Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-23
2004-06-08
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S331500
Reexamination Certificate
active
06747051
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to m-amino-phenylimino-imidazolidine derivatives with a new pattern of substituents at the phenyl ring and the use of m-amino-phenylimino-imidazolidine derivatives for the preparation of pharmaceutical compositions, particularly for treating urinary incontinence, and processes for preparing them.
BACKGROUND OF THE INVENTION
The compounds described within the scope of the present invention belong to the category of the m-amino-phenylimino-imidazolidines. Similar compounds are known from the prior art.
Thus, for example, EP-A-0 236 636, inter alia, describes m-amino-phenylimino-imidazolidine derivatives with a primary amino function in the 3 position and their use as hemostatic agents. Clonidine derivatives of this kind are also discussed in EP-A-0 070 084, EP-A-0081923, EP-A-01 17102, EP-A-0 149 140, DE-A-2806811 or DE-A-2854659. Furthermore, U.S. Pat. No. 4,587,257 and EP-A-0081924 disclose m-amino-phenylimino-imidazolidine derivatives having a primary or acetylated amino function which can be used in ophthalmology. Biochem. Pharmacol. 32 (12) (1983), pp. 1933-1940, in another context discloses, inter alia, 2-(3-amino-2,6-dichlorophenylimino)imidazolidines. U.S. Pat. No. 4,287,201, for example, describes 2-(3-diethylamino-2-methylphenylimino)imidazolidines for increasing egg production in hens. Among others, WO 95/19968 discloses aminophenyliminoimidazole derivatives which are used as alpha 2 agonists in anesthesia, in the treatment of pain, high blood pressure, or hyperglycemia, or as soporifics.
WO 96/32939, which is hereby incorporated by reference in its entirety, discloses phenylimino-imidazoles, including those in which the phenyl ring has a primary or tertiary amine, an amide or imide in the meta position to the imino function. The compounds described therein count as alpha-1L-agonists and can advantageously be used in this capacity for treating urinary incontinence.
By incontinence is meant the involuntary release of urine, i.e., weakness of the bladder. 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.
The use of alpha-IL-agonists in the treatment of urinary incontinence is advantageous because they act selectively on the adrenoceptors of the bladder and thus exert a major influence on the tone of the ureter without significantly affecting the cardiovascular system.
In the prior art the possibility of using imidazole derivatives to treat incontinence has long been discussed. Surprisingly, there are opinions which indicate that many imidazole derivatives can counteract weakness of the bladder, whereas other authors have observed an apparently directly opposite effect, namely that substances of this kind can relieve obstruction of the bladder. Still other authors, talking about some of the same substances, report that they would have no effect at all on bladder function.
Thus, it is reported that alpha 2 agonists such as clonidine would have a positive effect on nocturnal incontinence (Urology, 43 (3) (1994), pp. 324-327). On the other hand, in respect of clonidine itself, there is the contrary observation that this substance might even promote incontinence (Clin. Biol. Res. 78 (1981), pp. 101-103) and a similar observation is expressed in Jpn. J. Pharmacol. 58 (4) (1992), pp. 339-346. The authors find that clonidine does not have a distinct influence on bladder function but that phenyl-ethanol-amines such as phenylephrine, midodrine or ST 1059, which are similar to adrenaline, and are all alpha 1 agonists, do have such an effect. EP-A-0 416 841 also deals with the influence of alpha agonists on bladder function. It describes how alpha 1 adrenoceptor-blocking substances could be used to treat obstruction of the bladder. The observations according to U.S. Pat. No. 4,226,773, also point in this direction. According to this specification, pyrazolyliminoimidazole derivatives can be used to promote the release of urine. Other alpha 1 adrenergic imidazoles such as thiophene-pyrroles, for example, may be used to treat urinary incontinence (EP-A-0 599 697).
These different observations from the prior art lead one to conclude that up till now it has been impossible to predict the influence of imidazole derivatives on bladder function.
SUMMARY OF THE INVENTION
Compounds which may be used to treat urinary incontinence not only have to be sufficiently effective but should also have as few side effects as possible. In other words, if possible they should act selectively on the bladder only. Undesirable side effects include, among other things, a negative effect on the cardiovascular system. For particularly effective treatment of urinary incontinence, the bioavailability of the substances and their metabolism are also of particular importance. The bioavailability should be as great as possible and the metabolism should be such that the substances are not broken down too rapidly on the one hand and no toxic compounds or other compounds having undesirable pharmacological properties in this context are formed on the other hand.
It is therefore an objective of the present invention to find new alpha-1L-agonists from the category of the phenyliminoimidazolidines which are identical or similar in their activity to the compounds known from the prior art, which act selectively on the bladder without substantially affecting the cardiovascular system and have enhanced qualities in terms of their bioavailability or metabolism.
Surprisingly, it has been found that the m-amino-phenylimino-imidazolidines according to the invention meet the objective of the present invention and are therefore particularly suitable for treating urinary incontinence. For the use of these compounds in connection with urinary incontinence it is essential on the one hand that the amino group is a tertiary amine and on the other hand that the other positions of the phenyl ring are substituted in a particular way.
DETAILED DESCRIPTION OF THE INVENTION
According to the invention, the m-amino-phenylimino-2-imidazolidine derivatives of general formula I are used for the preparation of medicaments for the treatment of urinary incontinence:
wherein:
R
1
denotes F, Cl, Br, CH
2
F, CF
2
H, and/or CF
3
;
R
2
denotes NR
6
R
7
, where
R
6
denotes Me, Et, Pr or iPr,
R
7
denotes Me, Et or Pr; and
R
3
, R
4
, and R
5
independently of one another each denote H, Me, F, Cl, Br, CH
2
F, CF
2
H and/or CF
3
, and, in the event that R
4
denotes Me, F, Cl, Br or CF
3
, then R
1
additionally also denotes H or Me.
Me denotes methyl, CF
3
denotes trifluoromethyl, CH
2
F denotes fluoromethyl, CF
2
H denotes difluoromethyl, Et denotes ethyl, Pr denotes propyl, iPr denotes isopropyl, H denotes hydrogen, F denotes fluorine, Cl denotes chlorine, Br denotes bromine, and N represents nitrogen.
Of these compounds with the hereinbefore-given structural formula, compounds of formula I are preferred wherein:
R
1
denotes F, Cl, Br, or CF
3
;
R
2
denotes NR
6
R
7
, where
R
6
denotes Me or Et,
R
7
denotes Me or Et; and
R
3
, R
4
, and R
5
independently of one another each denote H, F, Cl, Br, and/or CF
3
.
Also preferred are those compounds of formula I wherein R
1
may additionally also denote H or Me if R
4
is F, Cl, Br or CF
3
.
Particularly preferred are compounds of formula I wherein:
R
1
denotes Me;
R
2
denotes NR
6
R
7
, where
R
6
denotes Me or Et, preferably Me,
R
7
denotes Me or Et, preferably Me;
R
3
denotes H, F, Br or CF
3
;
R
4
denotes Cl, Br or CF
3
; and
R
5
denotes H, Br or CF
3
,
and/or if R
1
denotes Cl, Br or CF
3
, then R
4
denotes H
Esser Franz
Kitagawa Hisato
Muramatsu Ikunobu
Pouzet Pascale
Sakai Kenji
Boehringer Ingelheim Pharma GmbH & Co. KG
Bottion Anthony P.
McKane Joseph K.
Raymond Robert P.
Saeed Kamal
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