Benzo(C)quinolizine derivatives and their use as 5α-reductases inhibitors
View Patent ↗A fully and partially reduced benzo(c)quinolizine compound of formula (1):
1. A benzo(c)quinolizine compound of formula (1):
wherein:
R 1 , R 2 , R 3 , R 4 and R 6 , which are the same or different, are chosen from the group consisting of: H, CN, COOR, CONRR′, C(═O)R, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, phenyl, biphenyl, naphthyl, or naphthyl-C 1-8 ;
R 5 is chosen from the group consisting of: H, C 1-8 alkyl, C 1-8 alkyl-phenyl, biphenyl, naphthyl, COOR, CN or phenyl;
X is chosen from the group consisting of: O, C(═O)R, COOR, NO 2 , and CONRR′, wherein R and R′ are the same or different and are chosen from the group consisting of H, C 1-8 alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norborane, camphane, adamantane, phenyl, biphenyl, napthyl;
Q is chosen from the group consisting of single-bond, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, CO, CONR, and NR, where R is as above defined;
W is chosen from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, trifluoromethyl, C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, phenyl, biphenyl, naphthyl-C 1-8 alkyl, phenyl, biphenyl, naphthyl, phenyloxy, biphenyloxy, naphthyloxy, phenylamino, biphenylamino, naphthylamino, C 1-8 alkyl-carbonyl, phenylcarbonyl, biphenylcarbonyl, naphthylcarbonyl, phenylcarboxyl, biphenylcarboxyl, naphthylcarboxyl, phenylcarboxyamide, biphenylcarboxyamide, naphthylcarboxyamide, halogen, CN, NRR′, C 1-8 alkylamino;
n is an integer of 1 to 4;
the symbol ------- means that the corresponding bonds a, b, c, d, e, f, g, h and i are single or double bonds, with the proviso that when b or f are a double bond, the group R 5 is absent; or a pharmaceutical acceptable salt thereof.
2. A benzo(c)quinolizine compound of formula (1) according to claim 1 , wherein R 5 =H, C 1-8 alkylphenyl, biphenyl, naphthyl;
X=O, COOH;
Q=single bond, CO, CONR, NR, wherein R is chosen from the group consisting of H, C 1-8 alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl, biphenyl, naphthyl or naphthyl-C 1-8 alkyl;
W=H, F, Cl, Br, Me, t-butyl, C 1-8 alkoxy, 2,5-dimethylhexyl, trifluoromethyl, 2,5-(di-trifluoromethyl)-phenyl, 4-methyloxy-phenyl, phenyl, phenyl-C 1-8 alkyl, C 1-8 alkylcarbonyl, phenylcarbonyl;
n=1 and 2;
R 1 , R 2 , R 3 , R 4 and R 6 =H, Me, CN, phenyl, COOR, CONRR′, C(═O)R, wherein R and R′ are the same or different and are chosen from the group consisting of H, C 1-8 alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl, biphenyl, naphthyl or naphthyl-C 1-8 .
3. A benzo[c]quinolizine compound according to claim 1 which is of the the formula:
2,3,4,4a,5,6,6a,7,8,9,10,10a-dodecahydro-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,4,4a,5,6,6a,7,8,9,10,10a-dodecahydro-( 1 H)-benzo[c]quinolizin-3-one;
2,3,4,4a,5,6,6a,7,8,9,10,10a-dodecahydro-8-methyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,4,4a,5,6,6a,7,8,9,10,10a-dodecahydro-4-methyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,4,4a,5,6,6a,7,8,9,10,10a-dodecahydro-1-methyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,4,4a,5,6,6a,7,8,9,10,10a-decahydro-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,4,4a,5,6,6a,7,8,9,10,10a-decahydro-( 1 H)-benzo[c]quinolizin-3-one;
2,3,4,4a,5,6,6a,7,8,9,10,10a-decahydro-8-methyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-4-methyl-( 1 H)-benzo [c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-1-methyl-( 1 H)-benzo [c]quinolizin-3-one;
(4aα,6β,10aα)-3,4,5,6,6a,7,8,9,10,10a-decahydro-(4a H )-benzo[c]quinoli-zin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-8-methyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-4-methyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-1-methyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-4-methyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-4,8-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-1-methyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-1,4-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-4-methyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-4,8-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-1-methyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-1,8-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-5-methyl-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-5-methyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-5,8-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-4,5-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-1,5-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-5-methyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-5-methyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-5,8-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-4,5-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-1,5-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-4,5-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-4,8-trimethyl-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-1,5-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-1,4,5-trimethyl-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-4,5-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-4,5,8-trimethyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-1,5-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-1,5,8-trimethyl-(4a H )-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-6-methyl-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-6-methyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-4,6-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-1,6-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-6,8-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-6,8-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-4,6-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-1,6-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-4,6-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-4,6,8-trimethyl-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-1,6-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-1,4,6-trimethyl-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-4,6-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-4,6,8-trimethyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-1,6-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-1,6,8-trimethyl-(4a H )-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-5,6-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-5,6-dimethyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-4,5,6-trimethyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-1,5,6-trimethyl-( 1 H)-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-5,6-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-5,6-dimethyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-5,6,8-trimethyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-4,5,6-trimethyl-(4a H )-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-1,5,6-trimethyl-(1 H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-1,5,6-trimethyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-4,5,6-trimethyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-4,5,6,8-tetramethyl-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9,10,10a-decahydro-1,5,6-trimethyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9,10,10a-decahydro-1,4,5,6-tetramethyl-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-4,5,6-trimethyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-4,5,6,8-tetramethyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-1,5,6-trimethyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-1,5,6,8-tetramethyl-(4a H )-benzo[c]quinolizin-3-one;
5,6,6a,7,8,9,10,10a-octahydro-(3 H )-benzo[c]quinolizin-3-one;
8-chloro-5,6,6a,7,8,9,10,10a-octahydro-(3 H )-benzo[c]quinolizin-3-one;
5,6,6a,7,8,9,10,10a-octahydro-8-methyl-(3 H )-benzo[c]quinolizin-3-one;
5,6,6a,7,8,9,10,10a-octahydro-4-methyl-(3 H )-benzo[c]quinolizin-3-one;
8-chloro-5,6,6a,7,8,9,10,10a-octahydro-4-methyl-(3 H )-benzo[c]quinolizin-3-one;
5,6,6a,7,8,9,10,10a-octahydro-4,8-dimethyl-(3 H )-benzo[c]quinolizin-3-one;
2,3,5,6,7,8,9,10-octahydro-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,7,8,9,10-octahydro-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,7,8,9,10-octahydro-8-methyl-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9-octahydro-( 1 H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6,6a,7,8,9-octahydro-( 1 H)-benzo[c]quinolizin-3-one;
2,3,5,6,6a,7,8,9-octahydro-8-methyl-( 1 H)-benzo[c]quinolizin-3-one;
4a-benzyl-3,4,5,6,6a,7,8,9,10,10a-decahydro-(4a H )-benzo[c]quinolizin-3-one;
4a-benzyl-8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-(4a H )-benzo[c]quinolizin-3-one;
4a-benzyl-3,4,5,6,6a,7,8,9,10,10a-decahydro-8-methyl-(4a H )-benzo[c]quinolizin-3-one;
4a-benzyl-3,4,5,6,6a,7,8,9,10,10a-decahydro-4-methyl-(4a H )-benzo[c]quinolizin-3-one;
4a-benzyl-3,4,5,6,6a,7,8,9,10,10a-decahydro-1-methyl-(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-4a-(4-pyridyl)methyl-(4a H )-benzo[c]quinolizin-3-one;
8-chloro-3,4,5,6,6a,7,8,9,10,10a-decahydro-4a-(4-pyridyl)-methyl(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-8-methyl-4a-(4-pyridyl)methyl(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-4-methyl-4a-(4-pyridyl)methyl(4a H )-benzo[c]quinolizin-3-one;
3,4,5,6,6a,7,8,9,10,10a-decahydro-1-methyl-4a-(4-pyridyl)methyl(4a H )-benzo[c]quinolizin-3-one.
4. A pharmaceutical composition wherein the active principle is a compound of formula (I) according to claim 1 or mixtures thereof in combination with suitable pharmaceutically acceptable excipients.
5. A method for the treatment of a pathology related to 5α reductase isoenzymes in an afflicted host where the pathology is selected from the group consisting of acne, baldness, in men and hirsutism in women, said method comprising administering an effective amount of a compound of claim 1 to an afflicted host.
6. A benzo(c)quinolizine compound of formula (1):
wherein:
R 1 , R 2 , R 3 , R 4 and R 6 which are the same or different, are chosen from the group consisting of: H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, phenyl, biphenyl or naphthyl;
R 5 is chosen from the group consisting of: H, C 1-8 alkyl, c 1-8 alkyl-phenyl, biphenyl, naphthyl, COOR, CN or phenyl;
X is chosen from the group consisting of: O, C(═O)R, COOR, NO 2 , and CONRR′, wherein R and R′ are the same or different and are chosen from the group consisting of H, C 1-8 alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norborane, camphane, adamantane, phenyl, biphenyl, napthyl;
Q is chosen from the group consisting of single-bond, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, CO, CONR, and NR, where R is as above defined;
W is chosen from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, trifluoromethyl, C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, phenyl, biphenyl, naphthyl-C 1-8 alkyl, phenyl, biphenyl, naphthyl, phenyloxy, biphenyloxy, naphthyloxy, phenylamino, biphenylamino, naphthylamino, C 1-8 alkyl-carbonyl, phenylcarbonyl, biphenylcarbonyl, naphthylcarbonyl, phenylcarboxyl, biphenylcarboxyl, naphthylcarboxyl, phenylcarboxyamide, biphenylcarboxyamide, naphthylcarboxyamide, halogen, CN, NRR′where R and R′ are as above defined;
n is an integer of 1 to 4;
the symbol ------- means that the corresponding bonds a, b, c, d, e, f, g, h and i are single or double bonds, with the proviso that when b or f are a double bond, the group R 5 is absent; and or a pharmaceutical acceptable salt thereof.
7. A benzo(c)quinolizine compound of formula (1):
wherein:
R 1 , R 2 , R 3 , R 4 and R 6 , which are the same or different, are chosen from the group consisting of: H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, phenyl, biphenyl or naphthyl;
R 5 is chosen from the group consisting of: H, C 1-8 alkyl, C 1-8 alkyl-phenyl, biphenyl, naphthyl, COOR, CN, phenyl;
X is chosen from the group consisting of: O, C(═O)R, COOR, NO 2 , and CONRR′, wherein R and R′ are the same or different and are chosen from the group consisting of H, C 1-8 alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norborane, camphane, adamantane, phenyl, biphenyl, napthyl;
Q is chosen from the group consisting of single-bond, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, CO, CONR, and NR, where R is as above defined;
W is chosen from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, trifluoromethyl, C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, phenyl, biphenyl, naphthyl-C 1-8 alkyl, phenyl, biphenyl, naphthyl, phenyloxy, biphenyloxy, naphthyloxy, phenylamino, biphenylamino, naphthylamino, C 1-8 alkyl-carbonyl, phenylcarbonyl, biphenylcarbonyl, naphthylcarbonyl, phenylcarboxyl, biphenylcarboxyl, naphthylcarboxyl, phenylcarboxyamide, biphenylcarboxyamide, naphthylcarboxyamide, halogen, CN, NRR′, C 1-8 alkylamino;
n is an integer of 1 to 4;
the symbol ------- means that the corresponding bonds a, b, c, d, e, f, g, h and i are single or double bonds, with the proviso that when b or f are a double bond, the group R 5 is absent; or a pharmaceutical acceptable salt thereof.