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US 5,691,369 AGranted
Cyclic ureas useful as antiarrhythmic and antifibrillatory agents
AssigneeThe Proctor & Gamble Company
InventorsStanford Salvatore Pelosi, Jr., Chia-Nien Yu
Life of this patent
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Abstract
The cyclic ureas, and the pharmaceutically-acceptable salts and esters thereof, of the present invention are useful as antiarrhythmic and antifibrillatory agents and have the following general structure: ##STR1## wherein X, Y, A, L, R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are defined as in the Specification.
Claims37
A cyclic urea compound which has the structure:
- ##STR12## wherein a) X is a saturated or unsaturated, substituted or unsubstituted 6-membered carbocycle;
- b) R is a covalent bond;
- c) Y is a saturated or unsaturated, substituted or unsubstituted 5-membered heterocycle, wherein said heterocycle has one or two heteroatoms selected from O, S or N;
- d) R.sub.1, R.sub.2, and R.sub.3 are substituents on the X moiety and are independently selected from the group consisting of H, Cl, F, Br, NH.sub.2, CF.sub.3, OH, SO.sub.3 H, CH.sub.3, SO.sub.2, NH, COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, amino alkyl, acylamino, and acyloxy;
- e) L is a linking moiety and is selected from the group consisting of alkylamino, alkenylamino, alkylimino, alkenylimino, and acylamino, wherein the carbon-containing end of L is bound, through R, at X;
- and wherein the nitrogen atom of L is bound to the nitrogen atom at the 3-position of the cyclic urethane ring moiety;
- f) R.sub.4 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkylacyl, and heteroalkyl;
- g) A is a substituted or unsubstituted;
- saturated or unsaturated, straight-chain or branched C.sub.1 -C.sub.8 heteroalkyl;
- or a substituted or unsubstituted, saturated or unsaturated, heterocycle having 5-, 6- or 7-members and one or two heteroatoms selected from O, N or S;
- and heteroalkyl A and heterocycle A have at least one nitrogen atom, which nitrogen atom is adjacent to R.sub.4 ;
- and
- h) R.sub.5 is a substituted or unsubstituted C.sub.1 alkyl;
- and the pharmaceutically-acceptable salts and esters thereof.
11 more elements
A cyclic urea compound having the following structure:
- ##STR14## wherein a) X is phenyl, pyridinyl, thienyl, pyrimidinyl, furanyl, cyclohexyl, oxazolyl, naphthyl, and quinolinyl;
- b) R is nil or a covalent bond;
- c) Y is phenyl, pyridinyl, thienyl, pyrimidinyl, furanyl, cyclohexyl, oxazolyl, naphthyl, and quinolinyl;
- d) R.sub.1, R.sub.2, and R.sub.3 are substituents on the X moiety and are independently selected from the group consisting of H, Cl, F, Br, NH.sub.2, CF.sub.3, OH, SO.sub.3 H, CH.sub.3, SO.sub.2, NH, COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acylamino, and acyloxy;
- e) L is a linking moiety and is selected from the group consisting of alkylamino, alkenylamino, alkenylimino, alkylimino, and acylamino, wherein the nitrogen atom thereof is bound to the nitrogen atom at the 1-position of the cyclic urea ring moiety;
- f) R.sub.4 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkyl, alkylacyl, and heteroalkyl;
- g) A is a substituted or unsubstituted;
- saturated or unsaturated, straight-chain or branched C.sub.1 -C.sub.8 heteroalkyl;
- or a substituted or unsubstituted, saturated or unsaturated, heterocycle having 6- or 7-members and one or two heteroatoms selected from N or S;
- and may not have an oxygen atom;
- and heteroalkyl A and heterocycle A has at least one nitrogen atom, and said nitrogen atom is adjacent to R.sub.4 ;
- and
- h) R.sub.5 is a substituted or unsubstituted C.sub.1 alkyl;
- and the pharmaceutically-acceptable salts and esters thereof.
11 more elements
A cyclic urea compound having the following structure:
- ##STR17## wherein a) wherein the "X-R-Y" portion of the structure is selected from one of the following:
- ##STR18## b) wherein R.sub.1, R.sub.2, and R.sub.3 are independently selected from the group consisting of H, Cl, F, Br, NH.sub.2, CF.sub.3, OH, SO.sub.3 H, CH.sub.3 SO.sub.2 NH, COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acyloxy, and acylamino;
- c) L is a linking moiety and is selected from the group consisting alkylamino, alkenylamino, alkenylimino, alkylimino, and acylamino;
- wherein the nitrogen atom thereof is bound to the nitrogen atom at the 1-position of the cyclic urea ring moiety;
- d) wherein R.sub.4 is selected from the group consisting of alkenyl, alkynyl, alkylacyl, and heteroalkyl;
- e) R.sub.5 is a substituted or unsubstituted C.sub.1 alkyl;
- and
- f) wherein the A portion of the structure is selected from one of the following:
- ##STR19## and the pharmaceutically-acceptable salts and esters thereof.
6 more elements
A cyclic urea compound having the following structure:
- ##STR20## a) wherein the "X-R-Y" portion of the structure is selected from one of the following:
- ##STR21## b) wherein R.sub.1, R.sub.2, and R.sub.3 are independently selected from the group consisting of H, Cl, F, Br, NH.sub.2, CF.sub.3, OH, SO.sub.3 H, CH.sub.3 SO.sub.2 NH, COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acyloxy, and acylamino;
- c) wherein R.sub.4 is selected from the group consisting of alkenyl, alkynyl, alkylacyl, and heteroalkyl;
- d) R.sub.5 is a substituted or unsubstituted C.sub.1 alkyl;
- and
- e) wherein the A portion of the structure is selected from one of the following:
- ##STR22## and the pharmaceutically-acceptable salts and esters thereof.
4 more elements
A cyclic urea compound having the general structure:
- ##STR23## wherein a) R.sub.1, R.sub.2, and R.sub.3 are independently selected from the group consisting of H, Cl, F, Br, NH.sub.2, CF.sub.3, OH, SO.sub.3 H, CH.sub.3 SO.sub.2 NH, COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acyloxy and acylamino;
- b) R.sub.4 is selected from a group consisting of an alkyl, alkenyl, alkynyl, alkylacyl, and heteroalkyl;
- c) A is a substituted or unsubstituted, saturated or unsaturated, straight-chain or branched C.sub.1 -C.sub.8 heteroalkyl or a substituted or unsubstituted, saturated or unsaturated heterocycle having 5-, 6-, or 7-members;
- wherein said heterocycle has one or more heteroatoms selected from nitrogen, sulfur, or oxygen;
- and
- d) R.sub.5 is a substituted or unsubstituted C.sub.1 alkyl;
- and the pharmaceutically-acceptable salts and esters thereof.
4 more elements
A cyclic urea compound having the following structure:
- ##STR24## wherein a) the "X-R-Y" portion of the structure is selected from the group consisting of 2-acetoxy-5-chlorophenyl;
- 3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridinyl;
- 2-thienyl;
- 4-pyrimidinyl;
- 5-methoxycarbonyl-2-furanyl;
- cyclohexyl;
- 5-chloro-2-hydroxyphenyl;
- 5-chloro-2-methoxyphenyl;
- 2-methanesulfonylaminophenyl;
- 3-aminophenyl;
- 2-methoxyphenyl;
- 5-ethyl-2-furanyl;
- 3-methoxyphenyl;
- 2-aminophenyl;
- 2-furanyl;
- 3,5-dimethyl-4-hydroxyphenyl;
- 5-acetyloxymethyl-2-furanyl;
- 5-(4-carboxyphenyl)-2-furanyl;
- 5-(4-methanesulfonylphenyl)-2-furanyl;
- 5-(3,4-dimethoxyphenyl)-2-furanyl;
- 5-(4-methanesulfonylaminophenyl)-2-furanyl;
- 5-(4-bromophenyl)-2-oxazolyl;
- 5-(4-methoxyphenyl)-2-furanyl;
- 5-(1-cyclohexen-1-yl)-2-furanyl;
- 5-cyclohexyl-2-furanyl;
- 5-(3-trifluoromethylphenyl)-2-furanyl;
- 5-(4-methylphenyl)-2-furanyl;
- 2-(4-chlorophenyl)-3-furanyl;
- 5-(4-chlorophenyl)-2-furanyl;
- 5-(4-fluorophenyl)-2-furanyl;
- 2-benzyloxy-5-chlorophenyl;
- 4-benzyloxyphenyl;
- 3-(4-t-butylphenyloxy)phenyl;
- 3-benzoyl-2,4-dichlorophenyl;
- 2-chloro-3-benzyloxyphenyl;
- 3-(4-chlorophenoxyl)phenyl;
- 1H-indol-3-yl;
- 2-fluorenyl;
- 2-naphthyl;
- 2-hydroxy-1-naphthyl;
- 2-quinolinyl;
- and 5-chloro-2-benzofuranyl;
- b) L is a linking moiety and is selected from the group consisting of alkylamino, alkenylamino, alkenylimino, alkylimino, and acylamino;
- wherein the nitrogen atom thereof is bound to the nitrogen atom at the 1-position of the cyclic urea ring moiety;
- c) R.sub.4 is selected from the group consisting of alkenyl, alkynyl, alkylacyl, and heteroalkyl;
- d) A is selected from the group consisting of dimethylamino;
- diethylamino;
- bis-2-hydroxy-ethylamino;
- bis-(1-methy)ethyl!amino;
- N-benzyl-N-methylamino;
- N-(2-hydroxyethyl)-N-methylamino;
- N-(1-methyl)ethyl!-2-hydroxy-2-(4-methanesulfonyl-amino)phenyl!ethyl!ami no;
- 4-phenyl-1-piperazinyl;
- 4(-2-hydroxyethyl)-1-piperazinyl;
- 4-(2-methyl)propyl!-1-piperazinyl;
- 4-(2-methyl)propyl!-1-piperazinyl;
- 4-hexyl-1-piperazinyl;
- 4-benzyl-1-piprazinyl;
- 1-piperazinyl;
- 4-hydroxy-1-piprazinyl;
- 1-piperazxinyl;
- 4-hydroxy-1-piperidinyl;
- 4-methyl-1-piperazinyl;
- piperazinyl;
- 4-n-butyl-1-piperazinyl;
- 4-ethyl-1-piperazinyl, 3-(4-methyl)-1-piperazinyl)-3-oxopropyl;
- 4-phenyl-1-piperazinyl;
- N-(2-pyridinyl)-1-piperazinyl;
- N-(2-pyrimidinyl)-1-piperazinyl;
- 4-(4-methoxyphenyl)-1-piperazinyl;
- 4-acetyl-1-piperazinyl;
- piperazinyl;
- 4-methyl-N-phenylamino;
- 1-imidazolyl,;
- 4-(2-methylphenyl)-1-piperazinyl;
- 4-(4-methanesulfonylamino phenyl)-1-9-erazinyl;
- N-morpholinyl;
- N-thiomorpholinyl;
- 4-oxo-1-piperidinyl;
- 2-(t-butoxycarbonyl)-1-pyrrolidinyl;
- pyrrolidinyl;
- 4-4-acetylphenyl)-1-piperazinyl;
- hexahydro-1H-azepin-1-yl.
80 more elements
A cyclic urea compound having the following structure:
- ##STR25## (a) wherein the "X-R-Y" portion of the structure is selected from one of the following:
- ##STR26## (b) L is a linking moiety and is selected from the group consisting of alkylamino, alkenylamino, alkenylimino, alkylimino, and acylamino;
- wherein the nitrogen atom thereof is bound to the nitrogen atom at the 1-position of the cyclic urea ring moiety;
- (c) wherein R.sub.4 is selected from the group consisting of alkenyl, alkynyl, alkylacyl, and heteroalkyl;
- (d) wherein the A portion of the structure is selected from one of the following:
- ##STR27## and the pharmaceutically acceptable salts and esters thereof.
3 more elements
A compound selected from the group consisting of 1-5-(4-(chlorophenyl)-2-furanyl!methylene!amino!-3-3-(dimethylamino)pr opyl!-2-imidazolidinone;
- 1-5-(4-chlorophenyl)-2-furanyl!methylene!amino!-3-4-(dimethylamino)but yl!-2-imidazolidinone;
- 1-5-(4-(chlorophenyl)-2-furanyl!methylene!amino!-3-4-(4-methyl-1-piper azinyl)butyl!-2-imidazolidinone;
- 1-5-(4-chlorophenyl)-2-furanyl!methylene!amino!-3-2-(dimethylamino)eth yl!-2-imidazolidinone;
- 1-3-(4-chlorophenoxy)phenyl!methylene!amino!-3-3-(dimethylamino)propyl !-2-imidazolidinone;
- 1-5-chloro-2-benzofuranyl)methylene!amino!-3-3-(dimethylamino)propyl!-2 -imidazolidinone;
- 1-3-benzoyl-2,4-dichlorophenyl)methylene!amino!-3-3-(dimethylamino)prop yl!-2-imidazolidinone;
- 1-5-(4-chlorophenyl)-2-furanyl!methylene!amino!-3-3-(dimethylamino)pro pyl!tetrahydro-2-(1 H)pyrimidinone;
- 1-5-(4-chlorophenyl)-2-furanyl!methylene!amino!-3-4-4-(2-hydroxyethyl )-1-piperazinyl!butyl!-2-imidazolidinone;
- 1-5-(4-chlorophenyl)-2-furanyl!methylene!amino!-3-3-(4-methyl-1-pipera zinyl)propyl!-2-imidazolidinone;
- 1-(cyclohexyl)methylene!amino!-3-3-(dimethylamino)propyl!-2-imidazolidi none, and the pharmaceutically acceptable hydrochloride and maleate salts thereof.
7 more elements
Dependencies are inferred from the claim text.