Patent EA-005136-B1 (EA)
Title: Formulation with an improved therapeutic range, containing nucleotide synthesis inhibitors
Inventor: LINDNER JURGEN
IPC: A61P37/02
Filed: 1999-12-01
Abstract: 1. A preparation comprising 1) at least one compound, from the group consisting of colestipol, colestyramine and active carbon which essentially prevents the enterohepatic circulation of the nucleotide synthesis inhibitors or a compound from the group consisting of uridine, purine, purine nucleotides or pyrimidine nucleotides which antagonizes the action of the nucleotide synthesis inhibitors with a displacement in time, and 2) at least one nucleotide synthesis inhibitor from the group consisting of 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, mizoribine and compounds of the formula I and II and/or an optionally stereoisomeric form of the compound of the formula I or II and/or a physiologically tolerable salt of the compound of the formula II, where R<1> is a) (C1-C4)-alkyl, b) (C3-C5)-cycloalkyl, c) (C2-C6)-alkenyl or d) (C2-C6)-alkynyl, R<2> is a) -CF3, b) -O-CF3, c) -S-CF3, d) -OH, e) -NO2, f) halogen, g) benzyl, h) phenyl, i) -O-phenyl, k) -CN or l) -O-phenyl, mono- or polysubstituted by 1) (C1-C4)-alkyl, 2) halogen, 3) -O-CF3 or 4) -O-CH3, R<3> is a) (C1-C4)-alkyl, b) halogen, or c) is a hydrogen atom, and X is a) a -CH group or c) a nitrogen atom. 2. A preparation as claimed in claim 1, where a compound of the formula I and/or II and/or an optionally stereoisomeric form of the compound of the formula I or II and/or a salt of the compound of the formula II is employed, where R<1> is a) methyl, b) cyclopropyl or c) (C3-C5)-alkynyl, R<2> is -CF3 or -CN, R<3> is a hydrogen atom or methyl, and X is a -CH group. 3. A preparation as claimed in claim 1 or 2, where N-(4-trifluoromethyl-phenyl)-5-methylisoxazole-4-carboxamide is employed as a compound of the formula I or N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide, 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide or N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxyhept-2-en-6-ynecarboxamide is employed as compound of the formula II. 4. A preparation as claimed in one or more of claims 1 to 3, wherein additional active compounds from the group consisting of antiuricopathics, analgesics, steroidal or nonsteroidal antiinflammatories, cytokines, cytokine agonists, platelet aggregation inhibitors, cytokine antagonists or immunosuppressant compounds such as cyclosporin A, FK 506 or rapamycin are contained. 5. A preparation as claimed in one or more of claims 1 to 4, which consists of compositions or combination packs in which the constituents are placed next to one another and are therefore used simultaneously, separately or sequentially on one and the same human or animal body. 6. A preparation as claimed in claim 5, wherein the administration of the compound of the formula I and/or II is carried out timewise before the administration of the compound which essentially prevents the enterohepatic circulation of the compound of the formula I or II. 7. The use of the preparation as claimed in one or more of claims 1 to 6 for the production of a pharmaceutical for treating immunological disorders, inflammatory and cytotoxic processes in connection with gene therapy interventions, carcinomatous disorders such as lung cancer, leukemia, ovarian cancer, sarcoma, Kaposi's sarcoma, meningioma, intestinal cancer, lymph node cancer, brain tumors, breast cancer, pancreatic cancer, prostate cancer or skin cancer, autoimmune disorders such as systemic lupus erythematosus or multiple sclerosis, rheumatic disorders, transplantations or graft-versus-host reactions or host-versus-graft reactions, disorders which are caused by strongly proliferating cells, psoriasis or atypic dermatitis, allergy, asthma, urticaria, rhinitis or uveitis, 18 type II diabetes, cystic fibrosis, colitis, liver fibrosis or sepsis, chronic inflammatory disorders such as arteriosclerosis, Crohn's disease or ulcerative colitis. 8. A process for the production of the preparation as claimed in claims 1 to 6, which comprises bringing at least one nucleotide synthesis inhibitor from the group consisting of 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)4-methyl-4-hexenoate, mizoribine and compounds of the formulae I and II and a compound from the group consisting of colestipol, colestyramine and active carbon which essentially prevents the enterohepatic circulation of the nucleotide synthesis inhibitors, or a compound from the group consisting of uridine, purine, purine nucleotides or pyrimidine nucleotides which antagonizes the action of the nucleotide synthesis inhibitors with a displacement in time into a suitable administration form with a pharmaceutically suitable and physiologically acceptable vehicle, and, if appropriate, further suitable active compounds, additives or excipients.