Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-02-01
1996-12-17
Datlow, Philip I.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514183, 514326, 514331, 514339, 514357, 514428, 540596, 540597, 540610, 546205, 546207, 546208, 546233, 546234, 546337, 5462777, 5462824, 5462681, 5462791, 546194, 548568, 548950, 544130, 544131, 544360, 544364, A61K 3144, A61K 3155, C07D40104, C07D40110
Patent
active
055853749
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 national stage application of international application PCT/GB93/01542, filed Jul. 22, 1993.
This invention relates to novel amide derivatives, to processes for their preparation, to their use and to pharmaceutical compositions containing them. The novel compounds act on the central nervous system by binding to 5-HT receptors (as more fully explained below) and hence can be used as medicaments for treating humans and other mammals. EP-A-0481744 discloses 2,3,4,5,6,7-hexahydro-1{4-[4-[1-[4-(2-methoxyphenyl)piperazinyl]]-2-phenyl butyryl}-1H-azepine and its salts that are 5-HT.sub.1A binding agents useful, for example, as anxiolytics. WO 92/06960 discloses other piperazinecarboxamides which are also useful as 5-HT.sub.1A binding agents. EP-A-0466585 discloses piperidine, tetrahydropyridine and pyrrolidine derivatives which are stated to have 5HT.sub.1A agonist or antagonist properties and useful in the treatment of hypertension, migraine, depression, anxiety, schizophrenia, stress and pain.
The novel compounds of the invention are those of general formula ##STR2## and the pharmaceutically acceptable acid addition salts thereof.
In formula I
a and b each represent 0,1,2 or 3 such that the sum of a +b is 0,1,2 or 3,
the dotted line represents an optional double bond which may be present in the ring, provided that a is at least 1,
A is an alkylene chain of 1 or 2 carbon atoms optionally substituted by one or more lower alkyl groups,
R is a mono or bicyclic aryl or heteroaryl radical,
R.sup.1 is hydrogen or lower alkyl,
R.sup.2 is an aryl, aryl (lower)alkyl, heteroaryl or heteroaryl (lower)alkyl radical,
R.sup.3 is hydrogen or lower alkyl, .sup.R.sup.4 is hydrogen, an alkyl group of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkyl(lower)alkyl, aryl or aryl(lower)alkyl
or
R.sup.3 and R.sup.4 together with the nitrogen atom to which they are both attached represent a saturated heterocyclic ring which may contain a further hereto atom [eg an azetidino, pyrrolidino, piperidino, hexahydroazepino, heptamethyleneimine, morpholino or piperazino ring which may be optionally substituted by, for example, lower alkyl, aryl, aryl(lower)alkyl), lower alkoxy, halogen or halo(lower)alkyl].
The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of "lower alkyl" radicals are methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, pentyl and isopentyl.
A cycloalkyl group can contain 3 to 12 carbon atoms. Preferably a cycloalkyl group is cyclopentyl, cyclohexyl or cycloheptyl, most preferably cyclohexyl. Cycloalkyl groups also include bicyclic, tricyclic and tetracyclic groups, eg adamantyl.
When used herein "aryl" means an aromatic radical having 6 to 12 carbon atoms (eg phenyl or naphthyl) which optionally may be substituted by one or more substituents. Preferred substituents are lower alkyl. lower alkoxy (eg methoxy, ethoxy, propoxy, butoxy), halogen, halo(lower)alkyl (eg trifluoromethyl), nitro, nitrile, amido, (lower)alkoxycarbonyl, amino, (lower)alkylamino or di(lower)alkylamino substituents. Two substituents on the aromatic ring may be connected together to form another ring system. For example R may be a bicyclic oxygen-containing radical of the formula ##STR3## wherein R.sup.5 represents hydrogen or one or more same or different substituents selected from lower alkyl, halogen, hydroxy, (lower)alkoxy, hydroxy(lower)alkyl, (lower)alkoxy(lower alkyl), lower alkanoyloxy(lower alkyl), (lower)alkylcarbonyl, (lower)alkylcarbonyl(lower)alkyl, (lower)alkylcarbonylamino, amino, (lower)alkylamino or di(lower)alkylamino and the heterocyclic ring containing the oxygen atom contains a total of 5 to 7 ring members, said heterocyclic ring being saturated or unsaturated, being optionally substituted (eg by one or more substituents R.sup.6 where R.sup.6 has the meaning given for R.sup.5 above and optionally containing one or more hetero ring members (eg --O--, --S--, --SO.sub.2 -- or --NR.sup.7
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J. Med. Chem., 12, 1969, pp. 940-941, Coutts et al.
Cliffe Ian A.
White Alan C.
Datlow Philip I.
John Wyeth & Brother Limited
Seifert Arthur G.
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