MXPA01000869A - Process for the synthesis of (1h - Google Patents

Abstract

The present invention refers to a process for the preparation of (1H)-benzo[c]quinolizin-3-ones derivatives of general formula (I) which involves only three steps and the use, as starting products, of commercially available, or easily preparable, compounds. The compounds of formula (I) are useful as inhibitors of 5&agr;-reductases.

Description

PROCESS FOR THE SYNTHESIS OE DERIVATIVES OF (1H) - BENZO [C] QÜINOLIZIN-3-ONAS Brief Description of the Invention The present invention relates to a process for the preparation of (1H) -benzo [c] quinozilin-3-ones derivatives of general formula (I), which involves only three steps and the use of compounds, as initial products, commercially available, or easily prepared. The compounds of formula (I) are useful as inhibitors of 5α reductases.

Field of the Invention The present invention relates to a process for the preparation of (1H) -benzo [c] quinozilin-3-ones derivatives of general formula (I) wherein: R1 R2, R3, R4, R5, equal or different, are chosen from the group consisting of: H, alkyl alkenyl C2_ Ref: 126618 8, C2_8 alkynyl, cycloalkyl, aryl, heterocycle, halogen, CN, azide, NRR ', alkylamino arylamino, alkyloxy aryloxy, COOR, CONRR 'wherein R and R', the same or different, are selected from the group consisting of: H, alkyl cycloalkyl, aryl, heterocycle, aryl alkylCg.g; Q is selected from the group consisting of: single bond, C1.a alkyl, C2.8 alkenyl, C2_8 alkynyl, cycloalkyl, CO, CONR, NR, wherein R is as. was defined before; W is selected from the group consisting of: H, Ci.g alkyl, C2-8 alkenyl, C2_8 alkynyl, cycloalkyl, trifluoromethyl, C18 alkoxy, alkoxy aryl C ^ alkyl, aryl, aryloxy, arylamino, alkylcarbonyl arylcarbonyl, arylcarboxyl, arylcarboxamide, halogen, CN, NRR ', alkylamino CX.B, heterocycle wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle groups may be substituted; n is an integer between 1 and 4; and its pharmaceutically acceptable salts or esters, from commercially available compounds, or easy to prepare, and which involve only three steps.

State of the art The compounds of general formula (I) as defined above are known to be 5a-reductase inhibitors useful for the treatment of pathologies mediated by the enzyme (for example acne, baldness, prostate cancer and hypertrophy in men and women). hirsutism in women) (see International Application No. PCT / EP97 / 00552). They are also active as growth regulators in plants. As described in the above patent application, hitherto the compounds of formula (I) are produced by a process involving several steps starting from a compound of formula II (H) According to the process, the amide group of compound II is protected as an N-Boc derivative, the compound obtained is reduced, reacted with a silyloxydiene produced "in situ" and hydrolyzed to obtain a compound of formula III (lll) Finally, the introduction of the double bond in position b is carried out by reaction with dichlorodicyanoquinone with the corresponding silylene ethers or by oxidation with mercuric acetate.

As you can see the process described above involves many steps that i. to. they have a negative effect on the final yields of the desired compounds. In view of the importance of these compounds as 5a-reductase inhibitors, the interest in making new processes available to prepare the desired compounds in a more efficient manner is evident.

DETAILED DESCRIPTION OF THE INVENTION The present invention also overcomes the above problems by a synthesis process that involves only three steps and also uses, as initial compounds, compounds that can be synthesized easily or are commercially available. According to the present invention in the compounds of the group of formula (I) alkyl C2-8 alkenyl and C2-8 alkynyl represent linear or branched alkyl radicals such as for example: methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, ethylene, propene, butene, isobutene, acetylene, propyne, butyne , etc. The term cycloalkyl represents: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camfano, adamantane. The term aryl represents: phenyl and naphthyl. The term heterocycle represents in particular: saturated or aromatic heterocycles containing one or more N atoms, more particularly: pyridine, imidazole, pyrrole, indole, triazoles, pyrrolidine, piperidine. Halogen indicates: fluorine, chlorine, bromine, iodine. The substituents of the above group W are preferably: halogen, OR, phenyl, NRR ', CN, COOR, CONRR', alkyl (where R and R 'are as defined above). In particular, the process according to the present invention allows the preparation of the compounds of formula (I) wherein: Q = simple bond, CO, CONR, NR (where R is as defined above) W = H, F, Cl, Br, Me, t-butyl, Ci-g alkoxy, 2,5-dimethylhexyl, trifluoromethyl, 2 , 5- (di-trifluoromethyl) -phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl, phenyl, phenyl-C 1-8 alkylcarbonyl phenylcarbonyl. n = 1 or 2 Ri. R2, R3. i .. R5 = H, Me, CN, phenyl, COOR, CONRR '(where 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. The specific compounds according to the process of the invention are: 2, 3, 5, 6-tetrahydro- (1H) -benzo [c] qui olizin-3-one; 8-chloro-2, 3, 5, 6-tetrahydro- (1H) -benzo [c] quinol i zin-3 -one; 2, 3, 5, 6-tetrahydro-8-methyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4-methyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-l-methyl- (1 H) -benzo [c] qui nol i zin-3 -one; 8-chloro-2,3,5,6-tetrahydro-4-methyl- (lH) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4,8-dimethyl- (1H) -benzo [c] quinol i zin-3 -one; 8-chloro-2,3,5,6-tetrahydro-1-methyl- (1 H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-1,4-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-6-methyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6-tetrahydro-6-met il- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-6,8-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4,6-dimethyl- (1 H) -benzo [c] quinol i zin-3-one; 2, 3, 5, 6-tetrahydro-l, 6-dimethyl- (1H) -benzo [c] quinol i zin-3 -one; 8-chloro-2,3,5,6-tetrahydro-4,6-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4,6,8-trimethyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-l, 6-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-1,4,6-trimethyl- (lH) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-5-methyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6-tet ra idro-5-methyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-5, 8-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4,5-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-l, 5-dimethyl- (1H) -benzo [c] quinol i zin-3 -one; 8-chloro-2,3,5,5,6-tetrahydro-4,5-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4,5,8-trimethyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6-tetrahydro-l, 5-dimethyl- (1H) -be zo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-1,4,4,5-trimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-5,6-dimethyl- (1 H) -benzo [c] quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-5,6-dimethyl- (1 H) -benzo [c] qui nol i zin-3 -one; 2, 3, 5, 6-tetrahydro-5,6-8-trimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4,5,6-trimethyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6-tetrahydro-4,5,6-trimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-1,5,6-trimethyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2,3,5,5,6-tetrahydro-1,5,6-trimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4,5,6,8-tetramethyl- (1H) -be zo [c] quinolizin-3-one. According to the invention, the compounds of formula (I) defined above can be prepared by starting with the compounds of general formula 2 and 3: where R? r R2, R3, R4, R5,, Q and n are as defined above. Compounds 2 and 3 are commercially available or can be prepared according to known techniques. As can be seen in Reaction Scheme 1, the preparation of compounds I according to the invention involves the N-alkylation of thioamide 3 with vinyl ketone 2 to give the N-alkylated thioamide 4 in the presence of a strong base, but not nucleophilic. The reaction is preferably carried out in an organic solvent (for example THF) at a temperature between 0 ° C - 30 ° C, for a time between two and four hours. The vinyl ketone is added more preferably to the thioamide intermittently. The characteristics of the base are crucial for the effectiveness of the reaction: in fact the strong nucleophilic bases cause the polymerization of vinyl ketone, while with moderate bases the reaction does not occur. Preferred bases having the above characteristics are: K2C03 / 18-crowned-6 or diazabicycloundecene (DBU). The N-alkylated thioamide 4 is then methylated to the sulfur atom, to give salt 5, which is usually not isolated, but stops reacting with a base to give the final compound I. Also for this step the conditions of reaction (temperature and time) and the type of base.

The best results were obtained using dimethyl sulfate as the methylating agent, a strong but non-nucleophilic base (for example DBU) and carrying out the reaction at reflux temperature in a solvent organic (for example toluene) for a time between half an hour and one hour. The synthesis of two compounds of formula (I) is reported in the following examples to better illustrate the invention.

EXAMPLE 1 Preparation of 6-chloro-l- (3-oxo-l-pentyl) - (1 H) -3,4-dihydroquinoline-2-thione [compound 4 wherein (QW) n = Cl, Rj. = R3 = R4 = Rs = H, R2 = Me] Under a nitrogen atmosphere, ethyl vinyl ketone (compound 2, where Ra = R5 = H, R2 = Me) (340 ml, 3.42 mmol) is added to a stirred suspension of 6-chloro- (1H) -3,4-dihydroquinoline-2-thione (compound 3 wherein (QW) n = Cl, R 3 = R 4 = H) (450 mg, 2.28 mmol), anhydrous K 2 CO 3 (692 mg, 5.01 mmol), and 18-capped-6 (60 mg, 0.23 mmol) in anhydrous THF (41 mL), while cooling to 0 ° C. The suspension is then allowed to warm to room temperature and, after 30 min of stirring, the suspension is cooled to 0 ° C and an additional amount of ethyl vinyl ketone (3.42 mmol) is added. After 1 h at room temperature the suspension is again cooled to 0 ° C and the last amount of ethyl vinyl ketone (3.42 mmol) is added. After 1 h at room temperature, the reaction is completed. The mixture of The reaction is filtered through a short pad of anhydrous Na2SO4 and the solvent is evaporated. The residual oil is subjected to chromatography (ethyl acetate: light petroleum ether, 1: 9, Rf = 0.29) which produces 6-chloro-1- (3-oxo-l-pentyl) - (1H) -3, 4 -dihydroquinoline-2-thione [compound 4 where (Q) n = Cl, Rx = R3 = R4 = R5 = H, R2 = Me] pure (277 mg, 45%) as a pale yellow solid (mp 68-) 70 ° C). As an alternative, thioamide 3 (450 mg, 2.28 mmol) is dissolved in 5 ml of anhydrous THF, DBU (69 ml, 0.46 mmol) is added and, while cooling to 0 ° C, ethylvinyl ketone 2 (275 ml) is added. , 2.76 mmol) dropwise under stirring and nitrogen atmosphere. After 2.5 h at 0 ° C an additional amount of ethyl vinyl ketone (113 ml, 1.38 mmol) is added, the reaction is left for another hour at 0 ° C and then the solvent is evaporated, the residual oil is diluted with CH2C12 (30 mL). ml), washed with 5% citric acid, NaHCO 3 (sat.) and water. The organic layer is dried with Na 2 SO 4, filtered and evaporated, obtaining a crude oil which is subjected. to chromatography as reported before. Compound 4 is thus obtained as a 1.6: 1 mixture with unreacted thioamide 3. Calculated yield of 4: 35%.

EX PQ 2 Preparation of 8-chloro-2,3,5,6-tetrahydro-4-methyl- (1H) -benzo [c] quinolizin-3-one [compound 1 wherein (QW) n = Cl, R- , = R3 = R4 = R5 = H and R2 = Me]. To a solution of 6-chloro-l- (3-oxo-l-pentyl) - (1H) -3,4-dihydroquinoline-2-thione [compound 4 where (QW) n = Cl, Ri = R3 = R4 = R5 = H, R2 = Me], (250 mg, 0.93 mmol) in anhydrous toluene (3 ml), Me2SO4 (149 ml, 1.57 mmol) is added under stirring and nitrogen atmosphere. The solution is heated to reflux and after 5 min a red oil begins to separate. After 10 min more, DBU (235 ml, 1.57 mmol) is added dropwise to the refluxing two-phase reaction mixture, causing a darkening of the mixture after a few minutes. The reflux is maintained for 20 min, then the solution is cooled to room temperature, diluted with dichloromethane (50 ml), washed with water (50 ml) and dried with Na 2 SO 4. After filtration and evaporation of the solvent the dark residual oil is subjected to chromatography (ethyl acetate: light petroleum ether, 1: 1, Rf = 0.28) which produces 8-chloro-2,3,5,6-tetrahydro- 4-methyl- (1H) -benzo [c] quinol i zin-3-one [compound 1 where (Q) n = Cl, Rx = R3 = R4 = R5 = H and R2 = Me] pure (90 mg, 41%) as an oil that solidifies at rest (mp 112-114 ° C).

EXAMPLE 3 Preparation of 6-methyl-1- (3-oxo-l-pentyl) - (1H) -3,4-dihydroquinoline-2-thione [compound 4 wherein (QW) n = Me, R? = R3 = R4 = R5 = H, R2 = Me] Under nitrogen atmosphere, ethyl vinyl ketone (compound 2, wherein Rx = R5 = H, R2 = Me) (380 ml, 3.81 mmol) is added to a stirred suspension of 6-methyl- (1H) -3,4-dihydroquinoline-2-thione (compound 3 wherein (QW) n = Me, R 3 = R 4 = H) (500 mg, 2.82 mmol), anhydrous K 2 CO 3 (900 mg, 6.5 mmol), and 18-capped-6 (89 mg, 0.28 mmol) in anhydrous THF (47 ml), while cooling to 0 ° C. The suspension is then allowed to warm to room temperature and, after 60 min of stirring, the suspension is again cooled to 0 ° C and an additional amount of ethyl vinyl ketone 2 (3.81 mmol) is added. After 2 h at room temperature the reaction is completed. The reaction mixture is filtered through a short pad of anhydrous Na 2 SO 4 and the solvent is evaporated. The residual oil is subjected to chromatography (ethyl acetate: light petroleum ether, 1: 9, Rf = 0.23) which produces 6-methyl-1- (3-oxo-l-pentyl) - (1H) -3, 4 -dihydroquinoline-2-thione [compound 4 where (Q) n = Me, R2 = R3 = R4 = R5 = H, R2 = Me] pure (500 mg, 68%) as a white solid (mp 70-71 °) C).

EXAMPLE 4 Preparation of 8-methyl-2, 3,5,6-tetrahydro-4-methyl- (1 H) -benzo [c] quinolizin-3-one [compound 1 wherein (Q) n = Me, Rx = R3 = R4 = R5 = H and R2 = Me]. To a solution of 6-methyl-l- (3-oxo-l-pentyl) - (1H) -3, -dihydroquinoline-2-thione [compound 4 where (QW) n = Me, R2 = R3 = R4 = R5 = H, R2 = Me], (350 mg, 1.40 mmol) in anhydrous toluene (4 ml), Me2SO4 (227 ml, 2.40 mmol) is added under stirring and nitrogen atmosphere. The solution is heated to reflux and after 5 min a red oil begins to separate. After 15 min more, DBU (365 ml, 2.40 mmol) is added dropwise to the refluxing two-phase reaction mixture, causing a darkening of the mixture after a few minutes. The reflux is maintained for 20 min, then the solution is cooled to room temperature, diluted with dichloromethane (50 ml), washed with water (50 ml) and dried with Na 2 SO 4. After filtration and evaporation of the solvent the dark residual oil is subjected to chromatography (ethyl acetate: light petroleum ether, 1: 1, Rf = 0.29) which produces 8-methyl-2, 3, 5, 6-tetrahydro- 4-methyl- (1H) -benzo [c] quinolizin-3-one [compound 1 where (QW) n = Me, Rx = R3 = R4 = R5 = H and R2 = Me] pure (152 mg, 50% ) as an oil that becomes a solid at rest (mp 143-145 ° C).

REACTION IMAGE 1 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (9)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Process for the preparation of compounds of formula (I) where: Ri. R. R3. . R5 / the same or different, are chosen from the group consisting of: H, alkyl C2_8 alkenyl, C2_8 alkynyl, cycloalkyl, aryl, heterocycle, halogen, CN, azide, NRR ', alkylamino arylamino, Ci-g alkyloxy, aryloxy, COOR, CONRR 'wherein R and R', the same or different, are selected from the group consisting of: H, C 1 -C 6 alkyl, cycloalkyl, aryl, heterocycle, aryl alkylC 4; Q is chosen from the group consisting of: simple link, alkyl C2_8 alkenyl, C2_8 alkynyl, cycloalkyl, CO, CONR, NR, wherein R is as defined above; W is selected from the group consisting of: H, CX.B alkyl, C2_8 alkenyl, C2_8 alkynyl, cycloalkyl, trifluoromethyl, Cj.b. alkoxy, Cj.sub.g-Cx-βalkyl, aryl alkyl aryl, aryloxy, arylamino, C128 alkylcarbonyl, arylcarbonyl, arylcarboxyl, arylcarboxyamide, halogen, CN, NRR ', alkylamino heterocycle wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle groups may be substituted; n is an integer between 1 and 4; and its pharmaceutically acceptable salts or esters, characterized in that: a thioamide 3 (wherein R3 and R4 are as defined above) is N-alkylated with vinyl ketone of formula 2: (wherein Rlf R2 and R_ are as defined above) 5 to give the corresponding compound 4: (wherein all substituents are as defined above) that is methylated, at the sulfur atom, to give the 5-salt: (where all substituents are as defined above) which is reacted directly with a base to give the desired compound I.

2. Process according to claim 1, characterized in that the reaction between compounds 2 and 3 is carried out in an organic solvent, in the presence of a strong base, but not nucleophilic.

Process according to claim 1 or 2, characterized in that the final cyclization step is carried out in an organic solvent in the presence of a strong base, but not a nucleophilic one.

4. Process according to claim 2, characterized in that the base is K2C03 / 18-crowned-6 or diazabicycloundecene (DBU).

Process according to claim 3, characterized in that the base is diazabicycloundecene (DBU).

6. Process according to claim 2, characterized in that the solvent is THF.

Process according to claims 1 and 3, characterized in that the methylating agent is dimethyl sulphate and the solvent is toluene at the reflux temperature.

8. Process according to claim 7, characterized in that the total reaction time is between half an hour and one hour.

9. Process according to claims 1-8, characterized in that the compound of formula (I) is: 2,3,5,6-tetrahydro- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6-tetrahydro- (1H) -benzo [c] qui olizin-3-one; 2, 3, 5, 6-tetrahydro-8-methyl- (1 H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4-methyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-l-methyl- (1 H) -benzo [c] quinol i zin-3 -one; 8-chloro-2, 3, 5, 6-tet rahydro-4-methyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, ß-tetrahydro-4, 8-dimethyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6-tet rahydro-1-methyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-l, 4-dimethyl- (1 H) -benzo [c] quinol i zin-3 -one; 2, 3, 5, 6-tetrahydro-6-methyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6-tetrahydro-6-met yl- (lH) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-6, 8-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4,6-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-l, 6-dimethyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2,3,5,6-tetrahydro-4,6-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4, 6, 8 -trimethyl- (1H) -benzo [c] quinol i zin-3 -one; 8-chloro-2,3,5,6-tetrahydro-l, 6-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-1,4,6-trimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-5-methyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6-tet rahydro-5-methyl- (1 H) -benzo [c] quinol i zin-3 -one; 2, 3, 5, 6-tetrahydro-5, 8-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4,5-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-l, 5-dimethyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2,3,5,5,6-tetrahydro-4,5-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4,5,8-trimethyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6-tetrahydro-l, 5-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-1,4,4,5-trimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-5,6-dimethyl- (1 H) -benzo [c] quinolizin-3-one; 8-chloro-2,3,4,5,6-tetrahydro-5,6-dimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-5,6-8-trimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tetrahydro-4,5,6-trimethyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2, 3, 5, 6-tetrahydro-4,5,6-trimethyl- (1H) -benzo [c] qui nol i zin-3-one; 2, 3, 5, 6-tetrahydro-1,5,6-trimethyl- (1H) -benzo [c] quinolizin-3-one; 8-chloro-2,3,5,5,6-tetrahydro-1,5,6-trimethyl- (1H) -benzo [c] quinolizin-3-one; 2, 3, 5, 6-tet rahydro-4, 5, 6, 8-tetramethyl- (1H) -benzo [c] quinolizin-3-one.