3-[4-[4-substituted-1-piperazinyl]-1-butyl]-1H-2,3-dihydroindoles
First Claim
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1. A compound selected from those of the following formula:
- ##STR13##wherein the dotted line indicates an optional bond present only when X is N;
X is CH2, N(H), or C═
O;
R1 is hydrogen, halogen, lower alkyl, lower alkenyl, trifluoromethyl, (lower alkyl means 1-6 carbon atoms, branched or unbranched);
R2 is hydrogen, lower alkyl or alkenyl (C1 -C6 inclusive, branched or unbranched) optionally substituted with one or two hydroxy groups, any hydroxy group present being optionally esterified with an aliphatic carboxylic acid having from two to twenty-four carbon atoms inclusive, or any of the following acyl groups ##STR14## in which R3 and R4 are hydrogen, alkyl (1-20 C-atoms), branched or unbranched, cyclo alkyl (3-6 C-atoms), adamantyl, aralkyl (4-13 C-atoms inclusive);
##STR15## in which Y is O or S;
Y'"'"' is H, O, S or CH2 ;
Z is O, S or CH2 ;
n is 1, 2 or 3; and
R5 is hydrogen, lower alkyl or alkenyl (C1 -C6 inclusive, branched or unbranched); and
a pharmaceutically acceptable acid addition salt and stereoisomer thereof.
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Abstract
The present invention relates to novel piperazinylbutylindoles, -indazoles, the corresponding 2,3-dihydro derivatives and 2-indolones which have been found to have central serotonin activity with preference for the serotonin 5-HTlA receptor.
Compared to the anxiolytic drug buspirone, and other clinically investigated compounds such as ipsapirone and gepirone, most of the present compounds have lower efficacy at the 5-HTlA receptor which implies less side effects related to activation of the receptors.
The invention also includes acid addition salts, methods of preparation, pharmacetical compositions and method of treating CNS disorders occuring in anxiety, depression, aggression and in alcohol abuse, or in states of disease related to the cardiovascular, gastrointestinal and renal systems, by administering the aforementioned derivatives.
Separation and use of the stereo isomers of the 2,3-dihydro derivatives and 2-indolones are also part of this invention.
79 Citations
12 Claims
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1. A compound selected from those of the following formula:
- ##STR13##wherein the dotted line indicates an optional bond present only when X is N;
X is CH2, N(H), or C═
O;R1 is hydrogen, halogen, lower alkyl, lower alkenyl, trifluoromethyl, (lower alkyl means 1-6 carbon atoms, branched or unbranched); R2 is hydrogen, lower alkyl or alkenyl (C1 -C6 inclusive, branched or unbranched) optionally substituted with one or two hydroxy groups, any hydroxy group present being optionally esterified with an aliphatic carboxylic acid having from two to twenty-four carbon atoms inclusive, or any of the following acyl groups ##STR14## in which R3 and R4 are hydrogen, alkyl (1-20 C-atoms), branched or unbranched, cyclo alkyl (3-6 C-atoms), adamantyl, aralkyl (4-13 C-atoms inclusive);
##STR15## in which Y is O or S;
Y'"'"' is H, O, S or CH2 ;
Z is O, S or CH2 ;
n is 1, 2 or 3; and
R5 is hydrogen, lower alkyl or alkenyl (C1 -C6 inclusive, branched or unbranched); and
a pharmaceutically acceptable acid addition salt and stereoisomer thereof. - View Dependent Claims (2, 3, 5, 6)
- ##STR13##wherein the dotted line indicates an optional bond present only when X is N;
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4. 3-[4-[4-(1,4-benzodioxan-5-yl)-1-piperazinyl]-1-butyl]-1H-2,3-dihydroindole;
- ;
or a pharmaceutically-acceptable acid addition salt thereof.
- ;
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7. A method for the alleviation of CNS disorders involving the neurotransmitter serotonin in a living animal in need thereof comprising the step of administering to the living animal an effective serotonergic amount of a compound selected from those of the following formula:
- ##STR16## wherein the dotted line indicates an optional bond;
X is CH, CH2, N(H), or C═
O;R1 is hydrogen, halogen, lower alkyl, lower alkenyl, trifluoromethyl, (lower alkyl) means 1-6 carbon atoms, branched or unbranched); R2 is hydrogen, lower alkyl or alkenyl (C1 -C6 inclusive, branched or unbranched) optionally substituted with one or two hydroxy groups, any hydroxy group present being optionally esterified with an aliphatic carboxylic acid having from two to twenty-four carbon atoms inclusive, or any of the following acyl groups ##STR17## in which R3 and R4 are hydrogen, alkyl (1-20 C-atoms), branched or unbranched, cyclo alkyl (3-6 C-atoms), adamantyl, aralkyl (4-13 C-atoms inclusive);
##STR18## in which Y is O or S;
Y'"'"' is H, O, S or CH2 ;
Z is O, S or CH2 ;
n is 1, 2 or 3; and
R5 is hydrogen, lower-alkyl, or alkenyl (C1 -C6 inclusive, branched or unbranched); and
a pharmaceutically-acceptable acid addition salt and stereoisomer thereof. - View Dependent Claims (8, 9, 10, 11, 12)
- ##STR16## wherein the dotted line indicates an optional bond;
Specification
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Current AssigneeH. Lundbeck A/S (Lundbeck Foundation)
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Original AssigneeH. Lundbeck A/S (Lundbeck Foundation)
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InventorsStenberg, John W., Perregaard, Jens
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Primary Examiner(s)TSANG, CECILIA J
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Application NumberUS07/456,938Time in Patent Office455 DaysField of Search544/366, 544/369, 544/373, 514/253, 514/254US Class Current514/254.06CPC Class CodesA61P 25/00 Drugs for disorders of the ...A61P 25/20 Hypnotics; SedativesA61P 25/24 AntidepressantsA61P 25/26 Psychostimulants, e.g. nico...A61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...C07D 209/14 Radicals substituted by nit...C07D 405/12 linked by a chain containin...
