Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-11-19
1998-09-29
Ramsuen, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514378, 544137, 544367, 5462721, 548 6, 548111, 548119, 548205, 548240, 548247, 548248, A61K 3142, A61K 31535, C07D26104, C07D41312
Patent
active
058146270
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/E95/00784 filed Mar. 3, 1995.
The present invention relates to pharmaceuticals for the prophylaxis and/or treatment of inflammations, asthma, rheumatic diseases and autoimmune diseases.
The mode of action of non-steroidal anti-inflammatory pharmaceuticals, e.g. acetylsalicylic acid and indomethacin, is already known. It is based on inhibition of the enzyme cyclooxygenase, an enzyme which is present in many cells and which is responsible for providing inflammation-promoting prostaglandins.
It is also already known that cyclooxygenase inhibitors of this type can be employed in rheumatism therapy (EP 245 825).
However, it has meanwhile become clear that, in addition to their undesirable effects, prostaglandins are also able to exert desirable cell-protective properties, for example in thrombocytes, in the gastroduodenum and in the kidney. For this reason, all cyclooxygenase inhibitors bring about undesirable side effects, such as prolongation of the bleeding time, generation of gastric ulcers and inhibition of renal function.
It can, consequently, be of advantage, instead of inhibiting the prostaglandins, to inhibit the particularly potent inflammation-mediators from the substance classes of the leukotrienes and the cytokines, such as interleukin 1 alpha and interleukin 1 beta, oxygen radicals and proteases, by blockading their formation.
It has now been found that while the compound of the formula I essentially exhibits no inhibitory effect on cyclooxygenase, it inhibits the formation of leukotriene, cytokines, oxygen radicals and proteases from white blood cells, and also demonstrates a positive effect in models for testing asthma, autoimmune diseases and rheumatic diseases.
The invention relates to a compound of the formula I ##STR1## and/or to a physiologically tolerated salt of the compound of the formula I formula II ##STR2## and the other radical R.sup.1 or R.sup.2 has the following meaning: a) pyridyl, ##STR3## where n is the number zero, 1, 2, 3, 4, 5 or 6, m is the number zero, 1, 2, 3 or 4, -C.sub.6)-alkyl, or ##STR4## in which o is the number zero or 1, and in which R.sup.9 and R.sup.10, independently of each other, have the following meaning: independently of each other, by ##STR5## 7) N-glycyl, 8) N-glycyl-(C.sub.1 -C.sub.4)-alkyl ester, ##STR6## in which R.sup.12 and R.sup.13, independently of each other, have the following meaning: them, a five- to seven-membered heterocycle which is unsubstituted or substituted once to three times by (C.sub.1 -C.sub.4)-alkyl, it being possible for a carbon atom to be replaced by a sulfur, oxygen or nitrogen atom, or CH.sub.2 radicals, ##STR7## in which Q.sub.1 is 1) --(CH.sub.2).sub.m --, where n is the number zero, 1, 2, 3 or 4, or ##STR8## in which Q.sub.2 is 1) --(CH.sub.2).sub.m, where m is the number zero, 1, 2, 3 or 4, or that the double bond and the radical R.sup.4 are not present simultaneously, bonded, an aliphatic ring which is composed of 3, 4 or 5 carbon atoms, and
The compounds of the formula I may be present in the pharmaceuticals as optical isomers, diastereomers or racemates, or as mixtures thereof. The designated alkyl or alkanoyl radicals may be present in either the straight-chain or branched form.
For the purposes of the present invention, five- to seven-membered heterocycles are, for example, pyrrole, pyridine, azepine, thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, thiazine, 1,2-oxazine, 1,3-oxazine, morpholine, pyridazine, pyrimidine, pyrazine, 1,2-thiazepine, 1,3-thiazepine, 1,4-thiazepine, 1,2-oxazepine, 1,3-oxazepine, 1,4-oxazepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine and partially or completely saturated variants thereof. Particular mention may be made of pyrrolidine, piperidine, morpholine, piperazine, N-methylpiperazine or pyridine.
The term "an amino acid" is understood to mean the stereoisomeric forms, e.g. D and L forms, of the following compounds: tryptophan, .beta.-alanine, lysine, proline, glycine, .gamma.-aminobutyrate, N.epsilon.-acetyllysine, N.delta.-acetylornithi
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patent: 5510361 (1996-04-01), Scherz et al.
Yasuo Isomura et al., Chemical and Pharmaceutical Bulletin, vol. 32,. 1, 1884 Tokyo JP pp. 152-165.
Chemical Abstractsvol. 100, No.5 Jan. 30, 1984, abst. #34538 JP A 58 148 858.
Flynn, Daniel L. et al., Journal of Medicinal Chemistry, vol. 34, No. 2 (Feb. 1991) pp. 518-521.
Anagnostopulos Hiristo
Bartlett Robert Ryder
Schleyerbach Rudolf
Schwab Wilfried
Weithmann Klaus Ulrich
Hoechst Aktienegesellschaft
Ramsuen Robert W.
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