Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-12-06
1996-12-10
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D22118
Patent
active
055832288
DESCRIPTION:
BRIEF SUMMARY
This is the national type application of PCT/HU93/00040.
This invention relates to 4-azaandrostene derivatives of formula (I) ##STR2## wherein R is hydrogen or a C.sub.1-3 alkyl group;
Furthermore, the invention relates to a process for the preparation of the above compounds.
The compounds of formula (I) can advantageously be used for the preparation of compounds inhibiting the 5.alpha.-reductase enzyme. For this synthetic purpose a compound of formula (I) is reacted with a primary or secondary alkylamine preferably in dimethylformamide medium, in a carbon monoxide atmosphere in the presence of palladium(II) acetate, triphenylphosphine and triethylamine and then, if desired, the double bond of the .DELTA..sup.16 17.beta.-carboxamido derivative is catalytically hydrogenated. (See Examples 9 and 10.)
The inhibitors of 5.alpha.-reductase enzyme impede the transformation of testosterone to dihydrotestosterone and therefore, they can be useful for healing dihydrotestosterone-dependent diseases, e.g. prostatic hyperplasia, acne, seborrhoea and female hirsutism.
BACKGROUND OF THE INVENTION
It is known [J. Chem. Soc. pages 470 to 476 (1962)] that 17-iodo-androsta-5,16-dien-3.beta.-ol is obtained by reacting the 17-hydrazone derivative of dehydroepiandrosterone with elemental iodine in the presence of triethylamine in tetrahydrofuran. By using pregnenolone-20-hydrazone as starting material, under similar reaction conditions 20-iodopregna-5,20-dien-3.beta.-ol can be prepared.
The further development of the above process by investigating the role of base and water is discussed in another literature reference [Tetrahedron Letters 24, pages 1605 to 1608 (1983)]. According to this publication the 17-hydrazone of dehydroepiandrosterone is similarly used as starting material, but tetramethylguanidine is employed as base. The transformation of non-steroid hydrazone derivatives is also exemplified.
The reaction of hydrazone derivatives with N-bromo-or N-chlorosuccinimide is discussed in a publication [Chem. Pharm. Bull. Japan 11, pages 1413 to 1417 (1963)]; according to this the 17-hydrazone derivative of epiandrosterone is used as starting material, which is reacted with N-bromo- or N-chlorosuccinimide. This reaction becomes complete within a few minutes, which can be observed on cessation of the evolution of nitrogen. After pouring onto water the reaction mixture is extracted and then the "vinyl halide-type" compounds formed are purified by chromatography or recrystallization.
A similar method is published also in the Hungarian patent No. 171,166. In this process the hydrazone of androst-2-en-17-one is reacted with an N-halogenosuccinimide in pyridine at a temperature between -30.degree. C. and +20.degree. C. to obtain the "vinyl halide-type" final product.
SUMMARY OF THE INVENTION
According to our invention the preparation of the compounds of formula (I) comprises ##STR3## wherein R and the ---- bond line are as defined above, with elemental iodine in the presence of a tertiary amine base in a halogenated hydrocarbon or an aromatic hydrocarbon solvent or in a mixture thereof, or in an ether-type solvent are as defined above, with N-chloro- or N-bromosuccinimide, respectively in pyridine optionally substituted by one or more C.sub.1-4 alkyl group(s) as solvent at a temperature between -10.degree. C. and +10.degree. C.
According to the above process a) the iodination is preferably carried out at room temperature. After completion of the reaction (indicated by cessation of the nitrogen gas evolution), the tertiary amine base and the excess of iodine are removed by treatment with dilute aqueous hydrochloric acid and then with sodium thiosulfate. Subsequently, the solvent is distilled off and the crude product obtained is purified by chromatography and recrystallization. The iodination reaction is preferably carried out in a halogenated or an aromatic hydrocarbon solvent, preferably in chloroform, benzene or a mixture of these solvents or an ether-type solvent, preferably tetrahydrofuran in the presence of a tertiary am
REFERENCES:
patent: 4377584 (1983-03-01), Rasmusson et al.
Back, T. G. et al. Journal of the Chemical Society, 1962, part 1, pp. 470-476.
Bartan, D. H. R. et al. Tetrahedron Letters, vol. 24, No. 15, 1983, pp. 1605-1608.
Bartan, D. H. R. et al. Journal of Organic Chemistry, 1989, 54(8), 1904-1910.
Bartan, D. H. R., Bashiardes, G., Fourrey, J-L "An Improved Preparation of Vinyl Iodides", Tetrohedron Letters, vol. 24, No. 15, pp. 1605-1608 (1983) .
Balogh G abor
Horv ath Judit
Lovas n ee Marsai M aria
Sz eles J anos
Tuba Zolt an
Dubno Herbert
Ivy C. Warren
Myers Jonathan
Richter Gedeon Vegyeszeti Gyar Rt.
Smith Lyman H.
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