FR2768054A1 - USE OF BENZENE SULFONAMIDE DERIVATIVES FOR OBTAINING A MEDICAMENT FOR THE TREATMENT OF RETROGRADE EJACULATION OR ASPERMIA - Google Patents

Abstract

The invention concerns the use of a compound of formula (I) in which: R1 represents a hydrogen or halogen atom, such a chlorine or fluorine, a linear or branched C1-C4 alkyl or C1-C4 alkoxy group; R2, R3, and R4 represent, independently of one another, a hydrogen atom, a linear or branched C1-C4 alkyl group, or a C3-C4 cycloalkyl group; and R5 represents a hydrogen atom, a C1-C2 alkyl, C1-C2 fluoroalkyl, or C1-C2 perfluoroalkyl group, for preparing a medicine useful for treating ejaculation disorders such as retrograde ejaculation or aspermia.

Description

The present invention relates to the use of benzene sulfonamide derivatives to obtain a medicament for the treatment of retrograde ejaculation or aspermia.

dans laquelle
R1 représente un atome d'hydrogène ou d'halogène, tel que chlore ou fluor, un groupe C14 alkyle ou C14 alcoxy, linéaire ou ramifié, un groupe C34 cycloalkyle
R2, R3, et R4 représentent, indépendamment les uns des autres, un atome d'hydrogène, un groupe C14 alkyle, linéaire ou ramifié, un groupe C34 cycloalkyle et Rs représente un atome d'hydrogène, un groupe C12 alkyle, C 2 fluoroalkyle, ou C12 perfluoroalkyle.The compounds correspond to the general formula (I)

in which
R1 represents a hydrogen or halogen atom, such as chlorine or fluorine, a linear or branched C14 alkyl or C14 alkoxy group, a C34 cycloalkyl group;
R2, R3, and R4 represent, independently of one another, a hydrogen atom, a linear or branched C14 alkyl group, a C34 cycloalkyl group and Rs represents a hydrogen atom, a C12 alkyl, C 2 fluoroalkyl group; , or C12 perfluoroalkyl.

The compounds of general formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers.

These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.

The compounds of general formula (I) may be in free base form or addition salts with pharmaceutically acceptable acids, which are also part of the invention.

The compounds of general formula (I) according to the invention may be prepared according to the processes described in patent application WO 97/06136.

The following table illustrates the structures of some compounds that can be used according to the invention.
Board

## EQU1 ##
<tb><SEP> 1 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CHRSORH <SEP> 156-161
<tb><SEP> 2 <SEP> CH3 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH3SO3H <SEP> 185
<tb><SEP> base <SEP> 217-220
<tb><SEP> 3 <SEP>(#)<SEP> OCH3 <SEP> H <SEP> H <SEP> H <SEP> H
<tb><SEP> CH3SO3H <SEP> 210-212
<tb><SEP> base <SEP> 217-220
<tb><SEP> 4 <SEP> (+) <SEP> OCH3 <SEP> H <SEP> H <SEP> H <SEP> H
<tb><SEP> CH3SO3H <SEP> 234
<tb><SEP> base <SEP> 217-220
<tb><SEP> 5 <SEP> (-) <SEP> OCH3 <SEP> H <SEP> H <SEP> H <SEP> H
<tb><SEP> CHXSORH <SEP> 235
<tb><SEP> 6 <SEP> O-iC3H7 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH3SO3H <SEP> 92
<tb><SEP> 7 <SEP> Cl <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH <SEP> Sa <SEP> H <SEP> 206-208
<tb><SEP> 8 <SEP> F <SEP> H <SEP> H <SEP> H <SEP> H <SEP> CH3S03H <SEP> 184
<tb><SEP> 9 <SEP> OCH <SEP> CH3 <SEP> H <SEP> H <SEP> H <SEP> CH3SO3H <SEP> 194-196
<tb><SEP> 10 <SEP> OCH3 <SEP> c-C3H5 <SEP> H <SEP> H <SEP> H <SEP> HCl <SEP> 231
<tb><SEP> 11 <SEP> OCH3 <SEP> C2H5 <SEP> C <SEP> H <SEP> H <SEP> H <SEP> CH3SO3H <SEP> 90-92
<tb><SEP> 12 <SEP> OCH3 <SEP> H <SEP> H <SEP> CH3 <SEP> H <SEP> oxalate <SEP> 154-156
<tb><SEP> 13 <SEP> OCH3 <SEP> H <SEP> H <SEP> c-C3H5 <SEP> H <SEP> HCl <SEP> 199-202
<tb><SEP> 14 <SEP> OCH <SEP> H <SEP> H <SEP> i-C3H7 <SEP> H <SEP> oxalate <SEP> 180
<tb><SEP> 15 <SEP> OCH <SEP> H <SEP> H <SEP> t-C4H9 <SEP> H <SEP> HCl <SEP> 203-205
<tb> 16 <SEP> anti <SEP> OCH <SEP> H <SEP> H <SEP> H <SEP> CH <SEP> base <SEP> 233-237
<tb><SEP> 17 <SEP> syn <SEP> OCH <SEP> H <SEP> H <SEP> H <SEP> CH3 <SEP> base <SEP> 176-177
<tb> 18 <SEP> (-) syn <SEP> n <SEP> OCH3 <SEP> H <SEP> H <SEP> H <SEP> CH3 <SEP> base <SEP> 143-145 <SEP>
<tb> i-C3H7 is isopropyl, t-C4H9 tert-butyl, c-C3H5 cyclopropyl; (+) represents a racemic; (+) represents the dextrorotatory enantiomer; (-) represents the levorotatory enantiomer; anti represents a mixture of RS diastereoisomers and
SR; syn represents a mixture of RR and SS diastereoisomers.

The compounds of the invention have been subjected to biological tests intended to demonstrate their contractile activity on the smooth muscles of the trigone and the arteries.

1. The in vitro activity of the compounds of the invention has been studied on trigonal smooth muscle and arteries. These tests were carried out on New Zealand female rabbits weighing from 3 to 3.5 kg. The animals were killed by cervical dislocation, and mesenteric artery tissue rings and trigon bands were prepared. These rings or strips of cloth were immersed in a solution of
Modified Krebs, oxygenated with a mixture of 95% Q and 5% CQ. Each tissue sample was tensioned at 1 g and then phenylephrine was added at cumulative doses and the concentration / response curve was established.

After rinsing the tissues, the test compound was introduced at cumulative doses and the concentration / response curve was established. The contractile effect of each compound is evaluated by the calculation of pD2 (negative logarithm of the agonist concentration which induces 50% of maximal contraction) as well as by the maximal effect expressed as a percentage of the contraction obtained with phenylephrine ( % Emax)
The results obtained show that the compounds in accordance with the invention exhibit a pD2 trine, usually between 4 and 6, a pD2 artery usually less than 5%, a% sema phenylephrinetrigone greater than 30%, usually between 40% and 90%, * an E, artery usually greater than 30%.

All the above results show that the compounds of the invention have a strong contractile action on the smooth muscle of the trigone and a low arterial contractile action.

They can be used as a medicament, particularly as a contracting agent for trigonal smooth muscle, and more particularly, in the treatment of ejaculation disorders such as retrograde ejaculation or aspermia. In this indication, the compounds according to the invention have good efficacy and, usually, lesser side effects than the drugs conventionally used for such treatment, in particular with regard to the side effects affecting the cardiovascular system.

The compounds according to the invention may be presented in different pharmaceutical forms suitable for administration by the digestive or parenteral route, where appropriate by combining with at least one pharmaceutical excipient. Suitable dosage forms are, for example, tablets, capsules, dragees, capsules, oral or injectable solutions, syrups, suppositories.

These dosage forms can be assayed to allow a daily dose of 1 μg / kg to 30 mg / kg.

Claims (2)

C1-2 fluoroalkyl, or C12 perfluoroalkyl, in the form of enantiomers, diastereoisomers or mixtures of these different forms, including racemic mixture, as well as addition salts with pharmaceutically acceptable acids, for the manufacture of a drug useful as a contracting agent of the smooth muscle of the trigone. R5 represents a hydrogen atom, a C12 alkyl group, R2, R3, and R4 represent, independently of each other, a hydrogen atom, a linear or branched C14 alkyl group, a C34 cycloalkyl group and R1 represents a hydrogen or halogen atom, such as chlorine or fluorine, a linear or branched C14 alkyl or C14 alkoxy group,  in which

1. Use of a compound of formula (I) 2. Use according to claim 1 characterized in that the drug is useful in the treatment of ejaculation disorders such as retrograde ejaculation or aspermia.