suitable> -diketone with an appropriate aminoalkylamine or aminoalkyleneamine as illustrated by the following diagram

in which X, Z, n, R1, R2 and R4 are as defined above. In one embodiment, the gam-gamma; -diketone and the aminoalkylamine are reacted with or without solvent such as acetic acid or ethanol at a temperature of 50 to 1200C for a period ranging from a few minutes 24 hours in the presence or absence of an acid catalyst such as hydrochloric acid.

 When R4 represents NO2, the nitre group can be reduced by known methods, for example by stirring a solution of the corresponding compound in glacial acetic acid on a Parr hydrogenator with a catalyst consisting of charcoal. In addition, when R4 represents 9r, the bromine can be displaced by a cyano group according to known methods such as for example by refaction with cuprous cyanide.

 The gastric anti-secretion and antiulcer activity of the substituted N-aminoalkylpyrroles used in the present invention can be demonstrated by using conventional methods of biological tests such as those described in the patents U, S.

4 G21 448 and 4 069 337. In particular, the method described by Shay et al. (Gastroenterology 5, 43 (1945)) can be used to determine gastric antisecretion activity. The anti-ulcer activity of the substituted N-alkyl-aminopyrroles can be determined using the method described by Selmici et al. Acta.

Physiol, Acad. Sci. Hung. 25 (1), 101-104 (1964).

 It is clear that the actual determination of the biological effects obtained for each compound compound can be easily determined according to conventional test methods by specialists in pharmacological test methods without too much experimentation.

 The substituted N-aminoalkylpyrroles are administered in an effective amount sufficient to inhibit in mammals the secretion of gastric fluids and or inhibit stomach ulceration, in particular in an amount of 10 mg / kg of body weight per day at 200 mg / kg of body weight per day. The compounds are preferably administered orally.

 The compositions based on substituted N-aminoalkylpyrroles can be prepared in the form of unit doses such as tablets or capsules intended for oral administration to patients or animals, either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, sodium bicarbonate, sodium lauryl sulfate, sugar, dextrose, mannitol, cellulose, gum arabic, etc.

The compounds can also be put into a form suitable for oral administration in aqueous alcohol, glycol or oily solutions or oil-water emulsions in the same den as conventional therapeutic substances. They can be put in a form suitable for oral use with food or mixed with food for veterinary use.

Claims (3)

 1. A composition for reducing gastric secretion or ulcer formation which comprises an effective amount of a substituted N-aminoalkylpyrrole, of formula

 in which Z is a straight or branched, saturated or olefinically unsaturated hydrocarbon chain having from 2 to 5 carbon atoms'. R1 is a hydrogen atom or an alkyl group of 1 to 3 carbon atoms, R2 is an alkyl group of 1 to 3 carbon atoms or a phenyl group; or R1 and R2 together with the nitrogen atom to which they are attached form a heterocycle chosen from the pyrrolidinyl, piperidino, piperazinyl imidazolidonyl and morpholino radicals; R is a hydrogen atom or a phenyl group or a substituted phenyl group; R4 is an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a halogen atom , a trifluoromethyl, hydroxy, nitro, cyano, amino, acetamide, phenyl or substituted phenyl group; n is an integer from 0 to 3 inclusive; X is an alkylene radical having 3 to 7 carbon atoms; and R5 is a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an alkoxy group having 1 or 2 carbon atoms or a halogen atom, or one of its addition salts with acids physiologically acceptable.  2. Composition according to claim 1, Z is a straight or branched, saturated, hydrocarbon chain having 2 or 3 carbon atoms; R3 is hydrogen or a phenyl group; R4 is a methyl, methoxy, bromo, chloro, fluoro, hydroxy, trifluoromethyl, nitro, amino or cyano group; X is a polymethylene radical having 3 to 6 carbon atoms; and R5 is a hydrogen atom, an alkyl group of 1 to 4 carbon atoms or a methoxy group.  3. Composition according to claim 2, characterized in that the substituted N-aminoalkylpyrrole is 1- (3-dimethylaminopropyl) -2-phenyl-1,4,5,6-tetrahydrocyclopenta [b] pyrrole, 1- (3 -dimethylaminopropyl) -2- (p-bromo-phenyl) -4,5,6,7-tetrahydroindole, 1- (3-dimethylaminopropyl) -2- (p-methoxyphenyl) -4,5,6,7, - tetrahydroindole, 1- (2-methylaminoethyl) 2- (m-trifluoromethylphenyl) -4,5,6,7-tetrahydroindole, 1 (3-dimethylaminopropyl) -2,3-diphenyl-4,5,6,7- tetrahydroindole, 1- (2-methylaminoethyl) -2-phenyl-1,4,5,6,7,8-hezahydrocyclohepta [b] pyrrole, 1- (3-diethylaminoproyl) -2-phenyl-1, 4, 5,6,7,8-hexahydrocyclohepta [b] pyrrole, 1- (3-diethylaminopropyl) -2-phenyl-1,4,5,6,7,8-hexahydrocyclohepta [b] pyrrole, 1- (1 -methyl-2-dimethylaminoethyl) -2-phenyl-1,4,5,6,7,8, hexahydrocycloheptaZb7pyrrole, 1- (3-methylaminopropyl) - 2- (p-methoxyphenyl) -1,4,5,6 , 6,8-hexahydrocyclohepta [b] pyrrole, 1- (2-ethylaminoethyl) -2-phenyl-4,5,6,7,8,9-hexahy drocycloocta [b] pyrrole, 1- (3-dimethylaminopr pyl) -2- (paminophenyl) -4,5,6,7,8,9-hexahydrocycloocta [b] pyrrole or one of their addition salts with physiologically acceptable acids.