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A non-hormonal approach to male contraception

A male and alkyl technology, applied in diseases, pharmaceutical formulations, organic active ingredients, etc., can solve problems such as poor metabolism and unacceptable testosterone preparations

Inactive Publication Date: 2005-08-17
UNITHER PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Available testosterone preparations are not fully acceptable
Third, there are many adverse metabolic effects of exogenous testosterone

Method used

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  • A non-hormonal approach to male contraception
  • A non-hormonal approach to male contraception
  • A non-hormonal approach to male contraception

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] The effect of oral administration of embodiment 1-NB-DNJ on male mice

[0126] To determine the effect of NB-DNJ on the fertility of male mice, 6-week-old C57BL / 6 males were treated with 2400 mg / kg NB-DNJ / day for increasing durations with weekly increments (Fig. 1a), followed by mating trials, During this time they were housed with untreated female mice for 1 week. Figure 1A It was shown that males gave birth and were able to reproduce a normal number of pups at the start of the experiment, and this ability was maintained after 2 or 3 weeks after NB-DNJ treatment. Mice were sterile after at least 3 weeks of drug consumption ( Figure 1A ). When the male mice were withdrawn after 5 weeks, their fertility was restored in the fourth week, and a normal number of pups were produced ( Figure 1A ). 13-week-old males treated with the same dose for 5 weeks also became completely sterile (data not shown). Therefore, under NB-DNJ treatment, male mice became sterile and this ...

Embodiment 2

[0127] Example 2 - Dose Response

[0128] Earlier work has demonstrated that the in vivo reduction in GSL levels caused by NB-DNJ is dose-dependent; for example, doses of 600-2400 mg / kg / day resulted in a 10-70% reduction in the levels of ganglioside GM1 on the surface of mouse splenocytes, respectively. % (Platt et al. (1997) J Biol Chem 272, 19365-72). It has been established that male mice become sterile when treated with 2400 mg / kg / day of NB-DNJ ( Figure 1A with 1B ), they were exposed to gradually decreasing doses of the compound to determine the lowest dose causing sterility. The result is as Figure 2A with 2B shown. Although 1mg / kg / day did not affect males, 5mg / kg / day weakened their fertility ( Figure 2A ) and litter size ( Figure 2B ), and 15 mg / kg / day they were completely sterile. Therefore, the mouse male reproductive system is exceptionally sensitive to NB-DNJ. Drug-induced fertility loss was not due to changes in mating behavior, such as the frequency ...

Embodiment 3

[0129] Example 3 - Fertility of female mice

[0130] Treatment of NB-DNJ at 1200 mg / kg / day did not cause sterility in female mice as compared to male mice. After a mating period of 4 days with untreated males, 100% of treated (n=5) as well as untreated females (n=4) were fertile; these mice had 6.2±2.7 and 7.8±1.0 pups per litter, respectively.

[0131] NB-DNJ was administered to 15-week-old female mice of strain 129 at 2400 mg / kg per day for 12 weeks. Thereafter, the drug was withdrawn and the females were housed with untreated males of the 129 line. All females conceived rapidly and had an average litter size of 6 pups. Mice in this experiment were heterozygous for disruption of the gene encoding ceramide galactosyltransferase. These mice are phenotypically indistinguishable from wild-type 129 mice and reproduce normally (Coetzee et al., (1996), Cell, 86:209-219).

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PUM

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Abstract

The present invention provides a method by which to reversibly render male mammals infertile. Thus, the disclosed N-substituted imino compounds, and pharmaceutical compositions thereof, completely impair the fertility of male mammals, but exhibit no effect on that of female mammals, and are thus useful as male contraceptives. Particularly efficacious compounds are imino sugars derived from N-alkylated piperidines of the formulae: wherein R2 is can be a linear or branched C1-18 alkyl, C2-18 alkenyl or alkynyl; or aralkyl; which may be optionally substituted with one or more of -OH; -F; -CI; -Br; -I; -NH2; alkyl- and dialkylamino; linear or branched C1-6 alkyl, C2-6 alkenyl and alkynyl; aralkyl; linear or branched C1-6 alkoxy, aryloxy; aralkoxy; -CN, -NO2, -COOH, -COO(alkyl); -COO(aryl); - C(O)NH(C1-6 alkyl); -C(O)NH(aryl); sulfonyl; (C1-6 alkyl)sulfonyl; arylsulfonyl; sulfamoyl, (C1-6 alkyl)sulfamoyl; (C1-6 alkyl)thio; (C1-6 alkyl)sulfonamide; arylsulfonamide; -NHNH2; and -NHOH.

Description

[0001] Cross-Referenced Related Applications [0002] This application claims priority to US Provisional Application No. 60 / 381,329 (filed May 20, 2002) and US Provisional Application No. 60 / 363,561 (March 13, 2002), the contents of which are incorporated herein by reference. technical field [0003] The invention relates to a method for reversibly contraceptive male mammals by administering special contraceptives to the male mammals. Background technique [0004] Glycosphingolipids (GSLs) are amphiphilic molecules located on the plasma membrane of mammals and composed of the hydrophobic compound ceramide and a variety of different oligosaccharide structures (see Svennerholm, (1994) Prog Brain Res 101, GSL nomenclature XI-XIV), GSLs are involved in a variety of physiological processes, including transmembrane signaling, cell adhesion, differentiation, migration and morphogenesis, oncogenic transformation and development ...

Claims

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Application Information

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IPC IPC(8): C07D211/46A61K31/40A61K31/4015A61K31/4025A61K31/445A61K31/454A61P15/16
CPCA61K31/454A61K31/445A61K31/4015A61K31/4025A61K31/40A61P15/16
Inventor 阿诺德·C·范德斯普尔M·杰亚库马T·D·布特尔斯R·A·德维克F·M·普拉特
Owner UNITHER PHARMA INC
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