MXPA99007466A - Process for preparing carboxamido-4-azasteroids - Google Patents

Abstract

A process for producing a compound of formula (I) wherein the dotted lines --- independently represent a single or double bond and R, R1, R2 and R3 are each hydrogen or an organic radical, comprises treating the corresponding 17&bgr;-carbonylimidazole intermediates with anhydrous acids in the presence of an amine and, optionally, hydrogenating the resulting compound.

Description

PROCESS FOR PREPARING CARB0XAMID0- -AZASTEROIDE S FIELD OF THE INVENTION The present invention relates to a process for preparing carboxamido-4-aα-asteroids and, more particularly, refers to a process for preparing 17β-carboxamido-4-aoids teroids, starting from the corresponding 17β-carbonylimidazole derivatives .

BACKGROUND OF THE INVENTION The teroid carboxamido acids, such as, for example, the 17 β-carboxamides do-4-az a-5a-andros t-3-ones and the andros, tenones or andros t adi enonas, unsaturated, related derivatives are compounds known in the art to be endowed with pharmacological activity, ie of an inhibitory activity of testosterone 5a-r eductase, and are thus useful in therapy, in the treatment of hyperandrogenic conditions. For a general reference to the pharmacological activity of these compounds see, REF. : 30826 for example, EP-A-0271220, WO 94/03475 and Current Pharmaceutical Design, 1996, 2, 59-84. Various processes for preparing the carboxamido-4-aoids, teroids, are known in the literature. For example, as reported in the international patent application WO 94/03475 in the name of the applicant, the 17β-carboxamido-4-azasteroids are prepared by reacting an appropriately activated 17β-carboxy-4-azasteroid with a suitable amine . Appropriately activated carboxy groups, which form amide bonds, include, for example, acyl chlorides, thioesters, hydroxybenzotr azol esters, mixed anhydrides and 1-imidazole derivatives. Although they are suitable for forming amide bonds, most of these activating groups can not be used to prepare the carboxamido-4-azas t ero ides because they react with the N atom of the azasteroid moiety or, if present, with the double bond found at position 5,6 of the andro s t-5-ene or androsta-1,5-diene moieties or, alternatively, because they are not reactive towards the selected amine. Therefore, for the purpose of finding a synthesis approach to prepare 17β-carboxamido-4-azo-asteroids, through the condensation of an amine with a 17β-carboxy-4-azas activated teroid, that activated group being not Reactive towards other functional groups present in the molecule, it was observed that the imidazolide derivatives could be used successfully. However, the hindered amines are thermally or little nucleophilic, and hence poorly reactive, do not react at all with the 17β-carbonyl imidazole-aroids or, alternatively, allowed to prepare the expected amides with yields even lower than 20% . For example, as reported by A. Bhattacharya et al, in Synthetic Communications, 30 (17), 2683-2690 (1990), the direct condensation of 3-oxo-4-azandrosros t-1-en-17 ß-aci 1 imi daz ol, with tert -but i 1 amine, to obtain the corresponding amide, was not successful, even under extreme reaction conditions. Likewise, in order to prepare fluorinated amides, the condensation between 3-oxo-4-aza-androst-5-en-17β-carbonyl imidazole and the fluorinated amine did not allow obtaining the corresponding amide, even working under drastic conditions , that is, under pressure in an autoclave. EP-A-0367502, in the name of Merck & Co., Inc., describes a process for preparing 3-oxo-4-aoids, including the 17β-carboxamido derivatives, by reacting the corresponding intermediate 17B-carbonyl imidazole, with a suitable amine, in the presence of a Grignard reagent. However, it is well known to the person skilled in the art that when Grignard reagents are used, particularly on an industrial scale, severe precautions are required to avoid the risks of dangerous reactions. Therefore, although it provides the desired amide with high yields, the industrial application of the aforementioned process could present some notorious drawbacks. further, the same methodology failed to achieve fluorinated 17β-carboxamides with acceptable yields and purity. In this respect it has surprisingly been found that the aforementioned imidazolide derivatives could unexpectedly be converted to the desired amide under mild conditions in the presence of acids. Therefore, the object of the present invention is a process for preparing the compounds of formula where the dotted lines, independently of each other, represent a single or double bond; R and Ri, the same or different, represent a hydrogen atom or an alkyl, phenylalkyl, alkylphenyl or alkyl phenylalkyl group, of 1 to 6 carbon atoms, straight or branched chain, wherein the alkyl groups are substituted by one or more fluorine atoms; R2 is a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, optionally substituted by one or more fluorine atoms; R3, whenever present, is a hydrogen atom; with the proviso that at least one of R and Ri contains one or more fluorine atoms and that when the dotted line, at position 5, 6, represents a double bond, R3 is absent; which comprises reacting an imidazolide derivative of formula 'where the dotted lines, R2 and R3 have the meanings reported above; with an anhydrous acid, in the presence of an amine of formula where R and Ri have the meanings reported above; and, if desired, hydrogenating the resulting compound of formula (I) wherein one of both dotted lines represents a double bond. The objective process of the present invention makes it possible to prepare the compounds of formula (I) under mild conditions and, even more importantly, makes it possible to obtain compounds of formula (I) from sparingly reactive amines, such as amines which are poorly soluble. and / or spherically prevented, for example, fluorinated amines and even voluminous fluorinated amines. In the present description, unless otherwise specified, with the term alkyl group of 1 to 4 carbon atoms or 1 to 6 carbon atoms, straight or branched chain, reference is made to methyl, ethyl, n -propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and imides. With the term phenylalkyl, alkylphenyl or alkyl phenyl group to which, from 1 to 6 carbon atoms, straight or branched chain, reference is made to a phenyl group linked to an alkyl portion of 1 to 6 carbon atoms, straight or branched chain, as indicated above. By the term "anhydrous acid" it is conventionally referred to an acid with a very low water content, wherein the acid is a mineral acid, a strong organic acid or a Lewis acid. Examples of strong mineral acids or organic acids are hydrogen chloride, hydrogen bromide, sulfuric acid, metronomical acid, p-toluenesulfonic acid, triflic acid, camphor-phonic acid, or the like. Examples of Lewis acids are, for example, zinc chloride, zinc bromide, aluminum chloride, aluminum bromide, ferric chloride, ferric bromide or the like. For a general reference to those acids and, in particular, to Lewis acids see, for example, J. March, Advanced Organic Chemistry, IV edition, 1992, John Wiley & Sons, Chapter VIII, pages 248-272. In the formulas (I-II) above, the dashed line Í '""' > which is in position 5 indicates a substituent in the a configuration, ie below the plane of the ring, and the coined lines in position 10, 13 and 17 (-1) indicate a substituent in the β-configuration , that is, above the plane of the ring. Preferred compounds, prepared according to the process of the present invention, are the compounds of formula (I) wherein one of R and Ri is a hydrogen atom and the other is an alkyl, phenylalkyl or alkyl phenylalkyl group, straight or branched chain, substituted by at least one fluorine atom in the alkyl portion. Even more preferred compounds, in this class, are the compounds of formula (I) wherein these alkyl groups are perfluoroalkyl groups of 1 to 3 carbon atoms, such as for example the trifluoromethyl, 1,1,1-trifluoroethyl groups, 1,1,1,3,3,3-hexafluoropropyl. The process according to the present invention is preferably carried out to prepare one of the following 17β-carboxamido-4-azasteroids: 1) N- (1, 1, 1, 3, 3, 3-hexafluoro-2-phenylprop-2-yl) -3-oxo-4-aza-5a-andros t-1-ene-17β-carboxamide; 2) N- (1, 1, 1, 3, 3, 3-hexafluoro-2-phenylprop-2-yl) 3-oxo-4-aza-5a-androstan-17β-carboxamide; 3) N- (1, 1, 1, 3,3,3-hexafluoro-2-phenylprop-2-yl) 3-oxo-4-azaandrost-1, 5-diene-17β-carboxamide; 4) N- (1, 1, 1, 3, 3, 3-hexaf luoro-2-phene Iprop-2-yl) 3-oxo-4-azaandrost-5-en-17β-carboxamide; ) N- [1, 1, 1, 3,3,3-hexafluoro-2- (p-methyl-phenyl-prop-2-yl] -3-oxo-4-aza-5 -androst-1-en- 17β-carboxamide; 6) N- [1, 1, 1, 3, 3, 3-hexafluoro-2- (p-methylphenyl) prop-2-yl] -3-oxo-4-aza-5a-androstan-17β-carboxamide; 7) N- [1, 1, 1, 3, 3, 3 -hexa fluoro-2 - (p-me ti 1 f eni 1) prop-2-yl] -3-oxo-4-azaandrost-1, 5 -diene-17β-carbo amide; 8) N- [1, 1, 3, 3, 3-hexafluoro-2- (p-methylphenyl) prop-2-yl] -3-oxo-4-azaandrost-5-en-17β-carboxy-ida; 9) N- (1,1,1-trifluoro-2-phenylprop-2-yl) -3-oxo-4-aza-5a-androst-1-en-17β-carboxamide; ) N- (1,1,1-trifluoro-2-phenylprop-2-yl) -3-oxo-4-aza-5a-androstan-17β-carboxamide; 11) N- (1,1-l-trifluoro-2-phenylprop-2-yl) -3 -oxo-4-azaandrost-1, 5-diene-17β-carboxamide; 12) N- (1,1-l-trifluoro-2-phenylprop-2-yl) -3-oxo-4-azaandrost-5-en-17β-carboxamide; 13) N- [1,1-l-trifluoro-2- (p-methylphenyl) prop-2-yl] -3-oxo-4-aza-5a-androst-1-en-17β-carboxamide; 14) N- [1,1-l-trifluoro-2- (p-methylphenyl) prop-2-yl] -3-oxo-4-aza-5a-androstan-17β-carboxamide; ) N- [1,1-l-trifluoro-2- (p-methylphenyl) prop-2-yl] -3-oxo-4-azaandrost-1, 5-diene-17β-carboamide; 16) N- [1,1-l-trifluoro-2- (p-methylphenyl) prop-2'-yl] -3-oxo-4-azaandrost-5-en-l-7-carboxamide.

The process according to the present invention is carried out by reacting a 17β-carbonyl 1-imide z-ol derivative of formula (II) with an anhydrous acid, in the presence of an amine of formula (III), under an atmosphere inert. As stated above, examples of acids are, for example, gaseous hydrogen chloride or hydrogen bromide, also gaseous, as well as sulfuric acid, methylenic acid, triflic acid, p-to luensul acid. phonyl, phonyl camphoric acid, or Lewis acids such as zinc chloride, zinc bromide, aluminum chloride, aluminum bromide, ferric chloride or ferric bromide. Preferably, these acids are mineral acids or strong, gaseous organic acids. The most preferred acids are even the most acidic acid or hydrogen chloride. These acids are used at least in equimolar quantities or, preferably, in a molar ratio of imidazolide derivative: acid = 1: 2. Higher acid surpluses are equally effective but are not useful. The reaction is carried out by adding the selected acid to a solution of the imidazolide derivative of formula (II) and of the amine of formula (III) in a suitable solvent, at a temperature ranging from room temperature to the reflux temperature of The reaction mixture, for a time that varied from 1 hour to 12 hours. Preferably, a reaction temperature between 40 ° C and 70 ° C is selected. Suitable solvents are chlorinated hydrocarbons having from 1 to 3 carbon atoms, such as, for example, methylene chloride, chloroform or 1,2-diol chloroethane, as well as acetonitrile, tetrahydrofuran or optionally substituted aromatic hydrocarbons such as Examples are toluene, fluorobenzene, a, a, tri-tri-fluorotoluene, and the like. Preferably the process of the present invention is carried out starting from the imidazolide derivatives of formula (II) which contain a single double bond at the 5,6 position of the spheroid portion. The imidazolide derivatives of formula (II) above, wherein the dotted line in position 1,2 represents a single bond, and the dotted line which is in position 5,6 represents a double bond, are new and represent a further object of the present invention. In an additional variant of the process, the imidazolide derivative of formula (II), dissolved in the solvents mentioned above, is first reacted with the anhydrous acid. The supposed addition salt of the imidazolide derivative of formula (II) is then reacted in itself, and hence without the need to be isolated and purified additionally, with a suitable amine of formula (III) in order to obtain the expected 17 ß-carboxyamides of formula (I). This reaction is carried out by directly mixing the salt and the appropriate amine in the same reaction system, at a temperature between room temperature and the reflux temperature of the reaction mixture, for a time ranging from 1 hour to 12 hours. hours . Preferably, a reaction temperature between 40 ° C and 70 ° C is selected. The compounds of formula (I) are thus obtained in good yields and are easily recovered and purified, according to conventional methods. The initial formula materials (II) are prepared according to conventional methods by reacting the corresponding carboxylic acid, optionally in the activated form, with an imidazole derivative, such as, for example, the carbonyl-di imidazole, the oxalyl-diimidazole or the sulphonyl 1- di imidazol. For a general reference regarding the preparation of the compounds of formula (II) see, for example, WO 94/03475 and EP-A-0367502, mentioned above. The novel derivatives of 4-azaandros t-5-en-17β-carboni-1-imidazole, of formula (II), are prepared as indicated above, by reacting a 3 -oxo-4-acid to zandros t-5-en- 17β-carboxy 1 formula wherein R2 represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms optionally substituted by one or more fluorine atoms; with carboni 1 -di imide zo 1, sulfonyl-diimidazole or oxalyl-diimidazole, in accordance with what is reported in the literature (see, for example, Angew, Chem. 1962, 74_, 407). For reference as to the preparation of the carboxylic acid derivatives of formula (IV) see, for example, the process described in WO 90/15045 in the name of Upj ohn & Co. Also, the amines of formula (III) are known or readily prepared according to known methods as reported, for example, in WO 94/03475 mentioned above. Starting from the appropriate derivative of formula (II) having one, two or no double bonds in the spheroid portion, the corresponding carboxamido- 4-a z e t eroi of formula (I) is thus obtained. It is clear to this point, for the person skilled in the art, that through the hydrogenation of a compound of formula (I) having one or two double bonds, according to the present invention, the corresponding saturated compounds of the present invention are obtained. Formula (I) where both dotted lines represent a simple link.

The aforementioned hydrogenation step is carried out in accordance with conventional techniques. As an example, the hydrogenation can be carried out in a suitable solvent such as methanol, ethanol, or acetic acid, in the presence of about 10 ° to 30 or conventional hydrogenation catalysts, such as for example, the catalysts based on palladium, platinum or rhodium, under a hydrogenation pressure of approximately 3 to 7 atmospheres, at a temperature between room temperature and 50 ° C, for a time ranging from half an hour to 18 hours. In a preferred embodiment of the present invention, a compound of formula (I) such as, for example, N- (1,1,1,3,3,3-hexafluoro-2-phenylprop-2-yl) -3- oxo-4-aza-5a-andros tan-17β-carboxamide, as a useful therapeutic agent, is prepared by reacting a t-5-en-17β-carboxylic acid 3-oxo-azandros derivative of formula (IV ), in a suitable solvent such as dimethylformamide, with an appropriate amount of 1,1 '-carbonyl-1-diimidazole.

The reaction mixture is kept under stirring at a temperature of 60 ° C for a period of 4 hours. The 3-oxo-4-azole t-5-en-17β-carboni-1-imidaz ol of formula (II), thus prepared, mixed with an appropriate amount of 1, 1, 3, 3, 3-hexafluoro -2-phenylprop-2-yl-amine of formula (III), is then treated slowly under nitrogen, at 60 ° C, and under good agitation, with an appropriate amount of an anhydrous strong acid such as me tansul acid anhydrous coon The reaction mixture is maintained at 60 ° C for 6 hours, with stirring. The N- (1, 1, 1, 3, 3, 3-hexafluoro-2-phenylprop-2-yl) -3-oxo-4-azaandrost-5-en-17β-carboxamide, thus obtained, of formula. { I), isolated and purified according to conventional techniques, is then hydrogenated catalytically, for example in a Parr apparatus, or in an autoclave, in the presence of catalytic amounts of 5% Pt on carbon, to obtain the N- (1, 1, 1, 3, 3, 3-hexaf luoro-2-phenylprop-2-yl) -3-oxo-4-aza-5a-androstan-17β-carboxamide of formula (I). The objective process of the present invention provides a synthetic route, very advantageous, to prepare derivatives of 17β-carboxamido-4- azas teroide, with good yields and under mild operating conditions, starting from known compounds or that are prepared easily, and even without the need to isolate the intermediates of the reaction . In addition, it makes it possible to prepare amides from spherically hindered amines and / or amines which are poorly reactive and hence poorly reactive. In order to better illustrate the present invention, without limiting it, the following examples are now presented.

Example 1 Preparation of 3-oxo-4-azaandrost-5-en-17β-carboni 1-1 -imi dazol 1,1-Carbonyldi imidazole was added (70.5 g, 0.435 mol) to a vigorously stirred suspension of 3-oxo-4-azaandrost-5-en-17β-carboxylic acid (115 g, 0.362 mol) in N, N-dimeti 1 formami da (1.44 L). The mixture was heated to 60 ° C for 4 hours and a precipitate formed. The reaction mixture was concentrated under vacuum with ethyl acetate; the precipitate was filtered, washed with ethyl acetate and dried under vacuum at 40 ° C to produce 3-oxo-4-azaandrost-5-en-17β-carbonyl-1-imidazole (116.7 g) as a solid of color pale yellow . Repeating the same treatment to the mother liquors, a second collection of the compound (7.23 g) was obtained. The total yield was 93.07% (p.f. 284-288 ° C with decomposition, purity greater than 98 ° through HPLC analysis). NMR (CDC13) d (ppm): 8.18 (s, H, H (2 ')), 8.10 (broad s, H, NH ()), 7.60 (s, H, H (5')), 7.10 ( s, ÍH, H (4 ')), 4.81 (, 1H, H (6)), 1.11 (s, 3H, Me (19)), 0.78 (s, 3H, Me (18)). 2 Preparation of N- (1,1,1,3,3-hexafluoro-2-phenylprop-2-yl) -3-oxo-4-azaandrost-5-en-17β-carboxamide 3-OXO- -az aandros t-5-en-17β-carbonyl-1-imidazole (29.05 g, 79.05 mmol) was dissolved in chloroform (174 L) under nitrogen atmosphere at room temperature. To the foregoing, 1, 1, 1, 3, 3, 3-hexafluoro-2-phenylprop-2-ylamine (38.45 g, 158.11 mmol) was added in one portion. The temperature of the reaction mixture was raised to 60 [deg.] C. and, under vigorous stirring, phosonic acid was added dropwise. (0.26 mL, 58.11 mmol). The mixture was stirred 60 ° C for 6 hours under nitrogen atmosphere and then cooled to room temperature, washed thoroughly with 0.5 N NaOH solution (300 mL + 250 m), with brine and dried over anhydrous sodium sulfate. After evaporating the solvent under vacuum, a yellowish solid (51.56 g) was obtained. The crude product was purified by treatment with refluxing ethyl acetate, by concentration and precipitation by the addition of ether t-butyl ether to produce, after filtration with suction and drying at 40 ° C under vacuum , N- (1, 1, 1, 3, 3, 3-hexafluoro-2-f-enylprop-2-yl) -3-oxo-4-azaandrost-5-en-17β-carboxamide (20.38 g, mp 251- 253 ° C with decomposition, purity: 99.11% by HPLC analysis). From the mother liquors, by means of an analogous treatment, a second collection of the compound was obtained (9.20 g, purity: 98% through HPLC analysis), raising the total yield up to 69%. NMR (CDC13) d (ppm): 7.60-.37 (, 6H, Fen. + NH (4)), 5.83 (s, 1H, NH (21)), 4.81 (m, 1H, H (6)), 1.11 (s, 3H, Me (19)), 0.76 (s, 3H, Me (18)). 3 Preparation of N- (1, 1, 1, 3, 3, 3-hexaf luoro-2-phenylprop-2-yl) -3-oxo-4-aa-5a-andros tan-17β-carboxamide A solution of N- (1,1,1,3,3,3-hexafluoro-2-phenylprop-2-yl) -3-oxo-4-azaandros t-5-en-l-7β-carboxamide was hydrogenated (23.04 g; 42.46 mmol) in glacial acetic acid (460 mL), in an autoclave, in the presence of 5% palladium on carbon (23.0 g), under a pressure of 7 bar of hydrogen at 50 ° C. The mixture was cooled to room temperature, the catalyst was filtered off and the filtrate was poured into water (3 L) X After neutralization with 15% of NaOH, the solid was collected by suction filtration, washed thoroughly with water and dried at 50 ° C under vacuum. N- (1,1,1,3,3,3-hexafluoro-2-phenylprop-2-yl) -3-oxo-4-aza-5a-androstan-17β-carboxamide was obtained (21.36 g; yield: 91.95%) as a white solid (mp 254-258 ° C with decomposition).

NMR (CDCl 3) d (ppm): 7.50-7.30 (m, 5H, Fen), 5.88 (broad s, H, NH (21)), 5.42 (broad s, H, NH (4)), 3.08 (dd, 1H, H (5a)), 2.42 (m, 2H, CH2 (2)), 0.90 (s, 3H, Me (19)), 0.76 (s, 3H, Me (18)).

Example 4 Preparation of 3 -oxo-az a-5a-andros t-1-en-17β-carbon i 1 - 1 -i i da zo 1 1, 1 '-carboni 1 imide zol (2.00 g, 12.36 mmol) and 3 -oxo-4-az a-5a-androst-1-en-17β-carboxylic acid (3.14 g, 9.89 mmol), in N, were suspended. , N '-dimet i 1 formamide (37 mL) under argon. The mixture was heated to 65 ° C for 4 hours. The solid dissolved initially and then a new precipitate formed. After cooling, the solvent was evaporated under vacuum and the resulting thick slurry was diluted with methyl tert-butyl ether. After storage at a temperature of +4 ° C, for 48 hours, the solid was filtered by suction filtration, washed with methyl tert-butyl ether and dried at a temperature of 50 ° C, under vacuum. 2.97 g (81.8%) of a light brown solid was obtained. NMR (CDC13) d (ppm): 8.43 (s, 1H, H (2 ')), 7.71. (s, 1H, H (5 ')), 7.40 (broad s, 1H, NH (4)), 7.05 (s, 1H, H (4')), 6.77 (d, ÍH, H (l)) , 5.57 (dd, 1H, H (2)), 3.42 (t, 1H, H (17)), 3.17 (dd, ÍH, H (5)), 0.82 (s, 3H, Me (19)), 0.63 (s, 3H, Me (18)).

Preparation of N- (1, 1, 1, 3, 3, 3-hexaf luoro-2-phenylprop-2-yl) -3-o or-4-aza-5a-andros t-1-en'- 17β -carboxamide To one. suspension of 3-oxo-4-aza-5-andros tl-en-17β-carboni 1- 1-imidazole (2.97 g, 8.08 mmol) in chloroform (17.8 mL) was added, under argon, 1, 1, 1, 3, 3, 3-hexaf luoro-2-phenylprop-2-yl-amine (hexa f luoro cumi lami na) (3.93 g, 16.16 mmol). The temperature was raised to 50 ° C and methanesulfonic acid (1.05 mL, 16.16 mmol) was added dropwise; then the light brown mixture was stirred for 7.5 hours at 60 ° C. After cooling to room temperature, the suspension was filtered on a Gooch funnel and the panel was washed with methylene chloride (10 mL); the clear filtrate was evaporated to dryness, under vacuum, dissolved in tetrahydrofuran (16 L) and treated with 2M NaOH solution, under good agitation, for 1 hour. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (3 x 25 mL). The collected organic extracts were washed with 0.5 M NaOH solution (20 mL), dried over sodium sulfate and the solvent was evaporated under vacuum to yield 5.63 g of the crude product. The crude product was purified by crystallization from ethyl acetate and methyl ether, dried in a furnace a 50 ° C for several hours, to produce 2.69 g (61.4%) of the pure white solid compound (m.p. 218-222 ° C). NMR (CDC13) d (ppm): 7.38-7.54 (, 5H, Fen.), 6.79 (d, 1H, H (l)), 5.89 (s, 1H (21)), 5.82 (dd, 2H, H (2)), 5.39 (s, 1H, NH (4)), 3.33 (dd, ÍH, H (5a)), 0.98 (s, 3H, Me (19)), 0.76 (s, 3H, Me (18)). MS (FAB-) (m / z): 5 4 1 [M-H], 4 7 1 [M-CH F 3] ~.

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

Claims (9)

1. A process to produce a compound of formula where dotted lines, independently of one another, represent a single or double bond; R and Ri, the same or different, represent a hydrogen atom or an alkyl, phenylalkyl, alkylphenyl or alkyl phenylalkyl group, of 1 to 6 carbon atoms, straight or branched chain, wherein the alkyl groups are substituted by one or more fluorine atoms; R2 is a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, optionally substituted by one or more fluorine atoms; R3, whenever present, is a hydrogen atom; with the proviso that at least one of R and Ri contains one or more fluorine atoms and that when the dotted line, at position 5,6, represents a double bond, R3 is absent; which process is characterized in that it comprises reacting an imidazolide derivative of formula wherein the dotted lines, R2 and R3, are defined as above, with an anhydrous acid in the presence of an amine of formula HNR) R3 (III wherein R and Ri are as defined above, and, if desired, hydrogenate a resulting compound of formula (I) wherein one or both of the dotted lines represent a double bond.

2. A process according to claim 1, characterized in that the anhydrous acid is selected from mineral acids, strong organic acids and Lewis acids.

3. A process according to claim 1 or 2, characterized in that the anhydrous acid is methanesulphonic acid or hydrogen chloride.

4. A process according to claim 1, characterized in that in the formula (I) one of R and Ri is hydrogen and the other is an alkyl, phenylalkyl or alkyl phenyl lalkyl group of 1 to 4 carbon atoms, straight or branched chain , substituted by at least one fluorine atom in the alkyl portion.

A process according to claim 1, characterized in that in formula (II), the dotted line in position 1,2 represents a single bond, and the dotted line in position 5,6 represents a double bond .

6. A process according to claim 1, characterized in that the compound of formula (I) is selected from: N- (1, 1, 1, 3, 3, 3-hexafluoro-2-phenylprop-2-yl) -3-oxo-4-aza-5a-androst-1-en-17β-carboxamide; N- (1, 1, 1, 3, 3, 3-hexafluoro-2-phenylprop-2-yl) -3'-oxo-4-aza-5a-androstan-17β-carboxamide; N- (1, 1, 1, 3,3,3-hexafluoro-2-phenylprop-2-yl) -3-oxo-4-azaandrost-1, 5-diene-7-carboxamide; N- (1, 1, 1, 3,3,3-hexafluoro-2-phenylprop-2-yl) -3-oxo-4-azaandrost-5-en-17β-carboxamide; N- [1, 1, 1, 3, 3, 3-hexafluoro-2- (p-methylphenyl) -prop-2-yl] -3-oxo-4-aza-5a-androst-1-en-17β- carboxamide; N- [1, 1, 1, 3, 3, 3-hexafluoro-2- (p-methylphenyl) -prop-2-yl] -3-oxo-4-aza-5a-androstan-17β-carboxamide; N- [1,1,1,3,3,3-hexafluoro-2- (p-methylphenyl) -prop-2-yl] -3-oxo-4-azaandrost-1, 5-diene-17β-carboxamide; N- [1, 1, 1, 3, 3, 3-hexafluoro-2- (p-methylphenyl) -prop-2-yl] -3-oxo-4-azaandrost-5-en-17β-carboxamide; N- (1,1-l-trifluoro-2-phenylprop-2-yl) -3-oxo-4-aza-5a-androst-1-en-17β-carboxamide; N- (1,1-l-trifluoro-2-phenylprop-2-yl) -3-oxo-4-aza-5a-androstan-17β-carboxamide; N- (1,1-l-trifluoro-2-phenylprop-2-yl) -3-oxo-4-azaandrost-1, 5-diene-17β-carboxamide; N- (1,1, l-trifluoro-2-phenylprop-2-yl) -3-OXO-4-azaandros t-5-en-l-7-carboxamide; N- [l, l, l-trifluoro-2- (p-methylphenyl) prop-2-yl] -3 oxo-4-aza-5a-andros t-1-en-17β-carboxamide; N- [1,1-l-trifluoro-2- (p-methylphenyl) prop-2-yl] -3-oxo-4-aza-5a-androstan-17β-carboxamide; N- [l, l, l-trifluoro-2- (p-methylphenyl) prop-2-yl] -3-oxo-4-azaandrost-1, 5-diene-l-7-carboxamide; N- [1,1-l-trifluoro-2- (p-methylphenyl) prop-2-yl] -3-oxo-4-azaandrost-5-en-l-7-carboxamide.

7. A compound characterized in that it has the formula (II): wherein R is hydrogen or an alkyl group of 1 to 4 carbon atoms, optionally substituted by one or more fluorine atoms.

8. A process for producing a compound as defined in claim 7, the process is characterized in that it comprises reacting a compound of formula wherein R2 is as defined in claim 7, with carbonyl-di imi dazole, oxalyl-diimidazole or sulfonyl-diimidazole.

9. a process to produce a compound of - "ordm (i): wherein one of R and Ri represents hydrogen, and the other is a phenylalkyl group of 1 to 4 carbon atoms, substituted by one or more fluorine atoms; and R2 is hydrogen or an alkyl group of 1 to 4 carbon atoms, optionally substituted by one or more fluorine atoms; The process is characterized in that it comprises (i) reacting a compound of formula (IV): wherein R 2 is as defined above, with carboni 1-di imidazole, oxalyl-diimidazole or sulphonyl 1-diimide 1, to obtain an imidazolide derivative of formula (II): wherein R2 is as defined above; (ii) reacting the compound of formula (II) with anhydrous methylsulfonic acid or hydrogen chloride, in the presence of an amine of formula HN (R) R: (III) wherein one of R and Ri represents a hydrogen atom and the other is a phenylalkyl group of 1 to 4 carbon atoms, substituted by one or more fluorine atoms; and (iii) hydrogenating the compound resulting from formula (I): wherein R, Ri and R2 are as defined above.