Title of Invention	"HALOGEN-SUBSTITUTED AND PSEUDOHALOGEN-SUBSTITUTED 17-METHYLEN-4-AZASTEROIDS"
Abstract	Halogen-substituted and pseudohalogen-substituted 17-methylen-4-azasteroids of general formula I wherein R1, R4, R10, R20 and R20a are as described in specification and claims and pharmaceutical compositions containing the same.

Full Text

Description The invention relates to novel 17-methylene-4-azasteroids of the general formula I (Figure Remove) in which R20 and R20a are separately fluoro, chloro, bromo and cyano groups, R4 and R10 are in each case a hydrogen atom or a methyl group, R1 and R2 are together in each case a hydrogen atom or an additional bond. Processes for the preparation of the novel compounds are described, and also for the preparation of their pharmaceutical compositions. The compounds according to the invention, 7-methylene- 4-azasteroids, are novel; their preparation and their biological activity have hitherto not yet been described. Preferred compounds according to the invention are named in Claim 3. The present invention further relates to pharmaceutical compositions which as active compounds contain at least one 17-methylene-4-aza- steroid of the general formula I, these compositions optionally comprising suitable excipients and vehicles. The compounds according to the invention are inhibitors of 5a-reductase. They are therefore suitable for the treatment of disorders which are the result of raised testosterone and ultimately dihydrotestosterone levels in blood and tissue. Disorders due to excessive androgenic effects can also occur in the case of normal testosterone levels in the blood if the conversion of testosterone to dihydrotestosterone is increased in the tissue. This is the case, for example, in idiopathic forms of hirsutism (REF). Progesterone plays an important role in the firm sealing of the mouth of the uterus (Mahendroo ) . Its softening before birth results from a local degradation of progesterone by 5a-reductase to give dihydro-progesterone, which is a very weak gestagen. Owing to the inhibition of the catabolism of progesterone in this part of the uterus, the substances according to the invention are therefore also suitable for preventing premature ripening and opening of the mouth of the uterus. Sa-reduced metabolites of progesterone (REF from Lancet) and other C21 steroids and their metabolites formed in the body, for example allo-pregnanolone, can act as neurosteroids and interact with neurosteroids. Disturbances of these functions can be reflected in impairments of state. Possible indications for the substances according to the invention are prostate disorders, male-type alopecia and acne and hirsutism, and also various gynaecological syndromes such as premenstrual syndrome. The occurrence of 5a-reduced metabolites of progesterone in the CNS plays an important role in its development. The premature opening of the mouth of the uterus can be induced by the increased degradation of progesterone to in this tissue to dihydroprogesterone. The substances according to the invention are suitable for preventing this catabolism and thus the premature ripening of the uterine cervix. The substances according to the invention can exert their action by the inhibition of the 5a-reduction of testosterone or progesterone in the organs and tissues affected by the disturbance. Added to this is the lowering of the blood levels of the corresponding Sa-reduced metabolites. The compounds according to the invention are furthermore intermediates for the synthesis of further pharmacologically highly active steroid products. The compounds according to the invention are prepared according to Claims 4 and 5. The compounds according to Claim 1 are accessible according to the invention from the 17-methylene-steroids of the general formula II and of the general formula VII. (Figure Remove) Compounds according to Claim 1 are obtained by reacting compounds of the general formula II in a manner known per se with NaIC-4 with catalytic mediation of KMnC-4 in a protic solvent, preferably t-BuOH, to give the 3,5-seco-keto acid, cyclizing this with NH4OAc in glacial acetic acid to give the unsaturated lactam and reducing with HCOOH/K2C03 in DMF to give the saturated lactam of the general formula III, (Figure Remove) then reacting the compounds of the general formula III with Mel and NaH in a dipolar aprotic solvent,- 4 - preferably DMF, to give the 4-methyl-substituted compounds of the general formula IV, (Figure Remove) or, on the other hand, leading the compounds of the general formula III in a silyl-mediated DDQ (2,3-di-chloro-5,6-dicyano-l,4-benzoquinone) oxidation in a dipolar aprotic solvent, such as dioxane, to the dehydrogenated lactams of the general formula V. (Figure Remove) The compounds of the general formula V are reacted with Mel and NaH analogously to the compounds of the general formula III to give the 4-methyl-substituted lactams of the general formula VI. (Figure Remove) Furthermore, compounds according to Claim 1 are obtained by subjecting compounds of the general formula VII to the same chemistry as the compounds of the general formula II and then obtaining compounds of the general formulae VIII, IX, X and XI. (Figure Remove) Examples: Evaluation of the antiandrogenic activity in the castrated male rat (see figures/table). Castrated immature male rats were treated over the course of 7 days with testosterone propionate (TP) and the substances according to the invention (0.1 mg of TP on its own and or 1 mg of 5a-reductase inhibitor/animal/ day s.c., n = 5-10/group) . Treatment with TP led to a great increase in the weights of the accessory sex glands (prostate and seminal vesicle) . In animals treated with the vehicle and with 5a-reductase inhibitor on its own, the weights of the organs investigated remain at low values. It was found that the substances according to the invention exerted inhibitory effects in the test systems selected. Table XX shows that the compounds J 1879 and J 1924 ........ markedly reduce the effects of TP on prostate and seminal vesicle. Table: Inhibition of the action of testosterone propionate (TP) on the growth of seminal vesicle and prostate. Test on sexually immature castrated male rats, n = 5-10/group, dose: TP 0.1 mg/animal/day s.c., 5a-reductase inhibitor: 1 mg/animal/day s.c. Difference between vehicle and TP controls = 100%. (Figure Remove) The investigations for the determination of the values for the 5a-reductase by the steroids J 1879 and J 1924 outside the genital tract were carried out in 4 different human bones cell lines (hOB cells) . The cells were incubated for 6 hours in each case with 0.5 uM of androstenedione (0.1 uM of [3H] androstenedione, 0.4 uM of androstenedione) with or without the addition of increasing concentrations of the inhibitors (10'11 -10"8 M) . After the incubation, the medium was extracted with chloroform:methanol (2:1; vol:vol) and the steroids (substrate and Sa-reduced metabolites) were separated by thin-layer chromatography and the DNA content of the cells of the samples was determined. The 5a-reductase activity (sum of the Sa-reduced metabolites formed: 5a-androstanedione, 5a-dihydrotestosterone, 5a-andro-stane-3a, 17p-diol, 5a-androstane-3(3,17p-diol expressed in pmol/ug of DNA/h) was in each case determined in duplicate samples. The relative 5a-reductase activity (5a-reductase activity of the samples with addition of the inhibitors in comparison to the corresponding values of the controls, i.e. the samples without addition of inhibitors) is in each case plotted in the figure as mean value ± SEM. The IC50 values of J1879 and J1924 for the 5a-reductase in bone cells are in each case In the course of the investigations for the determination of the IC50 values of J1879 and J1924, for comparison purposes, the inhibitory action of LY 191704, a non-steroidal specific inhibitor of the 5a-reductase of type 1, finasteride, a 4-azasteroid having mainly inhibitory action on the 5a-reductase of type 2, and progesterone, a physiological substrate of the 5a-reductase, was additionally determined in all 4 cell lines at a concentration of in each case 10~8 M. Figure .... shows that the substances according to the invention inhibit the 5a-reductase in the cell types investigated more strongly and in significantly lower concentrations than the natural substrates and reference substances mentioned. The invention is illustrated in greater detail by the following examples. Example 1 E-17-Chloromethylene-4-aza-5a-androstan-3-one 59 ml of formic acid (85% strength) and 115.8 mmol (16 g) of potassium carbonate are added with stirring to a solution of 3.1 mmol (1.0 g) of E-17-chloro-methylene-4-aza-5a-androst-5-en-3-one in 140 ml of dime thy Iformamide and the reaction mixture is heated under reflux for 8 hours. The reaction solution is subsequently treated with toluene and concentrated in vacuo. The residue is taken up in water and extracted with methylene chloride. The combined extracts are treated with saturated sodium carbonate solution, washed neutral with water, dried over sodium sulphate and concentrated. The resulting crude product is recrystallized from acetone/n-hexane and 543 mg of solid product (54%) are obtained M.p. = 148-151°C; [oc]D20 = +16° (CHC13) Example 2 E-17-Chloromethylene-4-methyl-4-aza-5a-androstan-3-one 3.08 mmol (123 mg) of sodium hydride (60% strength in oil) are added at room temperature and under an argon atmosphere to a suspension of 1.06 mmol (340 mg) of E-17-chloromethylene-4-aza-5a-androstan-3-one in 9 ml of dimethylformamide. The reaction mixture is stirred for 30 minutes and a solution of 5.3 mmol (0.33 ml) of methyl iodide in 3.0 ml of dimethylformamide is subsequently added dropwise. After about 60 minutes, 2 ml of methanol and, after a further 10 minutes, 9 ml of saturated aqueous ammonium chloride solution are added. The reaction mixture is diluted with water and extracted with toluene. The combined extracts are washed with water, dried over sodium sulphate and concentrated. The resulting crude product is recrystallized from acetone/n-hexane and 154 mg of solid product (43%) are obtained M.p. = 150-162°C; [a]D2° = -7° (CHC13) Example 3 E-17-Chloromethylene-4-aza-5a-androst-l-en-3-one 1.34 mmol (430 mg) of E-17-chloromethylene-4-aza-5a-androstan-3-one are suspended in 9 ml of dioxane at room temperature under an argon atmosphere and 1.5 mmol (340 mg) of 2,3-dichloro-5,6-dicyano-p-benzoquinone and 6.4 mmol (1.7 ml) of bis(trimethylsilyl)trifluoro-acetamide are subsequently added. The mixture is first stirred for 3 hours at room temperature and subsequently for 3 hours in an oil bath at about 100-110°C. The reaction solution is diluted with methylene chloride and subsequently washed with 2% strength aqueous sodium hydrogensulphite solution, 2N hydrochloric acid and water. The remaining extract is dried over sodium sulphate and concentrated. After recrystallization from acetone, 243 mg of solid product (57%) are obtained M.p. = 275-282°C; [a]D20 = -41° (CHC13) Example 4 E-17-Chloromethylene-4-methyl-4-aza-5a-androst-l-en-3-one 2.4 mmol (98 mg) of sodium hydride (60% strength in oil) are added at room temperature and under an argon atmosphere to a suspension of 0.87 mmol (279 mg) of E-17-chloromethylene-4-aza-5a-androst-l-en-3-one in 7 ml of dimethylformamide. The reaction mixture is stirred for 30 minutes and a solution of 7.5 mmol (0.47 ml) of methyl iodide in 3 ml of dime thyIformamide is subsequently added dropwise. After about 60 minutes, 2 ml of methanol and, after a further 10 minutes, 9 ml of saturated aqueous ammonium chloride solution are added. After dilution of the reaction mixture with water, it is extracted with toluene, and the extract is washed with water, dried over sodium sulphate and concentrated. The resulting crude product is recrystallized from ethyl acetate and 122 mg of solid product (42%) are obtained M.p. = 160-165°C; [a]D20 = -47° (CHC13) Example 5 E-17-Chloromethylene-4-aza-5a-estran-3-one 73.3 ml of formic acid (85% strength) and 121.55 mmol (16.8 g) of potassium carbonate are added with stirring to a suspension of 3.27 mmol (1 g) of E-17-chloro-methylene-4-azaestr-5-en-3-one in 150 ml of dimethyl-formamide and the reaction mixture is heated under reflux for 12 hours. The reaction solution is subsequently treated with toluene and concentrated in vacuo. The residue is taken up in water and extracted with methylene chloride. The combined extracts are treated with saturated sodium carbonate solution, washed neutral with water, dried over sodium sulphate and concentrated. The resulting crude product is recrystallized from acetone/n-hexane and 461 mg of solid product (46%) are obtained M.p. = (178-200) 262-82°C; [a]D20 = -21° (CHC13) Example 6 E-17-Chloromethylene-4-methyl-4-aza-5a-estran-3-one 1.7 mmol (73 mg) of sodium hydride (60% strength in oil) are added at room temperature and under an argon atmosphere to a suspension of 0.65 mmol (200 mg) of E-17-chloromethylene-4-aza-5a-estran-3-one in 5.8 ml of dimethylformamide. The reaction mixture is stirred for 30 minutes and a solution of 3.2 mmol (0.2 ml) of methyl iodide in 2 ml of dimethyl formamide is subsequently added dropwise. After about 60 minutes, 1 ml of methanol and, after a further 10 minutes, 4 ml of saturated aqueous ammonium chloride solution are added. The reaction mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulphate and concentrated. The resulting crude product is purified by chromatography on silica gel 60 (eluent methylene chloride/acetone = 8/2) and, after recrystallization from ethyl acetate, 131 rag of solid product (62%) are obtained M.p. = 161-171°C; [a]D20 = -88° (CHC13) Example 7 E-17-Chloromethylene-4-aza-5a-estr-l-en-3-one 1 mmol (310 mg) of E-17-chloromethylene-4-aza-5a-estran-3-one are suspended in 6.3 ml of dioxane at room temperature under an argon atmosphere and 2.3 mmol (522 mg) of 2,3-dichloro-5,6-dicyano-p-benzoquinone and 9.8 mmol (2.6 ml) of bis(trimethylsilyl)trifluoro- acetamide are subsequently added. The mixture is first stirred at room temperature for 3 hours and subsequently for 15 hours in an oil bath at 100-110°C. The reaction solution is diluted with methylene chloride and washed successively with 2% strength aqueous sodium hydrogensulphite solution, 2N hydro- chloric acid and water. The remaining extract is dried over sodium sulphate and concentrated. After purification by chromatography on silica gel 60 (eluent methylene chloride/methanol = 98/2), 57 mg of solid product (18.5%) are obtained [a]D20 = 37° (CHC13) We Claim: 1. Halogen-substituted and pseudohalogen-substituted 17-methylen-4-azasteroids of general formula I (Formula Removed) wherein R20 and R20a seperately denote fluoro-, chloro-, bromo-, azido-, rhodano-, C1-C4-alkyl or hydroxy-C1-C4-alkyl, R10 denotes a hydrogen atom or methyl group, R4 is selected from the group consisting of hydrogen and a C1- C4-alkyl group and R1 and R2 together denote a hydrogen atom or an additional bond. 2. Halogen-substituted and pseudohalogen-substituted 17-methylen-4-azasteroids as claimed in claim 1 wherein R4 = H, Me R20 and R20a separately = F, CI, Br. 3. 17-methylen-4-azasteroids as claimed in claim 1, namely E-17-chloromethylene-4-aza-5α-estra n-3-one, E-17-chloromethylene-4-aza-5α-androstan-3 -one, E-17 -chloromethylene-4-methyl-4-aza-5α-estran-3 -one, E-17 -chloromethylene-4-methyl-4-aza-5α-androstan-3-one, E-17-chloromethylene-4-aza-5α-estr-1 -en-3-one, E-l 7-chloromethylene-4-aza-5α-androst-l -en-3-one, E-17-chloromethylene-4-methyl-4-aza-5α-androst-1 -en-3 -one, E-17 -bromomethylene-4-methyl-4-aza-5α-estran-3 -one, E-l7 -cyanomethylene-4-methyl-4-aza-5 α-estran-3-one, Z-17-(1')-chloroethylidene-4-methyl-4-aza-5α-androstan-3-one, Z-l 7-(1')-chloroethylidene-4-methyl-4-aza-5α-estran-3-one, Z-17-(1')-bromoethylidene-4-methyl-4-a2a-5α-androstan-3-one, Z-l 7 -(1')-bromoethyliden-4-methyl-4-aza-5α-estran -3-one. 4. Pharmaceutical compositions containing at least one 7-methylene-4-azasteroid as claimed in claim 1, optionally together with pharmaceutically compatible auxiliary agents and carriers.

Documents:

1249-DELNP-2005-Abstract-(17-02-2010).pdf

1249-delnp-2005-abstract.pdf

1249-DELNP-2005-Claims-(17-02-2010).pdf

1249-delnp-2005-claims.pdf

1249-DELNP-2005-Correspondence-Others (17-02-2010).pdf

1249-delnp-2005-Correspondence-Others-(09-03-2010).pdf

1249-DELNP-2005-Correspondence-Others-(25-02-2010).pdf

1249-delnp-2005-correspondence-others.pdf

1249-delnp-2005-correspondence-po.pdf

1249-delnp-2005-description (complete).pdf

1249-delnp-2005-drawings.pdf

1249-DELNP-2005-Form-1-(17-02-2010).pdf

1249-DELNP-2005-Form-1-(25-02-2010).pdf

1249-delnp-2005-form-1.pdf

1249-delnp-2005-form-18.pdf

1249-delnp-2005-form-2.pdf

1249-delnp-2005-form-24.pdf

1249-DELNP-2005-Form-3-(17-02-2010).pdf

1249-DELNP-2005-Form-3-(25-02-2010).pdf

1249-delnp-2005-form-3.pdf

1249-DELNP-2005-Form-5-(25-02-2010).pdf

1249-delnp-2005-form-5.pdf

1249-DELNP-2005-GPA-(17-02-2010).pdf

1249-delnp-2005-gpa.pdf

1249-delnp-2005-pct-210.pdf

1249-delnp-2005-pct-301.pdf

1249-delnp-2005-pct-304.pdf

1249-delnp-2005-pct-306.pdf

1249-DELNP-2005-Petition 137-(17-02-2010).pdf

1249-delnp-2005-petition-others.pdf