Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-08-11
2000-07-04
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544231, A01N 4354
Patent
active
06083952&
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel compounds which are aminospiropiperidine quinazoline derivatives. The invention also concerns related aspects including processes for the preparation of the compounds, compositions containing them and their use as pharmaceuticals. There are also provided chemical intermediates useful for the production of the compounds.
BACKGROUND OF THE INVENTION
Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classes--constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time, two constitutive NOSs and one inducible NOS have been identified. Of the constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been particularly implicated in the pathogenesis of inflammatory diseases. Regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states (J. E. Macdonald, Ann. Rep. Med. Chem., 1996, 31, 221-230).
WO 97/14686 discloses, amongst other compounds, aminospiropiperidine quinazoline derivatives of the following formula: ##STR2## wherein R.sup.3 represents various substituents, for use as pharmaceuticals. The treatment or prophylaxis of inflammatory conditions is disclosed as a particular pharmaceutical use.
DISCLOSURE OF THE INVENTION
According to the present invention, there is provided a compound of formula (I) ##STR3## wherein: R.sup.1 and R.sup.2 independently represent hydrogen, C1 to 6 alkyl, C2 to 6 alkenyl, C2 to 6 alkynyl, C1 to 6 alkoxy, C1 to 6 alkylthio, halogen, hydroxy, trifluoromethyl or amino; hydrogen, C1 to 6 alkyl, C2 to 6 alkenyl, C2 to 6 alkynyl, C1 to 6 alkoxy, C1 to 6 alkylthio, halogen, hydroxy, trifluoromethyl, amino, cyano, nitro, trifluoromethoxy, methanesulphonyl, sulphamoyl, --NR.sup.4 R.sup.5, --COOR.sup.6, --CONR.sup.7 R.sup.8, benzyloxy, phenyl, or a 5-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms which may be the same or different and are selected from O, N and S, which phenyl or 5-membered heterocyclic aromatic ring is optionally substituted, the optional substituents being C1 to 6 alkyl, halogen, cyano, nitro, hydroxy, C1 to 6 alkoxy, trifluoromethyl and trifluoromethoxy; alkyl; phenyl, which phenyl is optionally substituted by one or more groups independently selected from C1 to 6 alkyl, halogen, cyano, nitro, hydroxy, C1 to 6 alkoxy, trifluoromethyl and trifluoromethoxy;
A represents an aromatic carbocyclic ring or a 5- or 6-membered heterocyclic aromatic ring containing 1 to 3 heteroatoms which may be the same or different and are selected from O, N and S; thereof.
The compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers, racemates and tautomers have the advantage that they are potent inhibitors of the inducible isoform of the enzyme nitric oxide synthase (iNOS) present in macrophages.
The invention further provides a process for the preparation of such compounds or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof.
According to the invention there is also provided a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof, for use as a medicament.
Another aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial.
A more particular aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof, in the manufacture of
REFERENCES:
patent: 5883102 (1999-03-01), Hamley et al.
Lochead et al, Abstract No. 1985:95488, "Use of chloroalkenylamines for the synthesis . . . ,", J. Chem. Soc., Perkin Trans. 1 (1984) (11) 2477-89.
Gesson et al, ".alpha.-N-Acyliminium IOn--2-Bromoalkene Cyclizations," Tetrahedron, vol. 49, No. 11, pp. 2239-2248 (1993).
Hamley Peter
Pimm Austen
Tinker Alan
Astra Pharmaceuticals Limited
Shah Mukund J.
Truong Tamthom N.
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