Patent EA-002831-B1 (EA)
Title: Benzo[c]quinolizine derivatives and their use as 5 alpha-reductases inhibitors
Inventor: GUARNA ANTONIO
IPC: A01N43/90
Filed: 1998-12-21
Abstract: 1.Fully and partially reduced benzo[c]-quinolizine compounds of formula (I)   wherein: R1, R2, R3, R4, R6, same or different, are chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl, biphenyl, naphtyl, saturated or aromatic heterocycle containing one or more N atoms, halogen, CN, azide, NRR', C1-8alkylamino, arylamino, C1-8alkyloxy, aryloxy, COOR, CONRR', C(=O)R, wherein R and R', same or different, are chosen in the group consisting of: H, C1-8alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbomane, canphane, adamantane, phenyl, biphenyl, naphtyl, saturated or aromatic heterocycle containing one or more N atoms, phenyl-, biphenyl-, naphtyl-C1-8alkyl; R5 is chosen in the group consisting of: H, C1-8alkyl, C1-8alkylphenyl, -biphenyl, -naphtyl, COOR, CN, phenyl, biphenyl, naphtyl, saturated or aromatic heterocycle containing one or more N atoms, C1-8alkyl-saturated or aromatic heterocycle containing one or more N atoms; C1-8alkyl-saturated or aromatic heterocycle containing one or more N atoms -ribosephosphate; X is chosen in the group consisting of: O, C(=O)R, COOR, NO2, CONR'R wherein R and R' are as above defined; Q is chosen in the group consisting of: simple bond, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, CO, CONR, NR, wherein R is as above defined; W is chosen in the group consisting of: H, C1-8alkyl, C2-8 alkenyl, C2-8alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, trifluoromethyl, C1-8alkoxy, C1-8 alkoxy-C1-8alkyl, phenyl-, biphenyl-, naphtyl-C1-8alkyl, phenyl, biphenyl, naphtyl, phenyloxy, biphenyloxy, naphtyloxy, phenylamino, biphenylamino, naphtylamino, C1-8alkylcarbonyl, phenylcarbonyl, biphenylcarbonyl, naphtylcarbonyl, phenylcarboxyl, biphenylcarboxyl, naphtylcarboxyl, phenylcarboxyamide, biphenylcarboxyamide, naphtylcarboxyamide, halogen, CN, NRR', C1-8alkylamino, saturated or aromatic heterocycle containing one or more N atoms wherein the groups alkyl, alkenyl, alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl, biphenyl, naphtyl, saturated or aromatic heterocycle containing one or more N atoms, can be substitued; n is an integer comprised between 1 and 4; the symbol --- means that the corresponding bonds a, b, c, d e, f, g, h and i can be a simple or a double bond; with the proviso that when b or f are a double bond then the group R5 is absent; their pharmaceutically acceptable salts and esters. 2. Benzo[c]-quinolizine compounds of formula (I) according to Claim 1, wherein R5 = H, C1-8alkylphenyl, -biphenyl, -naphtyl, COOR, CN, phenyl, biphenyl, naphtyl, saturated or aromatic heterocycle containing one or more N atoms, C1-8alkyl-saturated or aromatic heterocycle containing one or more N atoms; or a group C1-8alkyl-saturated or aromatic heterocycle containing one or more N atoms -ribosephosphate; X = O, COOH; Q = simple bond, CO, CONR, NR (wherein R is as above defined); W = H, F, Cl, Br, Me, tert-butyl, C1-8alkoxy, 2,5-dimethylhexyl, trifluoromethyl, 2,5-(di-trifluoromethyl)phenyl, 4-methoxyphenyl, 4-fluorophenyl, phenyl, phenyl-C1-8alkyl, C1-8 alkylcarbonyl, phenylcarbonyl; n=1 and 2; R1, R2, R3, R4, R6 = H, Me, CN, phenyl, COOR, CONRR' (wherein R and R' are as above defined). 3. Benzo[c]-quinolizine compounds according to Claim 1 of formula: 2,3,4,4a,5,6,6a,7,8,9,10,10a-dodecahydro-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,4,4a,5,6,6a,7,8,9,10,10a-dodecahydro-(1H)-benzo[c]quinolizin-3-one; 2,3,4,4a,5,6,6a,7,8,9,10,10a-dodecahydro-8-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,4,4a,5,6,6a,7,8,9,10,10a-dodecahydro-4-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,4,4a,5,6,6a,7,8,9,10,10a-dodecahydro-1-methyl-(1H)benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-8-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-4-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-1-methyl-(1H)-benzo[c]quinolizin-3-one; (4aα, 6aβ,10aα)-3,4,5,6,6a,7,8,9,10,10a-decahydro-(4aH)-benzo[c]quinolizin-3-one; (4aβ, 6aβ, 10aα)-3,4,5,6,6a,7,8,9,10,10a-decahydro-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-8-methyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-4-methyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-1-methyl-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-4-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-4,8-dimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-1-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-1,4-dimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-4-methyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-4,8-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-1-methyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-1,8-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-5-methyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-5-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-5,8-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-4,5-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-1,5-dimethyl-(1H)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-5-methyl-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-5-methyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-5,8-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-4,5-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-1,5-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-4,5-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-4,5,8-trimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-1,5-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-1,4,5-trimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-4,5-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-4,5,8-trimethyl-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-1,5-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-1,5,8-trimethyl-(4aH)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-6-methyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-6-methyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-6,8-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-4,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-1,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-6-methyl-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-6-methyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-6,8-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-4,6-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-1,6-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-4,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-4,6,8-trimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-1,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-1,4,6-trimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-4,6-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-4,6,8-trimethyl-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-1,6-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-1,6,8-trimethyl-(4aH)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-5,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-5,6-dimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-5,6,8-trimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-4,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-1,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-5,6-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-5,6-dimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-5,6,8-trimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-4,5,6-trimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-1,5,6-trimethyl-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-4,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-4,5,6,8-tetramethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-1,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one; 2,3,5,6,6a,7,8,9,10,10a-decahydro-1,4,5,6-tetramethyl-(1H)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,,8,9,10,10a-decahydro-4,5,6-trimethyl-(4aH)-benzo[c]quinolizin-3-one; 3,4,5,6,6a,7,8,9,10,10a-decahydro-4,5,6,8-tetramethyl-(4aH)-benzo[c]quinolizin-3-one; 8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-1,5,6-trimethyl-(4aH)-benzo[c]quinolizin-3-o