BG108036A - Novel alkyl phenylimino-imidazolidine derivatives for treating urinary incontinence - Google Patents

Abstract

The invention relates to m-alkyl phenylimino-imidazolidine derivatives of formula comprising a novel substituent pattern on the phenyl ring and to the use of said derivatives for producing medicaments, in particular for treating urinary incontinence.

Description

New alkyl-phenylimino-imidazolidine derivatives for the treatment of incontinence

Technical field

The present invention encompasses t-alkyl-phenyliminoimidazolidine derivatives with a new substituent on the phenyl ring and their use for the preparation of medicaments, in particular for the treatment of incontinence.

^w Background of the Invention

The compounds described within the scope of the present invention belong to the class of t-alkyl-phenyliminoimidazolidines. Such compounds are known in the art.

WO 96/32939, which is taken into account in its entirety, discloses phenylimino-imidazoles. These include those wherein the phenyl ring has, inter alia, amino-, amido-, imido-, halo-, heteroaryl-, cycloalkyl- and alkyl substituents. The compounds described therein are considered to be alphaC1L agonists and in this property can be advantageously used to treat incontinence.

Incontinence refers to the involuntary release of urine, hence weakness of the bladder. The various forms of incontinence are impulse incontinence, reflex incontinence, overflow incontinence, and stress or stress incontinence. The most common forms of incontinence include stress or stress incontinence. It particularly affects women after a less severe or more severe birth. The reason for this is that pregnancy and childbirth easily lead to the weakening of the base of the pelvis. Other causes of incontinence may be, for example, innervation disorders of the pelvis, congenital too short ureter, or damage to the closure muscle.

The use of alpha-11-agonists for the treatment of incontinence is therefore so advantageous, because they selectively influence the adrenoceptors of the bladder and thus exert a significant influence on the toning of the ureter, without affecting the cardiovascular system.

In the art, the use of imidazole derivatives for the treatment of incontinence has been discussed for some time. Among these, surprisingly, there are opinions that note that some imidazole derivatives may counteract bladder weakness, while other authors observe a seemingly almost opposite effect, namely that such substances may lead to relief from bladder obstruction . Other authors have again reported partly the same substances that they would not exert any effect on bladder function.

For example, it has been reported that alpha 2 agonists such as cponidine would exert a positive effect on nocturnal incontinence (Urology, 43 (3), (1994), 324-327). On the other hand, precisely with respect to cponidine, there is the opposite observation that this substance could even stimulate incontinence (Clin. Biol. Res. 78, (1981), 101-103). Such observation is expressed in Jpn. Pharmacol. 58 (4), (1992), 339

346. The authors find that clonidine does not have a clear effect on bladder function unlike phenyl-ethanol-amines such as adrenaline-like phenylephrine, midodrine or ST 1059, which are alpha 1 agonists. EP-A-0 416 841 also deals with the effect of alpha agonists on bladder function. It describes that alpha 1 adrenoceptor blocking substances have been used to treat bladder obstruction. Also, observations according to US-A-4 226 773 point in this direction. According to this work, pyrazolyl-imino-imidazole derivatives can be used to stimulate urine output. Other alpha 1 adrenergic imidazoles such as thiophene pyrroles can also be used to treat incontinence (EP-A-0 599 697).

These differing observations from the state of the art lead to the conclusion that so far it is not possible to predict the effect of imidazole derivatives on bladder function.

SUMMARY OF THE INVENTION

Compounds that may be involved in the treatment of incontinence should have sufficient efficacy and should exhibit little side effects when possible. In other words, they should only be able to act selectively on the bladder. Adverse side effects include, among other things, a negative effect on the circulatory system. Particularly important for the treatment of incontinence are the bioavailability of substances and their metabolism. Bioavailability should be as high as possible and metabolism such that on the one hand substances do not degrade rapidly and on the other hand they do not form toxic or other substances with undesirable pharmacological properties.

Therefore, one object of the present invention is to find novel alpha-11-agonists of the phenylimino-imidazolidine class that selectively act on the bladder without significantly affecting the circulatory system and exhibiting favorable bioavailability or metabolism properties.

It has surprisingly been found that the t-alkyl-phenyliminoimidazolidines of the invention fulfill the object of the present invention and are therefore particularly suitable for the treatment of incontinence.

Generally known from the prior art are alkyl-phenylimino-imidazolidines with branched alkyl groups.

For example, WO 92/21349 presents a number of phenylimino-imidazolidine derivatives for ophthalmic administration. DE 1 929 950 discloses, inter alia, 2'-bromo-5'-chloro-4'-tert-butyl-phenylimin-2-imidazolidine and DE 0 116 768 - 2,6-dichloro-4'-tert-butyl-phenylimino-imidazolidine . EP 0 035 393 also deals with alkyl-phenyliminoimidazolidines, but not for use in human medicine, but for the production of eggs.

DETAILED DESCRIPTION OF THE INVENTION

The alkyl-phenylimino-2-imidazolidine derivatives of the invention are characterized in that at least one of the two possible meta-positions relative to the imino group contains a branched alkyl group such as isopropyl, isobutyl, tert. butyl, isopentyl, neopentyl. Preferably it is isopropyl and / or tert. butyl group. Preferred compounds of the invention are described by the general formula I:

whereby

R 1 or R ₅ : independently of one another are H, F, Cl, Br, CH ₂ F, CHF ₂ , CF ₃ , Me or OMe,

R ₂ , respectively independent of each other, are H, iPr, tert. Bu, F, Cl, Br, CH ₂ F, CHF ₂ , CF ₃ or Me, wherein at least one of the groups R ₂ or R 4 is iPr or tert. You,

R ₃ : is H, F, Cl, Br, CH ₂ F, CHF ₂ , CF ₃ or Me.

In this case, they mean: Me: methyl, CH ₂ F: fluoromethyl, CHF ₂ : difluoromethyl, CF ₃ : trifluoromethyl, iPr: isopropyl, H: hydrogen, F: fluorine, CI: chlorine, Br: bromine and tert. You: terz. butyl.

When R ₅ is OMe, such compounds are preferred in which R ₂ is tert. You.

Of the compounds indicated, preferred are those in which

R 1 or R ₅ : independently of one another are H, F, Cl, Br, CF ₃ , Me or OMe,

R ₂ , R 4: independently of one another are H, iPr, tert. You and / or Me, wherein at least one of the groups R ₂ or R 4 is iPr or tert. You,

R ₃ : is H, F, Cl, Br or Me.

Among them are particularly preferred compounds where

Rf is H, Cl, Br or Me,

R ₂ : is iPr or Tert. You,

R ₃ : is H, Br or CI,

R4: is H, and

R ₅ : is H, Cl, Br or OMe.

Most preferred are the compounds wherein

Rf is H or Me,

R ₂ : is iPr or Tert. You,

With R ₃ : is H, Cl or Br,

R4: is H, and

R 5 is H, Cl or OMe.

In all cases R ₂ is preferred iPr, while R 4 is preferred H. Also in all cases R 1 is preferred other than OMe.

The compounds represented by formula I may be in tautomeric equilibrium with alkyl-anilino-2-imidazoline derivatives of formula II:

wherein the definition of the groups R _iz R _2, R _3, R4 and R ₅ is identical with the above-mentioned compounds of formula I, including those mentioned preferences.

Accordingly, the present invention also relates to the compounds of formula II wherein the groups R 1, R ₂ , R ₃ , R 4 and R ₅ fall within the definition set out in Formula I. The same applies to the preferred areas indicated for Formula I.

The compounds of the formulas I and II are equally, but independently of one another, preferred.

In connection with the nomenclature used within the scope of the present invention, it is to be understood that the term phen1'-yl-2-imidazolidine is understood to mean compounds having the following structural element:

Ie the imidazole ring atoms are numbered 1, 2, 3, etc., whereby one nitrogen atom corresponds to number 1 and the other nitrogen atom number 3. Therefore, the imino group is attached to the carbon atom to which number 2 corresponds. The phenyl ring atoms are numbered 1, 2 ', 3', etc., wherein the carbon atom of the phenyl ring attached to the imino group is generally designated 1 'and the branched alkyl substituent in the meta- position atom as 3 '.

It is explicitly mentioned that the corresponding tautomers of general formula II are equally encompassed by the invention and therefore the chemical names referring to the structure of formula I include the corresponding alkyl-anilino2-imidazolidine derivatives of formula II and vice versa.

For example, some alkyl-phen-N-yl-2-imidazolidines are referred to as representative of the compounds of general formula I or II below.

3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 1, preferably available as a free base,

3'-tert-butyl-6'-methoxy-phen-1'-yl-2-iminoimidazolidine 2, preferably available as a free base,

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

4'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 4, preferably available as a free base,

6'-bromo-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 5,

6'-bromo-3'-tert-butyl-phen-1'-yl-2-iminoimidazolidine 6, 4'-bromo-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 7,

5 ', 6'-dibromo-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 8,

5 ', 6'-dichloro-3'-isopropyl-2'-methyl-phen-N-yl-2-iminoimidazolidine 9,

2 ', 6'-dichloro-3'-isopropyl-phen-1'-yl-2-amino-imidazolidine 10,

4 ', 6'-dibromo-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 11,

4 ', 6'-dichloro-3'-isopropyl-2'-methyl-phen-N-yl-2-iminoimidazolidine 12,

2 ', 5'-dichloro-3'-isopropyl-phen-1'-yl-2-iminoimidazolidine 13,

2 \ 6'-dibromo-3'-isopropyl-phen-1'-yl-2-iminoimidazolidine 14,

6-bromo-5'-chloro-3'-isopropyl-2-methyl-phen-1'-yl-2-iminoimidazolidine 15,

6N5rom-4'-chloro-3'-isopropyl-2'-methyl-phen-1-yl-2-iminoimidazolidine 16,

6'-bromo-2'-chloro-3'-isopropyl-phen-1'-yl-2-iminoimidazolidine 17,

5'-Trifluoromethyl-3'-isopropyl-2'-methyl-phen-N-yl-2-iminoimidazolidine 18,

4 ' _/ 5'-dichloro-3'-isopropyl-2 ^, -methyl-phen-1-yl-2-iminoimidazolidine 19,

4'-bromo-2 ^, -chloro-3 ^, -isopropyl-phen-1 ^, -yl-2-iminoimidazolidine 20,

4'-bromo-6'-chloro-3 ^, -isopropyl-2 ^, -methyl-phen-1-yl-2-iminoimidazolidine 21,

4 ^, -bromo-5 ^, -chloro-3'-isopropyl-2'-methyl-phen-N-yl-2-iminoimidazolidine 22,

4 ' _/ 5'-dibromo-3 ^, -isopropyl-2 ^, -methyl-phen-1 ^, -yl-2-iminoimidazolidine 23,

2 \ 4'-dichloro-3'-isopropyl-phen-1-yl-2-iminoimidazolidine 24,

5'-bromo-2'-methyl-3'-isopropyl-phen-1 ^l- yl-2-iminoimidazolidine 25,

5H, 5-R-4H-lor-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 26,

5 N -or-3R 43 propropyl-2'-methyl-phen-N-yl-2-iminoimidazolidine 27,

5H-4-chloro-3'-isopropyl-2'-methyl-phen-1-yl-2-iminoimidazolidine 28,

6'-Trifluoromethyl-3'-isopropyl-2'-methyl-phen-N-yl-2-iminoimidazolidine 29,

^2, 5 \ ^{6 -tribrom-3-tert.butyl-phen-1-yl-2iminoimidazolidin} 30

5 \ 6'-dibromo-3'-tert-butyl-phen-1-yl-2-iminoimidazolidine 31,

_{^{5/6-dibromo-3-tert.butyl-2-chloro-phen-1-yl-2iminoimidazolidin}} 32

2 ', 5'-dibromo-3'-tert-butyl-6'-methoxy-phen-1'-yl-2-iminoimidazolidine 33,

2 ', 5'-dichloro-3'-tert-butyl-6'-methoxy-phen-1'-yl-2-iminoimidazolidine 34,

2; 6'-dibromo-3Chertz-butyl-5'-chloro-phen-1'-yl-2-iminoimidazolidine 35,

2 ', 6Chibrom-3'-tert-butyl-phen-1-yl-2-iminoimidazolidine 36,

6H5rom-3'-tert-butyl-2 ', 5'-dichloro-phen-1-yl-2-iminoimidazolidine 37,

^{6-bromo-3-tert.butyl-5 / chloro-phen-1-yl-2-} iminoimidazolidin 38

2H5rom-3'-tert-butyl-5'-chloro-6'-methoxy-phen-1-yl-2-iminoimidazolidine 39,

2H5rom-3'-tert-butyl-6'-chloro-phen-1'-yl-2-iminoimidazolidine 40,

2H5rom-3'-tert-butyl-6'-methoxy-phen-1-yl-2-iminoimidazolidine 41,

2'-chloro-3'-tert-butyl-6'-methoxy-phen-1-yl-2-iminoimidazolidine 42,

5'-bromo-3'-tert-butyl-6'-methoxy-phen-1-yl-2-iminoimidazolidine 43,

5'-chloro-3'-tert-butyl-6'-methoxy-phen-1-yl-2-iminoimidazolidine 44,

5'-bromo-3'-tert-butyl-2'-chloro-6'-methoxy-phen-1'-yl-2-iminoimidazolidine 45.

These compounds correspond to the structures:

iPn Me ^etc. Me tert.Bik Nr / fHJ ^π hr 4 h HJ ⁿ hr H - (/ < -HD with / H H CF, / No Nr 28 29 30 tert.Bik H H tert.Bik Cl 7 tert.Bik Nr 7 ⁿ \ 4 hL -fH J > J- D > Nr Nr / No Nr / No OMe 31 32 33 tert.Bik Cl H tert.Bik Br / H tert.Bik Nr H > $ HD ^H V ί -H _N U D $ -HD Cl OMe Cl \ Nr / H Nr 34 35 36 tert.Bik .7 H tert.Bu, H / 4: tert.Bik Nr H H— hd % ί $ HD c / X Nr cr Nr c / OMe 37 38 39 tert.Bik Nr H tert.Bik Br / H tert.Bik Cl H -! 'K _N 2 ^H V -HD D $ / H Cl H OMe / H OMe 40 41 42 tert.Bik H / H tert.Bik H tert.Bik Cl 1 hd H— -HD D $ -HD Nr OMe c / OMe / No OMe 43 44 45

Of these compounds, the following are preferred: 3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 1, 3'-tert-butyl-6'-methoxy-phen-1'-yl-2-iminoimidazolidine

2,

6'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 3,

4'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 4,

6'-bromo-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 5,

6'-bromo-3'-tert-butyl-phen-1-yl-2-iminoimidazolidine 6, 4'-bromo-3'-isopropyl-2'-methyl-1'-phen-yl-2-iminoimidazolidine 7.

Of these compounds, the following are particularly preferred: 3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 1, 3'-tert-butyl-6'-methoxy-phen-N-yl-2-iminoimidazolidine

2,

6'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 3,

4'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 4,

4'-bromo-3'-isopropyl-2'-methyl-1'-phenyl-2-iminoimidazolidine 7.

Of these compounds the most preferred are: 3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidin 1 3 ^{/ tert.butyl-6'-methoxy-phen-1-yl-2} -iminoimidazolidine

2,

6'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 3,

4'-bromo-3 ^, -isopropyl-2 ^, -methyl-1-phen-yl-2-iminoimidazolidine 7.

Preferred compounds also include all of the following:

4 ', 5'-dichloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 19,

2'-chloro-3'-tert-butyl-6'-methoxy-phen-1'-yl-2-iminoimidazolidine 42,

5'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 27.

** Examples 1, 3, 4, 5 and 7 to 29 refer to structures with one isopropyl group in the meta-position, examples 2, 6 and 30 to 45 refer to structures with one tert. butyl group in a meta position, which in turn form corresponding preferred groups.

Not only those compounds but also the corresponding pharmaceutically acceptable acid addition salts are included within the meaning of the present invention. Suitable acids may be of inorganic or organic nature.

Examples of suitable acids include: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, citric acid, lactic acid, acetic acid, malic acid, succinic acid, amino acids, more or glutinic acids aspartic acid, carboxylic acids and derived from carboxylic acids. Such salts may be important for galenic preparations, enhance stability, especially the long-term stability of the compound and / or lead to increased bioavailability. Hydrochloride salts are preferred, depending on the compound monohydrochlorides or dihydrochlorides. The same applies to preferred compounds.

As described initially, said compounds of the invention are characterized in addition to their efficacy, especially by their pharmacological properties regarding bioavailability and / or their metabolism. It goes without saying that compounds which have high efficacy and bioavailability for poor metabolic degradation are most preferred. Another important feature of the selection of particularly suitable compounds for the treatment of incontinence is the selectivity with which the compound acts on the bladder without affecting other bodily functions, in particular the cardiovascular system.

In addition to said compounds and their pharmacologically tolerable acid addition salts, the present invention also encompasses their use in the preparation of medicaments and pharmaceuticals. Such preparations include all forms suitable for medical use. These include, for example, solutions, suspensions, aerosols, powders, tablets, dragees, suppositories, creams, etc.

The compounds of the invention, their pharmacologically tolerable acid addition salts and / or pharmaceutical compositions containing them, may be used medically for the treatment of diseases, in particular bladder disease, in particular incontinence. It is strongly preferred to use the compounds of the invention for the treatment of stress incontinence.

Another aspect of the present invention relates to a method for the preparation of said compounds, their pharmacologically tolerable acid addition salts and / or pharmaceutical preparations, and the administration of the compounds described thereto for the preparation of other pharmacologically active derivatives.

Examples of carrying out the invention

1. Bioavailability

For the determination of bioavailability, a group of 8 male, non-rat test substances were given orally. In comparison, an identical second group of animals received intravenous test substances. Of the animals of the two groups, certain. intervals after administration (10 min, 30 min, 1 hour, 2 hours and 4 hours, for the oral group after an additional 6 hours), 1 ml of blood samples were taken. Samples were mixed for each group (8 ml). Plasma, after appropriate treatment, determined the content of the respective test substances in the blood for the appropriate time by HPLC (High Performance Liquid Chromatography) and correlated for the two groups.

Results

Compound Bioavailability in% 2 34 3 8 7 53

2. Metabolism

For the determination of metabolism, the CYP2D6 enzyme was exposed to the test substances. After 30 min, it was monitored how much of the substance used was degraded by the enzyme.

The degradation rat under the influence of the HLM enzyme / 60 min was similarly controlled.

Compound % substrate degradation after 30 min incubation with CYP2D6 % substrate degradation after 60 min incubation with HLM 1 18.2 13.5 2 0.7 2.7 3 6.1 11.7 4 7.6 5.5 5 8.7 7.5 6 3.0 2.8 7 5.0

3. Efficiency and selectivity

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

Compound Dog activity Human ureter activity Dog selectivity 1 78 11 0.7 2 71 30 0.6 3 70 41 0.7 4 59 0.5 5 34 0.4 6 28 Z 70 21 0.7

Maximum dog concentration and activity in the human ureter are contraction rates compared to noradrenaline.

Selectivity in the dog: percent control of canine femoral artery at 10 ' ⁵ M - percentage contraction of canine carotis at ΙΟ' ⁵ M.

4. Receipt

Examples of preparation

3'-Isopropyl-2'-methyl-phen-N-yl-2-iminoimidazolidine 1 Step 1

10g of 2-methyl-3-nitrobenzoic acid were added to a mixture of 100 ml of methylene chloride and 1 ml of dimethylformamide. 8.9 g of thionyl chloride were slowly added dropwise and the mixture was refluxed. After 6 hours, the solvent was concentrated under reduced pressure.

11.5 g of 2-methyl-3-nitro-benzoic acid chloride are obtained as an oil.

Step 2

In 70 ml of acetic ester, 11.7 g of diethyl ester of malonic acid, 3.5 g of anhydrous magnesium dichloride and 14.7 g of triethylamine were added one after the other and stirred for 0.5 hours at room temperature. After cooling to 10 ° C, 11.5 g of 2-methyl-3-nitro-benzoic acid chloride was slowly added dropwise. The mixture was then stirred at 60 ° C. After 3 hours, the methylene chloride was distilled off under reduced pressure. The residue was carefully mixed with 50 ml of water and adjusted to pH 1 with 4 N HCl solution. The reaction mixture was extracted with 3 x 100 ml of ethyl acetate. The combined organic phases were washed once more with water, dried and concentrated under reduced pressure. The oily residue was purified by chromatography (silica gel, eluent: cyclohexane / acetic ester (3/1)).

18.6 g of 2- (2-methyl-3-nitrobenzoyl) -malonic acid diethyl ester is obtained as a yellow oil.

Step 3

18.6 g of 2- (2-methyl-3-nitro-benzoyl) malonic acid diethyl ester was added to 15 ml of concentrated acetic acid. Slowly add 3.5 ml of distilled water and 3.5 ml of concentrated H ₂ SO ₄ . The mixture was refluxed. After 4 hours, it was cooled, diluted with 50 ml of water, basified on ice-cooling with 30% NaOH solution and extracted with 3 x 100 ml of ethyl acetate. The combined organic phases were dried and concentrated under reduced pressure.

8.3 g of 1- (2-methyl-3-nitro-phenyl) -ethanone are obtained as light yellow crystals.

Step 4 g of 1- (2-methyl-3-nitro-phenyl) -ethanone was dissolved in 50 ml of methanol and hydrogenated at 20 ° C and 5 bar with hydrogen using Raney-Nickel as a catalyst. The catalyst was removed and the filtrate was concentrated under reduced pressure. The product was purified by chromatography (silica gel, eluent: cyclohexane / acetic ester (3/1)).

3.5 g of 1- (2-methyl-3-amino-phenyl) -ethanone are obtained as light yellow crystals.

Step 5

0.9 g of 60% sodium hydride oil dispersion was mixed with 11.5 ml of DMSO. The slurry was stirred at 80 ° C until visible gas evolution ceased (30 min.). It was cooled to 10 ° C and then a solution of 3.5 g of 1- (2-methyl-3-amino-phenyl) -ethanone and 1 ml of DMSO was slowly added dropwise. The reaction temperature was raised to 45 ° C. After 10 minutes at ca. A solution of 8.2 g of methyltriphenylphosphonium bromide in 23 ml of DMSO was slowly added dropwise at 30 ° C. The mixture was stirred for an additional 4 hours without external heat flow (room temperature) and then mixed with 100 ml of methylene chloride and 100 ml of water. The aqueous phase was separated and extracted 2x more with 75 ml of methylene chloride. The combined organic phases are washed with water, dried and concentrated under reduced pressure. The product was purified by chromatography (silica gel, eluent: cyclohexane / acetic ester (3/1)).

3.4 g of 3-isopropenyl-2-methyl-aniline are obtained as a clear yellow oil.

Step 6 _k

15.4 g of 3-isopropenyl-2-methyl-aniline were dissolved in 150 ml of methanol and hydrogenated at 60 ° C and 12 bar with hydrogen using Raney-Nickel as a catalyst. The catalyst was removed and the filtrate was concentrated under reduced pressure.

14.4 g of 3-isopropyl-1-methyl-aniline are obtained as a clear colorless oil.

Step 7

7.45 g of 3-isopropyl-2-methyl-aniline and 8.7 g of N-acetylmethylmercaptoimidazolidine are refluxed for 3 hours in 100 ml of isopropanol. The solvent was distilled off under reduced pressure and the oily residue was refluxed in 100 ml of methanol. After 12 hours, the solution, under reduced pressure, was concentrated to low volume, basified under ice-cooling with 30% NaOH solution and extracted twice with acetic ester. The combined organic phases were dried and concentrated under reduced pressure. The oily residue was dissolved in 55 ml of HCl solution (1N) and 55 ml of water. The resulting solution was precipitated with fractions of NaOH solution (2N) at increasing pH and extracted with diethyl ether until the desired substance was obtained. After alkalisation with NaOH solution, a solid precipitates. It is separated, washed with water, dried.

6 g of 3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine are obtained as a white powder, Fp 133-135 ° C.

^w 6'-bromo-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 5 and

4'-bromo-3'-isopropyl-2'-methyl-1'-phen-yl-2-iminoimidazolidine 7

step 1

7.45 g of 3-isopropyl-2-methyl-aniline (Example 1, step 6) were dissolved in 75 ml of dimethylformamide and cooled to 5 ° C. A solution of 8.9 g of N-bromosuccinimide and 50 ml of DMF was carefully added dropwise over 45 minutes. The mixture was stirred for 1 hour at

3-5 ° C. The solution was then added to 11 ice water and extracted three times with ethyl acetate. The combined organic phases were dried and concentrated under reduced pressure. The two bromine isomers were isolated by chromatography (silica gel, eluent: toluene / acetone (9/1)).

1.87 g of 2'-bromo-5'-isopropyl-6'-methylaniline and 8 g of 4'-bromo-3'-isopropyl-2'-methylaniline are obtained as an oil.

Step 2

2.28 g of a mixed fraction of 6'-bromo-3'-isopropyl-2'-methylaniline and 4'-bromo-3'-isopropyl-2'-methylaniline were dissolved in 45 ml of acetonitrile. One by one, 1.67 g of 2-1,1-acetylimidazolidin-2-one and 4.6 g of POCl 3 were added. The mixture was refluxed for 4 hours and then stirred at room temperature. After 12 hours the solvent was distilled off under reduced pressure. The residue was treated with 50 ml of ice water and extracted twice with ethyl acetate. Upon cooling, the aqueous phase was basified with MH ₄ OH solution. 0.5 g of a white solid are precipitated, which is separated and dried (F1). The combined organic phases were concentrated under reduced pressure. The precipitate is treated with water. The aqueous phase was filtered and once again cooled with alkali with a 1 H ₄ OH solution and extracted twice with acetic ester. The combined organic phases were dried and concentrated under reduced pressure (F2-0.9 g). F1 and F2 are refluxed together in 20 ml of methanol. After 5 hours the solvent was distilled off under reduced pressure. The two bromine isomers were separated by chromatography (silica gel, eluent: methylene chloride / methanol / ammonia (9/1/1%)).

0.15 g of 6'-bromo-3'-isopropyl-2'-methyl-phenyl-1-yl-2-iminoimidazolidine are obtained as a hygroscopic white powder.

0.45 g of 4'-bromo-3'-isopropyl-2'-methyl-phenyl-2-iminoimidazolidine as a white powder are obtained, Fp 178-181 ° C.

6'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 3 and

4'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 4

step 1

7.45 g of 3-isopropyl-2-methyl-aniline were dissolved in 75 ml of dimethylformamide. A solution of 6.7 g of N-chlorosuccinimide in 50 ml of DMF was slowly added dropwise. The reaction is slightly exothermic. After overnight at room temperature, the solution was diluted with water and extracted with ethyl acetate. The combined organic phases were dried and concentrated under reduced pressure. The two chlorine isomers were isolated by chromatography (silica gel, eluent: petroleum ether / acetic ester (95/5)).

2.16 g of 6'-chloro-3'-isopropyl-2'-methylaniline and 3.95 g of 4'-chloro-3'-isopropyl-2'-methylaniline are obtained as oils.

Step 2

In the case of the 6'-chloro-3'-isopropyl-2'-methylaniline regioisomer, iminoimidazolidine is obtained as compound 1 - step 7.

3.95 g of 6'-chloro-3'-isopropyl-2'-methylaniline yield 3.03 g of 6'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (3) as hygroscopic brown dust.

In the case of 4'-chloro-3'-isopropyl-2'-methylaniline regioisomer, iminoimidazolidine is prepared analogously to compounds 5 and 7 - step 2.

2.16 g of 4'-chloro-3'-isopropyl-2'-methylamino yield 1.45 g of 4'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 4 as a hygroscopic brown powder.

3'-tert-butyl-6'-methoxy-phen-1'-yl-2-iminoimidazolidin 2

step 1

2.04 g of potassium isothiocyanate were dissolved at 10 ° C in 60 ml of acetone. 2.38 ml of benzoyl chloride were carefully added dropwise. The white suspension was refluxed for 10 minutes and cooled to 10 ° C. A solution of 40 ml of acetone and 3.63 ml of 5-tert-butyl-2-methoxyaniline was then added. The solution was then refluxed. The combined organic phases were dried and concentrated under reduced pressure. They are obtained. 9 g of brown substance which was refluxed with 11.1 ml of aqueous 50% KOH solution in 43 ml of ethanol. After 1 hour, the solution was cooled and mixed with 40 ml of water. The alcohol is distilled off under reduced pressure. The brown solution was buffered with 40 ml of saturated HCl solution. The precipitated product was separated and dried.

9.5 g (3-tert-butyl-6-methoxy-phenyl) thiourea are obtained as a brown powder.

Step 2

9.5 g (5-tert-butyl-2-methoxy-phenyl) -thiourea were dissolved in 130 ml of methanol. 1.9 ml of methyl iodide and

- the mixture is stirred at room temperature. After 2 hours the solvent was distilled off under reduced pressure. The oily residue was dissolved in 1.48 ml of ethylenediamine and 100 ml of acetonitrile and the solution heated to 105 ° C. After 12 hours the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of HCl (1M) and 20 ml of water and extracted with 2 x 40 ml of ethyl acetate. The organic phases are separated. The aqueous phase was neutralized with 12 ml NaOH (1 M) and extracted with 2 x 40 ml acetic ester. The organic phases are separated again. The aqueous phase was basified with 10 ml NaOH (IM) basic and extracted with 2 x 40 ml acetic ester. The three organic phases are combined, dried and concentrated under reduced pressure. The product was isolated by chromatography (silica gel, eluent: methylene chloride / methanol / ammonia (9/1/1%)).

0.85 g of 3'-tert-butyl-6'-methoxy-phen-1'-yl-2-iminoimidazolidine are obtained as a white powder, Fp 172-174 ° C.

6'-Bromo-3'-tert-butyl-phen-1'-yl-2-iminoimidazolidine 6 Step 1

From 2.5 g of 3'-tert-butylaniline by the same synthesis method as described for compound 2 (steps 1 and 2), 0.85 g of 3'-tert-butyl-phen-N-yl-2-iminoimidazolidine are obtained as a white powder.

Step 2

0.85 g of 3'-tert-butyl-phen-1'-yl-2-iminoimidazolidine are dissolved in 20 ml of methylene chloride and acidified with a few drops of ice vinegar. When cooling with an ice bath, 0.2 ml of bromine is carefully added. Decolouration is obtained. The solution was stirred at 0-5 ° C for 1 hour. The reaction mixture was then basified with conc. ICON solution. The organic phase was separated, dried and concentrated under reduced pressure. The product was isolated by chromatography (silica gel, eluent: methylene chloride / methanol / ammonia (9/1/1%)).

0.28 g of 6'-bromo-3'-tert-butyl-phen-1'-yl-2-iminoimidazolidine are obtained as a white powder, Fp 152-154 ° C.

5'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 27

step 1

14.9 g of 3-isopropyl-2-methyl-aniline were dissolved in 100 ml of tetrahydrofuran. With stirring, 9.55 ml of acetanhydride are added. After refluxing for an hour, the reaction mixture was cooled and mixed with petroleum ether.

The precipitated solid was separated, washed with petroleum ether and dried.

17.5 g of 3-isopropyl-2-methyl-acetanilide are obtained as white crystals.

Step 2

17.5 g of 3-isopropyl-2-methyl-acetanilide were dissolved in 90 ml of conc. sulfuric acid under ice-cold cooling to 20-25 ° C. 10.64 g of 1,3-dichloro-5,5 dimethylhydantoin were added portionwise with stirring. The reaction mixture was stirred for 24 hours at room temperature and then added to 500 g ice / water. It was extracted 2x with acetic ester and the combined organic phases were concentrated under reduced pressure. The remaining oil was dissolved in 90 ml of methanol, 90 ml of tetrahydrofuran and 90 ml of conc. hydrochloric acid and refluxed for 4 hours. After cooling, it is made alkaline with concentrated ammonia solution. It was extracted 2x with acetic ester and the combined organic phases were concentrated under reduced pressure.

Chromatographic purification of the residual oil (silica gel, eluent: petroleum ether / acetic ester 9/1) afforded 2.34 g of 5-chloro-3-isopropyl-2-methyl-aniline as an oil.

Steps 3-4

1.8 g of 5-chloro-3-isopropyl-2-methyl-aniline analogously to example 2 were converted through the corresponding thiourea to 1.4 g of 5'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine . The product is a solid with a melting point of 141-143 ° C.

The other compounds mentioned may be prepared in an analogous manner and / or in the prior art.

Claims (14)

Claims A compound of general formula I wherein R 1 or R ₅ : independently of one another are H, F, Cl, Br, CH ₂ F, ^w CHF ₂ , CF ₃ , Me or OMe, R ₂ , R 4: independently of one another are H, a branched C 3 -C 6 alkyl, F, Cl, Br, CH ₂ F, CHF ₂ , CF 3 or Me, wherein at least one of the groups R ₂ or R4 is branched C3-C6-alkyl, and R ₃ : is H, F, Cl, Br, CH ₂ F, CHF ₂ , CF ₃ or Me and / or a pharmacologically tolerated salt thereof, as well as the corresponding tautomeric forms of the compounds of formula II and / or a pharmacologically tolerated salt thereof. A compound and / or its pharmacologically tolerable salt according to claim 1, characterized in that R 1 or R ₅ : independently of one another are H, F, Cl, Br, CF ₃ , Me or OMe, R ₂ , Rf, respectively, independently of one another, are H, iPr, tert. Bu, F, Cl, Br, CF3 or Me, wherein at least one of the groups R ₂ or R 4 is iPr or tert. You, and R ₃ : is H, F, Cl, Br, CF ₃ or Me. A compound and / or a pharmacologically tolerated salt thereof according to any one of claims 1 or 2, characterized in that R 1 or R ₅ : independently of one another are H, F, Cl, Br, CF ₃ , Me or OMe, R ₂ , R ₄ : are independently H, iPr, tert, respectively. You or Me, wherein at least one of the R ₂ or R ₄ groups is iPr or tert. You, and R ₃ : is H, F, Cl, Br or Me. A compound and / or a pharmacologically tolerated salt thereof according to any one of claims 1 to 3, characterized in that Rf is H, Cl, Br or Me, R ₂ : is iPr or Tert. You, R ₃ : is H, Br or CI, R ₄ : is H, and R ₅ : is H, Cl, Br or OMe. 5. A compound and / or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4, characterized in that Rf is H or Me, R ₂ : is iPr or Tert. You, R ₃ : is H, Cl or Br, Rf is H, and R ₅ : is H or OMe. A compound and / or a pharmacologically tolerated salt thereof according to one of the preceding claims, characterized in that R2 is iPr or tert. Bu, R4 is H and that Ri is other than OMe. A compound and / or a pharmacologically acceptable salt and / or tautomer thereof according to any one of the preceding claims selected from the group consisting of: 3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 1, 3'-tert-butyl-6'-methoxy-phen-1'-yl-2-iminoimidazolidine 2, 6'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 3, 4'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 4, 6'-bromo-3'-isopropyl-2'-methyl-phen-1-yl-2-iminoimidazolidine 5, 6'-bromo-3'-tert-butyl-phen-1-yl-2-iminoimidazolidine 6, 4'-bromo-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine 7. A compound and / or a pharmacologically acceptable salt and / or tautomer thereof according to any one of the preceding claims, characterized in that the compound is 5'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl- 2-iminoimidazolidine 2Z A compound and / or a pharmacologically tolerated salt thereof according to any one of the preceding claims, characterized in that the compound of formula I is present as imino-imidazolidine. A compound and / or a pharmacologically acceptable salt thereof according to any one of the preceding claims, characterized in that the compound of formula II is present as amino-imidazoline. A compound and / or its pharmacologically tolerable salt according to any one of claims 1 to 10 as a medicament, in particular for the treatment of bladder diseases. Medicaments comprising a compound and / or a pharmacologically tolerated salt thereof according to any one of claims 1 to 10. Use of a compound and / or pharmacologically tolerated salt thereof according to any one of claims 1 to 10 for the preparation of medicaments, in particular - for the treatment of diseases of the bladder. Use of a compound and / or pharmacologically tolerated salt thereof according to any one of claims 1 to 10 for the treatment of bladder diseases, especially incontinence.