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US 4,908,367 AGranted
N-(1H-indole-4-yl)-benzamides
AssigneeRoussel Uclaf
InventorsFrancois Clemence, Jacques Guillaume, Gilles Hamon
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AssigneeRoussel Uclaf
InventorsFrancois Clemence, Jacques Guillaume, Gilles Hamon
Estimating the term…
Novel indole carboxamides of the formula ##STR1## wherein R and R.sub.1 are individually selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 4 to 7 carbon atoms and aralkyl of 7 to 12 carbon atoms optionally substituted with 1 to 3 members of the group consisting of halogen, methyl, ethyl, methoxy, ethoxy, --CF.sub.3, CH.sub.3 S--, --NH.sub.2 and --NO.sub.2 or R.sub.1 and R taken together with the nitrogen atom form an optionally unsaturated heterocycle optionally containing a member of the group consisting of --O--, --S-- and ##STR2## R' is selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, phenyl, naphthyl, aralkyl of 7 to 12 carbon atoms and substituted phenyl, R.sub.3 is selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 3 carbon atoms, chlorine, bromine, iodine, --NO.sub.2, --NH.sub.2, acylamide of an aliphatic carboxylic acid of 2 to 5 carbon atoms and mono and dialkylamino with alkyl of 1 to 5 carbon atoms, a and b form .dbd.O and c is hydrogen or a and c form a carbon-carbon bond and b is hydrogen, A is selected from the group consisting of --(CH.sub.2).sub.n -- and ##STR3## n is an integer from 2 to 5, m is an integer from 1 to 3, B is ##STR4## R.sub.2 is selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having remarkable anti-arrhytmic properties.
A compound of the formula ##STR46## wherein R.sub.1 and R form, with the nitrogen atom to which they are attached, ##STR47## in which Z is naphthyl, benzyl, phenethyl ##STR48## n.sub.1 is 1, 2, or 3 and X, X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5 and X.sub.6 are individually selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen, nitro, amino, monoalkylamino or dialkylamino radical, with the proviso that X, X.sub.1 and X.sub.2 are not all three hydrogen, A is --(CH.sub.2).sub.n, --n is 2, 3, 4 or 5 or ##STR49## in which m is 1, 2 or 3, B is --CO--NH-- or --NH--CO--, R.sub.3 is hydrogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 3 carbon atoms, chlorine, bronine or iodine, nitro or amino unsubstituted or substituted with an aliphatic acyl of 2 to 5 carbon atoms or with alkyl of 1 to 5 carbon atoms, a together with b is an oxo group, or together with c is a second bond between the carbons which bear them, b is hydrogen or together with a is an oxo, c is hydrogen or together with a is a second bond between the carbons which bear them, and R.sub.2 is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl or alkynyl of 2 to 5 carbon atoms or aralkyl of 7 to 12 carbon atoms unsubstituted or substituted with 1, 2 or 3 members of the group consisting of halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, methylthio, amino and nitro or cycloalkylalkyl of 4 to 7 carbon atoms and its non-toxic, pharmaceutically acceptable acid addition salts.
Dependencies are inferred from the claim text.
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Indoles; Hydrogenated indoles: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms…
Oxygen atoms: in position 2
Heterocyclic compounds
Term ended 13 Mar 2007 (estimated)
USPTO file history isn’t available for this patent, so only indexed dates are shown.
Related indoles are described in copending U.S. patent application Ser. No. 498,835 filed May 27, 1983, Ser. No. 853,030 filed Apr. 17, 1986, and Ser. No. 691,163 filed Jan. 14, 1985 and U.S. Pat. No. 4,333,951 and European Patent No. 89,426.
It is an object of the invention to provide the novel indole-carboxamides of formula I and their non-toxic, pharmaceutically acceptable acid addition salts and a novel process for their preparation.
It is another object of the invention to provide anti-arrythmic compositions and to a novel method of inducing anti-arrythmic activity in warm-blooded animals.
140 ml of triisobutylaluminum in solution in toluene at 1.1 mole/l were added to a solution of 18 g of 2-aminophenol-4-methylbenzenesulfonate in 300 ml of chloroform, and after stirring for 15 minutes, a solution of 12.15 g of methyl indol-4-carboxylate in 120 ml of chloroform was added. The mixture was refluxed for 20 hours and was then cooled to 0.degree. to -10.degree. C. and 500 ml of an N aqueous solution of hydrochloric acid were added with stirring over 15 minutes. The chloroform phase was then purified by chromatography over silica (eluent:methylene chloride) to obtain 25 g of N-[2-[(4-methylphenyl)sulfonyloxy]phenyl]-1H-indol-4-carboxamide melting at 135.degree. C.
250 ml of a solution of potassium hydroxide in ethanol at 10 g per 100 ml were added to a suspension of 25 g of N-[2-[(4-methylphenyl)sulfonyloxy]phenyl]-1H-indol-4-carboxamide in 50 ml of ethanol at 95.degree. C. with stirring under an inert atmosphere and the mixture was stirred for 21 hours. 1 liter of iced water was added, and the mixture was acidified with a concentrated aqueous solution of hydrochloric acid, followed by stirring for a further 15 minutes, filtering, drying and triturating at reflux in 1.5 liters of methylene chloride. After concentrating to about 300 ml, filtering and drying at 80.degree. C. under reduced pressure, 13 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide melting at .perspectiveto.208.degree. C. were obtained.
______________________________________ U.V. Spectrum (ethanol) ______________________________________ Max. at 230 nm E.sub.1.sup.1 = 1,012 .epsilon. = 25,500 Infl. at 265 nm E.sub.1.sup.1 = 208 Max. at 304 nm E.sub.1.sup.1 = 564 .epsilon. = 14,200 Infl. at 318 nm E.sub.1.sup.1 = 482 ______________________________________