MXPA00006219A - Benzo[c]quinolizine derivatives and their use as 5 alpha-reductases inhibitors - Google Patents

Abstract

The present invention refers to benzo[c]quinolizines derivatives, fully and partially saturated, having formula (I), and their pharmaceutically acceptable salts which proves useful for pharmaceutical and agricultural use being capable of inhibiting the 5a-reductase enzyme either selectively in respect of 5aR-I and 5aR-II or on both the iso-enzymes.

Description

BENZO DERIVATIVES [C] QUINOLYZINE AND ITS USE AS INHIBITORS OF THE 5a-REDUCTASES Field of the Invention The present invention relates to benzo [c] quinolizine derivatives partially and totally saturated of the general formula (I) and to their pharmaceutically acceptable salts or esters, to processes for their preparation and to a composition for pharmaceutical and agricultural use containing them. The present invention relates to benzo [c] quinolizine derivatives of the general formula (I) wherein: Ri, R2, R3, R4, Re, identical or different, are chosen from the group consisting of: H, alkyl with C? _8, alkenyl with C2-8, alkynyl with C2_8, cycloalkyl, aryl, Ref. 121260 heterocycle, halogen, CN, azide, NRR ', alkylamino with C? -8, arylamino, alkyloxy with C? _8, aryloxy, COOR, CONRR', C (= 0) R where R and R ', identical or different, are chosen from the group consisting of: H, alkyl with C? _8, cycloalkyl, aryl, heterocycle, arylC? _8alkyl; R5 is chosen from the group consisting of: H, alkyl with C? -8, alkylaryl with C? _8, COOR, CN, aryl, heterocycle, alkyl with C? _8-heterocycle; alkyl with C? _8-heterocycle-ribose-phosphateX is selected from the group consisting of: 0, C (= 0) R, COOR, N02, CONR'R wherein R and R 'are as defined above; Q is selected from the group consisting of: a single bond, alkyl with C? _s, alkenyl with C2-8, alkynyl with C2-8, cycloalkyl, CO, CONR, NR, wherein R is as defined above; W is selected from the group consisting of: H, alkyl with Ci-s, alkenyl with C2-.8, alkynyl with C2_8, cycloalkyl, trifluoromethyl, alkoxy with C? _8, alkoxy with C? -8-alkyl with C? _8 , aryl, aryloxy, arylamino, alkylcarbonyl with C? _s, arylcarbonyl, arylcarboxyl, arylcarboxyamide, halogen, CN, NRR ', alkylamino with Ci-s, heterocycle wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, they can be replaced; n is an integer between 1 and 4; the symbol means that the corresponding links to, b, c, d, e, f, g, h and i can be a single link or a double bond; with the proviso that when b and f are a double bond then the group R5 is absent; its pharmaceutically acceptable salts or esters, its preparation process and its use as inhibitors of steroidal 5a-reductases.

State of the Art The enzyme known as 5a-reductase (hereinafter referred to as 5a-reductase) is a system composed of two iso-enzymes (type I and type).

II or 5aR-I and 5aR-II respectively) which convert testosterone into dihydrotestosterone, the most powerful androgen circulating in the body. The iso-enzyme of type I (5aR-I) is present mainly in the liver and the skin while the iso-enzyme of the type II (5aR-II) is present mainly in the tissue of the prostate and in the male sexual organs and its activity is essential in the process of fetal development for the differentiation of the external sexual organs.

The production of dihydrotestosterone is associated with some pathologies which are widespread, such as benign hypertrophy of the prostate, cancer of the prostate, baldness and acne in men and hirsutism in women. More particularly iso-enzyme I plays a role in pathologies with respect to the skin while iso-enzyme II is involved in prostate pathologies. In recent years an international group of researchers have tried to isolate new compounds capable of inhibiting the enzyme of 5a-reductase to treat the above pathologies, especially, if possible, acting selectively on only one of the two iso-enzymes. Inhibitors of 5a-reductase, and also of iso-enzymes 5aR-I and 5aR-II have already been described [see for example J. 'Med. Chem. 36, 4313-15 (1993), J. Med. Chem 37, 3871-74 (1994), J. Med. Chem. 40, 1112 (1997) J. Med. Chem. 40, 3466 (1997)]; for example, finaster.erida was used successfully in the treatment of benign prostatic hypertrophy. In EP-703 221, EP-591 582, EP-591 583, EP-532 190 and EP-531 026 the benzoquinolin-3-ones as inhibitors of 5a-reductase are reported while WO 94/21614 describes derivatives of -phenanthridinone substituted that have the same action.

The Journal of the Chemical Society, Perkin Transaction 1, vol. 3, 1979 pages 584-590, describes i. to. a benzo [c] quinolizine (see compound 8), without indicating any use thereof. Therefore it is clear that the importance of developing new compounds capable of inhibiting the action of the enzyme 5a-reductase and in particular capable of acting selectively on the iso-enzyme 5aR-I which, as said, is responsible for widespread pathologies that have a high impact on baldness in men and hirsutism in women. Therefore the invention also relates to a method for the treatment of pathologies related to the enzymes of 5a-reductase and in particular for the treatment of acne, baldness, prostate cancer and prostatic hypertrophy in men and women. hirsutism in women. In addition it has also been found, and is another object of the present invention, that the compound of the formula (I) can inhibit the enzymes of 5a-reductase in plants and can therefore selectively regulate the growth of plants under conditions of light and darkness. The compounds according to the present invention can be used as phyto-pharmaceuticals in agriculture allowing to improve the morphogenesis and the development of commercially useful plants or as herbicides capable of inhibiting the growth of the infesting plants. The compounds can therefore be used in agricultural compositions to regulate the growth of the plants, in particular those that are distributed over the seeds and / or the plants to be treated.

Detailed description of the invention The present invention relates to new compounds capable of inhibiting 5a-reductase, either selectively with respect to 5aR-I and 5aR-II or both iso-enzymes, useful for the treatment of pathologies mediated by the enzyme or for agricultural uses as regulators of the growth of plants or herbicides. The products according to the invention have the general formula (0 where the substituents Ri, R2, R3, R, R5, Re, X, Q, W, n and the symbol are as defined above. According to the present invention, the alkyl groups with C? _s, C2-8 alkenyl, and C 2-8 alkynyl, are indicated as linear or branched alkyl radicals such as for example: methyl, ethyl, propyl, isopropyl, butyl, hexyl, heptyl, octyl, ethylene, propene, butene, isobutene, acetylene, propyne, butyne, etc. Suitable cycloalkyls are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane. As arils are indicated: phenyl, biphenyl and naphthyl. Heterocycle means in particular: saturated or aromatic heterocycles containing one or more N atoms, more particularly: pyridine, imidazole, pyrrole, indole, triazoles, pyrrolidine, piperidine. Phosphate means the anion of mono, di or riyosphoric acid. Halogen means; fluorine, chlorine, bromine, iodine. The substituents of the group W above are preferably: halogen, OR, phenyl, NRR ', CN, COOR, CONRR', alkyl with C? _8 (wherein R and R 'are as defined above). In particular, according to the present invention the compounds of the formula (I) are preferred, wherein: Rs = H, alkylaryl with Ci-e, COOR, CN, aryl, heterocycle, alkyl with C? _8-heterocycle; or an alkyl group with C? _8-heterocycle ribose phosphate X = 0, COOH Q = single bond, CO, CONR, NR (where R is as defined above), W = H, F, Cl, Br , Me, t-butyl, 'alkoxy with C? _8, 2,5-dimethylhexyl, trifluoromethyl, 2,5- (di-trifluoromethyl) -phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl, phenyl, phenyl- alkyl with C? _8, alkylcarbonyl with C 1-8, phenylcarbonyl. n = 1 and 2 Ri / R2, R3, R4, Re = H, Me, CN, phenyl, COOR, CONRR '(wherein R and R' are as defined above). Among the esters and pharmaceutically acceptable salts according to the present invention, the following may be mentioned: hydrochloride, sulfate, citrate, formate, phosphate. Preferred compounds according to the present invention are: 2, 3, 4, 4a, 5, 6, 6a, 7, 8, 9, 10, 10-dodecahydro- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 4, 4a, 5, 6, 6a, 7, 8, 9, 10, lOa-dodecahydro- (lH) -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, lOa-dodecahydro-1-methyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6, 6a, 7, 8, 9, 10, 10-decahydro- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2,3,5,6, 6a, 7, 8, 9, 10, lOa-decahydro- (lH) -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; (4aa, 6aβ, 10A) -3.4.5, 6, 6a, 7, 8, 9, 10, lOa-decahydro- (4aH) -benzo [c] quinolizin-3-one; (4aß, 6aß, lOaa) -3, 4, 5, 6, 6a, 7, 8, 9, 10, lOa-decahydro- (4aH) -benzo [c] quinolizin-3-one; 3, 4, 5, 6, 6a, 7, 8, 9, 10, lOa-decahydro- (4aH) -benzo [c] quinolizin-3-one; 8-chloro-3, 4, 5, 6, 6a, 7, 8, 9, 10, lOa-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-l-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, lOa-decahydro-1-methyl- (lH) -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-l-methyl- (4aH) -benzo [c] quinolizin-3-one; 3, 4, 5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-l, 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; 2,3,5, 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-l, 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, l-a-decahydro-4,5,8-trimethyl- (lH) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6, 6a, 7,8,9, 10, 10a-decahydro-l, 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-l, 5-dimethyl- (4aH) -benzo [c] quinolizin-3-one; 3, 4, 5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-l, 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, lOa-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-l, 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, ßa, 7,8,9,10,10a-decahydro-l, 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-l, 6-dimethyl- (4aH) -benzo [c] quinolizin-3-one; 3, 4, 5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-l, 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- (1 H) -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-l, 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-l, 5,6-trimethyl- (4aH) -benzo [c] quinolizin-3-one; 3,4,5,6,6a, 7,8,9,10,10a-decahydro-1,5,6,8-tetramethyl- (4aH) -benzo [c] quinolizin-3-one; 5, 6, 6a, 7, 8, 9, 10, lOa-octahydro- (3H) -benzo [c] quinolizin-3-one; 8-chloro-5, 6, 6a, 7, 8, 9, 10, lOa-octahydro- (3H) -benzo [c] quinolizin-3-one; 5, 6, 6a, 7,8,9, 10, 10a-octahydro-8-methyl- (3H) -benzo [c] quinolizin-3-one; 5, 6, 6a, 7, 8, 9, 10, 10a-octahydro-4-methyl- (3H) -benzo [c] quinolizin-3-one; 8-chloro-5, 6, 6a, 7, 8, 9, 10, 10a-octahydro-4-methyl- (3H) -benzo [c] quinolizin-3-one; , 6, 6a, 7, 8, 9, 10, 10a-octahydro-4,8-dimethyl- (3H) -benzo [c] quinolizin-3-one; 2,3,5,6,7,8,9,10-octahydro- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6, 7, 8, 9, 10-octahydro- (1H) -benzo [c] quinolizin-3-one; 2,3, 5, 6, 7, 8, 9, 10-octahydro-8-methyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6, 6a, 7,8,9-octahydro- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6, 6a, 7, 8, 9-octahydro- (1H) -benzo [c] quinolizin-3-one; 2,3,5, 6, 6a, 7, 8, 9-octahydro-8-methyl- (1H) -benzo [c] quinolizin-3-one; 4a-benzyl-3,4,5,6,6a, 7,8,19,10,1loa-decahydro- (4aH) -benzo [c] quinolizin-3-one; 4a-benzyl-8-chloro-3,4,6,6,6a, 7,8,9,10,1-a-decahydro- (4aH) -benzo [c] quinolizin-3-one; 4a-benzyl-3, 4,5,6,6a, 7,8,9,10,10a-decahydro-8-methyl- (4aH) -benzo [c] quinolizin-3-one; 4a-benzyl-3, 4,5,6, 6a, 7, 8, 9, 10, 10a-decahydro-4-methyl- (4aH) -benzo [c] quinolizin-3-one; 4a-benzyl-3, 4,5,6,6a, 7,8,9,10,10a-decahydro-l-methyl- (4aH) -benzo [c] quinolizin-3-one; 3,4,5,6,6a, 7,8,9,10,10a-decahydro-4a- (4-pyridyl) methyl- (4aH) -benzo [c] quinolizin-3-one; 8-chloro-3,4, 5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-4a- (4-pyridyl) ethyl- (4aH) -benzo [c] quinolizin-3-one; 3,4,5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-8-methyl-4a- (4-pyridyl) methyl- (4aH) -benzo [c] quinolizin-3-one; 3, 4.5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-4-methyl-4a- (4-pyridyl) methyl- (4aH) -benzo [c] quinolizin-3-one; 3,4, 5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-l-methyl-4a- (4-pyridyl) methyl- (4aH) -benzo [c] quinolizin-3-one. the dodecahydro-benzo [c] quinilizin-3-ones and the decahydro-benzo [c] quinolizin-3-ones according to the present invention, wherein the double bonds i and h are absent, can be prepared as shown in the scheme 1, according to the general preparation of benzo [c] quinolizin-3-ones already reported in WO 97/29107; in particular, for example, starting from the compounds of the formula 2 (2 ) wherein R3, R4, W, Q and n are as defined above.

The compounds 2 are commercially available or can be prepared according to known techniques. As can be seen from Scheme 1, the preparation of the compounds according to the invention involves the cyclization of ester 2 to enamide 3 by heating to 120 ° C of compounds 2 in formic acid in the presence of ammonium hydrogen carbonate . Enamide 3 is reduced to amide 4 transfused for example with sodium cyanoborohydride at pH 4, followed by protection of the amide group with a protecting group, for example tert-butoxycarbonyl (t-Boc), to give compound 5; compound 5 is reduced to compound 6, for example (when R5 is H) with sodium borohydride in ethanol (pH 4), particularly good yields are obtained when the reduction is effected with LiEt3BH in THF at -78 ° C, followed by the addition of an anhydrous solution of 2N HCl in ethanol to pH 4. The compound 6 thus obtained is then reacted with a siloxidiene 8, produced "in situ" starting from the vinyl ketones 7 (wherein Rl7 R2 and R6 are as defined above) with a silylating agent such as trimethylsilyltrifluoromethanesulfonic anhydride (TMSOTf) and thereafter hydrolyzed, for example in sodium acid carbonate, to give the compounds of the formula (I) wherein X = 0. The possible introduction of the double bonds and the transformation of the group X into one of the other groups mentioned above can be easily carried out according to the known techniques starting from the corresponding compound of the formula (I) or had as is indicated. For example, the introduction of double bonds at position a and / or b can be effected by the reaction of dichlorodicyanoquinone (DDQ) with the corresponding silylene ethers or by oxidation with mercuric acetate of the corresponding saturated compound obtained as described above. According to a different embodiment of the present invention it is possible to directly obtain the double bond in position "a" by effecting the reaction between products 6 and 8 (wherein Rx is 0CH3 and R2 and R6 are H) in the presence of TiCl4 or TMSOTf as the Lewis acids (the product 8 as defined above is in this case a commercially available product). By acting in this way it is also possible to direct the stereochemical result of the hydrogen atom in the 4a position (R5 = H) in the final compound. In particular when the TiCl 4 compound is used, wherein said above hydrogen atom is on the same side of the hydrogen at the 10a position, it is obtained while when the TMSOTf is used said previous hydrogen atom is on the opposite side with respect to to hydrogen at position 10a. The transformation of the group X can be effected by means of the corresponding enoltriflates and their carbonylation in the presence of palladium diacetate, triphenylphosphine and the appropriate nucleophilic reagent (alcohol, amino, nitro group). The compounds according to the present invention wherein the iohyb double bonds are present, can be prepared as shown in Scheme 2, for example starting from said previous compounds of the formula 2. The key step of the process is the thermal rearrangement -cyclization of isoxazolin-5-spirocyclopropane 14 to the final product 1. This process has already been applied for the synthesis of the other polycyclic compounds with nitrogen bridgehead as reported in J. Org. Chem. 1988, 53, 2426 and in J. Med. Chem. 1988, 53, 2426 and in J. Med. Chem. 1997, 40, 1112. As can be seen from Scheme 2, the preparation of the compounds in accordance with the invention involves the protection of the carbonyl of compound 2 (wherein R3 and R4 are as defined above) as a ketal, for example with ethylene glycol under acid catalysis, followed by the selective reduction of the ester group in compound 9 to the aldehyde., for example by DIBAL at -78 ° C. The transformation of aldehyde 10 to oxime 11, made for example by the reaction with hydroxylamine hydrochloride in pyridine, is followed by cycloaddition to methylene cyclopropene 12 (where R r and R 6 are as defined above) of nitrile oxide generated in situ by the reaction of oxime 11 with sodium hypochlorite and triethylamine. The isoxazoline-5-spirocyclopropane 13 is then unprotected under acid catalysis and subjected to thermal rearrangement in boiling DMF for 3-6 hours to give the compounds 1. The octahydrobenzo [c] quinolizin-3-ones of the formula 1, wherein Rl t R2, R3, R4, R6 are H, QW is H or -CH2CONHtBu (in position 8), n = 1 and both of the double bonds b and h (oi) that are present can be prepared starting from compound 2 where R3, R4 are H and QW is H or 5- (Nt-butyl) aceta gone and n = 1.

Example 1 Preparation of methyl 3- [2- (1, 3-dioxolan-2-yl) ciciohexyl] propanoate, [compound 9 where (QW) n = H, R3 = R = H] In a vessel provided with an apparatus Dean-Stark, methyl ester 2 (20.0 g, 109 mmol), ethylene glycol (60 ml, 1.08 mol) and p-TsOH (0.8 g, 5 mmol) are dissolved in toluene (550 ml) and the resulting solution is heated under Reflux. After 4 h the reaction is complete and the mixture is washed with 2 N NaHCO 3, water and dried over Na 2 SO. After filtration and evaporation of the solvent, a crude yellow oil is obtained. This is purified by distillation under reduced pressure, yielding 9 pure [15.9 g, 64%, e.g. 127-130 ° C (2 mbar)].

Example 2 Preparation of 3- [2- (1, 3-dioxolan-2-yl) ciciohexyl] propanal [compound 10 where (QW) n = H, R3 = R4 = H] To a solution of 9 (15.7 g, 69.1 mmol) in toluene (220 ml) cooled to -78 ° C, DIBA1-H (1.2 M solution in toluene, 116 ml, 135 mmol) was slowly added over 3 h. After 3 h of stirring, the mixture is poured into water (110 ml) and allowed to warm to room temperature. After filtration on a Celite layer, the organic phase is dried over Na2SO4.

After filtration and evaporation of the solvent the residual crude oil is purified by chromatography (petroleum ether-EtOAc, 2: 1, Rf 0.30), yielding the pure aldehyde 10 as an oil (6.6 g, 48%).

Example 3 Preparation of 3- [2- (1, 3-dioxolan-2-yl) ciciohexyl] propanal oxime [compound 11 where (QW) n = H, R3 = R = H].

A solution of aldehyde 10 (6.12 g, 31.0 mol) and NH20H »HC1 (2.76 g, 40.0 mmol) in pyridine (120 ml) is stirred for 2 h at room temperature. The mixture is extracted with Et20 and the organic layer is washed with water and dried over Na2SO4. After filtration and evaporation of the solvent the crude oil obtained is purified by chromatography (petroleum ether-EtOAc, 1.5: 1, Rf 0.5). Recrystallization from Et20-petroleum ether gave the pure oxime 11 (4.02 g, 61%, m.p., 74-75 ° C) as a 1: 1 mixture of the diastereomers E, Z.

Example 4 Preparation of 6- [2- [2- (1,3-dioxolan-2-yl) cydohexyl] ethyl] -4-oxa-5-azaspiro [2.4] hept-5-ene [compound 13 where (QW) n = H, Ri = R2 = R3 = R4 = R6 = H].

Liquid methylcyclopropane [compound 12 where Ri, R2 = R6 = H] (5 ml) is transferred through a double-pointed needle to a solution of oxime 11 (4.02 g, 18.8 min) and Et3N (226 mg, 2.23 mmol) ) in CH2C12 (35 ml) cooled to -60 ° C. The mixture is allowed to warm to 0 ° C and NaClO (8% solution, 54 ml) is added slowly in 3.5 h. The solution is stirred for 21 h, then the phases are separated, the aqueous phase is extracted with CH2C12 (3 X 25 mL) and the combined organic layers are dried over Na2SO4. After filtration and evaporation of the solvent, 13 crude (4.89 g, 73%) are obtained and used without purification in the next reaction.

Example 5 Preparation of 6- [2 (2-oxocyclohexyl) ethyl] -4 -oxa-5-azaspiro [2. 4] hept-5-ene [compound 14 where (QW) n = H, Ri = R2 = R3 = R4 = R6 = H].

Isoxazoline 13 (3.64 g, 13.7 mmol) and p-TsOH (392 mg, 2.23 mmol) were dissolved in acetone (90 ml) and water (30 ml) and the resulting solution was stirred at room temperature for 7 days. The product was extracted with CH2C12, the organic phase washed with NaHCO3 (2 N) and dried over Na2SO4. After filtration and evaporation of the solvent, a crude yellow oil (2.36 g) is obtained. This is first purified by chromatography (CH2Cl2-EtOAc, 12.5: 1, Rf 0.35) and then by recrystallization from Et20-petroleum ether, yielding pure isoxazoline 14 (1.43 g, m.p. 109 ° C).

Example 6 Preparation of 2, 3, 5, 6, 7, 8, 9, 10-octahydro- (1H) -benzo [c] quinolizin-3-one [compound 1 where (QW) n = H, Ri = R2 = R3 = R = Re = H and h = double bond]. and 2, 3, 5, 6, 6a, 7, 8, 9-octahydro- (3H) -benzo [c] quinolizin-3-one [compound 1 where (QW) n = H, Ri = R2 = R3 = R4 = R6 = H ei = double bond].

Isoxazoline 14 (476 mg, 2.15 mmoles) dissolved in dry DMF (50 ml) is heated under reflux for 3 h. After distillation of the solvent, a crude yellow oil (470 mg) is obtained, which contains a mixture of the rearrangement products. This oil is purified by chromatography (CH2Cl2-MeOH, 20: 1), yielding 1 pure (163 mg, 37%, Rf 0.36, oil) as a 10: 1 mixture of the two isomers having a double bond at the respectively.

Example 7 Preparation of methyl 3- [[2- (1, 3-dioxolan-2-yl) -5- (Nt-butyl) acetamido] ciciohexyl]] propanoate [compound 9 wherein (QW) = 5- (Nt-butyl ) acetamido n = 1, R3 = R4 = H].

Prepared as in example 1. Starting with compound 2 [where (QW) = 5- (Nt-butyl) acetamido n = l, R3 = R4 = H] (32.14 g, 108 mmol), the crude ketal 9 ( 22.2 g, 60%) was obtained as an oil. A portion (100 mg) of this crude oil was purified by chromatography (CH2Cl2-MeOH, 30: 1, 1% Et3N, Rf 0.31, oil), yielding 9 as a mixture of the cis and trans isomers.

Example 8 Preparation of 3- [[2- (1, 3-dioxolan-2-yl) -5- (Nt-butyl) acetamido] ciciohexyl]] -propanal oxime [compound 11 wherein (QW) = 5- (Nt-butyl ) acetamido n = 1, R3 = R4 = R6 = H] A solution of the ketal [compound 9 where (QW) = 5- (Nt-butyl) acetamido n = 1, R3 = R = H] (22.1 g, 64.7 mmoles) in toluene (500 ml) is cooled to -78 ° C; DIBAL-H (1 M solution in toluene, 288 ml) was then added slowly over 4 h and the resulting solution was stirred for 3 h. After addition of the water (260 ml), the mixture is allowed to warm to room temperature, extracted with CH2C12 (4 x 200 ml) and the organic layer is dried over Na2SO4. After filtration and evaporation of the solvent, a crude oil (17.2 g) is obtained, used without purification for the next step. Then, with stirring, to a solution of distilled oxalyl chloride (10.9 ml, 125 mmol) in CH2C12 (270 ml), cooled to -60 ° C, DMSO (15 ml, 211 mmol) is added, followed by slow addition. (25 minutes) of a previous crude oil solution in CHC12 (260 ml). After 15 minutes, Et3N (56 ml) is added slowly in 15 minutes. After 5 minutes of stirring, the mixture is warmed to room temperature and washed with water (535 ml); After separation of the phases, the aqueous phase is extracted with CH2C12 (3 x 250 mL) and the combined organic layers are dried over Na2SO4. After filtration and evaporation of the solvent, the aldehyde is obtained [compound 10 where (QW) = 5- (Nt-butyl) acetamido n = 1, R3 = R4 = H] as a crude oil (14.6 g), used without purification for the next reaction. A solution of this aldehyde (14.6 g) in pyridine (210 ml) was added to a solution of NH2OH * HCl (13.7 g, 196.9 mmol) in pyridine (107 ml) and the resulting mixture is stirred at room temperature for 20 h.

The mixture is poured into CH2Cl2 (800 mL) and washed with water; After separation of the phases, the aqueous phase is extracted with CH2C12 (3 x 200 ml and the combined organic layers are dried over Na2SO4) After filtration and evaporation of the solvent, the crude oxime [compound 11 where (QW ) = 5- (Nt-butyl) acetamido n = 1, R3 = R4 = H] (11.3 g was obtained, this was purified by chromatography eluting with CHCl3-MeOH, 50: 1, 1% Et3N, and then "with CHC13 -MeOH, 3: 1, 1% Et3N (Rf 0.32), producing the pure oxime ~ [compound 11 where (QW) = 5- (Nt-butyl) acetamido n = 1, R3 = R4 = H] (7.41 g , 35%, oil) as a mixture of the E / Z diastereoisomers.

Example 9 Preparation of 6- [2- [2- (1, 3-dioxolan-2-yl) -5- (Nt-butyl) acetamido] ciciohexyl] ethyl] -4-oxa-5-azaspiro [2.4] hept-5- eno [compound 13 where (QW) = 5- (Nt-butyl) acetamido n = 1, Rx = R2 = R3 = R4 = R6 = H] Prepared as in example 4. Starting from the oxime prepared above [compound 11 where (QW) = 5- (Nt-butyl) acetamido n = 1, R3 = R4 = H] (7.40 g, 22.6 mmol), the isoxazoline [ compound 13 where (QW) = 5- (Nt-butyl) acetamido n = 1, Rx = R2 = R3 = R4 = R6 = H] (4.96 g, 58%) was obtained as a crude oil used without purification in the next reaction Example 10 '...

Preparation of 6- [2- [2-oxo-5- [(Nt-butyl) acetamido] ciciohexyl] ethyl] -4-oxa-5-azaspiro [2.4] hept-5-ene [compound 14 where (QW) = 5- (Nt-butyl) acetamido n = 1, Ri = R2 = R3 = R4 = R6 = H].

The crude isoxazoline 13 [where (QW) = 5- (Nt-butyl) acetamido n = 1, Rx = R = R3 = R6 = H] (4.92 g, 13.1 mmol) was dissolved in acetone (150 ml) and H2SO4 (1.7 M solution in acetone, 9.8 ml) is added slowly, under vigorous stirring, at room temperature. When the reaction is complete, Na 2 CO 3 is added until pH 7; After filtration and evaporation of the solvent, the crude compound 14 was obtained. This is purified by chromatography, eluting with CH2Cl2-MeOH, 60: 1 and then 20: 1 (Rf 0.28), producing 14 pure as an oil [compound 14 where (QW) = 5- (Nt-butyl) acetamido n = 1, Ri = R2 - R3 = R4 = R6 = H] (1.45 g, 33% ) as a mixture of the cis and trans isomers.

Example 11 Preparation of 2, 3, 5, 6, 7, 8, 9, 10-octahydro- (1H) -8- (Nt-Butyl) acetamido-benzo [c] quinolizin-3-one [compound 1 where (QW) = 8-. { Nt-butyl) acetamido n = 1, Rx = R2 = R3 = R4 = R6 = H and h _ = double bond] and 2, 3, 5, 6, 6a, 7, 8, 9-octahydro- (1H) -8 - (Nt-Butyl) acetamido-benzo [c] quinolizin-3-one [compound 1 where (QW) = 8- (Nt-butyl) acetamido n = 1, Ri = R2 = R3 = R4 = Re = H ei == double link].

A solution of isoxazoline [compound 14 where (QW) = 5- (Nt-butyl) acetamido n = 1, Rx = R2 = R3 = R4 = R6 = H] (947 mg, 2.83 mmol) in DMF (109 ml) it is heated under reflux for 3 hours. After distillation under reduced pressure of the solvent, a crude oil containing a mixture of the rearrangement products was obtained. Chromatographic separation (CH2Cl2-MeOH, 25: 1, 1% NH3) yielded pure compound 1 (161 mg, 18%, Rf 0.32, oil) as a 10: 1 mixture of the two isomers having double bond in the hoi position respectively.

Example 12 Preparation of the (+/-) (4aa, 6aß, lOaa) - 3,, 5, 6, 6a, 7, 8, 9, 10, lOa-decahydro- (4aH) -benzo [c] uinolizin-3-one [compound 1 where (QW) n = H, Ri = R2 = R3 = R4 = Re = H and a = double bond] and (+/-) (4aß, 6aß, 10aa) -3,4,5,6,6a, 7,8,9,10, lOa- decahydro- (4aH) -benzo [c] quinolizin-3-one [compound 1 where (QW) n = H, x = R2 = R3 = R4 = R6 = H and a = double bond] The (+/-) trans-fused N-Boc-amide 5, [wherein (QW) n = H, R3 = R4 = H] prepared according to the known methods, was reduced to compound 6 [where (QW) n = H, R3 = R4 = H] according to the following procedure: A solution of 5 (4.1 mmoles in 12 ml of THF) is cooled to -78 ° C, and a 1 M solution of LiEt3BH in THF (8.2 ml) is added slowly. After 15 minutes of stirring at -78 ° C, 2N HCl in anhydrous EtOH is added dropwise until the pH of 3.5-4 was reached, immediately followed by the addition of 18 ml of ethanol. The mixture is allowed to warm to 0 ° C and after 30 minutes it is diluted with CH2C12. After usual work the product was purified by flash column chromatography and obtained in an 80% yield as a sticky oil. To a solution of compound 6 [where (QW) n = H, R3 = R4 = H] (500 mg, 1.76 mmol in 10 ml of CH2C12) at 0 ° C is added dropwise to l-methoxy-3-trimethylsilyloxy- 1, 3-butadiene [compound 8, where Ri = MeO, R2 = H, R6 = H] (608 mg, 3.53 immoles), NEt3 (0.5 ml, 3.53 mmol) and TMSOTf (4.4 mmol, 0.85 ml), the mixture is allowed to warm to ta (room temperature) under stirring for 30 minutes. Then the mixture is treated with NaHCO3 (saturated) for 24 h under agitation. Work and usual purification by flash column chromatography yielded the isomer 4ab (+/-) (4aa, 6aß, 10A) -3,4,5, 6, 6a, 7, 8, 9, 10, lOa-decahydro- ( 4aH) -benzo [c] quinolizin-3-one [compound 1 wherein (QW) n = H, Ri = R2 = R3 = R4 = R6 = H and a = double bond] with a yield of 20% as an oil. The preparation of the 4aa isomer was made as follows: 'To a solution of compound 6 [where (QW) n = H, R3 = R4 = H] (200 mg, 0.71 mmoles in 5 ml of CH2C12) and l-methoxy-3-trimethylsilyloxy-1,3-butadiene [compound 8, where Ri = MeO, R2 = H, R6 = H ] (244 mg, 1.42 mmol), at 0 ° C, TiCl4 (0.155 ml, from a 2M solution in CH2C12) was added dropwise and the mixture was allowed to warm to room temperature for 1 h. The mixture is then treated with NaHCO3 (saturated) for 30 minutes under stirring. Work and usual purification by flash column chromatography yielded the 4aa isomer. { +/-) (4aa, 6aß, lOaa) -3, 4, 5, 6, 6a, 7, 8, 9,10,10a-decahydro- (4aH) -benzo [c] quinolizin-3-one [compound 1 where (QW) n = H, Rx = R2 = R3 = R4 = R6 = H and a = double bond] in a yield of 16% as an oil.

Activity Test The potency of the inhibition of the prepared compounds with respect to isoenzymes 1 and 2 of 5a-reductase was determined using cellular systems (for example CHO cells) expressing human iso-enzymes 2 and 1. The samples are incubated in the presence of testosterone labeled with tritium and after that the amount of labeled dihydrotestosterone formed in the absence and presence of the inhibitor is measured. The compounds showed a high inhibitory power of the 5a-reductase enzyme (in particular of iso-enzyme 1) with an inhibition higher than 50% at the concentration of 10-100 nM. For example, the 10: 1 mixture of 2,3,5,6,7,8,9, 10-octahydro- (ÍH) -benzo [c] quinolizin-3-one [compound 1 where n (QW) n = H, R = R2 = R3 = R = Re = H and h = double bond] and 2, 3, 5, 6, 6a, 7, 8, 9-octahydro- (3H) -benzo [c] quinolizin-3-one [compound 1 where (QW) n = H, Ri = R2 = R3 = R = Re = H ei = double bond] prepared according to example 6, was the selective inhibitor towards the isoenzyme of type 1, which has an IC 50 value of 58 nM, whereas the IC50 towards the isoenzyme of type 2 was not determinable. For therapeutic administration the compounds according to the invention are prepared in the form of pharmaceutical compositions containing the active ingredient and the organic or inorganic excipients suitable for oral, parenteral or topical administration of the compositions. The pharmaceutical compositions can therefore be in the solid form (tablets, suppositories, creams, ointments), in the liquid form (solutions, suspensions, emulsions) and may possibly contain the stabilizers, preservatives, humectants, emulsifier, buffers or the salts used to balance the osmotic pressure, which are commonly used in the art. In general, the administration of the compounds is carried out in accordance with the modalities and amounts observed for the known agents used for the same purposes and taking into consideration the age and conditions of the patients.

NJ t? 3 It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following

Claims (17)

1. The benzo [c] quinolizine compounds partially and totally reduced in the formula (I) characterized in that: Ri, R2, R3, R Re, identical or different, are chosen from the group consisting of: H, alkyl with C? _8, alkenyl with C2-s, alkynyl with C2_8, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, phenyl, biphenyl, naphthyl, saturated or aromatic heterocycles containing one or more N atoms, halogen, CN, azide, NRR ', alkylamino with C? _s, arylamino, alkyloxy with Ci- s, aryloxy, COOR, CONRR ', C (= 0) R, wherein R and R', identical or different, are chosen from the group consisting of: H, alkyl with C_8, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane , cyclooctane, norbornane, camphane, adamantane, phenyl, biphenyl, naphthyl, saturated or aromatic heterocycles containing one or more N, phenyl-, biphenyl-, or naphthyl-alkyl atoms with C? -8; Rs is selected from the group consisting of: H, alkyl with C? -8, alkyl with C? -8-phenyl, -biphenyl, -naphthyl, COOR, CN, phenyl, biphenyl, naphthyl, saturated or aromatic heterocycles containing one or more N atoms, alkyl with C? _8-aromatic or saturated heterocycles containing one or more N atoms; alkyl with C? _8-aromatic or saturated heterocycles containing one or more N-ribose-phosphate atoms X is selected from the group consisting of: 0, C (= 0) R, COOR, N02, CONR'R wherein R and R 'are as defined above; Q is selected from the group consisting of: a single bond, alkyl with C? -8, alkenyl with 'C2-8, alkynyl with C2_8, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, CO , CONR, NR, where R is as defined above; W is selected from the group consisting of: H, alkyl with C? _8, alkenyl with C2-8, alkynyl with C2_8, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, trifluoromethyl, alkoxy with C ? 8, alkoxy with C? _8-alkyl with C? _8, phenyl-, biphenyl-, naphthyl-alkyl with C? _8, phenyl, biphenyl, naphthyl, phenyloxy, biphenyloxy, naphthyloxy, phenylamino, biphenyla ino, naphthylamino, alkyl with C8-carbonyl, phenylcarbonyl, biphenylcarbonyl, naphthylcarbonyl, phenylcarboxyl, biphenylcarboxyl, naphthylcarboxyl, phenylcarboxamide, biphenylcarboxamide, naphthylcarboxamide, halogen, CN, NRR ', alkylamino with C? -8, saturated or aromatic heterocycles containing one or more N atoms in where the groups of alkyl, alkenyl, alkynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane, adamantane, phenyl, biphenyl, naphthyl, saturated or aromatic heterocycles containing one or more carbon atoms. N, may be substituted; n is an integer between 1 and the symbol means that the corresponding links to, b, c, d, e, f, g, h and i can be a single link or a double bond; with the proviso that when b or f are a double bond then the group Rs is absent; its pharmaceutically acceptable salts and esters.

2. The benzo [c] quinolizine compounds of the formula (I) according to claim 1, characterized in that Rs = H, alkyl with C? _8-phenyl, -biphenyl, -naphthyl, COOR, CN, phenyl, biphenyl, naphthyl, saturated or aromatic heterocycles containing one or more N atoms, alkyl with C? _8-aromatic or saturated heterocycles containing one or more N atoms; or an alkyl group with C? -8-aromatic or saturated heterocycles containing one or more N-ribose phosphate atoms X = 0, COOH Q = a single bond, CO, CONR, NR (wherein R is as defined above) W = H, F, Cl, Br, Me, t-butyl, alkoxy with C? _8, 2,5-dimethylhexyl, trifluoromethyl, 2,5- (di-trifluoromethyl) -phenyl, 4-methoxy-phenyl , 4-fluoro-. phenyl, phenyl, phenyl-alkyl with C? -8, alkylcarbonyl with C? s, phenylcarbonyl, n = 1 and 2 Ri / R2 / R3, R4, Re = H, Me, CN, phenyl, COOR, CONRR '(in where R and R 'are as defined above).

3. The benzo [c] quinolizine compounds according to claim 1, characterized in that they are of the formula: 2, 3, 4, 4a, 5, 6, 6a, 7, 8, 9, 10, lOa-dodecahydro- (III) ) -benzo [c] quinolizin-3-one; 8-chloro-2,3,4,4a, 5, 6, 6a, 7, 8, 9,10, lOa-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, 10-decahydro- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3.5.6, 6a, 7, 8, 9, 10, lOa-decahydro- (lH) -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; (4aa, 6aβ, 10A) -3, 4, 5, 6, 6a, 7, 8, 9, 10, lOa-decahydro- (4aH) -benzo [c] quinolizin-3-one; (4aß, 6aß, 10aa) -3,4,5, 6, 6a, 7, 8, 9, 10, lOa-decahydro- (4aH) -benzo [c] quinolizin-3-one; 3, 4, 5, 6, 6a, 7, 8, 9, 10, lOa-decahydro- (4aH) -benzo [c] quinolizin-3-one; 8-chloro 3, 4, 5, 6, 6a, 7, 8, 9, 10, iOa-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-l-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-chlor? ' 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; 3,4,5,66a, 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-l-methyl- (4aH) -benzo [c-quinolizin-3-one; 3,4,5,6 6a, 7, 8, 9, 10, 10a-decahydro-l, 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, 7,8,8,10,10a-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; 2, 3, 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-l, 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-l, 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-l, 5-dimethyl- (4aH) -benzo [c] quinolizin-3-one; _ 3,4,5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-l, 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 [cj quinolizin-3-one; 2,3,5, 6, 6a, 7, 8, 9,10, 10a-decahydro-l, 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-decahydrole , 6-dimethyl- (4aH) -benzo [c] quinolizin-3-one; 8-chloro-2, 3,5,6,6a, 7,8,9,10,10a-decahydro-4,6-dimethyl - (ÍH) -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-l, 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; -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-l, 6 -dimethyl- (4aH) -benzo [c] quinolizin-3-one; 3, 4, 5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-l, 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- (1 H) -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-l, 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-4,5,6,6-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, a, 7,8,9,10,10a-decahydro-l, 5,6-trimethyl- (4aH) -benzo [c] quinolizin-3-one; 3,4,5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-l, 5, 6, 8-tetramethyl- (4aH) -benzo [c] quinolizin-3-one; 5, 6, 6a, 7, 8, 9, 10, lOa-octahydro- (3H) -benzo [c] quinolizin-3-one; 8-chloro-5, 6, 6a, 7, 8, 9, 10, lOa-octahydro- (3H) -benzo [c] quinolizin-3-one; 5, 6, 6a, 7, 8, 9, 10, 10a-octahydro-8-methyl- (3H) -benzo [c] quinolizin-3-one; 5, 6, 6a, 7, 8, 9, 10, 10a-octahydro-4-methyl- (3H) -benzo [c] quinolizin-3-one; 8-chloro-5, 6, 6a, 7, 8, 9, 10, 10a-octahydro-4-methyl- (3H) -benzo [c] quinolizin-3-one; 5, 6, 6a, 7, 8, 9, 10, 10a-octahydro-4,8-dimethyl- (3H) -benzo [c] quinolizin-3-one; 2,3,5,6,7,8,9,10-octahydro- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3,5,6,7,8,9, 10-octahydro- (1H) -benzo [c] uinolizin-3-one; 2, 3,5,6,7,8,9, 10-octahydro-8-methyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6, 6a, 7, 8, 9-octahydro- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6, 6a, 7, 8, 9-octahydro- (1H) -benzo [c] quinolizin-3-one; 2,3,5, 6, 6a, 7, 8, 9-octahydro-8-methyl- (1H) -benzo [c] quinolizin-3-one; 4a-benzyl-3, 4, 5, 6, 6a, 7,8,9, 10, lOa-decahydro- (4aH) -benzo [c] quinolizin-3-one; 4a-benzyl-8-chloro-3, 4,5,6,6a, 7,8,9,10,1-a-decahydro- (4aH) -benzo [c] quinolizin-3-one; 4a-benzyl-3, 4, 5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-8-methyl- (4aH) -benzo [c] quinolizin-3-one; 4a-benzyl-3, 4,5,6,6a, 7,8,9,10,15-decahydro-4-methyl- (4aH) -benzo [c] quinolizin-3-one; 4a-benzyl-3, 4,5,6, 6a, 7, 8, 9, 10, 10a-decahydro-l-methyl- (4aH) -benzo [c] quinolizin-3-one; 3,4,5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-4a- (4-pyridyl) methyl- (4aH) -benzo [c] quinolizin-3-one; 8-chloro-3, 4, 5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-4a- (4-pyridyl) methyl- (4aH) -benzo [c] quinolizin-3-one; 3,4,5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-8-methyl-4a- (4-pyridyl) methyl- (4aH) -benzo [c] quinolizin-3-one; 3,4,5, 6, 6a, 7,8, 9, 10, 10a-decahydro-4-methyl-4a- (4-pyridyl) ethyl- (4aH) -benzo [c] quinolizin-3-one; 3,4,5, 6, 6a, 7, 8, 9, 10, 10a-decahydro-l-methyl-4a- (4-pyridyl) methyl- (4aH) -benzo [c] quinolizin-3-one.

4. A process for the preparation of the compounds according to any of claims 1-3, characterized in that: the ester group of a compound of the formula (2) (wherein R3, R and (QW) n are as defined in claim 1) is cyclized to the enamide (3) (wherein R3, R4 and (QW) n are as defined in claim 1) which is reduced to the amide (wherein R3, R4 and (QW) n are as defined in claim 1) which is protected with a Boc protecting group to give the compound (5) (wherein R3, R4 and (QW) n are as defined in claim 1) which is reduced to the compound (6) (6) (wherein R3, R4, R5 and (QW) n are as defined in claim 1) and the compound (6) is reacted with a silyl ether (8) (wherein Ri, R2 and R6 are as defined in claim 1) prepared "in situ" by reacting a vinyl ketone (7) (wherein Ri, R2, R6 are as defined above) with a silylating agent such as trimethylsilyltrifluoromethanesulfonic anhydride (TMSOTf) and finally hydrolyzed, for example with sodium acid carbonate, to give the final compound of the formula (I) where X = O.

5. The process according to claim 4, characterized in that the possible introduction of the double bonds in position a or b is effected by the reaction of the dichlorodicyanoquinone (DDQ) with the corresponding silylene ethers or by the oxidation with mercury acetate of the saturated compound obtained as it was previously claimed and the possible transformation of the group X is effected by means of the corresponding enoltriflates and then the carbonylation in the presence of palladium diacetate, triphenylphosphine and the appropriate nucleophilic reagent.

6. The process according to claim 4, characterized in that the reaction between the compound (6) and the silyl ether (8) is carried out in the presence of TiCl 4.

7. The process according to claim 4, characterized in that the reaction between the compound (6) and the silyl ether (8) is carried out in the presence of TTMSOTf.

8. A process for the preparation of a compound of the formula (I) according to any of claims 1-3, characterized in that: the carbonyl group of a compound of the formula (2) (where R3, R4 and (QW) n are as defined above) is protected as a ketal to give a compound (9) (wherein R3, R4, QW and n are as defined above) which is reduced to the corresponding aldehyde (10) (where R3, R4, QW and n are as defined above) with DIBAL, and such aldehyde is transformed into the oxime (11) (wherein R3, R4, QW and n are as defined above) which is reacted with a derivative of methylenecyclopropane (12) (12) (where Ri, R2 and R < are as previously defined) to give isoxazoline (13) (wherein Ri, R2, R3, R, Rβ, QW and n are as defined above), which is deprotected to the corresponding isoxazoline (14) (where Ri R2, R3, R4, R6, QW and n are as defined above), which is rearranged to the final product of formula (I) where X = O, ioh is a double bond and the other substituents are as defined above.

9. The compound of the formula (6) wherein W, Q, n, R3, R4, R5 are as defined in claim 1.

10. A pharmaceutical composition, characterized in that the active ingredient is a compound of the formula (I) according to claim 1 or the mixtures thereof in combination with suitable pharmaceutically acceptable excipients.

11. The pharmaceutical composition according to claim 10, for use in the inhibition of iso-enzymes 5aR-I and / or 5aR-II.

12. The pharmaceutical composition according to claims 10 and 11, characterized in that it is in the form suitable for topical use.

13. A method for the treatment of pathologies related to 5a-reductase enzymes, characterized in that a pharmaceutically active amount of a pharmaceutical composition is administered to the patient according to claim 10.

14. The method according to claim 13, characterized in that the pathologies treated are acne, baldness, prostatic cancer and prostatic hypertrophy in men and hirsutism in women.

15. The use of the compounds of the formula (I) according to claim 1 as inhibitors of the steroid 5a-reductase enzymes in plants.

16. Agricultural compositions for the regulation of the growth of plants, characterized in that they contain as active ingredient a compound of the formula (I) according to claim 1 or the mixtures thereof possibly in combination with the additives commonly used in agriculture for this purpose.

17. A process for regulating the growth of plants, characterized in that an effective amount of a composition according to claim 16 is distributed on the seeds and / or on the plants to be treated.