WO2002032876A2

WO2002032876A2 - Novel m-amino-phenylimino-imidazolidine derivatives for treating urinary incontinence

Info

Publication number: WO2002032876A2
Application number: PCT/EP2001/011764
Authority: WO
Inventors: Franz Esser; Pascale Arielle Jane-Josee Pouzet; Hisato Kitagawa; Kenji Sakai; Ikunobu Muramatsu
Original assignee: Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority date: 2000-10-14
Filing date: 2001-10-11
Publication date: 2002-04-25
Also published as: MXPA03003162A; NO20031697L; KR20030046503A; SK4342003A3; YU28203A; CA2425563A1; EE200300177A; PL361359A1; EP1328517A2; AR035923A1; JP2004511547A; CN1471514A; IL155338A0; CZ20031333A3; WO2002032876A3; ECSP034517A; BG107711A; HUP0302245A2; EA200300460A1; BR0114603A

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

New m-amino-phenylimino-imidazolidine derivatives for the treatment of urinary incontinence

The present invention relates to m-aminophenylimino-imidazolidine derivatives with a new substituent pattern on the phenyl ring and to the use of m-aminophenylimino-imidazolidine derivatives for the production of medicaments, in particular for the treatment of urinary incontinence and the production process thereof.

State of the art

The compounds described in the context of the present invention belong to the class of m-amino-phenylimino-imidazolidines. Similar compounds are known from the prior art.

For example, EP-A-0 236 636 inter alia m-amino-phenylimino-imidazolidine derivatives, with a primary amino function in the 3-position and their use as hemostatic agents. Such clonidine derivatives are also described in EP-A-0 070 084, EP-A-0081923, EP-A-0117102, EP-A-0 149 140, DE-A-2806811 or DE-A -2854659 treated.

Furthermore, US-A-4587257 and EP-A-0081924 disclose m-aminophenyliminoimidazolidine derivatives with primary or acetylated amino function which can be used in ophthalmology. Biochem. Pharmacol. 32 (12) (1983) 1933-1940 discloses in a different context, among other things, 2- (3-amino-2,6-dichlorophenylimino) imidazolidine. US-A-4287201 describes, for example, 2- (3-diethylamino-2-methylphenylimino) imidazolidine for increasing the egg production. WO 95/19968 discloses inter alia aminophenyliminoimidazole derivatives which are used as alpha 2 agonists in anesthesia, in the treatment of pain, high blood pressure, hyperglucemia or as a sleep aid.

WO 96/32939, to which reference is hereby made in full, discloses phenylimino-imidazoles, including those in which the phenyl ring in the meta position to the imino function has a primary or tertiary amine, an amide or imide. These Compounds described are considered alpha-1 L agonists and can advantageously be used in this property for the treatment of urinary incontinence.

Incontinence is an involuntary loss of urine, i.e. a bladder weakness. The various manifestations of urinary incontinence include urge incontinence, reflex incontinence, overflow incontinence and stress or stress incontinence. One of the most common forms of urinary incontinence is stress incontinence or stress incontinence. This affects women in particular after more or less difficult births. The reason for this is that pregnancy and childbirth can easily weaken the pelvic floor. Other causes of incontinence can include innervation disorders of the pelvic floor, an inborn urethra that is too short, or injuries to the sphincter.

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 significant influence on the urethertonization without significantly influencing the cardiovascular system.

The possibility of using imidazole dehvates for the treatment of incontinence has been discussed for some time in the prior art. Surprisingly, there are both statements that indicate that some imidazole dehvates can counteract bladder weakness, while other authors observe an apparently almost opposite effect, namely that such substances can provide relief when the bladder is closed. Still other authors report the same substances, in part, that they would have no effect on bladder function.

It is reported that alpha 2 agonists such as clonidine would have a positive effect on night incontinence (Urology, 43 (3) (1994) 324-327). On the other hand, with clonidine in particular there is a contrary observation that this substance can even promote incontinence (Clin. Biol. Res. 78 (1981) 101-103). A similar observation is made in Jpn. J. Pharmacol. 58 (4) (1992) 339-346 uttered. The authors find that clonidine has no clear influence on bladder function, but phenylethanolamines, such as phenylephrine, midodrine or ST 1059, which are similar to adrenaline, are all alpha 1 agonists. EP-A-0 416 841 also deals with the influence of alpha agonists on bladder function. It describes that alpha 1 adrenoceptor blocking substances could be used to treat bladder occlusion. The observations according to US Pat. No. 4,226,773 also point in this direction. According to this document, pyrrazolyl-imino-imidazole derivatives can be used to promote urination. Other alpha 1 adrenergic imidazoles such as thiophene pyrroles can also be used to treat urinary incontinence (EP-A-0 599 697).

These different observations from the prior art lead to the conclusion that there is currently no way to predict the influence of imidazole dehvates on bladder function.

Description of the invention

Compounds that can be used to treat urinary incontinence must not only be sufficiently effective, but should also show as few side effects as possible. In other words, they should only act selectively on the bladder. Undesirable side effects include a negative impact on the cardiovascular system. The bioavailability of the substances and their metabolism are also of particular importance for a particularly effective treatment of urinary incontinence. The bioavailability should be as high as possible and the metabolism should be such that, on the one hand, the substances are not broken down too quickly and, on the other hand, no toxic or other compounds with undesirable pharmacological properties are formed.

It is therefore an object of the present invention to find new alpha- 1 L agonists from the class of the phenyimino-imidazolidines which are identical or similar in their action to the compounds known from the prior art, act selectively on the bladder without the To significantly influence the cardiovascular system and have better properties in terms of bioavailability or metabolism. Surprisingly, it was found that the m-aminophenylimino-imidazolidines mentioned in main claim 1 fulfill the object of the present invention and are therefore particularly suitable for the treatment of urinary incontinence. For the usability of these compounds in connection with urinary incontinence, it is crucial, 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 certain way.

Detailed description of the invention

According to the invention, m-amino-phenylimino-2-imidazolidine derivatives of the general formula I are used to produce medicaments for the treatment of urinary incontinence:

Formula I:

With

Ri: F, Cl, Br, CH ₂ F, CF ₂ H or CF ₃ ,

R ₂ : NR ₆ R ₇ , with

R ₆ : Me, Et, Pr or iPr,

R ₇ : Me, Et or Pr, R ₃ , R4, R ₅ : are each independently H, Me, F, Cl, Br, CH ₂ F, CF ₂ H and / or CF ₃

and if R 1 is Me, F, Cl, Br or CF, then R _{1 is} also H or Me.

CH ₂ F or CF ₂ H is less preferred as a substituent for R ₁ . Mean: Me: methyl, CF ₃ : trifluoromethyl,, CH ₂ F: fluoromethyl, CF ₂ H: difluoromethyl, Et: ethyl, Pr: propyl, iPr: isopropyl, H: hydrogen, F: fluorine, Cl: chlorine, Br : Bromine and N stands for nitrogen.

Among the compounds of the structural formula shown above, compounds of the formula I are preferred in which

R ₂ : NR ₆ R ₇ , with

R ₇ : Me or Et and R ₃ , R ₄ , R ₅ : are each independently H, F, Cl, Br and / or CF ₃

Likewise preferred are those compounds of the formula I in which Ri can also be H or Me if R _{4 is} : F, Cl, Br, CF ₃ .

Compounds of the formula I are particularly preferred in those

R.,: Me,

R ₂ : NR ₆ R ₇ , with

R ₆ : Me or Et, preferably Me,

R: Me or Et, preferably Me, R ₃ : H, F, Br or CF ₃ , R ₄ : Cl, Br or CF ₃ , R ₅ : H, Br or CF ₃ ,

and / or if

then R ₄ : H. Most preferred are compounds of formula I with

R ₂ : NR ₆ R, with

R ₆ : Me,

R ₇ : Me, R ₃ : H, F, preferably H, R Cl or Br, R ₅ : H or Br

and / or if

then R ₄ : H.

The compounds represented by the formula I can be in tautomeric equilibrium with the m-amino-anilino-2-imidazoline derivatives of the formula II:

Formula II

wherein the definition of the radicals R ^ R ₂ , R ₃ , R, R ₅ , RQ and R _{7 is} identical to the abovementioned compounds of the formula I and all the listed preferences. The present invention therefore also relates to the compounds covered by the general formula II in which the radicals R 1, R ₂ , R ₃ , R ₄ , R ₅ , R 6 and R ₇ fall within the scope of the definition given under the formula I. The same applies to the preferred ranges listed under formula I.

The compounds falling under the definition frames of the formulas I and II are equally, but independently, preferred. With regard to the nomenclature used in the context of the present invention, it should be noted that the term “phen-1'-yl-2-imidazolidine” is understood to mean compounds having the following structural element:

That the atoms of the imidazole ring are numbered 1, 2, 3, etc., number 1 being assigned to one nitrogen atom and number 3 assigned to the other nitrogen atom. Accordingly, the imino group is attached to the carbon atom to which the number 2 is assigned. The atoms of the phenyl ring are numbered 1 ', 2', 3 ', etc., the carbon atom of the phenyl ring which is bonded to the imino group being referred to as 1' throughout.

It should be expressly mentioned that the corresponding tautomers according to the general formula II are also meant, even if they are not called expressis verbis. The same applies to all m-amino-anilino-2-imidazolidine derivatives mentioned in the context of the present invention.

Representing all of the compounds covered by general formula I or formula II, some m-dialkylamino-phen-1'-yl-2-imidazolidines are listed below by way of example.

2'-bromo-3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine, preferably as hydrochloride,

3'-bromo-5'-diethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 2, preferably as hydrochloride,

3'-bromo-5'-dimethylamino-6'-methyl-phen-1 ^! -yl-2-iminoimidazolidine 3, preferably as a free base,

3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4, preferably as hydrochloride,

2'-3'-dibromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 5, preferably as a free base

2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 6, preferably as a free base

4'-bromo-2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 7, preferably as a free base

2'-bromo-6'-chloro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 8,

5'-bromo-2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 9, '-bromo-5'-dimethylamino-6'-fluorophen-1'-yl-2- iminoimidazolidin 10, 3'-chloro-6'-fluoro-5'-dimethylamino-phen-1 '-vl-2-iminoimidazolidine 11.'-chloro-4'-fluoro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 12, '-chloro-3'-fluoro-5'-dimethylamino-phen-1' -vl-2-iminoimidazolidine 13, '-chloro-3'-fluoro-5'-dimethylamino -6'-methyl-phen-1'-yl-2-iminoimidazolidine 14, '-6'-dichloro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 15,'-4'-dichloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine16,'-4'-difluoro-5'-dimethylamino-6'-methvl-phen-1'-yl-2-iminoimidazolidine 17, '-6'-difluoro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 18,'-dimethylamino-6'-methyl-2'-trifluoromethyl-phen-1'-yl-2-iminoimidazolidine 19, '-Dimethylamino-6'-methyl-3'-trifluoromethyl-phen-1'-yl-2-iminoimidazolidine 20. Preferred are:

2'-bromo-3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 1,3, 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 their pharmacologically acceptable salts , especially the hydrochloride.

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-iminoimidazoiidin 4, 2'-3'-dibromo-5'-dimethylamino-6 '-methyl-phen-1' -yl-2-iminoimidazolidine 5 and their pharmacologically acceptable salts, especially the hydrochlorides.

Most preferred

3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4 and its pharmacologically acceptable salts, especially the hydrochloride.

Another aspect of the present invention relates to the compounds of the above-mentioned general formulas I and / or II and their pharmacologically tolerable salts with the radicals R 1 to R ₅ in all of the definitions mentioned, and to medicaments which contain these compounds.

In the context of the present invention, all of the compounds mentioned not only mean the free bases, but also in each case pharmaceutically acceptable acid addition salts. Suitable acids can be both inorganic and organic in nature.

Examples of suitable acids are:

Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, citric acid, lactic acid, acetic acid, propionic acid, malic acid, succinic acid, amino acid, in particular glutamic acid or aspartic acid, carbohydrate acids and acids derived from carbohydrates. Such salts can be important both for the pharmaceutical preparation, increase the stability, in particular long-term stability, of the compound and / or lead to an increase in bioavailability. Hydrochloride salts are preferred, depending on the compound, the monohydrochlorides or dihydrochlorides. The same applies to the preferred compounds.

As already described at the outset, in the context of the present invention, the compounds mentioned are distinguished from the compounds known from the prior art by their pharmacological properties, in particular with regard to bioavailability and / or their metabolism. It goes without saying that the most preferred compounds are those which are highly effective and bioavailable with little metabolic degradation. Another feature that is important for the selection of particularly suitable compounds for the treatment of urinary incontinence is the selectivity with which the corresponding compound acts on the bladder function without significantly influencing other body functions, particularly the cardiovascular system.

In the context of the present invention, the compounds mentioned and their pharmacologically acceptable acid addition salts can be prepared in suitable pharmaceutical formulations. Such preparations include all formulations that are suitable for medical use. This includes e.g. Solutions, suspensions, aerosols, powders, tablets, coated tablets, suppositories, creams etc.

The compounds according to the invention, their pharmacologically acceptable acid addition salts and / or pharmaceutical preparations containing them can be used medically to treat diseases, especially for diseases of the bladder, especially for urinary incontinence. The use of the compounds according to the invention for the treatment of stress incontinence is most preferred.

Another aspect of the present invention relates to processes for the preparation of the compounds mentioned, their pharmacologically acceptable acid addition salts and / or pharmaceutical preparations, and the use of the compound described for the preparation of further pharmacologically active derivatives thereof.

Examples

1. Bioavailability

To determine the bioavailability, the test substances were administered orally to a group of 8 male fasting rats. For reference, animals from an identical second group were administered the test substances intravenously. 1 ml of blood samples were taken from the animals of both groups after defined times after administration (10 minutes, 30 minutes, 1 hour, 2 hours and 4 hours, the animals of the oral group additionally after 6 hours). The blood samples taken per group were mixed (8 ml). After further processing, the content of the corresponding test substances in the blood was determined from the plasma for the respective time by HPLC (High Performance Liquid Chromatography) according to standard methods and related to the two groups.

Results

2. Metabolism

For the determination of the metabolism, the enzyme CYP2D6 was allowed to act on the test substances. After 30 minutes, it was checked how much of the test substance used had been broken down by the enzyme.

Analogously, the decomposition rate is checked under the action of the HLM enzyme / 60 minutes.

3. Effectiveness and selectivity

The viability and selectivity of the compounds is determined as follows:

Maximum dog contraction and human urethra activity are percent contraction compared to noradrenaline. Selectivity in dogs: percent contraction of the canine femoral artery at 10 ^{~ 5} M - percent contraction of the canine carotid at 10 ^{~ 5} M.

4. Manufacturing

The compounds according to the invention can be prepared as described in WO 96/32939 on pages 11 to 16, which is hereby expressly incorporated by reference. Some of the compounds according to the invention can be prepared, for example, from the compounds described there, in particular 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 1

2 g of 2'-bromo-5'-dimethylamino-6'-methyl-phen-1-yl-2-iminoimidazolidine are dissolved in 6.7 ml of sulfuric acid at 0 ° C. and stirred with 0.8 g of 1,3- Dichloro-5,5-dimethylhydantoin added. The solution is heated at 55 ° C., diluted with ice after 3 days, alkalized with NH ₄ OH and extracted with ethyl acetate. The ethyl acetate extract is concentrated under reduced pressure and the remaining residue is worked up by chromatography (silica gel, mobile phase: CH ₂ Cl ₂ / methanol / conc. NH ₄ OH (90/10/1)).

1.1 g of 2'-bromo-3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine are obtained as a white powder, mp 239-240 ° C. ¹ H NMR (250 MHz, CD ₃ OD, TMS = 0 ppm): δ = 8.09 (1 H, s, aryl-H); 3.81 (4H, s, imidazolidine-CH ₂ -); 3.27 (6H, s, N (CH ₃₎ _2); 2.51 (3H, s, aryl-CH _3); interchangeable H below the solvent peak 4.88 ppm. MS m / z 331/333/335 (87/100/42).

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 250 ml of petroleum ether are added to the residue. The precipitated solid is filtered off and dried at 50 ° C.

106 g of N-acetyl-2-methyl-3-nitroaniline are obtained as a light brown powder.

Level 2:

106 g of N-acetyl-2-methyl-3-nitroaniline are dissolved in 500 ml of concentrated sulfuric acid. 93 g of 1,3-dibromo-5,5-dimethylhydantoin are added at RT and the mixture is stirred for approx. 24 hours with exclusion of light at RT and 2 hours at 50 ° C. 2.5 l of ice water are added and the precipitated crystals are filtered off, washed with water and dried.

67 g of a mixture of N-acetyl-4-bromo-2-methyl-3-nitroaniline and N-acetyl-4,5-dibromo-2-methyl-3-nitroaniline are obtained as a white powder.

Level 3:

67 g of the above mixture and 300 ml of HCl (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 filtered off and washed with HCl (0.5 M) and water. The crystals are suspended in about 500 ml of water. The aqueous phase is with solid Na ₂ CO ₃ alkalized and extracted with approx. 400 ml ether. The organic phase is filtered and concentrated under reduced pressure. The residue is recrystallized from hot ether.

18 g of 4-bromo-2-methyl-3-nitroaniline are obtained as yellow-orange-colored 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 yellow-orange crystals.

Level 4:

5.8 g of paraformaldehyde and 15 ml of formic acid are dissolved in 15 ml of DM F and heated at 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 poured into about 600 ml of ice water and the aqueous phase is extracted with 300 ml of ether. The organic phase is washed with Na ₂ CO ₃ (1 M), filtered and evaporated. The product is purified by chromatography (silica gel, eluent: petroleum ether / ethyl acetate (40/60).

15 g of N, N-dimethyl-4-bromo-2-methyl-3-nitroaniline are obtained as an orange-brown oil.

Level 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. and 5 bar of hydrogen using Raney nickel as a catalyst. 12 g of 2-bromo-5-dimethylamino-6-methylaniline are obtained as a brown oil.

Level 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 room temperature and the solution is refluxed. After about 6 hours, the solvent is evaporated and the oily residue is crystallized in about 50 ml of ethyl acetate.

2.5 g of 3'-bromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 3 are obtained as white powder, mp 140-143X. ¹ H NMR (250 MHz, CDCI ₃ , TMS = 0 ppm): δ = 6.80 (2H, s, aryl-H); 4.39 (2H, s, broad, NH); 3.49 (4H, s, imidazolidine CH ₂ -); 2.66 (6H, s, N (CH ₃₎ _2); 2.10 (3H, s, aryl-CH _3). MS m / z 297/299 (100/100).

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 dust and 2 ml of HCl (10%) are dissolved in 10 ml of ethanol loosened and refluxed. After 1 hour the reaction is filtered and the solvent is distilled off. The residue is treated with Na ₂ CO ₃ (1 M) with cooling and the product is extracted with ether. The ether extract is concentrated under reduced pressure. The remaining residue is taken up in methanol and acidified with HCl.

0.2 g of 3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4 (HCl) are obtained as a white powder (hygroscopic).

¹ H NMR (250 MHz, CD ₃ OD, TMS = 0 ppm): δ = 7.93; 7.60 (2H, 2d (J = 1.8 Hz), aryl-H); 3.80 (4H, s, imidazolidine-CH ₂ -); 3.31 (6H, s, N (CH ₃₎ _2); 2.45 (3H, s, aryl-CH _3); interchangeable H below 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

Stages 1, 2, 3 and 5 are analogous to those for the synthesis of compound 3

Level 4:

3.6 g of a mixture of 4-bromo-2-methyl-3-nitroaniline and 4,5-dibromo-2-methyl-3-nitroaniline are reacted as in Example 3, step 4. The product is purified by chromatography (silica gel, mobile phase: 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.

Level 6:

0.9 g of 2,3-dibromo-5-dimethylamino-6-methylaniline and 0.4 g of N-acetyl-2-imidazolidinone are dissolved in 8 ml of POCI ₃ at RT and the solution is stirred at 85 ° C. After about 8 hours the solvent is evaporated and 100 ml of water are added to the residue. The aqueous phase is extracted with ethyl acetate and the organic phase is alkalized with Na ₂ CO ₃ , filtered and evaporated. The product is purified by chromatography (silica gel, eluent: ethyl acetate).

0.7 g of N-acetyl-2 ', 3'-dibromo-5'-dimethylamino-6'-methyl-phenyl-2-iminoimidazolidine are obtained as a white powder.

Level 7:

0.7 g of N-acetyl-2 ', 3'-dibromo-5'-dimethylamino-6'-methyl-phenyl-2-iminoimidazolidih are refluxed in 60 ml of methanol. After 7 hours the solvent is evaporated. The residue is dissolved in CH ₂ CI ₂ and acidified with HCl (4N)

(pH 1). The precipitated crystals are filtered off, washed with ether and dried.

0.68 g of 2 ', 3'-dibromo-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 5 are obtained as a white powder (mp from 240 ° C. decomposition).

¹ H NMR (250 MHz, CD ₃ OD, TMS = 0 ppm): δ = 8.19 (1 H, s, aryl-H); 3.81 (4H, s, imidazolidine-CH ₂ -); 3.26 (6H, s, N (CH ₃₎ _2); 2.48 (3H, s, aryl-CH _3); interchangeable H below the solvent peak 4.89 ppm. MS m / z 375/377/379 (66/100/66).

Connection 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 200 ml of diethyl ether each time. The ether phases are dried over Na ₂ SO ₄ , filtered and evaporated.

30.4 g of N, N-dimethyl-2-chloro-3-nitroaniline are obtained as a red oil. The raw product is used without additional cleaning.

Level 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 bar of hydrogen using Raney nickel as a catalyst. The solvent is evaporated and the product is purified by chromatography (silica gel, eluent: petroleum ether / ethyl acetate (3/1)).

12.8 g of 2-chloro-3-dimethylamino-aniline are obtained as a brown oil.

Level 3:

4.4 g of 2-chloro-3-dimethylamino-aniline, 3.35 g of N-acetylimidazolidine and 30.5 ml of POCI ₃ are mixed together and stirred at RT. After 12 hours, POCI _{3 is} distilled off and the residue is poured onto ice. The aqueous phase is alkalized with a concentrated NH ₃ solution and extracted twice with 200 ml of methylene chloride. The organic phases are dried, filtered and evaporated. 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. The residue is dissolved in diethyl ether in an ultrasonic bath. The precipitated yellow crystals are filtered off, 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, mp 146-148 ° C. ¹ H NMR (250 MHz, CD ₃ OD, TMS = 0 ppm): δ = 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-CH ₂ -); 3.73 (6H, s, N (CH ₃₎ _2). MS m / z 239/241 (100/46).

Compound 7 4'-bromo-2'-chloro-3'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 7

1 g of 2'-chloro-3'-dimethylamino-phen-1'-yl-1-acetyl-2-iminoimidazolidine 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 each time. The organic phases are dried, filtered and evaporated. The product is purified by chromatography (silica gel, eluent: CH ₂ CI ₂ / MeOH / k. NH ₄ OH (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, mp 150-155 ° C.

¹ H NMR (400 MHz, DMSO-d6, TMS = 0 ppm): δ = 7.23; 6.54 (2H, 2d, J = 8.6 Hz, 2 aryl-H); 5.77 (2H, s, broad, NH); 3.28 (4H, s, imidazolidine CH ₂ -); 2.58 (6H, s, N (CH ₃₎ _2). MS m / z 317/319/321 (85/100/36).

Compound 8 2'-bromo-6'-chloro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 8

Stages 1 and 2 are carried out as described for compound 6.

Level 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 at 0 ° C. for 5 hours and then at RT. After 48 hours, 700 ml of ice Water added. The white precipitate is filtered off and the aqueous phase is extracted three times with 200 ml of diethyl ether each time. The organic phases are dried, filtered and evaporated.

17.5 g of 2-bromo-6-chloro-5-dimethylamino-aniline are obtained as a brown oil and used without further purification.

Level 4:

6.6 g KSCN are dissolved in 220 ml 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 boiled at reflux. After 3 hours, 500 ml of ice water are added and the aqueous phase is extracted three times with 100 ml of ethyl acetate each time. The organic phases are dried, filtered and evaporated. 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 without additional purification.

Level 5:

15 g of N-thioamido-2-bromo-6-chloro-5-dimethylamino-aniline and 4.6 ml of methyl iodide are stirred in 280 ml of methanol at reflux. After 2 hours the solvent is evaporated. 18.9 g of an orange-colored oil are obtained which is boiled with 3.1 ml of ethylenediamine in 190 ml of acetonitrile at reflux. After 18 hours the solvent is distilled off. The residue is mixed with 110 ml of HCI (1 M) and extracted with ethyl ether. The organic phase is dried, filtered and evaporated. The product is purified by chromatography (silica gel, eluent: CH ₂ CI ₂ / MeOH / k. NH ₄ OH (90/10/1)).

2.5 g of 2'-bromo-6'-chloro-5'-dimethylamino-phen-1'-yl-2-iminoimidazolidine 8 are obtained as a pink powder, mp 142-145 ° C. ¹ H NMR (250 MHz, CDCI ₃ , TMS = 0 ppm): δ = 7.30 (1 H, d, J = 9.2 Hz, aryl-H (5)); 6.74 (1H, d, J = 9.2 Hz, aryl-H (4)); 3.98 (2H, s, broad, NH); 3.53 (4H, s, imidazolidine CH ₂ -); 2.87 (6H, s, N (CH ₃₎ _2). MS m / z 318/319/321 (87/100/34).

Further compounds of the type described in the context of this invention can be prepared analogously to the examples mentioned above.

Claims

claims

1. Use of a compound of general formula I or general formula II for the manufacture of medicaments for the treatment of urinary incontinence, especially stress incontinence

Formula I Formula II

With

Ri: F, Cl, Br, CH ₂ F, CF ₂ H or CF _3>

R ₂ : NR ₆ R ₇ , with

R ₆ : Me, Et, Pr or iPr,

R ₇ : Me, Et or Pr, R3, R4, R5: are each independently H, Me, F, Cl, Br, CH ₂ F, CF ₂ H and / or CF ₃

and in the event that R ₄ : Me, F, Cl, Br, CH ₂ F, CF ₂ H or CF ₃ , then R is additionally H or Me and / or their pharmacologically acceptable salt.

2. Use according to claim 1, characterized in that R-,: H, Me, F, Cl, Br or CF ₃ , R ₂ : NR ₆ R ₇ , with

R ₆ : Me or Et,

R ₇ : Me or Et, R ₃ : H, F, Cl, Br or CF ₃ , F ^: F, Cl, Br or CF ₃ , R ₅ : H, F, Cl, Br or CF ₃ .

3. Use according to claim 1 or 2, characterized in that

R ₂ : NR ₆ R, with

R ₆ : Me or Et,

R ₇ : Me or Et, R ₃ : H, F, Br or CF ₃ , R ₄ : Cl, Br or CF ₃ , R ₅ : H, Br or CF ₃ .

4. Use according to claim 1, 2 or 3, characterized in that

Ri: Me,

R ₂ : NR ₆ R ₇ , with

R ₆ : Me,

R ₇ : Me, R ₃ : H or F, R ₄ : Cl or Br, R ₅ : H or Br.

5. Use according to claim 1, characterized in that

R ₂ : NR ₆ R ₇ , with

R ₇ : Me or Et,

R ₃ : H, F, Cl, Br or CF ₃ ,

R ₄ : H, F, Cl, Br or CF ₃ ,

R _{5 is} H, F, Cl, Br or CF ₃ .

6. Use according to claim 1 or 5, characterized in that

R ₂ : NR ₆ R ₇ , with

R ₇ : Me or Et, R ₃ : H, F, Br or CF ₃ ,

R _{5 is} H, Br or CF ₃ .

7. Use according to claim 1, 5 or 6, characterized in that

R ₂ : NR ₆ R ₇ , with

R ₆ : Me,

R ₇ : Me, R ₃ : H, F,

R ₅ : H or Br.

8. Use according to claim 1, characterized in that the compound 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 acceptable salt.

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

10. Use according to claim 1, 2, 3, 8 or 9, characterized in that the connection

3'-chloro-5'-dimethylamino-6'-methyl-phen-1'-yl-2-iminoimidazolidine 4, a tautomer thereof and / or a corresponding pharmacologically acceptable salt.

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

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

13. Use according to one of the preceding claims, characterized in that the compound of formula I is present as imino-imidazolidine.

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

15. A compound according to any one of claims 1 to 14.

16. Pharmaceutical preparation containing a compound and / or its pharmacologically acceptable salt according to claim 15.

17. A process for the preparation of a compound and / or its pharmacologically acceptable salt according to claim 15.

18. Method for the treatment of bladder diseases, in particular urinary incontinence, using a compound according to claim 15 and / or a pharmacologically acceptable salt thereof.