Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-02-15
1999-05-18
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514255, 544360, 544364, 544379, 544393, A61K31/495
Patent
active
059050802
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel amide and urea derivatives, processes for their preparation, and pharmaceutical compositions containing them.
EPA 0 533 266/7/8 disclose a series of benzanilide derivatives which are said to possess 5HT.sub.1D receptor antagonist activity. These compounds are alleged to be of use in the treatment of various CNS disorders.
A structurally distinct class of compounds have now been discovered and have been found to exhibit 5HT.sub.1D antagonist activity. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt thereof: ##STR1## in which P is phenyl or a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, C.sub.3-6 cycloalkenyl, C.sub.1-6 alkoxy, hydroxy, hydroxyC.sub.1-6 alkyl, acyl, nitro, trifluoromethyl, cyano, SR.sup.5, SOR.sup.5, SO.sub.2 R.sup.5, SO.sub.2 NR.sup.5 R.sup.6, CO.sub.2 R.sup.5, CONR.sup.5 R.sup.6, CONR.sup.5 (CH.sub.2)CO.sub.2 R.sup.6, NR.sup.5 R.sup.6, NR.sup.5 CO.sub.2 R.sup.6, CR.sup.5 .dbd.NOR.sup.6, where R.sup.5 and R.sup.6 are independently hydrogen or C.sub.1-6 alkyl and p is 1 to 3; to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, C.sub.3-6 cycloalkenyl, C.sub.1-6 alkoxy, hydroxy, hydroxyC.sub.1-6 alkyl, acyl, nitro, trifluoromethyl, cyano, SR.sup.5, SOR.sup.5, SO.sub.2 R.sup.5, SO.sub.2 NR.sup.5 R.sup.6, CO.sub.2 R.sup.5, CONR.sup.5 R.sup.6, CONR.sup.5 (CH.sub.2).sub.p CO.sub.2 R.sup.6, NR.sup.5 R.sup.6, NR.sup.5 CO.sub.2 R.sup.6, CR.sup.5 .dbd.NOR.sup.6, where R.sup.5, R.sup.6, and p are as defmed for R.sup.1 ; is 1 or 2.
The groups P and R.sup.1 can be aromatic or saturated heterocyclic rings. Examples of suitable aromatic heterocyclic rings include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl. When P or R.sup.1 is a saturated ring examples include piperidine, morpholine and piperazine rings. The groups P and R.sup.1 can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom.
Optional substituents for R.sup.1 phenyl and heterocyclic rings include halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.1-6 alkoxy, hydroxy, acyloxy, cyano, nitro, amino, CO.sub.2 R.sup.5 where R.sup.5 is hydrogen or C.sub.1-6 alkyl, or CONR.sup.6 R.sup.7 where R.sup.6 and R.sup.7 are hydrogen or C.sub.1-6 alkyl.
Preferably P is phenyl or thienyl.
Preferably R.sup.1 is hydrogen, halogen, phenyl, or pyridyl.
Preferably R.sup.2 is hydrogen or C.sub.1-6 alkyl, for example methyl.
Preferably R.sup.3 is C.sub.1-6 alkoxy such as methoxy.
The integer n can be 1 or 2. Preferably n is 1.
Preferably R.sup.4 is C.sub.1-6 alkyl such as methyl.
Suitably A is NH or an acyclic hydrocarbon chain having 1 to 6 carbon atoms. For the avoidance of doubt, the term `chain of 1 to 6 carbon atoms` means carbon atoms extending in a branched or unbranched chain between the group P and the amide group. The hydrocarbon chain A can be an alkylene chain, for example methylene or ethylene, or A can contain alkene or alkyne groups. Preferably A is NH or an C.sub.2-4 alkene group, in particular a CH.dbd.CH group.
C.sub.1-6 alkyl groups, whether alone or as part of another group, may be straight chain or branched.
Particularly preferred compounds of the invention include: rea, piperazinyl)phenyl!urea, or pharmaceutically acceptable salts thereof.
Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and the mixtures thereof including racemates. Tautomeric forms of compounds of formul
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Duckworth David Malcolm
Gaster Laramie Mary
Jenkins Sarah Maragaret
Jennings Andrew John
Mulholland Keith Raymond
Bernhardt Emily
Dustman Wayne J.
Kinzig Charles M.
SmithKline Beecham p.l.c.
Venetianer Stephen A.
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