Spiro-piperidine derivatives as inhibitors of nitric oxide synth

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...

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5142275, 5142295, 544 6, 544 71, A01N 4358

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active

061002461

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to novel compounds, as well as 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).


DISCLOSURE OF THE INVENTION

According to the invention, there is provided a compound of formula (I): ##STR2## wherein
A represents a benzo ring; a six membered heterocyclic aromatic ring containing 1 to 3 nitrogen atoms; or a five membered heterocyclic aromatic ring containing 1 to 3 heteroatoms which may be the same or different and are selected from O, N and S;
R.sup.2 and R.sup.3 independently represent hydrogen, C1 to 6 alkyl, C1 to 6 alkoxy, C1 to 6 alkylthio, halogen, hydroxy or amino;
R.sup.1 represents nitrogen atoms; or a five membered heterocyclic aromatic ring containing 1 to 3 heteroatoms which may be the same or different and are selected from O, N and S, the phenyl or heterocyclic aromatic ring being optionally substituted by C1 to 6 alkyl, C1 to 6 alkoxy, C1 to 6 alkylthio, C2 to 6 alkenyl, C2 to 6 alkynyl, C1 to 6 haloalkyl, C2 to 12alkoxyalkyl, C2 to 12 alkylthioalkyl, amino, halogen, hydroxy, cyano or nitro; or to 6 alkynyl, C1 to 6 haloalkyl, C2 to 12 alkoxyalkyl, C2 to 12 alkylthioalkyl, C7 to 12 arylalkyl, C7 to 12 aryloxyalkyl or halogen;
X represents CH.sub.2, CO, O or S(O).sub.n where n represents an integer from 0 to 2; and pharmaceutically acceptable salts, enantiomers, racemates and tautomers thereof.
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 a medicament, for the treatment or prophylaxis of inflammatory disease.
According to the invention, there is also provided a method of treating, or reducing the risk of, diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof.
More particularly, there is also provided a method of treating, or reducing the risk of, inflammatory disease in a person suffering from or at risk of, said disease, wherein the method comprises administering to the person

REFERENCES:
patent: 3686187 (1972-08-01), Cole et al.
patent: 4092414 (1978-05-01), Cragoe, Jr. et al.
Chemical Abstracts, Arch. Dermatol. Res., vol. 287, pp. 567-571 (1995).
Forstermann et al, "Induced RAW 264.7 macrophages express soluble and particulate nitric oxide . . . ," Eur. J. Pharmacol., vol. 225, pp. 161-165 (1992).
Macdonald et al, "Chapter 23: Nitric Oxide Synthase Inhibitors," Ann. Rep. Med. Chem., vol. 31, pp. 221-230 (1996).
J. Heterocyclic Chem., vol. 29, pp. 779-786 (1982).*
Bull. Chem. Soc. Japan, vol. 33, pp. 575-578 (1960).*

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