Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1997-06-17
1999-02-02
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514520, 514538, 514631, 558418, 560 27, 560 35, 564225, 564243, 564244, 564245, 564246, A61K 31155, C07C25714
Patent
active
058666125
DESCRIPTION:
BRIEF SUMMARY
This application is filed pursuant to 35 USC section 371 as a United States National Phase Application of International Application No. PCT/GB95/02978 filed Dec. 20, 1995 which claims priority from GB9425701.1 filed Dec. 20, 1994.
The present invention relates to acetamidine derivatives, to methods for their manufacture, to pharmaceutical compositions containing them and to their use in therapy, in particular their use as selective inhibitors of nitric oxide synthase.
It has been known since the early 1980's that the vascular relaxation brought about by acetylcholine is dependent on the presence of the endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years and NO is the active component of amylnitrite, glyceryltrinitrite and other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesised from the amino acid L-arginine by the enzyme NO synthase.
NO is the endogenous stimulator of the soluble guanylate cyclase enzyme and is involved in a number of biological actions in addition to endothelium-dependent relaxation including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al, Biochemical Pharmacology, 38, 1709-1715 (1989) and Moncada et al, Pharmacological Reviews, 43, 109-142 (1991)). It is now thought that excess NO production may be involved in a number of conditions, particularly conditions which involve systemic hypotension such as septic (toxic) shock and therapy with certain cytokines.
The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue, NG-monomethyl-L-arginine (L-NMMA), and the therapeutic use of L-NMMA for the treatment of septic (toxic) shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A-0446699.
It has recently become apparent that there are at least three isoenzymes of NO synthase (reviewed in Knowles and Moncada, Biochem. J. (1994) 298, 249-258) as follows:
(i) a constitutive, Ca++/calmodulin dependent enzyme (eNOS) which is present in vascular endothelial cells, and that releases NO in response to receptor or physical stimulation.
(ii) a constitutive, Ca++/calmodulin dependent enzyme (nNOS), located in the brain and some peripheral nervous systems, that releases NO in response to receptor or physical stimulation.
(iii) a Ca++ independent enzyme (INOS) which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once expressed, this inducible NO synthase synthesises NO for long periods.
The NO released by eNOS and nNOS acts as a transduction mechanism underlying several physiological responses. The NO produced by iNOS acts as a cytotoxic molecule for tumour cells and invading micro-organisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilatation and tissue damage, may result largely from the effects of NO synthesised by iNOS.
The NO synthase inhibitors proposed for therapeutic use so far, such as L-NMMA and nitroarginine, are non-selective in that they inhibit all the NO synthase isoenzymes. Use of such a non-selective NO synthase inhibitor requires that great care is taken in order to avoid the potentially serious consequences of over-inhibition of the eNOS including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of septic and/or toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment. Thus, whilst non-selective NO synthase inhibitors have therapeutic utility provided that approp
REFERENCES:
J. Oszczapowicz, et al, Chemical Abstracts, vol. 102, No. 10, 11 Mar. 1985 Columbus, Ohio, US; Et J.Chromatogr., vol. 315 (1984) pp. 95-100.
Saari, W. S., et al, Trichloroacetamidines, a new class of positive inotropic agents, Journal of Medicinal Chemistry, vol. 21, No. 12 (1978) Washington U.S., pp. 1283-1290.
T.T. Conway, et al., Chemical Abstracts, vol. 68, No. 21, 20 May 1968, Columbus, Ohio US; Et J. Pharm. Sci., vol. 57, No. 3 (1968) pp. 455-459.
Parulkar, A. P., et al, N-Heteroaralkyl substituted . alpha.-amidinium thiolsulfates, Journal of Heterocyclic Chemistry, vol. 3, No. 4 (1996) PROVO US, pp. 472-475.
Bolhoffer, W. A., et al. 2-Mercaptoacetamidines as gastric antisecretory agents, Journal of Medicinal Chemistry vol. 22, No. 3 (1979) Washington US, pp. 295-301.
Keir, W. F., et al. Amidinoacetamides in the synthesis of pyrimidines, imidazoles and purines, Journal of the Chemical Society, Perkin Transactions 1 (1976) Letchworth GB, pp. 1847-1852.
Database Crossfire, Beilstein Informationssysteme GmbH, Frankfurt DE, see BRN 2346409 Et Chem. Ber., vol. 93 (1960) pp. 2230-2238.
Database Crossfire, Beilstein Informationssysteme GmbH, Frankfurt DE, see BRN 3777937 Et Justus Liebigs Ann. Chem., vol. 575 (1952) p. 90ff.
Database Crossfire, Beilstein Informationssysteme GmbH, Frankfurt DE, see BRN 7088281, see BRN 7089080 Et Farmaco Ed. Sci., vol. 43, No. 1 (1988) pp. 103-112.
Database Crossfire, Beilstein Informationssysteme GmbH, Frankfurt DE, see BRN 1790943 Et J. Chem. Soc. (1947) p. 730.
Database Crossfire, Beilstein Informationssysteme GmbH, Frankfurt DE, see BRN 394415 Et Can. J. Chem., vol. 39 (1961) pp. 761-764.
Database Crossfire, Beilstein Informationssysteme GmbH, Frankfurt DE, see BRN 3278146 Et Recl. Trav. Chim. Pays-Bas, vol. 70 (1951) pp. 638, 641.
Database Crossfire, Beilstein Informationssysteme GmbH, Frankfurt DE, see BRN 2717900 Et GB,A, 861 526 (1958).
Database Crossfire, Beilstein Informationssysteme GmbH, Frankfurt DE, see BRN 746863 Et Bull Chem Soc. Jpn, vol. 45 (1972) pp. 2010-2015.
Database Crossfire, Beilstein Informationssysteme GmbH, Frankfurt DE, see BRN 473624 Et J. Indian Chem. Soc., vol. 39 (1962) pp. 208-210.
Database Crossfire, Beilstein Informationssysteme GmbH,Frankfurt DE, see BRN 113878 Et J. Heterocycl. Chem., vol. 12 (1975) p. 407.
Database Crossfire, Beilstein Informationssysteme GmbH, Frankfurt DE, see BRN 6423899 Et Gazz. Chim. Ital., vol. 113, No. 1-2 (1983) pp. 77-82.
Journal of Medicinal Chemistry, vol. 37, No. 23, Nov. (1994) Washington US, pp. 3886-3888.
Collins Jon Loren
Furfine Eric Steven
Garvey Edward Patrick
Oplinger Jeffrey Alan
Shearer Barry George
Glaxo Wellcome Inc.
Kumar Shailendra
Morgan Lorie Ann
LandOfFree
Acetamidine derivatives and their use as inhibitors for the nitr does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Acetamidine derivatives and their use as inhibitors for the nitr, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Acetamidine derivatives and their use as inhibitors for the nitr will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1117956