Patent EP-1623987-A1 (EP)
Inventor: REICHELT CLAUDIA
IPC: A61P37/08
Filed: 2004-08-02
Abstract: Tricyclic thiophene, furan or pyrrole derivatives (I) are new. Tricyclic thiophene, furan or pyrrole derivatives (I) of formulae (Ia)-(Id) and their salts, solvates, metabolites, tautomers and prodrugs are new, other than 2-dimethylamino-4,7-diethoxy-8-cyano-9-phenyl-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine, 1,4-dihydro-2,2-dimethyl-5-morpholino-10-propylthio-2H-pyrano[4",3":4',5']pyrido[3',2':4',5']thieno[3,2-d]pyrimidin-8(9H)-one, 1--butylthio-1,4-dihydro-2,2-dimethyl-5-morpholino-2H-pyrano[4",3":4',5']pyrido[3',2':4',5']thieno[3,2-d]pyrimidin-8(9H)-one and 2-methyl-5-(2thienyl)-1,2,3,4-tetrahydro-11H-7-thia-2,6,9,11-tetraaza-benzo[c]fluorene-8,10-dione. Y' : S, O or N; R 1>H; 1-10C (cyclo)alkyl, 2-12C (cyclo)alkenyl or 2-12C (cyclo)alkynyl, (6-12C)aryl(1-5C)alkyl, 5- to 14-membered mono- or bicyclic heterocyclyl with 1-4 heteroatoms, 1-10C (cyclo)alkoxy, (6-12C)aryl(1-5C)alkoxy, 2-12C alkanoyl, benzoyl, naphthoyl, alkylthio, alkylsulfinyl, alkoxysulfonyl or alkylsulfonyl, alkoxycarbonyl, alkylcarbamoyl or dialkylcarbamoyl, (hetero)arylthio, (hetero)arylsulfinyl or (hetero)arylsulfonyl, aryloxycarbonyl, arylcarbamoyl, arylamido, N-aryl-N-alkylamido, N-aryl-N-alkylcarbamoyl, aralkoxycarbonyl or aralkylcarbamoyl with 1-5C alkyl or 6-10C aryl, heterocyclylcarbonyl, heterocyclylcarbamoyl, heterocyclylamido, N-heterocyclyl-N-alkylamino, heterocyclylalkoxycarbonyl or heterocyclylalkylcarbamoyl, arylhydrazino or phenyl (all optionally substituted); 1- or 2-naphthyl; OH, SH, CHO, COOH, CONH 2, CN, SCN, NO 2, SO 3H; with heterocyclyl as above and 1-5C alkyl; halo; NH 2, 1-6C alkylamino or di(1-5C alkyl)amino, optionally substituted; heterocyclylamino or La-A-Lb-B; La : bond, NR', O, S, SO, SO 2; A : phenyl or naphthyl (both optionally substituted), heterocyclyl or tricyclic group; Lb : bond, NR', O, S, SO, SO 2, CHR, CH 2O, OCH 2, NR'CO, NR'CS, NR'CONR', NR'CSNR', NR'C(NH), NR'SO, NR'SO 2, N(R')=S(O)(R'), NR'C(NHOH), NHNR', N(NHR')CO, NHN=, N(OH)CS, NR'COO, NR'C(S)O, N(OH)CO; B : H; alkyl (optionally substituted); CONH 2; CONHQ; COOH; COOAlk; COQ; CH 2CONH 2; CH 2CONHQ; CH 2COOH; CH 2COOAlk; CH 2COQ; phenyl or naphthyl or 4- to 14-membered mono- or bicyclic heterocyclyl with 1-5 heteroatoms (optionally oxo-substituted) (all optionally substituted); Alk : alkyl (optionally substituted); Q : alkyl, aryl or heteroaryl (optionally substituted); R' : H or Alk; R 2>H, 1-12C alkyl, 2-12C alkenyl or alkynyl; phenyl(1-6C)alkyl (optionally substituted); phenacyl (optionally substituted); COOH, 1-4C alkoxycarbonyl, CONH 2 or mono- or di(1-6C alkyl)carbamoyl; COR'; CN, NO 2, NH 2, mono- or di(1-6C alkyl)amino, N=N-Ph, N=N-C 6H 4-R, 1,3-diphenyl-4-pyrazolyl, 2-thiazolinyl, 2-imidazolinyl or 3,4,5,6-tetrahydropyrimidinyl; R 3>H; OH, SH, CHO, COOH, CONH 2, CN, SCN, NO 2, halo; NH 2, or SO 3H or 1-10C (cyclo)alkyl, 2-12C (cyclo)alkenyl, 2-12C (cyclo)alkynyl, (6-12C)aryl(1-5C)alkyl, phenyl, 1- or 2-naphthyl, pyridyl N-oxide, 1-10C (cyclo)alkoxy, (6-12C)aryl(1-5C)alkoxy, 2-12C alkanoyl, benzoyl or 1- or 2-naphthoyl, alkylthio, alkylsulfinyl, alkoxysulfonyl or alkylsulfonyl, (hetero)arylthio, (hetero)arylsulfinyl or (hetero)arylsulfonyl, alkoxycarbonyl, alkylcarbamoyl or dialkylcarbamoyl, aryloxycarbonyl, arylcarbamoyl, arylamido, N-aryl-N-alkylamido, N-aryl-N-alkylcarbamoyl, aralkoxycarbonyl or aralkylcarbamoyl with 1-5C alkyl or 6-10C aryl, 1-6C alkylamino or di(1-5C alkyl)amino, 6-10C arylamino or arylhydrazino (all optionally substituted); R 4>2-14C alkyl, 3-14C cycloalkyl, 2-14C alkenyl, 3-14C cycloalkenyl, 2-14C alkynyl, phenyl or 1- or 2-naphthyl, 4- to 14-membered mono- or bicyclic heterocyclyl with 1-5 heteroatoms (all optionally substituted); SQ 1>, SOQ 1>, SO 2Q 1>; OR 6> or NR 7>R 8>; Q 1>1-8C alkyl, 2-8C alkenyl or 2-8C alkynyl, (optionally substituted); R 6>1-4C n-alkyl, t-Bu, CH 2CH 2OH, CH 2CH 2SH, CH 2CH 2SMe, CH 2CF 3, CH 2CCl 3, CH 2CHF 2, CH 2CHCl 2, CH 2CH 2F, CH 2CH 2Cl, CH 2CH 2Br; 3-7C cycloalkyl, 2-5C alkenyl or alkynyl; 3-7C cycloalkenyl; aryl or heteroaryl; 1- or 2-naphthyl (all optionally substituted); pyridyl, isoquinolinyl, quinolinyl, acridinyl; NR 7>R 8>morpholino, thiomorpholino or its S,S-dioxide, pyrrolidino, piperidino, 1-piperazino, 1-homopiperazino, 4-(1-6C alkyl)-1-piperazino or 4-aryl-1-piperazino (each optionally substituted); or the residue of a 5- to 14-membered mono- or polycyclic alicyclic amine (optionally substituted); R 7>, R 8>H; 1-6C alkyl, benzyl, phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl, 2-thienyl, 2-furyl, (all optionally substituted); provided that R 5> is OR 6> if R 7>= R 8>= H; R 5>OR 6>; NR 7>R 8>, provided that R 4> is not also NR 7>R 8> and that NR 7>R 8> is not morpholino when R 4>= aryl; N 3, NHOH, 1-3C alkoxyamino, N-(1-3C alkyl)hydroxylamino, N,N-di(1-3C alkyl)hydroxylamino; hydrazino, 1-4C alkylhydrazino, di(1-4C alkyl)hydrazino; benzylhydrazino, acylhydrazino, N,N-diacylhydrazino; NHCONH 2; 1-imidazolyl, 1,2,4-triazol-1-yl, 1-pyridinium; 1-pyrazinium, 1-pyridazinium, optionally substituted by alkyl; A : fused carbocyclic ring with 5-8 ring atoms, fused bicyclic ring system with 6-11 ring atoms, optionally containing N, O and/or S or a fused heterocyclic ring with 5-8 ring atoms inclusing N, O and/or S atoms (all optionally substituted). [Image] ACTIVITY : Antiasthmatic; Antiinflammatory; Antirheumatic; Antiarthritic; Osteopathic; Neuroprotective; Antiulcer; Antipsoriatic; Dermatological; Antiallergic; Ophthalmological; Immunosuppressive; Antidiabetic; Nootropic; Antiparkinsonian; Nephrotropic; Analgesic; Antiarteriosclerotic; Cardiant; Cerebroprotective; Cytostatic; Virucide. 4-Ethoxy-7-(4-(2-furyl)phenyl)-9-methyl-2-(1-piperazinyl)thieno[2,3-d:4,5-d']dipyrimidine had a cytotoxic effect on 60-85 % of chronic lymphatic leukemia cells at a concentration of 1 microM. MECHANISM OF ACTION : Phosphodiesterase 4 (PDE4) inhibitor; Tumor necrosis factor alpha release inhibitor.