Substituted guanidines and diaminonitroethenes, their preparation and use
AssigneeNovo Nordisk A/S
InventorsJohn Patrick Mogensen, John Bondo Hansen, Tina Moller Tagmose
Life of this patent
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Abstract
Guanidine and diaminonitroethene derivatives represented by the formula ##STR1## wherein X, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are defined in the description, compositions thereof and methods for preparing the compounds are described. The se compounds are useful in the treatment of diseases of the central nervous system, cardiovascular system, pulmonary system, gastrointestinal system and endocrinologic system.
Claims40
A compound of formula I ##STR5## wherein R.sup.1 and R.sup.2 are independently hydrogen, trifluoromethyl or halogen;
- R.sup.3 is trifluoromethyl, methoxy or halogen;
- R.sup.4 is straight or branched C.sub.1-12 -alkyl substituted with C.sub.3-8 -cycloalkyl, halogen, hydroxy, aryloxy, arylalkoxy, C.sub.1-6 -alkoxy, C.sub.1-6 -alkylthio, arylthio, C.sub.1-6 -alkylamino, C.sub.1-6 -dialkylamino, heteroaryl, heteroarylalkyl or aryl, wherein the heteroaryl is optionally substituted with halogen or trifluoromethyl;
- or R.sup.4 is C.sub.2-12 -alkenyl, C.sub.2-12 -alkynyl or C.sub.3-8 -cycloalkyl optionally substituted with C.sub.3-8 -cycloalkyl, halogen, hydroxy, aryloxy, arylalkoxy, C.sub.1-6 -alkoxy, C.sub.1-6 -alkylthio, arylthio, C.sub.1-6 -alkylamino, C.sub.1-6 -dialkylamino, heteroaryl, heteroarylalkyl or aryl, wherein the heteroaryl is optionally substituted with halogen or trifluoromethyl;
- or R.sup.4 is Y--R.sup.5, wherein Y is --O--or --N(R.sup.6)--;
- R.sup.5 and R.sup.6 are independently straight or branched C.sub.1-12 -alkyl, C.sub.2-12 -alkenyl, C.sub.2-12 -alkynyl or C.sub.3-8 -cycloalkyl optionally substituted with C.sub.3-8 -cycloalkyl, halogen, hydroxy, heteroaryl, heteroarylalkyl, aryloxy or aryl, wherein the aryl or heteroaryl is optionally substituted with halogen or trifluoromethyl;
- or R.sup.5 and R.sup.6 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be substituted with nitrogen, oxygen or sulfur, wherein each of these ring systems is optionally mono- or polysubstituted with halogen. C.sub.1-6 -alkyl, hydroxy, C.sub.1-6 -alkoxy, C.sub.1-6 -alkoxy-C.sub.1-6 -alkyl, nitro, amino, cyano, trifluoromethyl, C.sub.1-6 -monoalkyl- or dialkylamino or oxo;
- X is N--CN;
- or a pharmaceutically acceptable salt thereof, or an optical isomer or mixture of optical isomers thereof, or a tautomeric form thereof.
A compound of claim 19, wherein R.sup.4 is C.sub.3-8 -cycloalkyl substituted with C.sub.3-8 -cycloalkyl, aryloxy, arylalkoxy, C.sub.1-6 -alkoxy, C.sub.1-6 -alkylthio, arylthio, C.sub.1-6 -alkylamino, C.sub.1-6 -dialkylamino, heteroaryl, or aryl, wherein the heteroaryl is optionally substituted with halogen or trifluoromethyl.
A compound which is:
- N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(3-methylbutyl)guanidine,
- N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(1,2,2-trimethylpropyl)guani dine,
- N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(1,2-dimethylpropyl )guanidine,
- N-Cyano-N'-[3,5-bis(trifluoromethyl)phenyl]-N"-propyl-guanidine,
- N-Cyano-N'-[3,5-bis(trifluoromethyl)phenyl]-N"-(1,1-dimethylpropyl)guanidin e,
- N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(1-methylethyl)-guanidine,
- N-Cyano-N'-(3-methoxy-5-trifluoromethylphenyl)-N"-(3-methylbutyl)guanidine;
- or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 28 together with one or more pharmaceutically acceptable carriers or diluents.
The pharmaceutical composition of claim 29 in the form of an oral dosage unit or parenteral dosage unit.
A compound which is:
- N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(2-chlorobenzyl )guanidine,
- N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(3-chlorobenzyl)guanidine,
- N-Cyano-N'-(3,5-dichlorophenyl)-N"-(2-chlorobenzyl )guanidine,
- N-Cyano-N'-cyclopentyl-N"-(3,5-dichlorophenyl)guanidine,
- N-Cyano-N'-cyclopentyl-N"-(3-methyloxy-5-trifluoromethylphenyl)guanidine,
- N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(2-(4-pyridinyl)ethyl)guanid ine;
- or a pharmaceutically acceptable salt thereof.
A compound which is:
- N-Cyano-N'-(3,5-dichlorophenyl)-N"-(3-cyclopentylpropyl)guanidine,
- N-Cyano-N'-(3,5-dichlorophenyl)-N"-(3-cyclopentyl)guanidine,
- N-Cyano-N'-(3,5-dichlorophenyl)-N"-(2-cyclopropylethyl)guanidine,
- N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(3-cyclopentylpropyl)guanidi ne,
- N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(2-cyclopropylethyl)guanidin e,
- N-Cyano-N'-(3,5-bis(trifluoromethyl)phenyl)-N"-(cyclopentyl)guanidine,
- N-Cyano-N'-(3-trifluoromethylphenyl)-N"-cyclopentylguanidine;
- N-Cyano-N'-cyclopentyl-N"-(3-methyloxy-5-trifluoromethylphenyl)guanidine
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.