IL39294A - Method of inducing infertility and inhibiting the growth of the prostate in male animals by 3,5-bis(substituted amino)-1,2,4-dithiazolium salts or 1,5-bis(substituted)-dithiobiurets - Google Patents

Description

39294/3 'n o »wy Ί3Τ aa m»n ss neoonsn oi» itn»n»1-4 , 2 , 1 - ( nan i a Ί3'ηκ)ο»η-5,3 o*BTis»iis*n'i-( ama)o"»a-5,1 Method of inducin infertility and inibiting the growth of the prostate in male animals by 3,5-bis(substituted amino)- 1,2,4-dithiazolium salts or l,5-bis(substituted) dithiobiuretv ORTHO PHARMACEUTICAL CORPORATION 0837294 -la- 39294/2 This invention relates to a method of inducing infertility and inhibiting the growth of the prostate in male animals by administering thereto 3,5-bis(substitutedamino)-1.2,4-dithiazolium salts or their dithiobiuret intermediates.

The possibility of chemically inducing; infertility In the male has intrigued Investigators for a number of years and many have worked toward the discovery of an antispermatogenatic agent. Such a compound would, by definition, interfere with one or more phases of the complex series of cellular events which constitutes the process of spermatogenesis. While some such compounds have been found which are active in man, clinical usefulness is limited by the delay in the onset of sterility, the delay in the return of fertility once medication is terminated, and a narrow margin of safety.

One approach to the problem has been to attempt to synthesize potent non-hormonal antigonadotrophic agents with localized effect on the germinal epithelium to induce sterility as a consequence of androgen deprivation. Such a compound would also cause marked atrophy of the Leydlg cells, the prostate gland, and the seminal vesicles. Depopulation of spermatids from the seminiferous epithelium wduld also be a normal consequence of the androgen deprivation. 39294/2 It has now been discovered that compounds the general formula : wherein X represents an anion of an acid having an ionization constant of at least 1x10 , is dialkylamino and is monoalkylamino or dialkylamino having from 2 to 36 carbon atoms, diar lamino having from 12 to 20 carbon atoms, alkylarylamino having from 7 to 12 carbon atoms, piperidino, morpholino, pyrrolidino or piperazino, are potent antigonadotrophic agents when administered in effective non-toxic doses to the male animal.

It has also been found that the dithiobiurets which are isolatable intermediates in the preparation of the above-noted compounds are also active antigonadotrophic agents. It is hypothesized that either these compounds undergo cyclization to active dithiazolium salts in vivo or the dithiazolium salts undergo degradation in vivo to the corresponding dithiobiurets. The active dithiobiurets are, therefore, those of the class, S S II II R1-C-NH-C-i¾2 wherein R7 and R9 are as heretofore defined.

The compounds utilized in the method of this invention are, for the most part, disclosed and claimed in Israel Patent Specification No. 22700, in which it is disclosed that these compounds are useful as defoliants. The compounds used in the method of this invention are thus prepared in the manner described in Specification No. 22700 (corresponding to United States Patent 3,166,564). 3,5-Bis(dimethylamin0)-l,2,4-dithiazolium chloride is also reported in J. Econ. Entomol. 1969, 62(2), pp. 522-4 (C^A. JO, 105422η (1969) as causing sterility in houseflies.

An example or the use of the compounds of the above-defined class may be illustrated by mating studies carried out with 3,5-*>is(dlalkyl aralno)-l,2, -dithiazolium chloride.

Adult male rats of e Wlstar derived strain are housed five to a cage in air-conditioned animal quarters and maintained on laboratory chow and tap water ad libitum.

The compound is dissolved in propylene glycol and administered once daily intragastrically for 14 consecutive days. An equal number of controls receive only the propylene glycol. At the end of the treatment, each male is cohabited with a proestrus female. Each morning the vaginal washings are taken and examined for the presence of sperm. The males are sacrificed and the reproductive organs examined. Nine days post-mating, the females are autopsied and examined for implantations.

Males failing to mate, judged by the absence of sperm in vaginal washings, are re-cohabited with proestrus females until mating does occur. While a reduction in libido as well as fertility is noted at higher doses, the entifertility effects even at those doses cannot be attributed wholl to A careful examination of the organs of the sacrificed male rats indicates that treatment with as little as 0.1 mg^ per kg (approximately 25 micrograms per rat per day) of the compound, cause marked atrophy of the Leydig cells, the prostate gland, and the seminal vesicles. Depopulation of spermatids from the seminiferous epithelium is also observed. At this dosage level, loss of libido is not significant. Of the four male rats successfully mated, two mates are found to be pregnant, thus indicating that there is also local action on the spermatozoide resident in the epididymis. It is also found that when the above-noted compound and testostrone propionate are simultaneously administered, there is a neutralized response on the male accessory organs thus indicating that the effect of the compound is not due to the peripheral antagonism to testicular steroid hormones. Thus, it is hypothesized that interference with the action of pituitary gonadotrophlns or the formation or secretion of gonadotrophin is the way in which this compound asserts its effects. The local effect on the spermatozolds resident in the epididymis is more pronounced at slightly higher doses as is illustrated by the fact that treatment with 0.5 mgs per kg, of the rats successfully mated, none are found to be pregnant at this dosage level. The effect on libido is still minor.

Because of the potency of the compounds Involved, the dosage for a particular species and compound must be carefully chosen. It has, for example, been found that at from 10-20 mgs per kg per day, the compounds are substantially toxic in the rat and doses of greater than 1.0 mg per kg per The specific dose and regimen utilized will depend on the species and specific compound chosen. An effective dose for a particular species and compound can be rapidly determined by routine clinical and laboratory screens .

The effect of the administration of the compounds of this invention on the prostate and the seminal vesicle can be seen in Figure 1 and Figure 2 which lllus-trate the size of those organs of the rats treated as above described. -6- 39294/2 .

Claims (1)

1. A method of inhibiting fertility in male ; animals and of inhibiting the growth of, or reducing the size of, the prostate and the seminal vesicle in male animals, comprising orally administering to male animal other than humans, an effective non-toxic dose of a compound of the general formula: 1x10-7, is dialkylamino and R2 is monoalkylamino or dialkylamino having from 2 to 36 carbon atoms, diar lamino having from 12 to 20 carbon atoms, alkylarylamino■ having from 7 to 12 carbon atoms, piperidino, morpholino, pyrrolidino or piperazino, or a compound of the general formula: S S wherein R^ and 2 are as heretofore defined. For the Applicants