Patent EA-000975-B1 (EA)
Title: BENZO[C]QUINOLIZINE DERIVATIVES, THEIR PREPARATION AND USE AS 5alpha-REDUCTASES
Inventor: GUARNA ANTONIO
IPC: C07D215/22
Filed: 1997-02-07
Abstract: 1. 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-C8-alkyl, C2-C8-alkenyl, C2-C8-alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl, naphtyl, saturated or aromatic heterocycle containing one or more N atoms, halogen, CN, azide, NRR', C1-C8-alkylamino, arylamino, C1-C8-alkyloxy, aryloxy, COOR, CONRR' wherein R and R', same or different, are chosen in the group consisting of: H, C1-C8-alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl, naphtyl, saturated or aromatic heterocycle containing one or more N atoms, ary C1-C8-alkyI; R5 is chosen in the group consisting of: H, C1-C8-alkyl, COOR, CN, phenyl, naphtyl, saturated or aromatic heterocycle containing one or more N atoms; 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, C,_galkyl, C^_ galkenyl, C-galkinyl, 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-C8-alkyl, C2-C8-alkenyl, C2-C8-alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, trifluoromethyl, C1-C8-alkoxy, C1-C8-alkoxy- C1-C8-alkyl, aryl- C1-C8-alkyl, phenyl, naphtyl aryloxy, arylamino, C-, oalkylcarbonyl, arylcarbonyl, halogen, CN, NRR', C1-C8-alkylamino, saturated or aromatic heterocycle containing one or more N atoms, wherein the groups alkyl, alkenyl, alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl, naphtyi, saturated or aromatic heterocycle containing one or more N atoms can be substitued by halogen, OR, phenyl, NRR', CN, COOR, CONRR', C1-C8-alkyl (wherein R and R' are as above defined) ; n is an integer comprised between 1 and 4; the symbol ----- means that the corresponding bonds a, b, c. d e, f, and g can be simple or double bonds; with the proviso that when b or f are a double bond then the group Re is absent; and with the proviso that the following two compounds are excluded from the claims: 4-carbonitril-2,3-dihydro-(1H)-benzo[c]quinolizine-3-one and 3,4-dihydro-l-phenyl-4aH-benzo[c]quinolizine-3-one. their pharmaceutically acceptable salts or esters. 2. Benzo[c]-quinolizine compounds of formula (I) according to claim 1 wherein R5 = H, saturated or aromatic heterocycle containing one or more N atoms; X = O; Q = simple bond, CO, CONR, MR (wherein R is as above defined) ; W = H, F, Cl, Br, Me, t-butyl, C1-C8-alkoxy, 2,5-dimethylhexyl, trifluoromethyl, 2,5-(di-trifluoromethyl)-phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl, phenyl, phenyl-C1-8-galkyl, C1-8-galkylcarbonyl, phenylcarbonyl; n = 1 and 2; R1 R2, R3, R4, R5, R6 = H, Me, CN, phenyl, COOR, CONRR' (wherein R nd R' are as above defined). 3. Benzo[c]-quinolizine compounds according to claim 1 of formula  1,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one; 8-chloro-l,2,4,4a,5,6 hexahydro-(11H)-benzo[c]quinolizine-3-one; 1,2,4,4a,5,6 hexahydro-8-methyl-(11H)-benzo[c]quinolizine-3-one; 1,2,4,4a,5,6 hexahydro-4-methyl-(11H)-benzo[c]quinolizine-3-one; 1,2,4,4a,5,6 hexahydro-1-methyl-(11H)-benzo[c]quinolizine-3-one; 1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one; 8-chloro-l,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one; 8-methyl-l,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one; 4-methyl-l,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one; 1-methyl-1,2,4,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one; 4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one; 5,6-dihydro-(11H)-benzo[c]quinolizine-3-one; 8-chloro-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one; 8-chloro-l-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one; 8-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one; 4-methyl-4,4a,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans); 8-chloro-4-methyl-l,2,5,6 tetrahydro-(11H)-benzo[clquinolizine-3-one; 4,8-dimethyl-1,2,5,6 tetrahydro-(11H)-benzo[c]quinolizine-3-one; 4,8-dimethyl-4,4a,5,6 tetrahydro-(11H)-benzo[clquinolizine-3-one (cis) and (trans) ; 8-chloro-4-methyl-4,4a,5,6-tetrahydro-(11H)-benzo[c]quinolizine-3-one (cis) and (trans). 4. Process for the preparation of compounds according to claim 1 wherein: the amide-group of a compound of formula (2)   is protected with a protecting group Z to give the compound (3)   the above said compound (3) is reduced to compound (4), for example with sodium borohydride in ethanol (pH3)   and compound (4) is reacted with a silyl ether (6)   prepared "in situ" by reacting a vinyl-ketone (5)   (wherein R1, R2, R6 are as above defined) with a silylating agent as trimethylsilyltrifluorometansulphonic anhydride (TMSOTf) and are finally hydrolized, for example with sodium hydrogencarbonate, to give the final compound of formula (I) wherein X = O. 5. Process according to claim 4 wherein the possible introduction of the double bonds in position a or b is performed by reaction of dichlorodicianoquinone (DDQ) with the corresponding silylenolethers or by oxidation with quicksilver acetate of the saturated compound obtained as claimed above and the possible transformation of the group X is performed via the corresponding enoltriflaces and following carbonylation in the presence of palladium diacetate, triphenylphosphine and the suitable nucleophilic reagent. 6. Compound of formula (4)   wherein W, Q, n, R3, R4 R5 are as defined in claim 1 and Z -is a protecting group for the amide-group with the proviso chat when R3 = R4 = R5 = (WQ)n = H than Z is not a group ethoxycarbonyl. 7. Pharmaceutical composition wherein the active principle is a compound of formula (I) wherein:   R1, R2, R3 R4, R6, same or different, are chosen in the group consisting of: H, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl, naphtyl, saturated or aromatic heterocycle containing one or more N atoms, halogen, CM, azide, NRR', C,galkylamino, arylamino, C-galkyloxy, aryloxy, COOR, CONRR' wherein R and R' , same or different, are chosen in the group consisting of: H, C1-C8-alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl, naphtyl, saturated or aromatic hefcerocycle containing one or more N atoms aryl- C1-C8-alkyl; R5 is chosen in the group consisting of: H, C1-C8-alkyl, COOR, CN, phenyl, naphtyl, saturated or aromatic heterocycle containing one or more N atoms ; 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-C8-alkyl, C2-C8-alkenyl, C2-C8-alkinyl, 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-C8-alkyl, C2-C8-alkenyl, C2-C8-alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, trifluoromethyl, C1-C8-alkoxy, C1-C8-alkoxy- C1-C8-alkyl, aryl-C1-C8-alkyl, phenyl, naphtyl, aryloxy, arylamino, C1-C8-alkylcarbonyl, arylcarbonyl, halogen, CN, NRR', C1-8-alkylamino, saturated or aromatic heterocycle containing one or more N atoms wherein the groups alkyi, alkenyl, alkinyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane, phenyl, naphtyl, saturated or aromatic heterocycle containing one or more N atoms can be substitued by halogen, OR, phenyl, NRR', CN, COOR, CONRR', C1-C8-alkyl (wherein R and R' are as above defined); n is an integer comprised between 1 and 4; the symbol ----- means that the corresponding bonds a, b, c, d e, f, and g can be simple or double bonds; with the proviso that when b or f are a double bond then the group Re is absent; their pharmaceutically acceptable salts or esters, or mixtures thereof in combination with the suitable pharmaceutical acceptable excipients. 8. Pharmaceutical composition according to claim 7 for use in the inhibition of the 5-alphaR-I and/or 5-alphaR-II iso-emzymes. 9. Pharmaceutical composition according to claims 7 and 8 in the form suitable for topic use. 10. Use of a compound of formula (I) according to claim 7 as a medicament. 11. Use of a compound of formula (I) according to claim 7 for the preparation of a pharmaceutical composition for the treatment of acne, baldness, prostatic cancer and prostatic hypertrophy in men and hirsutism in women. 12. Method for the treatment of pathologies related to 5-alpha-5 reductase enzymes by administration to the patient of a pharmaceutically active amount of a pharmaceutical composition according to claims 7. 13. Method for treatment of acne, baldness, prostatic cancer and prostatic hypertrophy in men and hirsutism in women, by administration 10 of a pharmaceutically active amount of a pharmaceutical composition according to claims 7.