Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-01-22
1998-06-30
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514351, 514352, 514445, 514447, 514452, 514466, 514469, 514470, 514472, 514524, 514648, 514657, 546300, 546304, 549 65, 549 68, 549365, 549437, 549466, 549467, 549471, 549479, 549480, A61K 31135, C07C21752
Patent
active
057734631
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/02409, filed Jul. 21, 1994.
The present invention relates to carbocylic derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular as calcium channel antagonists, e.g. for the treatment of ischaemic stroke.
Stroke is reportedly the third most common cause of death in the developed world. Current therapies for ischaemic stroke are limited and have a number of disadvantages, such as the risk of exacerbating haemorrhage. There is therefore a need for new and improved treatments for ischaemic stroke.
EPA 303961 describes compounds of the formula ##STR2## wherein R.sub.1 is C.sub.1-3 alkylene, n and p are each inter alia zero, R.sub.2 and R.sub.3 represent inter alia hydrogen or lower alkyl, X is inter alia lower alkyl, lower alkoxy, CF.sub.3 or halogen and q is zero, 1 or 2. The compounds are said to be useful as antidepressants and as inhibitors of synaptic norepinephrine and serotonin uptake.
EPA 371508 describes similar compounds of the formula: ##STR3## wherein R.sub.1, R.sub.2, R.sub.3, n, p, q and X may have the values recited hereinabove and R.sub.4 is oxy or thio, which compounds are said to be useful for the treatment of drug-resistant malaria and other drug-resistant protozoal infections.
We have now found that certain carbocyclic derivatives, such as indanes and tetralins, exhibit activity as calcium channel antagonists.
The present invention therefore provides in a first aspect the use of a compound of formula (I): ##STR4## wherein X represents O, S or NH; C.sub.3-6 cycloalkyl, or C.sub.1-4 alkyl-C.sub.3-6 cycloalkyl; from: trifluoromethyl, trifluoromethoxy, CN, NO.sub.2, amino, mono- or di-alkylamino, optionally substituted benzoyl and Ph(CH.sub.2).sub.r Y(CH.sub.2).sub.s -- where Ph is optionally substituted phenyl, Y is oxygen or a bond and r and s each independently represent 0-4 provided that the sum of r+s is not greater than 4, or ring system containing 5 or 6 ring members, or an optionally substituted, unsaturated or partially saturated bicyclic aryl or heteroaryl ring system containing 8-10 ring members, medicament for the treatment of disorders wherein a calcium channel antagonist is indicated.
The invention also provides novel compounds of formula (IA): ##STR5## wherein X represents O, S or NH; allyl; from: trifluoromethyl, trifluoromethoxy, CN, NO.sub.2, amino, mono- or di- alkylamino, optionally substituted benzoyl and Ph(CH.sub.2).sub.r Y(CH.sub.2).sub.s -- where Ph is optionally substituted phenyl, Y is oxygen or a bond and r and s each independently represent 0-4 provided that the sum of r+s is not greater than 4, or ring system containing 5 or 6 ring members, or an optionally substituted, unsaturated or partially saturated bicyclic aryl or heteroaryl ring system containing 8-10 ring members, phenyl group or phenyl substituted by lower alkyl, lower alkoxy, trifluoromethyl or halogen;
In the compounds of formula (I) and formula (IA) when Ar represents phenyl this is advantageously substituted by optionally substituted benzoyl group or a group Ph(CH.sub.2).sub.r Y(CH.sub.2).sub.s -- and preferably the group is in the 4- or 3-position, particularly the 4-position. Preferably r and s independently represent zero or 1, such that the sum of r and s does not exceed 1. Suitable substituents for the group Ph and for benzoyl include halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, trifluoromethyl and trifluoromethoxy. Preferably the substituents would be 4-fluoro, 4-chloro, 3-fluoro, 3-chloro or 3,4-dichloro; 4-fluoro is a particularly preferred substituent because this blocks metabolic hydroxylation of the phenyl group. In this sub-group preferably Ar represents phenyl substituted by optionally substituted benzyl, benzyloxy, phenoxy or benzoyl, and preferably the substituent is at the 4-position of the phenyl group. Additionally, in the compounds of formula (I) and the compounds of formula (IA) in which X is nitrogen, Ar is preferably 3,4-dichlorophenyl.
When Ar represents a bicyclic aryl
REFERENCES:
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patent: 5149714 (1992-09-01), Freedman
Harling John David
Orlek Barry Sidney
Hall Linda E.
Lentz Edward T.
Raymond Richard L.
SmithKline Beecham p.l.c.
Venetianer Stephen A.
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