2′-Halo-3′,5′-dialkoxyphen-1′-yl-imi...

Details 2′-Halo-3′,5′-dialkoxyphen-1′-yl-imi... 2′-Halo-3′,5′-dialkoxyphen-1′-yl-imi...

2003-01-24

2004-03-09

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S333100

Reexamination Certificate

active

06703409

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to 2′-halo-3′,5′-dialkoxyphen-1′-yl-imino-2-imidazolidine, the tautomeric 2′-halo-3′,5′-dialkoxyanilino-2-imidazolines and/or the pharmacologically acceptable salts thereof and their use as pharmaceutical compositions, particularly for treating urinary incontinence.
BACKGROUND
Numerous examples of the category of phenylimino-imidazoles and -imidazolidines are known. The best known is possibly clonidine, 2′,6′-dichlorophen-1′-yl-imino-2-imidazolidine.
With regard to the compound according to the invention, the number of structurally similar examples known is limited by their nature.
DE 2220906 describes a category of phenylimino-imidazoles of therapeutic benefit to which the compound according to the invention are structurally related. The compounds according to the invention or their properties in relation to the treatment of urinary incontinence are not disclosed.
JP 48-76870 discloses a category of phenylimino-imidazoles to which the compound according to the invention are structurally related. The compounds described therein count as vasoconstrictors and hypotensive agents. Specifically, 2-(phenylamino)-2-imidazoline and clonidine are disclosed.
The compounds according to the invention or their properties in relation to the treatment of urinary incontinence are not disclosed.
WO 96/32939, to which reference is hereby expressly made in its entirety, discloses a category of phenylimino-imidazolidines for the treatment of urinary incontinence to which the compound according to the invention are structurally related. The compounds according to the invention are not disclosed.
EP0887346 discloses another class of phenylimino-imidazolidines, phenylmethylen-imidazolidines, phenyloxymethylen-imidazolidines in that the phenyle-group mandatorily is substituted by an ureido (RR′NCONR″—), an sulfamoylaminio-group (RR′NSO
2
NR″—) or sulfonamido- (RR′NSO
2
—)-group. Theses compounds shall have an alpha 1L agonistic effect.
U.S. Pat. No. 4,244,957 discloses phenyliminoimidazolidines which are substituted at one of imiazolidine-nitrogen atom for treating hypertension. The compounds of the present invention are not disclosed.
DE2521709 discloses phenyliminoimidazolidines which again are substituted at one of imiazolidine-nitrogen atom for treating hypotension. The compounds of the present invention are not disclosed.
EP0202461 discloses phenyliminoimidazolidines which are substituted at an imino-nitrogen atom for treating heart-diseases. The compounds of the present invention are not disclosed.
FR2208671 discloses phenyliminoimidazolidines which are substituted at the imino-nitrogen atom and/or an imiazolidine-nitrogen atom which shall have hypotensive, sedative, anagetic and antisecretoric effect. The compounds of the present invention are not disclosed.
For the sake of completeness a search report also made reference to EP0902218, which however does not deal with chemical compounds.
In the context of the present invention, by incontinence is meant the involuntary release of urine, i.e. weakness of the urethral contraction. The various forms of urinary incontinence include urge incontinence, reflex incontinence, overflow incontinence and stress or load incontinence. The most common forms of urinary incontinence include load incontinence or stress incontinence. These affect women in particular after more or less difficult childbirth. The reason for this is that pregnancy and childbirth can easily lead to weakening of the pelvic floor. Other causes of incontinence may be found, for example, in damage to the nerves of the pelvic floor, a congenitally short urinary tract or damage to the sphincter muscle.
SUMMARY OF THE INVENTION
It has now surprisingly been found that the compounds of formula I have an outstanding agonistic effect on alpha-1L-receptors. The substances have a highly selective effect on the urethra and prevents urinary incontinence.
One aspect of the present invention is therefore to develop a drug with which urinary incontinence can be treated better, i.e more selectively.
Another aspect of the invention consists in developing drugs which act on the contracting mechanisms of the urethra without seriously affecting other organs such as peripheral blood vessels.
Another objective is to develop a non-toxic drug with few side effects.
Overall, therefore, the aim of the present invention is to find an active substance with one or more of the abovementioned profiles and to develop a suitable medicament from it.
DETAILED DESCRIPTION OF THE INVENTION
The compounds according to the invention are represented by the following structure (formula I):
whereby
R stands for F, Cl, Br, CF
3
, CH
2
F or CHF
2
,
R
1
and R
2
independently of each other may be any C
1
to C
6
-alkyl, like methyl (Me), ethyl (Et), propyl (Pr), isopropyl (iPr), 1-butyl (Bu), 2-butyl (2-Bu), tert.butyl (tBu), pentyl (Pen), hexyl (Hex) etc.
Preferred are compounds with
R being F, Cl, Br or CF
3
and
R
1
and R
2
independently of each being an unbranched C
1
to C
6
-alkyl.
More preferred are compounds with
R being Cl, Br or CF
3
and
R
1
and R
2
both being the same unbranched C
1
to C
4
-alkyl.
Even more preferred are compounds with
R being Cl or Br and
R
1
and R
2
both being methyl, ethyl or propyl.
Most preferred are compounds with
R being Cl and
R
1
and R
2
both being methyl or ethyl.
In the context of the present invention these compounds represented by formula I are named as 2′-halo-3′,5′-dialkoxyphen-1′-yl-imino-2-imidazolidine. In the context of the present invention the term “imidazolidine” stands for 4,5-dihydroimidazole, whereby one starts counting by one nitrogen atom and goes to the next nitrogen atom by passing the one-carbon-bridge. In case of any conflicts between a representation by a structure-formula or by a name, the representation by the structure formula shall prevail.
Likewise, the compounds may also be present in the tautomeric form according to Formula II:
whereby the substituents R, R
1
and R
2
, are as defined above.
In the context of the present invention these compounds represented by formula II are named as 2′-halo-3′,5′-dialkoxyphen-1′-yl-amino-2-imidazolines (2′-halo-3′,5′-dialkoxyanilino-2-imidazolines). In case of any conflicts between a representation by a structure-formula or by a name, the representation by the structure formula shall prevail.
Among these compounds the preferred compounds are
2′-chloro-3′,5′-dimethoxyphen-1′-yl-imino-2-imidazolidine (based on formula I R=Cl, R
1
=Me, R
2
=Me),
2′-chloro-3′,5′-diethoxyphen-1′-yl-imino-2-imidazolidine, (based on formula I R=Cl, R
1
=Et, R
2
=Et),
2′-chloro-3′,5′-dipropyloxyphen-1′-yl-imino-2-imidazolidine, (based on formula I R=Cl, R
1
=Pr, R
2
=Pr),
2′-bromo-3′,5′-dimethoxyphen-1′-yl-imino-2-imidazolidine, (based on formula I R=Br, R
1
=Me, R
2
=Me),
2′-bromo-3′,5′-diethoxyphen-1′-yl-imino-2-imidazolidine, (based on formula I R=Br, R
1
=Et, R
2
=Et),
2′-bromo-3′,5′-dipropyloxyphen-1′-yl-imino-2-imidazolidine, (based on formula I R=Br, R
1
=Pr, R
2
=Pr),
the tautomeric forms of any of theses compounds according to formula II or pharmacologically acceptable salts of any of the two tautomeric forms of theses compounds.
Among these compounds are more preferred
2′-chloro-3′,5′-dimethoxyphen-1′-yl-imino-2-imidazolidine, (based on formula I R=Cl, R
1
=Me, R
2
=Me),
2′-bromo-3′,5′-dimethoxyphen-1′-yl-imino-2-imidazolidine, (based on formula I R=Br, R
1
=Me, R
2
=Me),
the tautomeric forms of these compounds according to formula II or pharmacologically acceptabl

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