Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-06
2002-01-08
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S575000
Reexamination Certificate
active
06337326
ABSTRACT:
The present invention relates to N-aryl-homopiperazinyl-cyclohexylamine derivatives having pharmacological activity, and to their use in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression and anxiety.
BACKGROUND OF INVENTION
Pharmaceuticals with enhance serotonergic neurotransmission are of useful benefit for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affection drugs operated through a variety of physiological functions which endowed them with several side effect liabilities. The more currently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier.
Wustrow et al. have disclosed a series of 3-[[4-aryl-1-piperazinyl)alkyl]cyclohexyl]-1H-indoles as dopamine D
2
partial agonists in
J. Med. Chem.
1997, 40, 250.
Cipollina et al. have disclosed a series of indolylcycloalkylamines as serotonergic vasoconstrictors for the treatment of vascular or migraine headaches in European Patent Application EP 666258.
Shiota et al. have disclosed a series of cyclic diarylalkyl derivatives (including aryl homopiperazines) as chemokine receptor antagonists in PCT Int. Patent Application WO 9744329. Hidaka et al. have disclosed a series of aryl cyclic diamines (including aryl homopiperazines) as anti-ulcer agents in U.S. Pat. No. 5,244,895 and European Patent Application 513691. Hidaka et al. have also disclosed a series of aryl cyclic diamines (including aryl homopiperazines) as blood vessel relaxants in U.S. Pat. Nos. 5,081,246; 5,216,150 and 5,245,034.
DESCRIPTION OF THE INVENTION
The present invention provides N-aryl-homopiperazinyl-cyclohexylamine derivatives having pharmacological activity as 5-HT transporters, and to their use in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression and anxiety.
In accordance with this invention there, is provided a group of compounds represented by the formula I:
wherein:
Ar is an aryl group of 4 to 10 carbon atoms or a heteroaryl group of 4 to 10 carbon atoms, the aryl or heteroaryl group being optionally substituted by from 1 to 3 groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, perfluoralkyl of 1 to 6 carbon atoms, hydroxy, nitro, amino, or cyano;
R
1
and R
2
are independently, hydrogen, straight chain alkyls of 1 to 12 carbon atoms, branched alkyls of 3 to 10 carbon atoms or cycloalkyls of 3 to 10 carbon atoms;
R
3
is H, straight chain alkyl of 1 to 12 carbon atoms, branched alkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, halogen, alkoxy group of 1 to 12 carbon atoms, haloalkyl of 1 to 12 carbon atoms, hydroxy, nitro, nitrile, amino, cyano, carboxy, alkoxycarbonyl of 1 to 12 carbon atoms, alkylcarbonyl of 1 to 12 carbon atoms, aminocarbonyl and alkylaminocarbonyl of 1 to 12 carbon atoms; and all crystalline forms or a pharmaceutically acceptable salt thereof.
Among the preferred compounds of this invention are those of formula I wherein:
Ar is an aryl group of 5 or 6 carbon atoms or a heteroaryl group of 5 to 10 carbon atoms;
R
1
and R
2
are independently, H, straight chain alkyls of 1 to 8 carbons or branched alkyls of 3 to 8 carbon atoms;
R
3
is H, straight chain alkyl of 1 to 8 carbon atoms, branched alkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy or 1 to 6 carbon atoms, hydroxy, nitro, nitrile, amino, cyano, carboxy, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, aminocarbonyl and alkylaminocarbonyl of 1 to 6 carbon atoms;
and all crystalline forms or a pharmaceutically acceptable salt thereof.
In still more preferred aspects of the invention are provided compounds of formula I wherein:
Ar is an aryl group of 6 carbon atoms or a heteroaryl group or a heteroaryl group of 5 to 10 carbon atoms;
R
1
and R
2
, are independently, H, straight chain alkyls of 1 to 3 carbons or branched alkyls of 3 to 6 carbon atoms;
R
3
is H, halogen, cyano CONH
2
, or CO
2
H;
and all crystalline forms or a pharmaceutically acceptable salt thereof.
Alkyl, whether used alone or as part of another group include straight and branched chain alkyl groups containing from 1 to 12 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are encompassed by the term alkyl. In some embodiments of the present invention alkyl may refer to substituted or unsubstituted alkyl. Carbon number refers to carbon backbone and does not include carbon atoms of substituents such as alkoxy substitutions and the like. Halogen, as used herein means chlorine, bromine, iodine and fluorine.
Aryl, as used herein refers to single or multiple 4 to 10 membered aromatic ring radicals including but not limited to phenyl, benzyl, naphthalene, anthracene, phenanthrene, indene and indacene. Preferred are phenyl, benzyl and naphthalene. In some embodiments of the present invention, the aryl group may be substituted by alkyl groups, perfluoroalkyl groups, preferably trifluoromethyl groups, alkoxy groups, and halogens.
Heteroaryl as used herein refers to single or multiple 4 to 10 membered aromatic ring radicals having from 1 to 3 heteroatoms selected from S, O or N including, but not limited to, furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, napthyridine, pteridine, pyridine, pyrazine, pyrimidine, pyridazine, pyran, triazine, indole, isoindole, indazole, indolizine, and isobenzofuran. Preferred heteroaryls include furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline, and isoquinoline. More preferred heteroaryls include furan, thiophene, imidazole, isoxazole, quinoline and pyrazole. In some embodiments of the present invention, the heteroaryl group is substituted.
Preferably, the substituted aryl group is substituted with from 1 to 3 groups. The substituted heteroaryl group is preferably substituted with 1 to 3 groups and more preferably 1 to 2 groups. Alkyl and cycloalkyl groups may also be substituted. Suitable substitutions include, but are not limited to halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, nitrile, amino, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, alkoxycarbonylalkyl and alkylcarbonyloxy.
Among the most preferred compounds of the present invention are:
3-{4-[4-(2-Methoxy-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-1H-indole;
8-{4-[4-(1H-Indol-3-yl)-cyclohexyl-]-[1,4]diazepan-1-yl}-quinoline;
3-{4-[4-(2-Methoxy-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-5-fluoro-1H-indole;
3-{4-[4-(2-Methoxy-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-5-cyano-1H-indole;
3-{4-[4-(2-Methoxy-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-6-fluoro-1H-indole;
8-{4-[4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-[1,4]diazepan-1-yl}-quinoline;
8-{4-[4-(5-Cyano-1H-indol-3-yl)-cyclohexyl]-[1,4]diazepan-1-yl}-quinoline;
8-{4-[4-(6-Fluoro-1H-indol-3-yl)-cyclohexyl]-[1,4]diazepan-1-yl}-quinoline;
3-{4-[4-(3-Trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-5-fluoro-1H-indole;
3-{4-[4-(3-Trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-5-cyano-1H-indole;
3-{4-[4-(3-Trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-6-fluoro-1H-indole;
or a pharmaceutically acceptab
Gilbert Adam M.
Mewshaw Richard E.
American Home Products Corporation
Ford John M.
Mazzarese Joseph M.
LandOfFree
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