Patent EA-004182-B1 (EA)
Title: Benzocycloheptenes, pharmaceutical preparations containing these compounds, and their use for producing medicaments
Inventor: BOHLMANN ROLF
IPC: C07C327/28
Filed: 1999-07-19
Abstract: 1. Benzocycloheptenes of general formula I in which R<1> and R<2>, independently of one another, stand for a hydrogen atom, a hydroxy group, an optionally substituted C1-C10 alkoxy group, an optionally substituted C1-C10 alkanoyloxy group or an optionally substituted C7-C15 aroyloxy group, and SK stands for a side chain -A-B-Z, whereby A means a direct bond or an oxygen atom, B means a straight-chain or branched-chain, optionally substituted alkylene, alkenylene or alkinylene group with up to 10 carbon atoms, Z means a group -D-SOX-E-G, an amino group -NR<7>R<8> or a substituent G, in which D means a direct bond or a group -NR<3>(R<4>-), R<3> means a straight-chain or branched-chain alkyl, alkenyl or alkinyl group with up to 10 carbon atoms, and R<4> means a straight-chain or branched-chain, optionally substituted alkylene, alkenylene or alkinylene group with up to 10 carbon atoms, whereby the nitrogen atom also can be incorporated in a 4- to 7membered ring system, x means 0, 1 or 2, E means a straight-chain or branched-chain, optionally substituted alkylene, alkenylene or alkinylene group with up to 10 carbon atoms, G means a partially or completely fluorinated, straight-chain or branched-chain alkyl group with up to 5 carbon atoms, an optionally substituted aryl or heteroaryl radical, a carbamoyl radical -C(O)-NR<5>R<6> with R<5> and R<6> in the meaning of R<7> and R<8>, a halogen atom or a hydrogen atom, R<7> and R<8>, independently of one another, mean a hydrogen atom, a straight-chain or branched chain, optionally partially fluorinated alkyl, alkenyl or alkinyl radical with up to 14 carbon atoms, which can be interrupted by one to three heteroatoms -O- and -S- and groupings -NR<9>-, in which R<9> means a hydrogen atom or a C1-C3 alkyl radical, an aryl or heteroaryl radical that is optionally substituted in one or two places, a C3-C10 cycloalkyl radical that is optionally substituted in one or two places, a C4-C15 cycloalkylalkyl radical that is optionally substituted in one or two places, a C7-C20 aralkyl radical that is optionally substituted in one or two places, a heteroaryl-C1-C8 alkyl radical that is optionally substituted in one or two places or an optionally substituted aminoalkyl radical, a biphenylene radical or a radical of formula -C(O)R<10>, in which R<10> can have the meanings that are indicated above for R<7> or R<8>, R<7> and R<8> with the nitrogen atom, to which they are bonded, form a saturated or unsaturated heterocycle with 5 or 6 chain links, which optionally contains one or two additional heteroatoms, selected from nitrogen, oxygen and sulfur, and optionally is substituted, and in -A-B-Z, if A stands for an oxygen atom and Z stands for G, G cannot be a hydrogen atom or a halogen atom, or if A stands for an oxygen atom and Z stands for an amino group NR<7>R<8>, in which R<7> and R<8> in each case mean a methyl group or together with the nitrogen atom form a pyrrolidine ring, B has at least 3 carbon atoms, and excluding the compound of general formula I, in which R<1> and R<2> are identical and stand for hydrogen, SK stands for a side chain -A-B-Z, A = O, B = -(CH2)2- and Z = N(C2H5)2. 2. Compounds of general formula I according to claim 1, in which R<1> and/or R<2> stand for a hydrogen atom. 3. Compounds of general formula I according to claim 1, in which A is an oxygen atom. 4. Compounds of general formula I according to claim 1, in which B is a straight-chain alkylene chain with 1 to 6 carbon atoms. 5. Compounds of general formula I according to claim 1, in which side chain SK is selected from the group of the following side chains -O-(CH2)5S(CH2)3C2F5, -O-(CH2)5SO(CH2)3C2F5, -O-(CH2)5SO2(CH2)3C2F5, -O-(CH2)2-N(CH3)-(CH2)3-S-(CH2)3C2F5, -O-(CH2)2-N(CH3)-(CH2)3-SO-(CH2)3C2F5, -O-(CH2)5S(CH2)-C(O)N(CH3)-(CH2)3CH3, -O-(CH2)5SO(CH2)-C(O)N(CH3)-(CH2)3CH3, -O-(CH2)2-NH(CH2)OH, -O-(CH2)2-N(CH3)-(CH2)2-SO(CH2)-C(O)N(CH3)-(CH2)3CH3, -O-(CH2)2-N(CH3)-(CH2)2-SO2(CH2)-C(O)N(CH3)-(CH2)3CH3, -O-(CH2)6S(CH2)-C(O)N(CH3)-(CH2)3CH3, -O-(CH2)6SO(CH2)-C(O)N(CH3)-(CH2)3CH3, -O-CH3, -O-(CH2)5-F, -O-(CH2)4-F, -O-(CH2)3-F, -O-(CH2)2-F, -O-(CH2)5-Cl, -O-(CH2)4-Cl, -O-(CH2)3-C, -O-(CH2)2-Cl, -O-(CH2)6S(CH2)3C2F5, -O-(CH2)6SO(CH2)3C2F5, -O-(CH2)6SO(CH2)-2-Pyridyl, -O-(CH2)5SO(CH2)-2-Pyridyl, -O-(CH2)5S(CH2)2C3F7, -O-(CH2)4S(CH2)3C2F5, -O-(CH2)4SO(CH2)3C2F5, -O-(CH2)4SO2(CH2)3C2F5, -O-(CH2)4S(CH2)-2-Pyridyl, -O-(CH2)4SO(CH2)-2-Pyridyl, -O-(CH2)5S(CH2)-2-Pyridyl, -O-(CH2)5SO(CH2)-2-Pyridyl, -O-(CH2)6S(CH2)-2-Pyridyl, -O-(CH2)6SO(CH2)-2-Pyridyl, -O-(CH2)5S(CH2)-2-Furyl, -O-(CH2)5SO(CH2)-2-Furyl, -O-(CH2)5SO2(CH2)-2-Furyl, -O-(CH2)5S(CH2)-2-Thienyl, -O-(CH2)5SO(CH2)-2-Thienyl, -O-(CH2)5S(CH2)4-F, -O-(CH2)5SO(CH2)4-F, -O-(CH2)5S(CH2)3-CF3, -O-(CH2)5SO(CH2)3-CF3, -O-(CH2)5-N-(CH3)-(CH2)3-C2F5, -O-(CH2)5S(CH2)-Phenyl, -O-(CH2)5SO(CH2)-2-Phenyl, -O-(CH2)5S(CH2)-p-Tolyl, -O-(CH2)5SO(CH2)-p-Tolyl, -O-(CH2)5S(CH2)-p-CF3-Phenyl, -O-(CH2)5SO(CH2)-p-CF3-Phenyl, -O-(CH2)5S-Phenyl, -O-(CH2)5SO-Phenyl, -O-(CH2)5S-(p-Tolyl), -O-(CH2)5SO-(p-Tolyl), -O-(CH2)5S-(p-CF3-Phenyl), -O-(CH2)5SO-(p-CF3-Phenyl). 6. Compounds of general formula I according to claim 1, in which side chain SK is selected from the group of the following side chains: -(CH2)5N(CH3)(CH2)3C2F5, -(CH2)5N(CH3)(CH2)6C2F5, -(CH2)5N(CH3)(CH2)7C2F5, -(CH2)5N(CH3)(CH2)8C2F5, -(CH2)6N(CH3)(CH2)7C2F5, -(CH2)6N(CH3)(CH2)8C2F5, -(CH2)5N(CH3)(CH2)2C4F9, -(CH2)5N(CH3)(CH2)3C6F13, -(CH2)5N(CH3)(CH2)3C8F17, -(CH2)5N(CH3)(CH2)6C4F9, -(CH2)5N(CH3)(CH2)6C6F13, -(CH2)5N(CH3)(CH2)6C8F17, -(CH2)5N(CH3)H, -(CH2)5N(CH3)(CH2)9H, -(CH2)5N-1-Pyrrolidinyl, -(CH2)9S(CH2)3C2F5, -(CH2)9SO(CH2)3C2F5, -(CH2)9SO2(CH2)3C2F5. 7. Compounds of general formula I according to claim 1, in which side chain SK is selected from the general partial formula whereby a is 4, 5 or 6, b is 0, 1 or 2, c is 0, 1 or 2, R<X> is a hydrogen atom or a C1-5alkyl group, R<Y> and R<Z> are each a hydrogen atom, or R<X> and R<Y> together are an alkylene group -(CH2)d- with d = 2, 3, 4 or 5, and R<Z> is a hydrogen atom or R<X> and R<Z> together are an alkylene group -(CH2)c- with e = 2, 3 or 4 and R<Y> is a hydrogen atom, and U is an unsubstituted ethyl radical or an ethyl radical that is fluorinated in one to five places, or the terminal substituent -(CH2)3-U in the side chain is replaced by an optionally substituted aryl or heteroaryl radical, which is bonded directly or via a mono-, di- or trimethylene group to the sulfur atom. 8. Compounds of general formula I according to claim 7, in which SK is the side chain -(CH2)5N(CH3)(CH2)3S(CH2)3C2F5. 9. Compounds of general formula I according to claim 7, in which SK is the side chain (CH2)5N(R<X>)(CHR<Y>)CH2S(CH2)3C2F5 with R<X> + R<Y> = -(CH2)3-. 10. Compounds of general formula I, namely comprising: (4,4,5,5,5-Pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfide; (4,4,5,5,5-pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfoxide; methyl-[3-(4,4,5,5,5-pentafluoropentylthio)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amine; methyl-[3-(4,4,5,5,5-pentafluoropentylsulfinyl)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amine; S-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-thioacetate; N-butyl-N-methyl-2-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamide; N-butyl-N-methyl-2-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentanesulfinyl}-acetamide; 5-{4-[5-(4,4,5,5,5-pentafluoro-pentylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol; 5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol; 5-[4-(2-{methyl-[3-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-propyl]-amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol; 5-[4-(2-{methyl-[3-(4,4,5,5,5-pentafluoro-pentylthio)-propyl]-amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol; N-butyl-N-methyl-2-{5-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamide; 5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol; N-butyl-N-methyl-2-{5-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentanesulfinyl}-acetamide; N-butyl-2-[2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy)-ethyl}-methyl-amino)-ethanesulfinyl]-N-methyl-acetamide; N-butyl-2-[2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfonyl]-N-methyl-acetamide; 6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol; N-butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexanesulfinyl}-N-methyl-acetamide; N-butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexylthio}-N-methyl-acetamide; 6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol; 6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentane-sulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol; 5-{4-[4-(4,4,5,5,5-pentafluoro-pentylthio)-butyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol; 6-phenyl-5-{4-[4-(pyridin-2-ylmethylthio)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol; 6-phenyl-5-{4-[5-(pyridin-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol; 6-phenyl-5-{4-[6-(pyridin-2-ylmethylthio)-hexyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol; 5-{4-[4-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-butyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol; 6-phenyl-5-{4-[4-(pyridin-2-ylmethanesulfinyl)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol; 5-{4-[6-(4,4,5,5,5-pentafluoro-pentylthio)-hexyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohept