Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-05
2003-01-21
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S061000
Reexamination Certificate
active
06509466
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a process for obtaining 17&bgr;-(N-tert-butylcarbamoyl) -3-one-4-aza-steroids, optionally unsaturated between carbons 1-2 or 5-6, useful as inhibitors of 5&agr;-reductase or synthetic intermediates thereof.
BACKGROUND OF THE INVENTION
4-aza-steroids are known that are useful as inhibitors of the enzyme 5&agr;-reductase, an enzyme that converts testosterone into the more potent androgen, 5&agr;-dihydro-testosterone, which is the main mediator of the androgenic activity in some organs. The inhibitors of testosterone-5&agr;-reductase may prevent or reduce the symptoms of hyperandrogenic stimulation.
U.S. Pat. No. 4,760,071 describes some 17&bgr;-(N-alkyl-carbamoyl)-4-aza-5&agr;-androst-1-en-3-ones useful as inhibitors of 5&agr;-reductase. A representative example of said compounds is finasteride [17&bgr;-(N-tert-butyl-carbamoyl)-4-aza-5&agr;-androst-1-en-3-one], an active substance with multiple therapeutic applications, for example, in the treatment of benign prostatic hyperplasia and alopecia.
Known processes for obtaining 17&bgr;- (N-tert-butylcarbamoyl)-3-one-4-aza-steroids comprise the formation of a N-tert-butylcarbamoyl group.
The general processes for obtaining amides consist of reacting a derivative of carboxylic acid with the corresponding amine. The derivative of carboxylic acid may be an acid halide, an ester, a derivative of carbonyl or thionyl imidazole, a derivative of dicyclohexylcarbodiimide, etc.
When the derivative of carboxylic acid is an ester, its reaction with the amine to form the amide occurs satisfactorily when the ester and the amine have certain characteristics, such as high reactivity and absence of steric hindrance. When the structure of the ester and that of the amine are complex, the reactivity between both compounds reduces and the level of transformation may be practically zero. This occurs, for example, in the formation of 17&bgr;-(N-tert-butylcarbamoyl)-3-one-4-aza-steroids starting from 17&bgr;-(alkoxycarbonyl)-3-one-4-aza-steroids and tert-butyl-amine. In this case, said esters are not very reactive and the amine [tert-butylamine] presents a clear steric hindrance.
The solutions proposed in the state of the art for solving the problem of low reactivity between said esters and tert-butylamine may be sorted out in 3 groups:
a) those in which the amine is allowed to react with another derivative of carboxylic acid that confers on it greater reactivity, such as an acid halide; a representative example of this group is mentioned in U.S. Pat. No. 5,670,643, where the conversion of 17&bgr;-carboxy-4-aza-5&agr;-androst-1-en-3-one into the corresponding acid chloride is described [see Example 1 of said U.S. Pat. No. 5,670,643]. This alternative, applied to an ester as a starting material, would imply the conversion of the ester into the acid and, subsequently, the conversion of the acid into the corresponding derivative, which would suppose the need of some additional synthetic steps that draw out the process and reduce the yield;
b) those in which the amine is activated by means of the formation of the corresponding derivative of magnesium-alkylamine by reacting the amine with a Grignard compound [see Examples 1 and 2 of the European patent application EP-A-0 655 458]. This alternative has the drawback that side reactions are produced by the presence of the Grignard compound in the reaction medium which may react with the ester group itself; and
c) those which combine the conversion of the ester into a more reactive derivative and the activation of the amine, for example, the conversion of 17&bgr;-carboxy-4-aza-5&agr;-androst-1-en-3-one into the corresponding derivative of imidazole and the conversion of the amine into the corresponding derivative of alkylaminomagnesium [see Example 5 of the patent application EP-A-0 367 502]. This alternative has the drawbacks of the alternatives a) and b).
The process of the present invention overcomes the whole or part of the drawbacks present in the processes of the state of the art.
REFERENCES:
patent: 4760071 (1988-07-01), Rasmusson et al.
patent: 5670643 (1997-09-01), Davis et al.
patent: 0 367 502 (1990-05-01), None
patent: 0 599 376 (1994-06-01), None
patent: 0 655 458 (1995-05-01), None
patent: 2 338 234 (1999-12-01), None
patent: WO 95/00531 (1995-01-01), None
Peng Xia et al., “Synthesis of N-Substituted 3-Oxo-17&bgr;-Carboxamide-4-Aza-5&agr;- Androstanes And The Tautomerism of 3-Oxo-4-Aza-5-Androstenes1”, Heterocycles, vol. 47, No. 2, pp. 703-716, (1998).
Blanco Fernandez Cristina
Bonde-Larsen Antonio Lorente
Guisasola Luis Octavio Silva
Juarez Jorge Martin
Akin Gump Strauss Hauer & Feld L.L.P.
Davis Zinna Northington
Raga Consultores, S.L.
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