Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1997-07-11
1999-01-26
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514648, 564304, 564315, 564425, A61K 31135, C07C21142
Patent
active
058639527
DESCRIPTION:
BRIEF SUMMARY
This application is a .sctn.371 application of PCT/EP96/00206, filed Jan. 10, 1996.
The present invention relates to carbocyclic 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.
Our International Patent application PCT/EP94/02410 (filed 21 Jul. 1994) describes compounds of formula (I): ##STR4## wherein: X represents O, S, NH or a bond; 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,
The compounds of formula (A) contain two asymmetric centres; such compounds can exist in diastereomeric forms (cis and trans), each of which can exist as optical isomers (enantiomers). In relation to the diastereoisomers, the substituents on the carbocyclic (e.g. indane) nucleus may both lie on the same side with respect to the plane of the ring (cis-configuration) or on opposite sides (trans-configuration).
The specific examples of formula (A) described in PCT/EP94/02410 include the compound: salt), which is a mixture of enantiomers.
The present invention now provides the specific enantiomers of this compound, namely:
Both enantiomers may conveniently be represented by the structural formula (I): ##STR5##
It will be appreciated that this single formula is not intended to represent a mixture of enantiomers, but each individual enantiomer.
It will also be appreciated that an enantiomer according to the present invention, for example a (+)- enantiomer, will be substantially free from the corresponding (-) enantiomer, and vice versa. Preferably, a specific enantiomer of the invention will contain less than 10%, eg less than 5% and advantageously less than 1%, eg less than 0.5%, of its opposite enantiomer.
For the avoidance of doubt, formulae (I), (II) and (III) depicted herein are intended to represent a single enantiomer, unless otherwise stated; enantiomeric mixtures of each compound are designated as "a mixture of the enantiomers" of formula (I), (II) or (III) respectively. "A single enantiomer" means one of the individual enantiomers of a given compound substantially free of the other.
It will be further appreciated that for use in medicine a salt of a compound (I) should be pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, methanesulphonate or similar pharmaceutically acceptable inorganic
REFERENCES:
patent: 5639913 (1997-06-01), Lidor et al.
Harling John David
Orlek Barry Sidney
Dustman Wayne J.
Kinzig Charles M.
Raymond Richard L.
SmithKline Beecham Plc
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