CA2425563A1

CA2425563A1 - Novel m-amino-phenylimino-imidazolidine derivatives for treating urinary incontinence

Info

Publication number: CA2425563A1
Application number: CA002425563A
Authority: CA
Inventors: Franz Esser; Pascale Arielle Jane-Josee Pouzet; Hisato Kitagawa; Kenji Sakai; Ikunobu Muramatsu
Original assignee: Individual
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2000-10-14
Filing date: 2001-10-11
Publication date: 2002-04-25
Also published as: KR20030046503A; EP1328517A2; IL155338A0; AR035923A1; SK4342003A3; MXPA03003162A; AU2002215943A1; YU28203A; BR0114603A; EE200300177A; WO2002032876A2; ECSP034517A; CN1471514A; EA200300460A1; HUP0302245A2; PL361359A1; CZ20031333A3; NO20031697L; BG107711A; JP2004511547A

Abstract

The invention relates to m-amino-phenylimino-imidazolidine derivatives with a novel substituent pattern on the phenyl ring, of general formula (I) or of general formula (II), wherein R1 is F, Cl, Br, CH2F, CF2H or CF3, R2 is NR6R7, R6 being Me, Et, Pr or iPr and R7 being Me, Et or Pr; and R3, R4 and R5 are each, independently of each other, H, Me, F, Cl, Br, CH2F, CF2H and/or CF3 and if R4 is Me, F, Cl, Br, CH2F, CF2H or CF3, then R1 is additionally also H or Me; and or their pharmacologically compatible salts, to the use thereof for producing medicaments, especially for treating urinary incontinence, and to a method for producing the same.

Description

base 1/1153 ff ' ' Boehringer Ingelheim Pharma KG

74337pct.205 New m-amino-phenylimino-imidazolidine derivatives for treating urinary incontinence 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.
Prior art 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 haemostatic agents. Clonidine derivatives of this kind are also discussed in EP-A-0 070 084, EP-A-0081923, EP-A-0117102, EP-A-0 149 140, DE-A-2806811 or DE-A-2854659.
Furthermore, US-A-4587257 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) 1933 -1940 in another context discloses inter alia 2-(3-amino-2,6-dichlorophenylimino)-imidazolidines. US-A-4287201 for example describes 2-(3-diethylamino-2-methylphenylimino)-imidazolidines for increasing egg production in hens. Among others, WO

discloses aminophenyliminoimidazole derivatives which are used as alpha 2 agonists in anaesthesia, in the treatment of pain, high blood pressure, hyperglycaemia or as soporifics.
WO 96/32939, to which reference is hereby made 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 Case 1/1153 ff ' Boehringer Ingelheim Pharma KG

compounds described therein count as alpha-1 L-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-1 L-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) 324 - 327). On the other hand, in respect of clonidine itself, there is the contrary observation that this substance might even promote incontinence (Clin. BioLRes. 78 (1981 ) 101 -103). A
similar observation is expressed in Jpn. J. Pharmacol. 58 (4) (1992) 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.

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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 US-A-4 226 773 also point in this direction. According to this specification, pyrazolyl-imino-imidazole 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.
Description 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-1 L-agonists from the category of the phenylimino-imidazolidines 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 Case 1/1153 ff Boehringer Ingelheim Pharma KG

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:
Formula I:

N
R3 ~ ~ N
N
H
R2 R~
wherein R~ denotes F, CI, Br, CH2F, CF2H and/or CF3, R2 denotes: NR6R~, where R6 denotes Me, Et, Pr or iPr, R~ denotes Me, Et or Pr, R3, Ra, R5 independently of one another each denote H, Me, F, CI, Br, CH2F, CF2H and/or CF3 and in the event that R4 denotes Me, F, CI, Br or CF3, then R~ additionally also denotes H or Me.
Me denotes Methyl, CF3 denotes trifluoromethyl, CH2F denotes fluoromethyl, denotes difluoromethyl, Et denotes ethyl, Pr denotes propyl, iPr denotes isopropyl, H
denotes hydrogen, F denotes fluorine, CI denotes chlorine, Br denotes bromine and N represents nitrogen.

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Of these compounds with the hereinbefore-given structural formula, compounds of formula I are preferred wherein R~ denotes F, CI, Br or CF3, R2 denotes NRsR~, where R6 denotes Me or Et, R~ denotes Me or Et and R3, R4, R5 independently of one another each denote H, F, CI, Br and/or CF3.
Also preferred are those compounds of formula I wherein R~ may additionally also denote H or Me if R4 is F, CI, Br or CFs.
Particularly preferred are compounds of formula I wherein R~ denotes Me, R2 denotes NR6R~, where Rs denotes Me or Et, preferably Me, R~ denotes Me or Et, preferably Me, R3 denotes H, F, Br or CF3, R4 denotes CI, Br or CFs, R5 denotes H, Br or CFs and/or if R~ denotes CI, Br or CF3, then R4 denotes H.
Of these, the most preferred are compounds of formula I wherein R~ denotes Me, R2 denotes NR6R~, where Rs denotes Me, R~ denotes Me, R3 denotes H, F, preferably H, R4 denotes CI or Br, R5 denotes H or Br Case 1/1153 ff ' ' Boehringer Ingelheim Pharma KG

and/or if R~ denotes CI or Br, then R4 denotes H.
The compounds represented by formula I may be present in tautomeric equilibrium with the m-amino-anilino-2-imidazoline derivatives of formula II:
Formula II

R3 ~ ~ N \
H
N
R2 R~
in which the definitions of the groups R~, R2, R3, R4, R5, Rs and R~ are identical to the abovementioned compounds of formula I and all the preferences listed.
Therefore, the present invention also relates to the compounds which come under general formula II wherein the groups R~, R2, Rs, R4, R5, R6 and R~ fall within the scope of the definitions given under formula I. The same is true of the preferred ranges mentioned under formula I.
The compounds which fall within the scope of definitions of formulae I and II
are equally preferred, but independently of one another.
With regard to the nomenclature used within the scope of the present invention, it should be pointed out that the term "phen-1'-yl-2-imidazolidine" denotes compounds having the following structural element:

base 1 /1153 ff ' ~ Boehringer Ingelheim Pharma KG
H
N
N
This means that the atoms of the imidazole ring are numbered 1, 2, 3, etc., with one nitrogen atom being numbered 1 and the other nitrogen atom being numbered 3.
Consequently, the imino group is bound to the carbon atom, which is assigned the number 2. The atoms of the phenyl ring are numbered 1', 2', 3', etc., while the carbon atom of the phenyl ring which is bound to the imino group is designated 1' throughout.
It is expressly mentioned that the corresponding tautomers according to general formula II are also included, even when they are not specifically mentioned.
The same is true of all the m-amino-anilino-2-imidazolidine derivatives mentioned in the context of the present invention.
As representatives of all the compounds which come under general formula I or formula II, some m-dialkylamino-phen-1 '-yl-2-imidazolidines are mentioned hereinafter by way of example.
2'-Bromo-3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 1, preferably in the form of the hydrochloride, Me2N Me H
H / \ N N
H ~~
N
CI Br Gase 1/1153 ff ' Boehringer Ingelheim Pharma KG
3'-bromo-5'-diethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 2, preferably in the form of the hydrochloride, Et2N Me H
H / \ N N
H--~~ ~
N
Br H
3'-bromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 3, preferably in the form of the free base, Me2N Me H
N
H ~I
N
Br H
3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4, preferably in the form of the hydrochloride, Me2N Me H
H / \ N N
H~~ ~
N
CI H
2'-3'-dibromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 5, preferably in the form of the free base Me2N Me H
N
Br Br Case 1 /1153 ff ' Boehringer Ingelheim Pharma KG

~'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 6, preferably in the form of the free base Me2N CI
H
N
N
H H
4'-bromo-2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 7, preferably in the form of the free base Me2N CI
H
N
3r ~ \ H \
N
H H
2'-bromo-6'-chloro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 8, Me2N CI
H
N
N
H Br 5'-bromo-2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 9, 2'-bromo-5'-dimethylamino-6'-fluoro-phen-1'-yl-2-iminoimidazolidine 10, 3'-chloro-6'-fluoro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 11, 3'-chloro-4'-fluoro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 12, 6'-chloro-3'-fluoro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 13, 4'-chloro-3'-fluoro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 14, 3'-6'-dichloro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 15, 3'-4'-dichloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 16, Case 1/1153 ff ' Boehringer Ingelheim Pharma KG
3'-4'-difluoro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 17, 3'-6'-difluoro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 18, 5'-dimethylamino-6'-methyl-2'-trifluoromethyl-phen-1'-yl-2-iminoimidazolidine 19, 5'-dimethylamino-6'-methyl-3'-trifluoromethyl-phen-1'-yl-2-iminoimidazolidine 20.
Of these, the following are preferred:
2'-bromo-3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 1, 3'-bromo-5'-diethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 2, 3'-bromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 3, 3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4, 2'-3'-dibromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 5, 2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 6, 4'-bromo-2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 7, 2'-bromo-6'-chloro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 8, 5'-bromo-2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 9 and the pharmacologically acceptable salts thereof, particularly the hydrochlorides.
The following are particularly preferred:
2'-bromo-3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 1, 3'-bromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 3, 3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4, 2'-3'-dibromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 5 and the pharmacologically acceptable salts thereof, particularly the hydrochlorides.
Most preferred is 3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4 and the pharmacologically acceptable salts thereof, particularly the hydrochloride.
Another aspect of the present invention relates to the compounds of the abovementioned general formulae I and/or II and the pharmacologically compatible salts thereof with the groups R~ to R5 in all known definitions, as well as pharmaceutical compositions which contain these compounds.

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Within the framework of the present invention, the definition of all named compounds is not only to include the free bases but also the respective pharmaceutically-acceptable acid addition salts.
Acids suitable for this purpose may be both inorganic and organic by nature.
Examples of suitable acids include:
Hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, citric acid, lactic acid, acetic acid, propionic acid, malic acid, succinic acid, amino acid, particularly gfutamic acid or aspartic acid, carbohydrate acids and acids derived from carbohydrate. Salts of this kind may be important for galenic preparations both for increasing the stability, especially the long-term stability of the compounds and/or for increasing the bioavailability. Hydrochloride salts are preferred, either the monohydrochlorides or dihydrochlorides, depending on the particular compound.
The same is true of the preferred compounds.
As already described hereinbefore, within the framework of the present invention the abovementioned compounds are distinguished over the compounds known from the prior art by their pharmacological properties, particularly with regard to their bioavailability andlor metabolism. It goes without saying that the most preferred compounds are those which have a high level of activity and bioavailability and a low metabolic breakdown. Another feature which is crucial when selecting particularly suitable compounds for treating urinary incontinence is the selectivity with which the compound in question acts on bladder function without seriously affecting other bodily functions, particularly the cardiovascular system.
Within the framework of the present invention, the named compounds and their pharmacologically-compatible acid addition salts can be prepared in suitable pharmaceutical formulations. This includes all formulations capable of being used medicinally. These are, for example, solutions, suspensions, aerosols, powders, tablets, coated tablets, suppositories, creams, etc.
The compounds according to the invention, the pharmacologically acceptable acid addition salts thereof andlor pharmaceutical preparations containing them may be Case 1 /1153 ff ' ' Boehringer Ingelheim Pharma KG

used medicinally for treating diseases, especially diseases of the bladder, particularly in urinary incontinence. The compounds according to the invention are most preferably used for treating stress incontinence.
According to another aspect, the present invention relates to processes for preparing the abovementioned compounds, the pharmacologically acceptable acid addition salts and/or pharmaceutical preparations thereof, and the use of the compound described for preparing other pharmacologically active derivatives thereof.
Examples 1. Bioavailability In order to determine bioavailability the test substances were administered orally to a group of 8 male rats which had been fasted. As a comparison, the test substances were administered intravenously to animals in an identical second group. 1 ml blood samples were taken from the animals of both groups at specified times after administration (10 minutes, 30 minutes, 1 hour, 2 hours and 4 hours, and additionally after 6 hours in the case of the animals treated by oral route). The blood samples taken in each group were mixed together (8 ml). After further working up the content of the test substances in the blood for the particular time was determined from the plasma by HPLC (High Performance Liquid Chromatography) using standard methods and compared for the two groups.
Results compound bioavailability 4, hydrochloride11 5, dihydrochloride0.8%

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2. Metabolism To determine the metabolism the enzyme CYP2D6 was allowed to act on the test substances. After 30 minutes a check was made to see how much of the test substance put in had been broken down by the enzyme.
The rate of breakdown under the effect of the enzyme HLM / 60 minutes is tested analogously.
compound % breakdown of substratebreakdown of substrate after 30 minutes' after 60 minutes incubation with CYP2D6' incubation with HLM

1, hydrochloride40.5 32.1 3, base 33.9 17.0 4, hydrochloride36.5 17.1 5, dihydrochloride22.2 22.0 - -6 base _ 7.4 7 base 46.4 ~ 55.8 3. Efficacy and selectivity The efficacy and selectivity of the compounds is determined as follows:
compound activity in activity on humanselectivity the dog in the urethra dog 1, in the form of 109 100 0.92 the hydrochloride 3, in the form of 87 72 0.76 the base 4, in the form of 116 137 0.99 the hydrochloride 5, in the form of 89 113 0.71 the dihydrochloride Case 1/1153 ff ~ Boehringer Ingelheim Pharma KG

The maximum contraction in the dog and the activity on the human urethra are given as percentages of contraction compared with noradrenalin.
Selectivity in the dog: percentage contraction on the femoral artery in the dog at 10-5 M - percentage contraction on the carotid artery in the dog at 10-5 M.
4. Preparation The compounds according to the invention may be prepared as described in WO
96/32939 on pages 11 to 16, to which reference is hereby expressly made. Some of the compounds according to the invention may be prepared, for example, starting from the compounds described therein, particularly the 2'-bromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine described on page 16.
Preparation Examples Compound 1:
2'-Bromo-3'-chloro-5'-dimethylamino-6'-methyl-phen-1 '-yl-2-iminoimidazolidine 2 g of 2'-bromo-5'-dimethylamino-6'-methyl-phen-1-yl-2-iminoimidazolidine are dissolved at 0°C in 6.7 ml of sulphuric acid and combined with 0.8 g of 1,3-dichloro-5,5-dimethylhydantoin with stirring. The solution is heated to 55°C, then after 3 days diluted with ice, made alkaline with NH40H and extracted with ethyl acetate.
The ethyl acetate extract is concentrated by evaporation under reduced pressure and the residue remaining is worked up by chromatography (silica gel, eluant:
CH2C121methanol/conc. NH40H (90/10/1 )).
1.1 g of 2'-bromo-3'-chloro-5'-dimethylamino-6'-methyl-phen-1 '-yl-2-iminoimidazolidine 1 are obtained as a white powder, melting point 239-240°C.
' H NMR (250 MHz, CD30D, TMS = 0 ppm): 8 = 8.09 (1 H, s, aryl-H); 3.81 (4H, s, imidazolidine-CH2-); 3.27 (6H, s, N(CH3)2); 2.51 (3H, s, aryl-CHs);
exchangeable H
under the solvent peak 4.88 ppm. MS m/z 331/3331335 (87/100/42).

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Compound 3 3'-Bromo-5'-dimethylamino-6'-methyl-phen-1 '-yl-2-iminoimidazolidine 3 Step 1:
84 g of 2-methyl-3-nitroaniline are dissolved in 550 ml of THF. 53 ml of acetic anhydride are slowly added dropwise. The mixture is then stirred at 70°C. After about 1 hour THF is distilled off and the residue is combined with 250 ml of petroleum ether. The solid precipitate is filtered off and dried at 50°C.
106 g of N-acetyl-2-methyl-3-nitroaniline are obtained as a light brown powder.
Step 2:
106 g of N-acetyl-2-methyl-3-nitroaniline are dissolved in 500 ml of concentrated sulphuric acid. 93 g of 1,3-dibromo-5,5-dimethylhydantoin are added at RT and the mixture is stirred for about 24 hours at RT with the exclusion of light and for 2 hours at 50°C. 2.5 I of ice water are added and the crystals precipitated are filtered off, washed with water and dried.
67 g of a mixture of N-acetyl-4-brom-2-methyl-3-nitroaniline and N-acetyl-4,5-dibromo-2-methyl-3-nitroaniline are obtained as a white powder.
Step 3:
67 g of the above mixture and 300 ml of HCI (32%) are dissolved in a mixture of 300 ml of methanol and 300 ml of THF and the solution is stirred at 90°C.
After about 2 hours the organic solvent is distilled off. The crystalline precipitate is suction filtered and washed with HCI (0.5 M) and water. The crystals are suspended in about 500 ml of water. The aqueous phase is made alkaline with solid Na2COs and extracted with about 400 ml of ether. The organic phase is filtered and concentrated by evaporation under reduced pressure. The residue is recrystallised from hot ether.
18 g of 4-bromo-2-methyl-3-nitroaniline are obtained as orange-yellow crystals. In addition, about 32 g of a mixture of 4-bromo-2-methyl-3-nitroaniline and 4,5-dibromo-2-methyl-3-nitroaniline are obtained as orange-yellow crystals.

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Step 4:
5.8 g of paraformaldehyde and 15 ml of formic acid are dissolved in 15 ml of DMF
and heated to 90-100°C. A solution of 18 g of 4-bromo-2-methyl-3-nitroaniline in 15 ml of DMF is added dropwise within 10 minutes. After 2 hours the mixture is added to about 600 ml of ice water and the aqueous phase is extracted with 300 ml of ether.
The organic phase is washed with Na2C03 (1 M), filtered and evaporated down.
The product is purified by chromatography (silica gel, eluant: petroleum ether/ethyl acetate (40/60).
15 g of N,N-dimethyl-4-bromo-2-methyl-3-nitroaniline are obtained as a brownish-orange oil.
Step 5:
15 g of N,N-dimethyl-4-bromo-2-methyl-3-nitroaniline are dissolved in about 200 ml of THF and hydrogenated at 20°C under 5 bars of hydrogen using Raney nickel as catalyst. 12 g of 2-bromo-5-dimethylamino-6-methylaniline are obtained as a brown oil.
Step 6:
2.4 g of 2-bromo-5-dimethylamino-6-methylaniline and 3.2 g of N-acetyl-2-methylthioimidazolidinone are dissolved in 50 ml of ethanol at ambient temperature and the solution is refluxed. After about 6 hours the solvent is evaporated and the oily residue is crystallised from about 50 ml of ethyl acetate.
2.5 g of 3'-bromo-5'-dimethylamino~'-methyl-phen-1 '-yl-2-iminoimidazolidine 3 are obtained as a white powder, melting point 140-143°C.
'H NMR (250 MHz, CDC13, TMS = 0 ppm): 8 = 6,80 (2H, s, aryl-H); 4,39 (2H, s, broad, NH); 3,49 (4H, s, imidazolidine-CH2-); 2,66 (6H, s, N(CH3)2); 2,10 (3H, s, aryl-CH3). MS m/z 297/299 (100/100).

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Compound 4 3'-Chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4 0.37 g of 2'-bromo-3'-chloro-5'-dimethylamino-6'-methyl-phen-1-yl-2-iminoimidazolidine, 0.350 mg of zinc powder and 2 ml of HCI (10%) are dissolved in ml of ethanol and refluxed. After 1 hour the reaction mixture is filtered and the solvent is distilled off. The residue is treated with Na2C03 (1 M) while cooling and the product is extracted with ether. The ether extract is concentrated by evaporation under reduced pressure. The residue remaining is taken up in methanol and acidified with HCI.
0.2 g of 3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4 (NCI) are obtained as a (hygroscopic) white powder.
' H NMR (250 MHz, CD30D, TMS = 0 ppm): 8 = 7.93; 7.60 (2H, 2d (J = 1.8 Hz), aryl-H); 3.80 (4H, s, imidazolidine-CH2-); 3.31 (6H, s, N(CH3)2); 2.45 (3H, s, aryl-CH3);
exchangeable H under the solvent peak 4.88 ppm. MS m/z 253/255 (100/43).
Compound 5 2',3'-Dibromo-5'-dimethylamino-6'-methyl-phen-1 '-yl-2-iminoimidazolidine 5 Steps 1, 2, 3 and 5 are analogous to those of the synthesis of compound 3.
St- ep 4:
3.6 g of a mixture of 4-bromo-2-methyl-3-nitroaniline and 4,5-dibromo-2-methyl-nitroaniline are reacted as in Example 3, Step 4. The product is purified by chromatography (silica gel, eluant: cyclohexane/ethyl acetate (90/10).
1.9 g of N,N-dimethyl-4,5-dibromo-2-methyl-3-nitroaniline are obtained as a yellow powder.

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step 6:
0.9 g of 2,3-dibromo-5-dimethylamino-6-methylaniline and 0.4 g of N-acetyl-2-imidazolidinone are dissolved at RT in 8 ml of POC13 and the solution is stirred at 85°C. After about 8 hours the solvent is evaporated off and the residue is combined with 100 m I of water. The aqueous phase is extracted with ethyl acetate and the organic phase is made alkaline with Na2C03, filtered and evaporated down. The product is purified by chromatography (silica gel, eluant: ethyl acetate).
0.7 g of N-acetyl 2',3'-dibromo-5'-dimethylamino~'-methyl-phenyl-2-iminoimidazolidine are obtained as a white powder.
Step 7:
0.7 g of N-acetyl-2',3'-dibromo-5'-dimethylamino-6'-methyl-phenyl-2-iminoimidazolidine are refluxed in 60 ml of methanol. After 7 hours the solvent is evaporated. The residue is dissolved in CH2C12 and acidified with HCI (4N) (pH
1 ).
The crystals precipitated are suction filtered, washed with ether and dried.
0.68 g of 2',3'-dibromo-5'-dimethylamino-s'-methyl-phen-1 '-yl-2-iminoimidazolidine 5 are obtained as a white powder (melting point from 240°C, decomposition).
'H NMR (250 MHz, CD30D, TMS = 0 ppm): 8 = 8.19 (1 H, s, aryl-H); 3.81 (4H, s, imidazolidine-CH2-); 3.26 (6H, s, N(CH3)2); 2.48 (3H, s, aryl-CH3);
exchangeable H
under the solvent peak 4.89 ppm. MS m/z 375/377/379 (66/100/66).
Compound 6 2'-Chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 6 Step 1:
25 g of N,N-dimethyl-3-nitroaniline are dissolved in 225 ml of DMF. 20 g of N-chlorosuccinimide dissolved in 190 ml of DMF are slowly added dropwise and the solution is stirred at RT. After 24 hours the solvent is evaporated. About 500 ml of ice are added to the red residue. The suspension is extracted three times with about Case 1/1153 ff Boehringer Ingelheim Pharma KG

200 ml of diethylether. The ether phases are dried over Na2S04, filtered and evaporated down.
30.4 g of N, N-dimethyl-2-chloro-3-nitroaniline are obtained as a red oil. The crude product is used further without any additional purification.
Step 2:
30.4 g of N,N-dimethyl-2-chloro-3-nitroaniline are dissolved in about 300 ml of MeOH
and hydrogenated at 20°C and 5 bars of hydrogen using Raney nickel as catalyst.
The solvent is evaporated down and the product is purified by chromatography (silica gel, eluant: petroleum ether/ethyl acetate (3/1 )).
12.8 g of 2-chloro-3-dimethylamino-aniline are obtained as a brown oil.
Step 3:
4.4 g of 2-chloro-3-dimethylamino-aniline, 3.35 g of N-acetylimidazolidine and 30.5 ml of POC13 are mixed together and stirred at RT. After 12 hours the POC13 is distilled off and the residue is added to ice. The aqueous phase is made alkaline with a concentrated NH3 solution and extracted twice with 200 ml of methylene chloride.
The organic phases are dried, filtered and evaporated down. 6.2 g of 2'-chloro-3'-dimethylamino-phen-1'-yl-1-acetyl-2-iminoimidazolidine are obtained as a yellow oil.
The crude product is refluxed in methanol. After 2 hours the solvent is evaporated off.
The residue is dissolved in diethylether in an ultrasound bath. The yellow crystals precipitated are suction filtered, washed and dried.
2.2 g of 2'-chloro-3'-dimethylamino-phen-1'-yl-1-acetyl-2-iminoimidazolidine 6 are obtained as a white powder, melting point 146-148°C.
'H NMR (250 MHz, CD30D, TMS = 0 ppm): ~ = 7.11 (1 H, t, J = 7.9 Hz, aryl-H(5));
6.83; 6.74 (2H, 2dd, J = 7.9; 1.5 Hz, aryl-H(4/6)); 3.45 (4H, s, imidazolidine-CH2-);
3.73 (6H, s, N(CHs)2). MS m/z 239/241 (100/46).

Case 1/1153 ff ' Boehringer Ingelheim Pharma KG
Compound 7 4'-Bromo-2'-chloro-3'-dimethylamino-phen-1 '-yl-2-iminoimidazolidine 7 1 g of 2'-chloro-3'-dimethyfamino-phen-1'-yl-1-acetyl-2-iminoimidazofidine is dissolved in 10 ml of DMF and the mixture is cooled to 0°C. A solution of 0.75 g of N-bromosuccimide in 4.5 ml of DMF is slowly added dropwise and the resulting mixture is stirred at 0°C. After 5 hours 60 ml of water are added. The aqueous phase is extracted three times with 50 ml of ethyl ether. The organic phases are dried, filtered and evaporated down. The product is purified by chromatography (silica gel, eluant:
CH2C12/MeOH/ k. NH40H (90/10/1 )).
0.14 g of 4'-bromo-2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 7 are obtained as a yellow powder, melting point 150-155°C.
' H NMR (400 MHz, DMSO-d6, TMS = 0 ppm): s = 7.23; 6.54 (2H, 2d, J = 8.6 Hz, 2 aryl-H); 5.77 (2H, s, broad, NH); 3.28 (4H, s, imidazolidine-CH2-); 2.58 (6H, s, N(CH3)2). MS m/z 317/319/321 (85/100/36).
Compound 8 2'-Bromo-6'-chloro-5'-dimethylamino-phen-1 '-yl-2-iminoimidazolidine 8 Steps 1 and 2 are carried out as described for compound 6.
Step 3:
12.8 g of 2-chloro-3-dimethylamino-aniline are dissolved in 180 ml of DMF and stirred at 0°C. A solution of 13.4 g of N-bromosuccinimide in 80 ml of DMF is slowly added dropwise, so that the temperature does not rise above 2°C. The mixture is stirred for 5 hours at 0°C and then at RT. After 48 hours 700 ml of ice-water are added. The white precipitate is filtered off and the aqueous phase is extracted three times with 200 ml of diethyl ether. The organic phases are dried, filtered and evaporated down.
17.5 g of 2-bromo-6-chloro-5-dimethylamino-aniline are obtained as a brown oil and used further without any additional purification.

Case 111153 ff ' ' CA 02425563 2003-04-llBOehrlnger Ingelheim Pharma KG

Step 4:
6.6 g of KSCN are dissolved in 220 ml of acetone at 10°C. 8 ml of benzoyl chloride are added. The solution is refluxed for 10 minutes and then cooled to 10°C. A
solution of 17.5 g of 2-bromo-6-chloro-5-dimethylamino-aniline in 150 ml of acetone is slowly added dropwise. The mixture is refluxed. After 3 hours, 500 ml of ice water are added and the aqueous phase is extracted three times with 100 ml of ethyl acetate. The organic phases are dried, filtered and evaporated down. The residue is dissolved in 150 ml of ethanol and refluxed with 39 ml of aqueous KOH (50%).
After 2 hours the solvent is distilled off.
15 g of N-thioamido-2-bromo-6-chloro-5-dimethylamino-aniline are obtained and used further without any additional purification.
Step 5:
15 g of N-thioamido-2-bromo-6-chloro-5-dimethylamino-aniline and 4.6 ml of methyl iodide are stirred into 280 ml of methanol under reflux. After 2 hours the solvent is evaporated off. 18.9 g of an orange-coloured oil are obtained which is refluxed with 3.1 ml of ethylenediamine in 190 ml of acetonitrile. After 18 hours the solvent is distilled off. The residue is combined with 110 ml of HCI (1 M) and extracted with ethyl ether. The organic phase is dried, filtered and evaporated down. The product is purified by chromatography (silica gel, eluant: CH2C12/MeOH/ k. NH40H (90/10/1 )).
2.5 g of 2'-bromo-6'-chloro-5'-dimethylamino-phen-1 '-yl-2-iminoimidazolidine are obtained as a pink powder, melting point 142-145°C.
H NMR (250 MHz, CDC13, TMS = 0 ppm): 8 = 7.30 (1 H, d, J = 9.2 Hz, aryl-H(5));
6.74 (1 H, d, J = 9.2 Hz, aryl-H(4)); 3.98 (2H, s, broad, NH); 3.53 (4H, s, imidazolidine-CH2-); 2.87 (6H, s, N(CH3)2). MS m/z 318/3191321 (87/100/34).
Other compounds of the type described within the scope of this invention may be prepared analogously to the Examples provided above.

Claims

1. Use of a compound of general formula I or of general formula II for the preparation of medicaments for the treatment of urinary incontinence, especially stress incontinence wherein R1 denotes F, Cl, Br, CH2F, CF2H and/or CF3, R2 denotes: NR6R7, where R6 denotes Me, Et, Pr or iPr, R7 denotes Me, Et or Pr, R3, R4, R5 independently of one another each denote H, Me, F, Cl, Br, CH2F, CF2H and/or CF3 and in the event that R4 denotes Me, F, Cl, Br, CH2F, CF2H or CF3, then R1 additionally also denotes H or Me, and/or the pharmacologically acceptable salt thereof.

2. Use according to claim 1, characterised in that R1 denotes H, Me, F, Cl, Br or CF3, R2 denotes NR6R7, where R6 denotes Me or Et, R7 denotes Me or Et, R3 denotes H, F, Cl, Br or CF3, R4 denotes F, Cl, Br or CF3, R5 denotes H, F, Cl, Br or CF3.

3. Use according to claim 1 or 2, characterised in that R1 denotes Me, R2 denotes NR6R7, where R6 denotes Me or Et, R7 denotes Me or Et, R3 denotes H, F, Br or CF3, R4 denotes Cl, Br or CF3, R5 denotes H, Br or CF3.

4. Use according to claim 1, 2 or 3, characterised in that R1 denotes Me, R2 denotes NR6R7, where R6 denotes: Me, R7 denotes Me, R3 denotes H or F, R4 denotes Cl or Br, R5 denotes H or Br.

5. Use according to claim 1, characterised in that R1 denotes F, Cl, Br or CF3, R2 denotes NR6R7, where R6 denotes Me or Et, R7 denotes: Me or Et, R3 denotes H, F, Cl, Br or CF3, R4 denotes H, F, Cl, Br or CF3, R5 denotes H, F, Cl, Br or CF3.

6. Use according to claim 1 or 5, characterised in that R1 denotes Cl, Br or CF3, R2 denotes NR6R7, where R6 denotes Me or Et, R7 denotes Me or Et, R3 denotes H, F, Br or CF3, R4 denotes H, R5 denotes H, Br or CF3.

7. Use according to claim 1, 5 or 6, characterised in that R1 denotes Cl or Br, R2 denotes: NR6R7, where R6 denotes Me, R7 denotes Me, R3 denotes H, F, R4 denotes H, R5 denotes H or Br.

8. Use according to claim 1, characterised in that the compound is 2'-bromo-3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 1, 3'-bromo-5'-diethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 2, 3'-bromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 3, 3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4, 2'-3'-dibromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 5, 2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 6, 4'-bromo-2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 7, 2'-bromo-6'-chloro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 8 and/or 5'-bromo-2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 9, a tautomer thereof and/or a corresponding pharmacologically-compatible salt.

9. Use according to claim 1, 2, 3 or 8, characterised in that the compound is 2'-bromo-3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 1, 3'-bromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 3, 3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4 and/or 2'-3'-dibromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 5, a tautomer thereof and/or a corresponding pharmacologically-compatible salt.

10. Use according to claim 1, 2, 3, 8 or 9, characterised in that the compound is 3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4, a tautomer thereof and/or a corresponding pharmacologically-compatible salt.

11. Use according to claim 1, 5, 6, 7 or 8, characterised in that the compound is 2' chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidin 6, a tautomer thereof and/or a corresponding pharmacologically-compatible salt.

12. Use according to claim 1, 5, 6 or 8, characterised in that the compound is 4'-bromo-2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 7, a tautomer thereof and/or a corresponding pharmacologically-compatible salt.

13. Use according to one of the preceding claims, characterised in that the compound according to formula I occurs as an imino-imidazolidine.

14. Use according to one of the preceding claims, characterised in that the compound according to formula II occurs as an amino-imidazoline.

15. Compound according to one of claims 1 to 14.

16. A medicament preparation containing a compound and/or the pharmacologically-compatible salt thereof according to claim 15.

17. A process for the preparation of a compound and/or the pharmacologically-compatible salt thereof according to claim 15.

18.A method for the treatment of diseases of the bladder, especially urinary incontinence, using a compound according to claim 15 and/or a pharmacologically-compatible salt thereof.