Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-11
2001-07-31
Higel, Floyd D. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S331500, C548S333100
Reexamination Certificate
active
06268389
ABSTRACT:
The present invention relates to the use of &agr;
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 (XL-subtype of the adrenergic receptor has a significant effect on the continence mechanism of urether tonicisation.
The invention relates to the use of &agr;
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
—, —OCH
2
—, —O—CHCH
3
—, —CH═N—NH—, —N═N— or —NZ—, wherein Z═—CH
2
—CH═CH
2
or 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
, R
2
1
R
3
, R
4
and R
5
denote, 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, —CF
3
, —OCF
3
or —NR R
7
wherein
R
6
denotes 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
7
denotes 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
6
and R
7
together 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
6
and R
7
together with the nitrogen atom form phthalimido;
or R
1
and R
2
together form a fused pyrazole of formula
wherein R
8
is C
1-3
-alkyl, preferably methyl;
or a fused thiadiazole of formula
wherein R
3
, R
4
and R
5
are 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
1
denotes hydrogen, ethyl, methyl, fluorine, chlorine, bromine or CF
3
,
R
2
denotes methyl, fluorine, chlorine, bromine or —NR
6
R
7
, wherein
R
6
denotes hydrogen, C
1-4
-alkyl, preferably methyl, C
2-4
-acyl, preferably acetyl and
R
7
denotes hydrogen, C
1-4
-alkyl, preferably methyl, C
2-4
-acyl, preferably acetyl or
R
6
and R
7
together with the nitrogen atom form phthalimido;
R
3
denotes hydrogen, fluorine, chlorine, bromine, C
1-4
-alkyl, preferably methyl, NH
2
or cyclopropyl;
R
4
denotes hydrogen, C
1-4
-alkyl, preferably methyl, fluorine, chlorine, bromine or CF
3
;
R
5
denotes hydrogen, C
1-4
-alkyl, preferably ethyl or methyl, fluorine, chlorine, bromine or CF
3
; or
R
1
and R
2
together form a fused pyrazole of formula
wherein R
8
is methyl,
or a fused thiadiazole of the formula
wherein R
3
, R
4
and R
5
are as hereinbefore defined, and preferably represent hydrogen; particularly those wherein
R
1
is hydrogen or methyl;
R
2
is methyl, chlorine, CF
3
, NH
2
or N(CH
3
)
2
;
R
3
is hydrogen, methyl, chlorine or bromine;
R
4
is hydrogen;
R
5
is 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
6
R
7
are as follows: pyrrole, &Dgr;
2
-pyrroline, &Dgr;
3
-pyrroline, tetrahydropyrrole, pyrrolidine, pyrrolidinone, imidazole, imidazoline, 1,3-thiazole, piperidine, piperazine, 4-C
1-4
-aclkylpiperazine, 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
1
denotes 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, —CF
3
or —OCF
3
;
R denotes -NR
6
R
7
wherein
R
6
denotes 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
7
denotes 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
6
and R
7
together 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 R
6
, and R
7
together with the nitrogen atom from phthalimido;
R
3
denotes hydrogen, halogen, C
1-6
-alkyl, preferably C
1-4
-alkyl, most preferably methyl, C
1-6
-alkoxy, preferably C
1-4
-alkoxy, most preferabl
Esser Franz
Kitagawa Hisato
Luettke Sven
Muramatsu Ikunobu
Staehle Helmut
Boehringer Ingelheim KG
Higel Floyd D.
Raymond R. P.
Stempel A. R.
Witkowski T. X.
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