US20020040150A1

US20020040150A1 - Skin treatment compositons containing a cationic polymer and a microparticle or nanoparticle vector

Info

Publication number: US20020040150A1
Application number: US09/536,728
Authority: US
Inventors: Franz Esser; Helmut Stahle; Sven Luttke; Ikonobu Muramatsu; Hisato Kitagawa; Shujil Uchida
Original assignee: Individual
Current assignee: Individual
Priority date: 1995-04-20
Filing date: 2000-03-28
Publication date: 2002-04-04
Also published as: CN1119148C; ES2279521T3; RU2230061C2; IL117956A0; JP3379960B2; BG64116B1; AU719710B2; CA2214338A1; CZ327197A3; JP4141763B2; HRP960187A2; ZA963131B; PL184881B1; US6858594B2; PE44297A1; MX9707570A; AR002043A1; YU24496A; TW403739B; US6268389B1

Abstract

The present invention relates to the use of α_1L-agonists for treating urinary incontinence.

Description

The present invention relates to the use of α _1L-agonists for treating urinary incontinence, particularly stress incontinence.

The cause of stress incontinence in women is usually weakness of the pelvic floor, e.g. after numerous difficult births. However, it may also be due to nerve disorders of the pelvic floor, a congenitally short urethra or, occasionally, damage to the sphincter caused by surgery. The reduction in the oestrogen levels post-menopause further encourages stress incontinence.

The term stress incontinence refers to a sudden loss of urine, which is caused by incompetence of the bladder outlet during unobtrusive movement of the bladder as a result of interabdominal increases in pressure due to coughing, pressing, sneezing, heavy lifting, etc.

Surprisingly, it has been found that the α _1L-subtype of the adrenergic receptor has a significant effect on the continence mechanism of urether tonicisation.

The invention relates to the use of α _1L-adrenoceptor agonists for treating urinary incontinence, particularly stress incontinence, and for preparing drugs for treating urinary incontinence, particularly stress incontinence. It is particularly interesting to use amino imidazolines of general formula

and the pharmacologically acceptable acid addition salts thereof.

In general formula I

Y denotes an optionally substituted phenyl or napthyl group or

Y denotes a 5- or 6-membered, optionally fully unsaturated, optionally substituted heterocyclic ring which contains oxygen, sulphur or nitrogen as heteroatoms, and

X denotes —NH—, —CH ₂—, —OCH₂—, —O—CHCH₃—, —CH═N—NH—, —N═N—or —NZ—, wherein Z═—CH₂—CH═CH₂or cyclopropylmethyl.

Preferred compounds are those wherein X is —NH—and/or Y is an optionally substituted thienyl, furyl, pyrrole, tetrahydropyrrole, pyridyl, pyrazinyl, pyranyl, 1,3-thiazolyl, imidazolyl, imidazolinyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, isothiazolyl, pyrimidinyl, thiazolyl, thiadiazinyl or piperidinyl, bound to the group X via a C atom. It is preferred to use tiamenidine.

Preferred compounds for this purpose are imidazolines of general formula

or imidazolines of general formula

wherein

R ¹, R², R³, R⁴, and R⁵denote, independently of one another:

hydrogen, C _1-6-alkyl, preferably C_1-4-alkyl, most preferably methyl, C_3-6-cycloalkyl, preferably cyclopropyl, C_1-6-alkoxy, preferably C_1-4-alkoxy, most preferably methoxy, halogen, preferably chlorine or bromine, —CF₃, —OCF₃or —NR⁶R⁷wherein

R ⁶denotes hydrogen, C_3-6-cycloalkyl, C_1-6-alkyl, preferably C_1-4-alkyl, most preferably methyl, or C_2-4-acyl, most preferably acetyl,

R ⁷denotes hydrogen, C_3-6-cycloalkyl, preferably cyclopropyl, C_1-6-alkyl, preferably C_1-4-alkyl, most preferably methyl, or C_2-4-acyl, most preferably acetyl; or

R ⁶and R⁷together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated ring which may contain up to two further heteroatoms selected from oxygen, sulphur or nitrogen, whilst each additional nitrogen atom may be substituted by C_1-4-alkyl, preferably methyl;

or R ⁶and R⁷together with the nitrogen atom form phthalimido; or

R ¹and R²together form a fused pyrazole of formula

wherein R ⁸is C_1-3-alkyl, preferably methyl; or a fused thiadiazole of formula

wherein R ³, R⁴and R⁵are as hereinbefore defined, and preferably denote hydrogen, and the pharmacologically acceptable acid addition salts thereof.

Formulae I and I′ and Ib and II are equivalent tautomeric structures. The preparation of one structure (e.g. Ib) includes the other structure (e.g. II) in each case.

Also preferred are imidazolines of general formula Ib

wherein

R ¹denotes hydrogen, ethyl, methyl, fluorine, chlorine, bromine or CF₃,

R ²denotes methyl, fluorine, chlorine, bromine or —NR⁶R⁷, wherein

R ⁶denotes hydrogen, C_1-4-alkyl, preferably methyl, C_2-4-acyl, preferably acetyl and

R ⁷denotes hydrogen, C_1-4-alkyl, preferably methyl, C_2-4-acyl, preferably acetyl or

R ⁶and R⁷together with the nitrogen atom form phthalimido;

R ³denotes hydrogen, fluorine, chlorine, bromine, C_1-4-alkyl, preferably methyl, NH₂or cyclopropyl;

R ⁴denotes hydrogen, C_1-4-alkyl, preferably methyl, fluorine, chlorine, bromine or CF₃;

R ⁵denotes hydrogen, C_1-4-alkyl, preferably ethyl or methyl, fluorine, chlorine, bromine or CF₃; or

R ¹and R²together form a fused pyrazole of formula

wherein R ⁸is methyl, or a fused thiadiazole of the formula

wherein R ³, R⁴and R⁵are as hereinbefore defined, and preferably represent hydrogen; particularly those wherein

R ¹is hydrogen or methyl;

R ²is methyl, chlorine, CF₃, NH₂or N(CH₃)₂;

R ³is hydrogen, methyl, chlorine or bromine;

R ⁴is hydrogen;

R ⁵is hydrogen, methyl, methoxy, chlorine or bromine.

Particular mention should be made of the use of 2-(3-dimethylamino-2-methylphenylimino)imidazolidine, 2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine, 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine, 2-(3-amino-2- methylphenylimino)-imidazolidine or 2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine.

Examples of heterocyclic groups —NR ⁶R⁷are as follows:

pyrrole, Δ ²-pyrroline, Δ³-pyrroline, tetrahydropyrrole, pyrrolidine, pyrrolidinone, imidazole, imidazoline, 1,3-thiazole, piperidine, piperazine, 4-C_1-4-alkylpiperazine, C_1-4-alkylpiperazine, 2,5-diketopiperazine, preferably N-methylpiperazine, morpholine, thiomorpholine, phthalimido or succinimido.

Examples of alkyl within the above definitions, including those which are components of other groups, are branched or unbranched C _1-6-alkyl groups, e.g. methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, isobutyl, sec.-butyl and tert.-butyl, n-pentyl, isopentyl, neopentyl, hexyl and isohexyl.

Cycloalkyl generally represents a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms which may optionally be substituted with a halogen atom or several halogen atoms, a hydroxy group, an alkyl group, preferably methyl, which may be the same as or different from one another. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl.

Some of the imidazolines defined in general formula Ib are new. The invention therefore also relates to new substituted 2-phenylimino-imidazolidines, their use in pharmaceutical compositions and to processes for preparing them.

2-(Phenylimino)-imidazolidines, the preparation thereof and their use as pharmaceutical compositions are known, for example from German Patent Application Nos. DE-OS-19 29 950 and DE-OS-23 16 377, in which the hypotensive properties of the compounds described are particularly emphasised.

New substituted 2-(phenylimino)-imidazolidines of general formula II

have surprising pharmacological properties and are particularly suitable for treating urinary incontinence.

The invention thus relates to compounds of general formula II

wherein

R ¹denotes hydrogen, C_1-6-alkyl, preferably C_1-4-alkyl, most preferably methyl, C_3-6-cycloalkyl, preferably cyclopropyl, C_1-6-alkoxy, preferably C_1-4-alkoxy, most preferably methoxy, halogen, preferably chlorine or bromine, —CF₃or —OCF₃;

R ²denotes —NR⁶R⁷wherein

R ⁶denotes hydrogen, C_3-6-cycloalkyl, C_1-6-alkyl, preferably C_1-4-alkyl, most preferably methyl, C_2-4-acyl, most preferably acetyl;

R ⁷denotes hydrogen, cyclopropyl, C_3-6-cycloalkyl, C_1-6-alkyl, preferably C_1-4-alkyl, most preferably methyl, C_2-4-acyl, most preferably acetyl; or

R ⁶and R⁷together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated ring which may contain up to two additional heteroatoms selected from the group of oxygen, sulphur or nitrogen, whilst each additional nitrogen atom may be substituted by C_1-4-alkyl, preferably methyl; or R⁶and R⁷together with the nitrogen atom from phthalimido;

R ³denotes hydrogen, halogen, C_1-6-alkyl, preferably C_1-4-alkyl, most preferably methyl, C_1-6-alkoxy, preferably C_1-4-alkoxy, most preferably hydrogen, methoxy, —CF₃or —OCF₃;

R ⁴denotes hydrogen, C_1-6-alkyl, preferably C_1-4-alkyl, most preferably methyl, hydrogen or halogen;

R ⁵denotes hydrogen, C_1-6-alkyl, preferably C_1-4-alkyl, most preferably methyl, C_1-6-alkoxy, preferably C_1-4-alkoxy, most preferably methoxy, halogen, —CF₃or —OCF₃,

and the pharmacologically acceptable acid addition salts thereof, with the exception of 2-(3-diethylamino-2-methyl)-imidazolidine.

Preferred compounds of general formula II are those wherein

R ¹denotes hydrogen, C_1-4-alkyl, cyclopropyl, C_1-4-alkoxy, halogen, CF₃or —OCF₃;

R ²denotes —NR₆R₇wherein

R ⁶is hydrogen, C_3-6-cycloalkyl, C_1-4-alkyl or acetyl,

R ⁷is hydrogen, cyclopropyl C_1-4-alkyl or acetyl, or

R ⁶and R⁷together with the nitrogen atom form phthalimido;

R ³is hydrogen, halogen, C_1-4-alkyl, C_1-4-alkoxy, CF₃or —OCF₃;

R ⁴is hydrogen, C_1-4-alkyl, methyl, halogen;

R ⁵is hydrogen, C_1-4-alkyl, C_1-4-alkoxy, halogen, CF₃or —OCF₃; particularly those wherein

R ¹is hydrogen, C_1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C_1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, CF₃;

R ²denotes —NR₆R₇wherein

R ⁶is hydrogen, cyclopropyl, C_1-4-alkyl, preferably methyl,

R ⁷denotes hydrogen, C_1-4-alkyl, preferably methyl, or R⁶and R⁷together with the nitrogen atom form phthalimido;

R ³denotes hydrogen, C_1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C_1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, CF₃;

R ⁴denotes hydrogen, C_1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C_1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine;

R ⁵denotes hydrogen, C_1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C_1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, CF₃; particularly those wherein

R ¹is hydrogen or methyl,

R ²is —NR⁶R⁷wherein

R ⁶and R⁷independently of each other denote hydrogen, methyl or methoxy or

R ⁶and R⁷together with the nitrogen atom form phthalimido;

R ³denotes hydrogen, methyl, fluorine, chlorine or bromine;

R ⁴denotes hydrogen,

R ⁵denotes hydrogen, methyl, chlorine or bromine;

and the pharmacologically acceptable acid salts thereof, especially the hydrobromides or hydrochlorides thereof.

Particular mention should be made of the following compounds, for example:

2-(3-dimethylamino-2-methylphenylimino)imidazolidine, 2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine, 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine and 2-(3-amino-2-methylphenylimino)-imidazolidine.

The compounds of general formula I and II may be prepared according to analogous processes known per se from the prior art. A selection of the preferred processes are shown in the following synthetic schemes with reference to concrete Examples.

The preferred processes for preparing the compounds according to the invention will be explained with reference to individual Examples. [0090]
The methylation of the starting material, 2-methyl-3-nitro-aniline, may also be carried out analogously to the Leuckart-Wallach reaction using HCOOH/CH[0091] ₂O or using dimethylcarbonate instead of dimethylsulphate.
Compound 2 can be prepared by bromination of compound 1 under conventional reaction conditions [0092]
The following synthetic scheme illustrates the preparation of compounds 2, 3 and 4 [0093]
Other alternative methods of synthesis are illustrated below. [0094]
Compound 5 and compounds of similar structure can be prepared analogously to a method described by N. R. Ayyangar (Synthesis 1987, 64). [0095]

EXAMPLE 1

2-(3-Dimethylamino-2-methylphenylimino)imidazolidine [0096]
1st Step 83.6 g of 2-methyl-3-nitroaniline, 190 g of K[0097] ₂CO₃and 260 ml of water are together heated to 100° C. 27 ml of dimethylsulphate are added dropwise over 1 hour, then the mixture is heated for a further hour. After cooling to ambient temperature, the top layer is removed and the aqueous phase remaining is extracted four times with ether.
The combined ether extracts are combined with the upper layer, dried with MgSO[0098] ₄and evaporated down in vacuo. 73 g of N, N-dimethyl-2-methyl-3-nitroaniline are obtained.
2nd Step 73 g of N,N-dimethyl-2-methyl-3-nitroaniline are dissolved in 800 ml of methanol and hydrogenated at 20° C. under 5 bar of hydrogen using Raney nickel as catalyst. 57 g of 3-dimethylamino-2-methylaniline are obtained. [0099]
3rd Step 57 g of 3-dimethylamino-2-methyl-aniline. 1.15 liters of acetone, 36.6 g of KSCN and 43.8 ml of benzoylchloride are refluxed together for 3 hours. After cooling to ambient temperature the reaction mixture is poured onto 2.4 kg of crushed ice. The precipitate obtained is heated to 60° C. for 2 hours together with 85 g of KOH, 85 ml of water and 255 ml of ethanol. After the addition of 850 ml of water the ethanol is distilled off under reduced pressure. After the resulting precipitate has been worked up, 72 g of N-(3-dimethylamino-2-methylphenyl)-thiourea are obtained. [0100]
4th Step [0101]
72 g of the thiourea from Step 3 are taken up in 345 ml of methanol and after the addition of 22.6 ml of methyliodide the mixture is refluxed for 2 hours. The resulting solution is evaporated down under reduced pressure; 120 g of N-(3-dimethylamino-2-methylphenyl)-S-methyl-isothiourea hydroiodide are obtained. [0102]
5th Step [0103]
120 g of the thiourea from Step 4 in 350 ml of methanol are combined with 34.4 ml of 1,2-diaminoethane and refluxed for 17 hours. The reaction mixture is then evaporated down in vacuo and the residue is taken up in water. The pH is adjusted to 7 using dilute hydrochloric acid. The aqueous phase is extracted 3 times with ethyl acetate. Then the aqueous phase is made alkaline with 5N NaOH and extracted a further 3 times with ethyl acetate, these extracts are combined, dried with MgSO[0104] ₄and evaporated down in vacuo. An oil is obtained which is chromatographed over silica gel (eluant toluene, dioxane, ethanol, ammonia 10:8:3:1=“Super-T”).
17.9 g of 2-(3-dimethylamino-2-methylphenyl-imino)-imidazolidine are obtained. Melting point 116-118° C. [0105]

EXAMPLE 2

2-(6-Bromo-3-dimethylamino-2-methylphenylimino)Imidazolidine [0106]
6.55 g of 2-(3-Dimethylamino-2-methylphenyl-imino)-imidazolidine are dissolved in 75 ml of chloroform and 1.53 ml of bromine are added, with stirring, at 0° C. After 2 hours at 0° C. the solution is evaporated down under reduced pressure and the residue thus obtained is mixed with dilute hydrochloric acid. The aqueous solution is extracted twice with ether, then the aqueous phase is made alkaline with dilute NaOH and extracted three more times with ether. The combined ether extracts are evaporated down under reduced pressure and the residue remaining is worked up by chromatography (silica gel, eluant “Super-T” (Example 1)). [0107]
3.4 g of 2-(6-bromo-3-dimethylamino-2-methyl-phenylimino)-imidazolidine are obtained, Mp. 157 -158° C., as a white powder. [0108]
The following compounds were prepared analogously to the processes described: [0109]
2-(4-bromo-3-dimethylamino-2-methylphenylimino)-imidazolidine 2-(4,6-dibromo-3-dimethylamino-2-methylphenylimino)-imidazolidine 2-(6-chloro-3-dimethylamino-2-methylphenylimino)-imidazolidine 2-(3-acetylamino-6-chlorophenylimino)-imidazolidine, Mp. 236-238° C. 2-(2-methyl-3-phthalimidophenylimino)-imidazolidine, Mp. 189-190° C. 2-(6-chloro-3-phthalimidophenylimino)-imidazolidine, Mp. 239-241° C. 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine, Mp. 155-157° C. 2-(3-amino-4-fluorophenylimino)-imidazolidine, (2HCl ), Mp. 222° C. 2-(3-amino-4-methylphenylimino)-imidazolidine, (HCl), 2-(3-amino-6-methylphenylimino)-imidazolidine, (HCl), Mp. 194-196° C. 2-(3-amino-6-chlorophenylimino)-imidazolidine, (HCl), Mp. 197-198° C. 2-(3-amino-4,6-dibromo-2-methylphenylimino)-imidazolidine, Mp. 154-155° C. 2-(3-amino-2-methylphenylimino)-imidazolidine, (HCl ), Mp. 204-206° C. [0110]
The following compounds are specifically mentioned by name: [0111]
2-(2,6-diethylphenyl-imino)-imidazolidine 2-(2-chloro-6-methylphenylimino)-imidazolidine 2-(2,6-dichloro-phenylimino)-imidazolidine 2-(2-chloro-4-methylphenylimino)-imidazolidine 2-(2,4-dichlorophenylimino)-imidazolidine 2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine 2-(5fluoro-2-methylphenylimino)-imidazolidine 2-(3-bromo-2-methylphenylimino)-imidazolidine 2-(2-chloro-3-methylphenylimino)-imidazolidine 2-(2-fluoro-6-trifluoromethylphenylimino)-imidazolidine 2-(2-chloro-4-cyclopropylphenylimino)-imidazolidine 2-(4-amino-3,5-dibromophenylimino)-imidazolidine 2-(3-fluoro-4-methylphenylimino)-imidazolidine 2-(6-bromo-2-fluorophenylimino)-imidazolidine 4-(2-imidazolin-2-ylamino)-2-methylindazole 5-chloro-4-(imidazolin-2-yl-amino)-benzothiadiazole (Tizanidine) 2-[(2-chloro-4-methyl-3-thienyl)amino]-2-imidazoline (Tiamenidine) 2-(2,5-dichlorophenylimino)-imidazolidine [0112]
The compounds of general formulae I and II according to the invention may be converted into their physiologically acceptable acid addition salts in the usual way. Examples of acids suitable for salt formation include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, hydrofluoric acid, sulphuric acid, phosphoric acid, nitric acid or organic acids such as acetic acid, propionic acid, butyric acid, caproic acid, capric acid, valerie acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, maleic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulphonic acid and ethanephosphonic acid. [0113]
The corresponding hydrobromides and hydrochlorides are preferred as the acid addition salts. [0114]
Pharmaceutical compositions comprising the compounds described may be used in the form of capsules, suppositories, solutions, syrups, emulsions or dispersible powders. Corresponding tablets may be obtained, for example, by mixing the active substance or substances with known excipients such as inert diluents, e.g. calcium carbonate, calcium phosphate or lactose, disintegrates such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents for obtaining delayed release, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also consist of several layers. [0115]
Coated tablets may be produced accordingly, by coating cores made analogously to the tablets with agents conventionally used for tablet coating, e.g. collide or shellac, gum arabic, talc, titanium dioxide or sugar. In order to achieve delayed release or prevent incompatibilities, the core may also consist of several layers. Similarly, the tablet coating may consist of several layers in order to achieve delayed release, and the excipients mentioned for the tablets may be used. [0116]
Syrups of the active substances or combinations of active substances according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavour enhancer, e.g. ea flavoring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents, e.g. condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoate. [0117]
Injectable solutions are prepared in the usual way, e.g. by adding preservatives such as p-hydroxybenzoate or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid and are then transferred into injection vials or ampoules. [0118]
The capsules containing the active substance or combination of active substances may be prepared, for example, by mixing the active ingredients with inert carriers such as lactose or sorbitol and packaging the mixture in gelatine capsules. [0119]
Suitable suppositories may be produced, for example, by mixing with carriers provided for this purpose such as neutral fats of polyethyleneglycol or derivatives thereof. [0120]
For transdermal application the active substances according to the invention may be incorporated in suitable carriers (plasters), e.g. made of polyacrylates. Suitable adjuvants may be used in order to increase the release rate. [0121]
For oral administration a dosage of 1 to 50 mg is proposed as a therapeutically single dose. [0122]

Example A

Tablets



	2-(3-Dimethylamino-2-methylphenylimino)-	10 mg
	imidazolidine.HBr
	Lactose	65 mg
	Corn starch	125 mg
	sec. Calcium phosphate	40 mg
	Soluble starch	3 mg
	Magnesium stearate	4 mg
	Colloidal silica	4 mg
	Total	251 mg

Preparation [0124]
The active substance is mixed with some of the excipients, kneaded intensively with an aqueous solution of the soluble starch and granulated with a sieve in the usual way. The granules are combined with the remaining excipients and compressed into tablet cores weighing 250 mg which are then coated in the usual way using sugar, talc and gum arabic. [0125]

Example B

Ampoules [0126]

2-(3-Dimethylamino-2-methylphenylimino)- 1.0 mg

imidazolidine.HBr

Sodium chloride 18.0 mg

Sufficient distilled water to make up to 2.0 ml
Preparation [0127]
The active substance and sodium chloride are dissolved in water and transferred into glass ampoules under nitrogen. [0128]

Example C

Drops



2-(3-Dimethylamino-2-methylphenylimino)-	0.02	g
imidazolidine.HBr
Methyl p-hydroxybenzoate	0.07	g
Propyl p-hydroxybenzoate	0.03	g
Sufficient demineralised water to make up to	100	ml

Example D

Injectable Solution



	2-(3-Dimethylamino-2-methylphenylimino)-	1.5 parts
	imidazolidine.HBr
	Sodium salt of ethylenediamine tetraacetic acid	0.2 parts
	Sufficient distilled water to make up to	100.0 parts

Preparation [0131]
The active substance and the sodium salt of ethylenediamine tetraacetic acid are dissolved in sufficient water and topped up to the desired volume with water. The solution is filtered to remove any suspended particles and transferred into 2 ml ampoules under aseptic conditions. Finally, the ampoules are sterilized and sealed. Each ampoule contains 20 mg of active substance. [0132]
One advantage of the compounds described is that they act primarily on the urethra and have little or no effect on the cardiovascular system. [0133]
The selective pharmacological activity of the compounds according to the invention is demonstrated by the compound of Example 2—2-(6-bromo-3-dimethylamino-2-methylphenylimino)-imidazolidine—and a comparison compound, Phenyleprine, by measuring the intraluminal pressure of the urethra and blood pressure in the rabbit. [0134]
Female Japanese white rabbits (weighing 3.0 to 3.5 kg) are anaesthetised with urethane (1 g/kg i.p.). A polyethylene cannula is inserted in the urinary bladder by means of a small incision. The changes in the intraluminal pressure are recorded by means of balloon in the urethra which contains about 1.5 ml of water at 37° C. The intraurethral pressure is recorded on a polygraph by means of a pressure-voltage transducer. [0135]
The neck is opened up and the carotid artery is cannulated in order to measure the blood pressure and at the same time the trachea is intubated in order to maintain breathing. The changes in blood pressure are recorded on a polygraph by means of a pressure-voltage transducer. Heart rate is measured using a tachometer. [0136]
Phenylephrine and the compound of Example 2 are introduced into the Vena femoralis i.v. through a polyethylene cannula. Dosages of 30 μg/kg of Phenylephrine are compared with 10 μg/kg of the compound of Example 2. [0137]
Compared with Phenylephrine the compound of Example 2 according to the invention exhibits a potency which is higher by a factor of 2.73 with regard to the contraction of the urethra and with a duration of effect which is longer by a factor of 4.3. By comparison, the increase in blood pressure with the compound according to the invention is only 1.39 times that of the comparison compound Phenylephrine. It is notable that the increase in blood pressure is prolonged only to an insignificant degree (by a factor of 1.17) compared with Phenylephrine. These experiments show that the compounds according to the invention have a selective effect on the urethra. Being selective α[0138] _1L-adrenoreceptor agonists, the compounds according to the invention are suitable for treating problems of urinary incontinence, particularly for treating stress incontinence.
The test results are shown in Table 1. [0139]

TABLE 1

Contraction Increase

of the Duration in blood Duration

urethra of effect pressure of effect

Phenylephrine 100 100 100 100

Example 2 273 430 139 117

Claims

1. Use of α_1L-agonists for the preparation of pharmaceutical compositions for treating urinary incontinence, particularly stress incontinence.

2. Use according to claim 1, in which the α_1L-agonists have the general formula I

wherein

Y denotes an optionally substituted phenyl or napthyl group or

X denotes —NH—, —CH₂—, —OCH₂—, —O—CHCH₃—, —CH═N—NH—, —N═N—or —NZ—, wherein Z═—CH₂—CH═CH₂or cyclopropylmethyl,

and the pharmacologically acceptable acid addition salts thereof.

3. Use according to claim 2, wherein X in the compound of formula I denotes —NH—.

4. Use according to claim 2 or 3, wherein in the compound of formula I Y is an optionally substituted thienyl, furyl, pyrrole, tetrahydropyrrolyl, pyridyl, pyrazinyl, pyranyl, 1,3-thiazolyl, imidazolyl, imidazolinyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, isothiazolyl, pyrimidinyl, thiazolyl, thiadiazinyl or piperidinyl, which is bound to the group X via a carbon atom.

5. Use according to one of claims 2 to 4, wherein the compound of formula I is tiamenidine.

6. Use of phenylaminoimidazolines of general formula Ib

wherein R¹, R², R³, R⁴and R⁵denote, independently of one another:

hydrogen, C_1-6-alkyl, C_3-6-cycloalkyl, C_1-6-alkoxy, halogen, —CF₃, —OCF₃or —NR⁶R⁷wherein

R⁶denotes hydrogen, C_3-6-cycloalkyl, C_1-6-alkyl or C_2-4-acyl,

R⁷denotes hydrogen, C_3-6-cycloalkyl, C_1-6-alkyl or C_2-4-acyl; or

R⁶and R⁷together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated ring which may contain up to two additional heteroatoms from the group comprising oxygen, sulphur or nitrogen, whilst each additional nitrogen atom may be substituted by C_1-4-alkyl; or

R⁶and R⁷together with the nitrogen atom form phthalimido; or

R¹and R²together form a fused pyrazole of the formula

wherein R⁸is C_1-3-alkyl, or a fused thiadiazole of the formula

wherein R³, R⁴and R⁵are as hereinbefore defined, and the pharmacologically acceptable acid addition salts thereof, for preparing pharmaceutical composition for treating urinary incontinence, particularly stress incontinence.

7. Use of phenyliminoimidazolines of general formula Ib according to claim 6,

wherein R¹, R², R³, R⁴and R⁵independently of one another denote:

hydrogen, C_1-4-alkyl, preferably methyl, cyclopropyl, C_1-4-alkoxy, preferably methoxy, halogen, CF₃, —OCF₃or NR⁶R⁷wherein

R⁶is hydrogen, C_3-6-cycloalkyl, C_1-4-alkyl, preferably methyl, or acetyl,

R⁷denotes hydrogen, cyclopropyl, C_1-4-alkyl, preferably methyl, or acetyl; or

R⁶and R⁷together with the nitrogen atom form phthalimido; or

R¹and R²together form a fused pyrazole of the formula

wherein R⁸is methyl, or a fused thiadiazole of the formula

wherein R³, R⁴and R⁵are as hereinbefore defined, and preferably represent hydrogen.

8. Use of phenylaminoimidazolines of general formula Ib according to claim 6,

wherein R¹, R², R³, R⁴, R⁵independently of one another denote:

hydrogen, ethyl, methyl, cyclopropyl, fluorine, chlorine, bromine, —CF₃or —NR⁶R⁷wherein

R⁶denotes hydrogen, methyl or acetyl,

R⁷denotes hydrogen, methyl or acetyl; or

R⁶and R⁷together with the nitrogen atom form phthalimido; or

R¹and R²together form a fused pyrazole of the formula

wherein R⁸is methyl, or a fused thiadiazole of the formula

wherein R³, R₄and R⁵are as hereinbefore defined, and preferably represent hydrogen.

9. Use of phenylaminoimidazolines of general formula Ib according to claim 6,

wherein

R¹denotes hydrogen, ethyl, methyl, fluorine, chlorine, bromine or —CF_3,

R ²denotes methyl, fluorine, chlorine, bromine or —NR⁶R⁷, wherein

R⁶denotes hydrogen, C_1-4-alkyl, preferably methyl, C_2-4-acyl, preferably acetyl and

R⁷denotes hydrogen, C_1-4-alkyl, preferably methyl, C_2-4-acyl, preferably acetyl or

R⁶and R⁷together with the nitrogen atom form phthalimido;

R³denotes hydrogen, fluorine, chlorine, bromine, C_1-4-alkyl, preferably methyl, —NH₂or cyclopropyl;

R⁴denotes hydrogen, C_1-4-alkyl, preferably methyl, fluorine, chlorine, bromine or —CF_3;

R⁵denotes hydrogen, C_1-4-alkyl, preferably ethyl or methyl, fluorine, chlorine, bromine or —CF₃; or

R¹and R²together form a fused pyrazole of formula

wherein R⁸is methyl, or a fused thiadiazole of the formula

10. Use of phenylaminoimidazolines of formula Ib according to claim 6, wherein

R¹is hydrogen or methyl;

R²is methyl, chlorine, —CF₃, —NH₂or —N(CH₃)_2;

R³is hydrogen, methyl, chlorine or bromine;

R⁴is hydrogen;

R⁵is hydrogen, methyl, methoxy, chlorine or bromine.

11. Use of phenylaminoimidazolines of formula Ib according to claim 6, wherein the compound is 2-(3-dimethylamino-2-methylphenylimino)imidazolidine, 2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine, 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine, 2-(3- amino-2-methylphenylimino)-imidazolidine or 2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine.

12. New phenyliminoimidazolidines of general formula II

wherein

R¹denotes hydrogen, C_1-6-alkyl, C_3-6-cycloalkyl, C_1-6-alkoxy, halogen, —CF₃or —OCF_3;

R²denotes —NR⁶R⁷wherein

R⁶is hydrogen, C_3-6-cycloalkyl, C_1-6-alkyl, C_2-4-acyl,

R⁷is hydrogen, C_3-6-cycloalkyl, C_1-6-alkyl, C_2-4-acyl, or

R⁶and R⁷together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated ring which may contain up to two further heteroatoms from the group comprising oxygen, sulphur or nitrogen, whilst each additional nitrogen atom may be substituted by C_1-4-alkyl, preferably methyl; or R⁶and R⁷together with the nitrogen atom form phthalimido;

R³denotes hydrogen, halogen, C_1-6-alkyl, C_1-6-alkoxy, —CF₃or —OCF_3;

R⁴denotes hydrogen, C_1-6-alkyl or halogen;

R⁵denotes hydrogen, C_1-6-alkyl, C_1-6-alkoxy, halogen, —CF₃or —OCF_3,

13. Phenyliminoimidazolidines according to claim 12, wherein

R¹denotes hydrogen, C_1-4-alkyl, cyclopropyl, C_1-4-alkoxy, halogen, —CF₃or —OCF_3;

R²denotes —NR₆R₇wherein

R⁶is hydrogen, C_3-6-cycloalkyl, C_1-4-alkyl or acetyl,

R⁷is hydrogen, cyclopropyl C_1-4-alkyl or acetyl, or

R⁶and R⁷together with the nitrogen atom form phthalimido;

R³is hydrogen, halogen, C_1-4-alkyl, C_1-4-alkoxy, —CF₃or —OCF_3;

R⁴is hydrogen, C_1-4-alkyl, methyl, halogen;

R⁵is hydrogen, C_1-4-alkyl, C_1-4-alkoxy, halogen, —CF₃or —OCF_3.

14. Phenyliminoimidazolidines according to claim 12, wherein

R¹is hydrogen, C_1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C_1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, —CF_3;

R²denotes —NR₆R₇wherein

R⁶is hydrogen, cyclopropyl, C_1-4-alkyl, preferably methyl,

R⁷denotes hydrogen, C_1-4-alkyl, preferably methyl, or R⁶and R⁷together with the nitrogen atom form phthalimido;

R³denotes hydrogen, C_1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C_1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, —CF_3;

R⁴denotes hydrogen, C_1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C_1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine;

R⁵denotes hydrogen, C_1-3-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C_1-3-alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, —CF_3.

15. Phenyliminoimidazolines according to claim 12, wherein

R¹is hydrogen or methyl,

R²is —NR⁶R⁷wherein

R⁶and R⁷independently of each other denote hydrogen, methyl or methoxy or

R⁶and R⁷together with the nitrogen atom form phthalimido;

R³denotes hydrogen, methyl, fluorine, chlorine or bromine;

R⁴denotes hydrogen,

R⁵denotes hydrogen, methyl, chlorine or bromine.

16. A phenyliminoimidazolidine according to claim 12, which is 2-(3-dimethylamino-2-methylphenylimino)-imidazolidine, 2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine, 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine or 2-(3-amino-2-methylphenylimino)-imidazolidine.

17. Pharmaceutical preparation comprising a compound of general formula II according to one of claims 12 to 16 as well as conventional diluents, excipients and/or carriers.

18. Process for preparing pharmaceutical preparations according to claim 17, characterised in that compounds of general formula II are mixed with conventional galenic diluents, excipients and/or carriers.

19. Use of compounds of general formula II as defined in any one of claims 12 to 16 for preparing pharmaceutical compositions for the treatment of urinary incontinence, particularly stress incontinence.

20. Analogy processes for preparing compounds of general formula

according to any one of claims 12 to 16 characterised in that an aniline of general formula

wherein R¹to R⁵are as hereinbefore defined is reacted with one of the following compounds

or

and

the compounds obtained according to one of processes a-c are optionally converted into the pharmacologically acceptable acid addition salts thereof.