Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-02-09
2000-08-22
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514252, 544224, 544238, A61K 3150, C07D23704, C07D40112, C07D40312
Patent
active
061072958
DESCRIPTION:
BRIEF SUMMARY
The invention relates to arylalkanoylpyridazine erivatives of the formula I ##STR2## in which B is A, OA, NH.sub.2, NHA, NAA' or an unsaturated heterocycle which has 1 to 4 N, O and/or S atoms and which can be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or OA, OR.sup.5, --S--R.sup.5, --SO--R.sup.5, --SO.sub.2 --R.sup.5, Hal, --NO.sub.2, --NH.sub.2, --NHR.sup.5 or --NR.sup.5 R.sup.6, cycloalkyl having 3-7 C atoms, methylenecycloalkyl having 4-8 C atoms or alkenyl having 2-8 C atoms, C atoms and which can be substituted by 1 to 5 F and/or Cl atoms and
1-Benzoyltetrahydropyridazines have been described as progesterone receptor ligands, for example in J. Med. Chem. 38, 4878 (1995).
The invention was based on the object of finding novel compounds which have valuable properties, n particular those which can be used for the reparation of pharmaceuticals.
It has been found that the compounds of the formula I and salts thereof have highly valuable harmacological properties and are well tolerated.
In particular, they inhibit selectively phosphodiesterase IV, which causes an increase of the intracellular cAMP level (N.Sommer et al., Nature Medicine, 1, 244-248 (1995)). The PDE IV inhibition can be determined analogously to e.g. C. W. Davis in Biochim. biophys. Acta 797, 354-362 (1984).
The compounds of the formula I can be employed for the treatment of asthmatic diseases. The antiasthmatic activity of PDE IV inhibitors is known from T. J. Torphy et al. in Thorax, 46, 512-523 (1991) and can be determined, for example, by the method of T. Olsson, Acta allergologica 26, 438-447 (1971).
As cAMP inhibits bone decreasing cells and stimulates bone increasing cells (S. Kasugai et al., M681 and K. Miyamoto, M 682, in Abstract of the American Society for Bone and Mineral Research 18.sup.th annual meeting 1996), the compounds of formula I can be employed for the treatment of osteoporosis.
Moreover, the compounds have an inhibitory effect on the formation of TNF (tumor necrosis factor) and are therefore suitable for the treatment of allergies and inflammatory diseases, autoimmune diseases and transplant rejection reactions. They can furthermore be used for the treatment of dysmnesia, tumors, atherosclerosis, rheumatoid arthritis, multiple sclerosis, Morbus Crohn, atopic dermatitis, diabetes mellitus, ulcerative colitis and AIDS.
PDE IV inhibitors are potent compounds for the treatment of asthmatic and inflammatory diseases, diabetes mellitus, atopic dermatitis, psoriasis, AIDS, tumor growth or tumor metastasis (see e.g. EP 77 92 91).
The antiinflammatory effect of the compounds of the formula I and their potency for the treatment of e.g. autoimmune diseases, multiple sclerosis or rheumatoid arthritis can be determined analogously to the methods of N. Sommer et al., Nature Medicine, 1, 244-248 (1995) or L. Sekut et al., Clin. Exp. Immunol., 100, 126-132 (1995).
PDE IV inhibitors are effective in the treatment of tumors (see e.g. WO 95 35 281, WO 95 17 399 or WO 96 00 215) The compounds of the formula I can be employed as pharmaceutically active ingredients in human and veterinary medicine. Furthermore, they can be employed as intermediates for the preparation of other pharmaceutically active ingredients.
Accordingly, the invention relates to the compounds of the formula I and to a process for the preparation of compounds of the formula I according to claim 1 and salts thereof, characterized in that a compound of the formula II ##STR3## in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the abovementioned meanings ##STR4## in which B and Q have the abovementioned meanings and L is Cl, Br, OH or a reactive esterified OH group, ##STR5## in which R.sup.1 R.sup.2 , R.sup.3, R.sup.4 and Q have the abovementioned meanings is reacted with a compound of the formula V compound of the formula I is converted into a salt thereof by treatment with an acid.
The radicals, R.sup.1, R.sup.2, R.sup.3, R.sup.4, B, Q and L hereinabove and hereinbelow have the meanings given for the formulae I, II, III, IV and V, unless expressly stat
REFERENCES:
patent: 5684151 (1997-11-01), Combs
D. Combs, "Nonsteroidal Progesterone Receptor", Ligands 1.3-Aryl-1-Benzoyl-Tetrahydropyrid Azines, Journal of Medicinal Chemistry, vol. 38, No. 25, 1995, pp. 4878-4879, XP002047380.
WO9401412-English Abstract, Jan. 20, 1994.
Beier Norbert
Kluxen Franz-Werner
Rochus Jonas
Wolf Michael
Merck Patent Gesellschaft mit beschrankter Haftung
Powers Fiona T.
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