Patent DE-19738005-A1 (DE)
Title: Use of known and new bis:phosphonate compounds
Inventor: BRANDS MICHAEL DR
IPC: C07F9/553
Filed: 1997-08-30
Abstract: Known and new 1,1-bisphosphonates are used for the treatment of cardiovascular and retroviral diseases.  - - LTreatment of cardiovascular and retroviral diseases in humans and animals comprises the administration of substituted 1,1-bisphosphonates of formula (I) or their salts or isomeric forms.  R1-R4 = H or alkyl; A+D = O, CH-R11 or N-R12; or D = H; and A = -(CO)a-(CH2)bNR5R6, -(CH2)-(S)c-R7 or -C(S)-NHR8; E, L = O or S; a, b c = 0 or 1; R5 = H or alkyl; R6 = H, alkyl or aryl, heteroaryl, cycloalkyl, anthraquinon-2-yl, 2-anthryl, N-benzyl-piperazinyl, S,S-dioxo-tetrahydrothiophen-3-yl or 4,7-benzphenanthren-2-yl (all optionally substituted by halo, CF3, phenyl, COOH, OH, CN or alkyl, alkoxy or alkoxycarbonyl); R7, R8 = cycloalkyl, optionally benz-fused heterocyclyl or aryl (all optionally substituted by halo, NO2, alkyl, alkoxy, alkenyloxycarbonyl, NHCOCH3 or CN-phenyl) or alkyl optionally substituted by aryl, benzylthio or optionally benz-fused heterocyclyl (all optionally substituted by halo, COOH, NO2, alkyl, alkoxy, CO2R9 or NHCOR9R10); or R7 = 4-(1-bisphosphonyl-ethyl)-thiomethyl-benzyl, (1-benzylthio-ethyl)thiomethyl, 1-phenyl-4-methyl-2,5-dioxo-pyrrolin-3-yl, N<4>-benzylpiperazinylmethyl, 4-(1-bisphosphonyl-ethyl)thiophenyl, benzimidazol-2-yl, 2-naphth1,2-dthiazol-2-yl or 4-(p-tolylamino)-phenylaminocarbonylmethyl; or R7 = halo when c = 0; R9 = H, cycloalkyl, alkyl or alkenyl; R10 = alkyl; R11, R12 = benzbinden-2-yl, 4-benzyloxyphenyl, phenanthren-6-yl or thiazol-2-yl, heteroaryl, alkyl, cycloalkyl or aryl optionally substituted by halo, NO2, NH2, benzyloxy, alkyl or alkoxy.  The full definitions are given in the DEFINITIONS (Full Definitions) Field. Independent claims are also included for: (A) new compounds (I) in which R<1>-R<4> = H, E and L = O, D = H and A = 1-chloronaphth-2-ylaminocarbonyl, 4,7-benzphenanthren-3-ylaminocarbonyl, 2- or 4-trifluoromethylphenylamino, (3-phenylpropyl)thiomethyl, 5-(methyl or chloro)-benzthiazol-2-ylthiomethyl, benzthiazol-2-ylthiomethyl, anthraquinon-2-ylaminomethyl, 2-(p-tolylmethylthio)ethylthiomethyl, (6-ethoxybenzthiazol-2-yl)thiomethyl, 4-(n-butyl)-phenylaminocarbonyl, naphth1,2-dthiazol-2-ylthiomethyl, 4-(1,1-bisphosphonyl-ethyl)thiophenylthiomethyl, (4-nitrophenyl)thiomethyl, 4'-biphenylylaminomethyl, phenanthren-2-ylaminomethyl, 6-methylnaphthalen-2-ylthiomethyl, 3-chlorophenylamino, benzimidazol-2-thiomethyl, n-octylthiomethyl, 2-ethyl-1-naphthylaminocarbonyl, S,S-dioxo-tetrahydrothiophen-3-ylamino, 3-trifluoromethylphenylamino, benzyl, 3-(2-cyano-phenyl)-benzyl, 2-methoxycarbonylphenylamino, 2-isopropoxy-6-methylphenylamino, 2-naphthylthiomethyl, 2-naphthylmethyl, (6-nitrobenzthiazol-2-yl)thiomethyl, 2-fluorophenylamino, 2-methoxyphenylamino, (4-acetylaminophenyl)thiomethyl, 4-benzylpiperazin-1-ylmethyl, (3,4-dimethoxyphenyl)thiomethyl, 2-ethylphenylamino, 2-(octadeca-9-enyloxycarbonyl)phenylthiomethyl, 2-chloro-3-methylphenylamino, (benzbinden-2-yl)vinyl, (4-benzyloxyphenyl)vinyl, phenanthren-6-ylvinyl, 3-methyl-but-1-enyl, cyclopropylvinyl, (2-methoxy-4-methyl-5-chlorophenyl)methylthiomethyl, cyclohexyloxycarbonylmethylthiomethyl, (5-chlorophenyl)methylthiomethyl, 3,4-dichlorophenylimino, benzylaminothiocarbonyl, 2,5-dichlorophenylimino, cyclohexylimino, thiazolylvinyl, 2-chlorophenylimino, 2,4,5-trichlorophenylimino, 2-chloro-4-nitrophenylimino, dimethylamino, 2-naphthylthiomethyl, cyclopentylamino, p-tolylamino, 2-nitrophenylvinyl, 1-phenyl-4-methyl-2,5-dioxo-pyrrolin-3-yl, 2-naphthylvinyl, 3-methoxy-2-naphthylvinyl, furan-3-ylmethyl tricyclohexylamine salt, pentafluorophenylvinyl, o-tolylvinyl, 2-(pyrazin-2-yl)ethylthiomethyl, phenylaminothioxo, 4-(phenylamino)-phenylaminocarbonyl-methylthiomethyl, phenylvinyl, thiophen-2-ylmethylthiomethyl, (4-tertbutylphenyl)thiomethyl, (4-benzyloxyphenyl)vinyl, 2,5-dichloro-3-methylphenylamino, N-ethyl-N-(2,5-dichloro-3-methylphenyl)amino, 3-methylphenylamino, 2