Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-06
2001-09-04
Qazi, Sabiha (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S107000, C540S108000, C540S109000, C546S077000
Reexamination Certificate
active
06284887
ABSTRACT:
The present invention refers to a process for preparing carboxamido-4-azasteroids and, more in particular, it relates to a process for preparing 17&bgr;-carboxamido-4-azasteroids starting from the corresponding 17&bgr;-carbonylimidazole derivatives.
Carboxamido-4-azasteroids such as, for instance, 17&bgr;-carboxamido-4-aza-5&agr;-androstan-3-ones and related unsaturated androstenones or androstadienones derivatives are compounds known in the art to be endowed with pharmacological activity, i.e. testosterone 5&agr;-reductase inhibitory activity, and are thus useful in therapy in the treatment of hyperandrogenic conditions.
For a general reference to the pharmacological activity of the said compounds see, for instance, EP-A-0271220, WO 94/03475 and Current Pharmaceutical Design, 1996, 2, 59-84. Several processes for preparing carboxamido-4-azasteroids are known in the literature.
For instance, as reported in the international patent application WO 94/03475 in the name of the applicant, 17&bgr;-carboxamido-4-azasteroids are prepared by reacting a properly activated 17&bgr;-carboxy-4-azasteroid with a suitable amine.
Properly activated carboxy groups forming amide bonds include, for instance, acyl chlorides, thioesters, hydroxybenzotriazole esters, mixed anhydrides and acyl-imidazole derivatives.
Although suitable to form amide bonds, most of these activating groups cannot be used to prepare carboxamido-4-azasteroids because reacting with the N-atom of the azasteroid moiety or, if present, with the double bond in position 5,6 of the androst-5-ene or androsta-1,5-diene moieties or, alternatively, because unreactive towards the selected amine.
Therefore, with the aim to find a synthetic approach for preparing 17&bgr;-carboxamido-4-azasteroids by condensing an amine with an activated 17&bgr;-carboxy-4-azasteroid, being the said activated group unreactive towards other functional groups present in the molecule, we noticed that imidazolide derivatives could be successfully used.
However, steric hindered or low nucleophilic and hence scarcely reactive amines did not react at all with 17&bgr;-carbonylimidazole-4-azasteroids or, alternatively, enabled to prepare the expected amides in yields even lower than 20%.
For instance, as reported by A. Bhattacharya et al. in Synthetic Communications, 30(17), 2683-2690 (1990), the direct condensation of 3-oxo-4-aza-androst-1-ene-17&bgr;-acylimidazole with tert-butylamine so as to get the corresponding amide was unsuccessful, even under extreme reaction conditions.
Likewise, with the aim to prepare fluorinated amides, the condensation between 3-oxo-4-aza-androst-5-ene-17&bgr;-carbonylimidazole and the fluorinated amine did not enabled us to get the corresponding amide even operating under drastic conditions, i.e. under pressure in autoclave.
EP-A-0367502, in the name of Merck & Co. Inc., discloses a process for preparing 3-oxo-4-azasteroids, among which 17&bgr;-carboxamido derivatives are comprised, by reacting the corresponding 17&bgr;-carbonylimidazole intermediate with a suitable amine in the presence of a Grignard reagent.
However, it is well-known to the man skilled in the art that when using Grignard reagents, in particular on industrial scale, severe precautions so as to avoid the risks of hazardous reactions are required.
Therefore, although affording the desired amide in high yields, the industrial application of the aforementioned process could present some remarkable drawbacks.
In addition, the same methodology failed to achieve fluorinated 17&bgr;-carboxamides in acceptable yields and purity.
In this respect, we have surprisingly found that the said imidazolide derivatives could be unexpectedly converted into the desired amide, under mild conditions, in the presence of acids.
Therefore, it is the object of the present invention a process for preparing the compounds of formula
wherein
the dotted lines - - - , independently from each other, represent a single or double bond;
R and R
1
, the same or different, represent a hydrogen atom or a straight or branched C
1
-C
6
, alkyl, phenylalkyl, alkylphenyl or alkylphenylalkyl group, being the said alkyl groups substituted by one or more fluorine atoms;
R
2
is a hydrogen atom or a C
1
-C
6
alkyl group optionally substituted by one or more fluorine atoms;
R
3
, whenever present, is a hydrogen atom;
provided that at least one of R and R
1
contain one or more fluorine atoms and that when the dotted line in position 5, 6 represents a double bond, R
3
is absent;
which comprises reacting an imidazolide derivative of formula
wherein
the dotted lines, R
2
and R
3
have the above reported meanings;
with an anhydrous acid, in the presence of an amine of formula
HN(R)R
1
(III)
wherein R and R
1
have the above reported meanings; and, if desired, hydrogenating the resultant compound of formula (I) wherein one of both the dotted lines represent a double bond.
The process object of the present invention allows to prepare the compounds of formula (I) in mild conditions and, even more important, it enables to obtain compounds of formula (I) from scarcely reactive amines such as low nucleophilic and/or sterically hindered amines, e.g. fluorinated and even bulky fluorinated amines.
In the present description, unless otherwise specified, with the term straight or branched C
1
-C
4
or C
1
-C
6
alkyl group we intend a methyl, ethyl, n.propyl, isopropyl, n.butyl, sec-butyl, isobutyl, tert-butyl, n.pentyl, n.hexyl and the like.
With the term straight or branched C
1
-C
6
phenylalkyl, alkylphenyl or alkylphenylalkyl group we intend a phenyl group bonded to a straight or branched C
1
-C
6
, alkyl moiety as above indicated.
With the term anhydrous acid we conventionally intend an acid with a very low content of water, being the said acid a mineral acid, a strong organic acid or a Lewis acid. Examples of mineral or strong organic acids are hydrogen chloride, hydrogen bromide, sulphuric acid, methanesulphonic acid, p.toluenesulphonic acid, triflic acid, camphorsulphonic acid, or the like.
Examples of Lewis acids are, for instance, zinc chloride, zinc bromide, aluminium chloride, aluminium bromide, ferric chloride, ferric bromide or the like.
For a general reference to the said acids and, in particular, to Lewis acids see, for instance, J. March, Advanced Organic Chemistry, IV ed. 1992, John Wiley & Sons, Chapter 8, pages 248-272.
In the formulae (I-II) as above, the dotted line
in position 5 indicates a substituent in the &agr;-configuration, i.e. below the plane of the ring, and the wedged lines in position 10, 13 and 17
indicate a substituent in the &bgr;-configuration, i.e. 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 R
1
is a hydrogen atom and the other is a straight or branched C
1
-C
4
alkyl, phenylalkyl or alkylphenylalkyl group, substituted by at least a fluorine atom in the alkyl moiety.
Even more preferred compounds, in this class, are the compounds of formula (I) wherein the said alkyl groups are C
1
-C
3
perfluoroalkyl groups such as, for instance, trifluoromethyl, 1,1,1-trifluoroethyl, 1,1,1,2,2-pentafluoroethyl or 1,1,1,3,3,3-hexafluoropropyl groups.
The process according to the present invention is preferably carried out to prepare one of the following 17&bgr;-carboxamido-4-azasteroids:
1) N- (1,1,1,3,3,3-hexafluoro-2-phenylprop-2-yl)-3-oxo-4-aza-5&agr;-andros-1-ene-17&bgr;-carboxamide;
2) N- (1,1,1,3,3,3-hexafluoro-2-phenylprop-2-yl)-3-oxo-4-aza-5&agr;-androstane-17&bgr;-carboxamide;
3) N- (1,1,1,3,3,3-hexafluoro-2-phenylprop-2-yl)-3-oxo-4-aza-5&agr;androstane-1,5-diene-17&bgr;-carboxamide;
4) N- (1,1,1,3,3,3-hexaflouro-2-phenylprop-yl)-3-oxo-4-azaandrost-5-ene-17&bgr;-carboxamide;
5) N-[1,1,1,3,3,3-hexafluoro-2-(p-methylphenyl)prop-2-yl]-3-oxo-4-aza-5&agr;-androst-1-ene-17&bgr;-carboxamide;
6) N-[1,1,1,3,3,3-hexafluoro-2-(p-methylphenyl)prop-2-yl]-3-oxo-4-aza-5&agr;-androstane-17&bgr;-carboxamide;
7) N-[1,1,1,3,3,3-hexafluoro-2-(p-methyl
D'Anello Matteo
Longo Antonio
Nesi Marcella
Panzeri Achille
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Pharmacia & Upjohn SpA
Qazi Sabiha
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