Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-02-11
2000-11-07
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514275, 514307, 514308, 514310, 544332, 546141, 546143, 546146, A61K 31505, A61K 3147, C07D23902, C07D21722, C07D21700
Patent
active
06143762&
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel tetrahydroisoquinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, as modulators of dopamine D.sub.3 receptors, in particular as antipsychotic agents.
U.S. Pat. No. 5,294,621 describes tetrahydropyridine derivatives of the formula: ##STR1## wherein ##STR2## is an optionally substituted thienyl or optionally substituted phenyl ring; R.sup.1, R.sup.2 and R.sup.3 are each inter alia hydrogen; X is inter alia (CH.sub.2)mNR.sup.7 CO; m is 2-4; and Ar.sup.1 is an optionally substituted heterocyclic ring or an optionally substituted phenyl ring. The compounds are said to be useful as antiarrhythmic agents.
We have now found a class of tetrahydroisoquinoline derivatives which have affinity for dopamine receptors, in particular the D.sub.3 receptor, and thus potential in the treatment of conditions wherein modulation of the D.sub.3 receptor is beneficial, eg as antipsychotic agents.
In a first aspect the present invention provides compounds of formula (I): ##STR3## wherein: R.sup.1 represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, arylC.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkoxyC.sub.1-4 alkyl, C.sub.3-6 cycloalkylC.sub.1-4 alkoxy, C.sub.1-4 alkanoyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylsulphonyl, C.sub.1-4 alkylsulphonyloxy, C.sub.1-4 alkylsulphonylC.sub.1-4 alkyl, arylsulphonyl, arylsulphonyloxy, arylsulphonylC.sub.1-4 alkyl, C.sub.1-4 alkylsulphonamido, C.sub.1-4 alkylamido, C.sub.1-4 alkylsulphonamidoC.sub.1-4 alkyl, C.sub.1-4 alkylamidoC.sub.1-4 alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC.sub.1-4 alkyl, arylcarboxamidoC.sub.1-4 alkyl, aroyl, aroylC.sub.1-4 alkyl, or arylC.sub.1-4 alkanoyl group; a group R.sup.3 OCO(CH.sub.2).sub.p, R.sup.3 CON(R.sup.4)(CH2)p, R.sup.3 R.sup.4 NCO(CH.sub.2).sub.p or R.sup.3 R.sup.4 NSO.sub.2 (CH.sub.2).sub.p where each of R.sup.3 and R.sup.4 independently represents a hydrogen atom or a C.sub.1-4 alkyl group or R.sup.3 R.sup.4 forms part of a C.sub.3-6 azacyloalkane or C.sub.3-6 (2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar.sup.1 Z, wherein Ar.sup.1 represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring and Z represents a bond, O, S, or CH.sub.2 ; substituted 5- or 6-membered aromatic heterocyclic ring; or an optionally substituted bicyclic aromatic or heteroaromatic ring system;
In the compounds of formula (I) above an alkyl group or moiety may be straight or branched. Alkyl groups which may be employed include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and any branched isomers thereof such as isopropyl, t-butyl, sec-pentyl, and the like.
When R.sup.1 represents an arylC.sub.1-4 alkoxy, arylsulphonyl, arylsulphonyloxy, arylsulphonylC.sub.1-4 alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC.sub.1-4 alkyl, arylcarboxamidoC.sub.1-4 alkyl, aroyl, aroylC.sub.1-4 alkyl, or arylC.sub.1-4 alkanoyl group, the aryl moiety may be selected from an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heterocyclic ring. In the group R.sup.1 an aryl moiety may be optionally substituted by one or more substituents selected from hydrogen, halogen, amino, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, C.sub.1-4 alkylamido, C.sub.1-4 alkanoyl, or R.sup.5 R.sup.6 NCO where each of R.sup.5 and R.sup.6 independently represents a hydrogen atom or C.sub.1-4 alkyl group.
A halogen atom present in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine.
When q is 2, the substituents R.sup.1 may be the same or different. Preferably q represents 1.
An optionally substituted 5- or 6-membered heterocyclic aromatic ring, as defined for either of the groups Ar or Ar.sup.1 may contain from 1 to 4 heteroatoms selected from O, N or S. W
REFERENCES:
patent: 4925850 (1990-05-01), George et al.
patent: 5294621 (1994-03-01), Russell
patent: 6046210 (2000-04-01), Stemp et al.
Chemical Abstract, vol. 107, No. 11, Sep. 14, 1987, abstract No. 089337, Patsenko et al. "Interaction of simple tetahydroisoquinolines with opiate and high affinity dopamine (D3) receptors of rat striatum", XP002048675.
Boyfield et al. "A novel series of 2-aminotetralins with high affinity and selectivity for the dopamine D3 receptor" Bioorg. Med. Chem. Lett.97; vol. 7 (15); pp. 1995-1998, XP002048674.
Nash David John
Stemp Geoffrey
Kinzig Charles M.
Schroeder Ben
Shah Mukund J.
SmithKline Beecham plc
Stein-Fernandez Nora
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