KR20030076653A - Novel alkyl-phenylimino-imidazolidine derivatives for treating urinary incontinence - Google Patents

Abstract

The present invention relates to m-alkyl phenylimino-imidazolidine derivatives comprising a novel substituent pattern on a phenyl ring and in particular the use of such derivatives for the manufacture of a medicament for the treatment of incontinence.

Description

Novel alkyl-phenylimino-imidazolidine derivatives for treating urinary incontinence

Compounds described within the scope of the present invention belong to the class of m-alkyl-phenylimino-imidazolidines. Similar compounds are known in the art.

WO 96/32939, incorporated herein by reference in its entirety, describes phenylimino-imidazole. The phenylimino-imidazoles include compounds in which the phenyl ring contains especially amino, amido, imido, halo, heteroaryl, cycloalkyl and alkyl substituents. The compounds described in this patent are contemplated as alpha-1L-agonists and can be advantageously used as applications for treating such incontinence.

Incontinence means unconscious urine release, that is, weakness in the bladder. Various signs of urinary incontinence include urge incontinence, reflex incontinence, predominant incontinence, and stress incontinence. The most common form of urinary incontinence is stress incontinence. In particular, some postpartum women suffer from stress incontinence. The cause of this is pregnancy and childbirth, which easily leads to weakening of the pelvic floor. Other causes of urinary incontinence can be, for example, nerve damage of the pelvic floor, innately short urethral or sphincter injury.

It is advantageous to use alpha-1L-agonists in the treatment of urinary incontinence, which acts selectively on the adrenergic receptors of the bladder and thus decisively affects the tension of the urethra without seriously affecting the cardiovascular system. Because it is crazy.

For some time, the possibility of using imidazole derivatives to treat urinary incontinence has been discussed in the prior art. Surprisingly, while the opinion suggests that many imidazole derivatives can offset bladder weakness, other authors have clearly observed that side effects, ie, these substances alleviate bladder obstruction. Other authors also report that this same substance would have no effect on bladder function.

Thus, it has been reported that alpha 2 agonists such as clonidine have a positive effect on nocturnal enuresis (Urology, 43 (3) (1994) 324-327). On the other hand, in the case of clonidine, the opposite result was observed that this substance could promote nocturnal enuresis [Clin. Biol. Res. 78 (1981) 101-103. Similar observations can be found in J. Pharmacol. 58 (4) (1992) 339-346. The authors of the document found that clonidine had no apparent effect on bladder function, but similar to adrenaline and all alpha 1 agonists, such as phenylephrine, midoderine or phenyl-ethanol-amine, such as ST 1059. EP-A-0 416 841 also relates to the effect of alpha agonists on bladder function. It is described herein that alpha 1 adrenergic receptor-blocking substances can be used to treat bladder obstruction. Observations according to US-A-4 226 773 are also described in this direction. According to the above specification, pyrazole-imino-imidazole derivatives can be used to promote the release of urine. For example, other alpha 1 adrenergic imidazoles, such as thiophene-pyrrole, can be used to treat urinary incontinence (EP-A-0 599 697).

This observation, different from the prior art, may conclude that it is impossible to predict the effects of imidazole derivatives on bladder function.

Description of the invention

Compounds that can be used to treat urinary incontinence must not only be practically effective but also have no possible side effects. In other words, the compound should selectively act only on the bladder as possible. Unwanted side effects include side effects, particularly on the cardiovascular system. Particularly important for the effective treatment of urinary incontinence is the bioavailability of the substance and its metabolism. Bioavailability should be as high as possible, and metabolism, on the one hand, should be such that the substance does not degrade too quickly and no other compounds are formed that are toxic or have undesirable pharmacological properties in this category.

Accordingly, one of the objectives of the present invention is a novel 1L- that selectively acts on the bladder and has desirable properties with regard to bioavailability or metabolism without substantially affecting the cardiovascular system from the class of phenylimino-imidazolidines. Find agonists.

Surprisingly, it has been found that the m-alkyl-phenylimini-imidazolines according to the invention achieve the object of the invention and are therefore suitable for the treatment of urinary incontinence.

Alkyl-phenylimino-imidazolines having branched alkyl groups are known in principle from the prior art.

Thus, for example, WO 92/21349 describes a number of ophthalmic phenylimini-imidazolidine derivatives. DE 1929950 especially describes 2'-bromo-5'-chloro-4'-tert butyl-phenylimini-2-imidazolidine, and DE 0116768 describes 2,6-dichloro-4'-3 Grade butyl-phenyliminoimidazolidines are described. EP 0035393 also relates to alkylphenylimino-imidazolidine for egg production, although not for human medicine.

The present invention relates to m-alkyl-phenylimino-imidazoline derivatives having a novel substituent pattern on a phenyl ring and to the use thereof in the preparation of pharmaceutical compositions for the treatment of incontinence in particular.

Alkyl-phenylimino-2-imidazolidine derivatives according to the present invention may be prepared by branching C ₃ -C ₆ -alkyl groups, such as isopropyl, iso, at one or more of the two possible meta positions for the imino group. Butyl, tertiary butyl, isopentyl or neopentyl. Preferably, isopropyl and / or tertiary butyl groups are present. Preferred groups according to the invention are described by the following formula (1).

In the above formula,

R ₁ or R ₅ are independently of each other H, F, Cl, Br, CH ₂ F, CHF ₂ , CF ₃ , Me or OMe,

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

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

Me means methyl, CH ₂ F means fluoromethyl, CHF ₂ difluoromethyl, CF ₃ means trifluoromethyl, iPr means isopropyl, H is hydrogen F means fluorine, Cl means chlorine, Br means bromine and tert.Bu means tertiary butyl.

When R ₅ is OMe, compounds wherein R ₂ is tert.Bu are preferred.

Among the compounds specified, preferred compounds are

R ₁ or R ₅ are independently of each other H, F, Cl, Br, CF ₃ , Me or OMe,

'R ₂ or R ₄ are each independently of each other H, iPr, tert.Bu and / or Me, and at least one of the groups R ₂ or R ₄ is iPr or tert.Bu,

R ₃ is H, F, Cl, Br or Me.

Among them, particularly preferred compounds are

R ₁ is H, Cl, Br or Me,

R ₂ is iPr or tert.Bu,

R ₃ is H, Br or Cl,

R ₄ is H,

R ₅ is H, Cl, Br or OMe.

R ₁ is H or Me,

R ₂ is iPr or tert.Bu,

R ₃ is H, Cl or Br,

R ₄ is H,

Most preferred are compounds wherein R ₅ is H, Cl or OMe.

In all cases R ₂ is preferably iPr or tert.Bu and R ₄ is preferably H. Again, in all cases R ₁ is preferably different from OMe.

The compounds of formula (I), the group R _1, R _2, R _3, R ₄ and R ₅ are all preferred compounds wherein one group of compounds of formula (I) R _1, R _2, R _3, including the R base ₄ and It may exist as a tautomer in equilibrium with an alkyl-anilino-2-imidazoline derivative of formula (II) identical to R ₅ . Accordingly, the present invention also relates to compounds corresponding to formula (II), wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ fall within the scope of the definitions described in formula (I). The same is true of the preferred ranges mentioned under formula (I).

Compounds falling within the scope of the definitions of formulas (I) and (II) are equally preferred but independent of one another.

With regard to the nomenclature used in the present invention, it should be noted that the term "phen-1'-yl-2-imidazolidine" means a compound having the following structural components:

This means that the number of atoms of the imidazole ring is numbered 1, 2, 3, etc., where one nitrogen atom is located first and the other nitrogen atom is located third. Thus, the imino group is bonded to the carbon atom located second. The atoms of the phenyl ring are numbered 1 ', 2', 3 ', etc., and the carbon atoms of the phenyl ring linked to the imino group are designated as 1' in total, and the atoms having side chain alkyl substituents at the meta position are 3 'Is specified.

Corresponding tautomers according to formula (II) are also included in the present invention, so that the chemical names specifying the structure of formula (I) also include corresponding alkyl-anilino-2-imidazolidine derivatives according to formula (II) and vice versa. It should be clearly noted.

Some alkyl-phen-1'-yl-2-imidazolidines are hereinafter described as representative examples of all compounds corresponding to Formula I or Formula II.

3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (1), preferably in free base form,

3'-tert-butyl-6'-methoxy-phen-1'-yl-2-iminoimidazolidine (2), preferably in free base form,

6'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (3), preferably in free base form,

4'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (4), preferably in free base form,

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-1'-2-iminoimidazolidine (9),

2 ', 6'-dichloro-3'-isopropyl-phen-1'-yl-2-iminoimidazolidine (10),

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

4 ', 6'-dichloro-3'-isopropyl-2'-methyl-phen-1'-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),

6'-bromo-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-1'-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-1'-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'-yl-2-iminoimidazolidine (25),

5'-bromo-4'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (26),

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

5'-chloro-4'-fluoro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (28),

6'-trifluoromethyl-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (29),

2 ', 5', 6'-tribromo-3'-tert-butyl-phen-1'-yl-2-iminoimidazolidine (30),

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

5 ', 6'-dibromo-3'-tert-butyl 2'-chloro-phen-1'-yl-2-iminoimidazolidine (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-3'-tert-butyl 5'-chloro-phen-1'-yl-2-iminoimidazolidine (35),

2 ', 5'-dibromo-3'-tert-butyl-phen-1'-yl-2-iminoimidazolidine (36),

6'-bromo-3'-tert-butyl-2 ', 5'-chloro-phen-1'-yl-2-iminoimidazolidine (37),

6'-bromo-3'-tert-butyl-5'-chloro-phen-1'-yl-2-iminoimidazolidine (38),

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

2'-bromo-3'-tert-butyl-6'-chloro-phen-1'-yl-2-iminoimidazolidine (40),

2'-bromo-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 following structures:

Among the above compounds, the following is preferable:

3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (1),

Tertiary 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),

Tertiary 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),

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

Among the above compounds, the following are most preferred:

3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (1),

Tertiary 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-phen-1'-yl-2-iminoimidazolidine (7).

The following are also preferred compounds:

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 relate to structures having isopropyl groups at meta positions, and Examples 2, 6 and 30 to 45 relate to structures having tertiary butyl groups at meta positions, and are preferred. Form a group.

In addition to the compounds mentioned above, pharmaceutically acceptable acid addition salts thereof are claimed in the present invention. Acids suitable for this purpose may naturally be inorganic or organic.

Examples of suitable acids include acids derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, citric acid, lactic acid, acetic acid, propionic acid, malic acid, succinic acid, amino acids, in particular glutamic acid or aspartic acid, carbohydrate acids and carbohydrates. These salts may also be important in the case of herbal preparations and may increase the stability of the compound, especially long term stability and / or lead to an increase in bioavailability. The hydrochloride salt is preferably monohydrochloride or dihydrochloride depending on the compound. The same applies to a preferable compound.

As already indicated above, the compounds according to the invention described above are characterized by their efficacy as well as their pharmacological properties on bioavailability and / or metabolism. Naturally the most preferred compounds are those that exhibit minimal metabolic degradation with high potency and bioavailability. Another important feature in selecting a suitable compound for the treatment of urinary incontinence is the selectivity that the compound acts on bladder function without seriously affecting other physical functions, especially the cardiovascular system.

In addition to the aforementioned compounds and pharmacologically acceptable acid addition salts thereof, the present invention also encompasses their use for the manufacture of medicaments and pharmaceutical preparations. Such formulations include all formulations suitable for medical use. Such formulations include, for example, liquids, suspensions, aerosols, powders, simple tablets and epidermal tablets, suppositories, creams and the like.

The compounds according to the invention, pharmaceutically acceptable acid addition salts thereof and / or pharmaceutical preparations containing them can be used medically for the treatment of diseases, in particular bladder diseases, more particularly incontinence. The compounds according to the invention are used to treat bags preferably with stress incontinence.

In another aspect, the present invention relates to the aforementioned compounds, pharmacologically acceptable acid addition salts and / or pharmaceutical preparations thereof, as well as their use for the preparation of other pharmacologically active derivatives of the described compounds.

1. Bioavailability

To measure bioavailability, the test substance is orally administered to a group of eight fasted male rats. As a control, the test substance is administered intravenously to the same second group of animals. At the indicated times (10 minutes, 30 minutes, 1 hour, 2 hours and 4 hours after administration and an additional 6 hours for animals in the oral group), 1 ml of blood samples are taken from both groups of animals. Blood samples taken from each group are mixed together (8 ml). The content of the corresponding test substance in the blood for the appropriate time is further post-treated by HPLC (high performance liquid chromatography) and then measured from plasma using standard methods and correlated for both groups.

result

compound Bioavailability (%) 2 34 3 8 7 53

2. Ambassador

To measure metabolism, enzyme CYP2D6 is allowed to act on the test substance. After 30 minutes, a test is made to see how much of the added test substance has been degraded by the enzyme.

The degradation rate under the effect of enzyme HLM / 60 minutes is similarly tested.

compound % Substrate degradation after incubation with CYP2D6 for 30 minutes Incubate with HLM for 60 minutes and then degrade the substrate One 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. Efficacy and Selectivity

The potency and selectivity of the compounds are measured as follows:

compound Activity in dogs Activity in the human urethra Selectivity in dogs One 78 11 0.7 2 71 30 0.6 3 70 41 0.7 4 59 0.5 5 34 0.4 6 28 7 70 21 0.7

Maximum contraction in dogs and activity in human urethra is the percentage of contraction compared to noradrenaline. Selectivity in dogs:% contraction of the femoral artery of the dog at 10 ⁻⁵ M −% contraction of the carotid artery of the dog at 10 ⁻⁵ M.

4. Manufacture

Manufacturing Example

3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (1)

Step 1

10 g of 2-methyl-3-nitrobenzoic acid are placed in a mixture of 100 ml of methylene chloride and 1 ml of dimethylformamide. 8.9 g of thionyl chloride is slowly added dropwise and the mixture is refluxed. After 6 hours, the solvent is evaporated under reduced pressure. 11.5 g of 2-methyl-3-nitro-benzoic acid chloride are obtained as an oil.

Step 2

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

18.6 g of diethyl 2- (2-methyl-3-nitro-benzoyl) -malonate is obtained as a yellow oil.

Step 3

18.6 g of diethyl 2- (2-methyl-3-nitro-benzoyl) -malonate is placed in 15 ml of concentrated acetic acid. 3.5 ml of distilled water and 3.5 ml of concentrated H ₂ SO ₄ are slowly added. The mixture is refluxed. After 4 h it is cooled, diluted with 50 ml of water and made alkaline with 30% NaOH solution while cooling with ice and extracted with 3 x 100 ml of ethyl acetate. The combined organic phases are dried and evaporated under reduced pressure.

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

Step 4

5 g of 1- (2-methyl-3-nitro-phenyl) -ethanone are dissolved in about 50 ml of methanol and hydrogenated with hydrogen at 20 ° C. and 5 bar using Raney nickel as catalyst. The crystals are separated and the filtrate is evaporated under reduced pressure. The product is purified by chromatography (silica gel, eluent: cyclohexane / ethyl acetate (3/1)). 3.5 g of 1- (2-methyl-3-amino-phenyl) -ethanone are obtained as pale yellow crystals.

Step 5

0.9 g of 60% sodium hydride oil dispersion is placed in 11.5 ml of DMSO. The suspension is stirred at 80 ° C. until no further gas evolution is seen (about 30 minutes). After cooling to 10 ° C., a solution of 3.5 g of 1- (2-methyl-3-amino-phenyl) -ethanone and 1 ml of DMSO is slowly added dropwise. The reaction temperature is raised to 45 ° C. After 10 minutes, a solution of 8.2 g of methyl-triphenylphosphonium bromide in 23 ml of DMSO is slowly added dropwise at about 30 ° C. The mixture is stirred for 4 h again without any external heat supply (RT) and then combined with 100 ml of methylene chloride and 100 ml of water. The aqueous phase is separated off and extracted twice with 75 ml of methylene chloride. The combined organic phases are washed with water, dried and concentrated under reduced pressure. The product is purified by chromatography (silica gel, eluent: cyclohexane / ethyl acetate (3/1)). 3.4 g of 3-isopropenyl-2-methyl-aniline is obtained as a clear yellow oil.

Step 6

15.4 g of 3-isopropenyl-2-methyl-aniline are dissolved in about 150 mL of methanol and hydrogenated with Raney nickel as catalyst at 20 ° C. and 20 bar. The catalyst is separated and the filtrate is evaporated under reduced pressure. 14.4 g of 3-isopropyl-1-methyl-aniline is obtained as a clear colorless oil.

Step 7

7.45 g of 3-isopropyl-2-methyl-aniline and 8.7 g of N-acetyl-methylmercapto-imidazolidine are refluxed in 100 ml of isopropanol for 3 hours. The solvent is distilled off under reduced pressure and the oily residue is refluxed in 100 ml of methanol. After 12 hours, the solution is concentrated to a small volume under reduced pressure, made alkaline with 30% NaOH solution while cooling with ice and extracted twice with ethyl acetate. The combined organic phases are dried and evaporated under reduced pressure. The oily residue is dissolved in 55 mL of HCl solution (IN) and 55 mL of water. The solution formed is precipitated with NaOH solution (2N) fractionally with increasing pH and extracted with diethyl ether until it contains the desired material. After being made alkaline with NaOH solution, the solid material is precipitated. It is suction filtered, washed with water and dried. 6 g of 3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine is obtained as a white powder (melting point: 133 to 135 ° C).

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) are dissolved in 75 ml of dimethylformamide and cooled to 5 ° C. A solution of 8.9 g N-bromo-succinimide and 50 ml DMF was added dropwise carefully within 45 minutes. The mixture is stirred at 3-5 ° C. for 1 hour. The solution is then added to about 1 L of ice water and extracted three times with ethyl acetate. The combined organic phases are dried and evaporated under reduced pressure. Two bromine isomers are separated 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 oils.

Step 2

2.28 g of a mixture of 6'-bromo-3'-isopropyl-2'-methylaniline and 4'-bromo-3'-isopropyl-2'-methylaniline are dissolved in 45 ml of acetonitrile. 1.67 g of 2-N-acetylimidazolidin-2-one and 4.6 g of POCl ₃ are then added in order. The mixture is refluxed for 4 hours and then stirred at ambient temperature. After 12 hours, the solvent is distilled off under reduced pressure. The residue is treated with 50 ml of ice water and extracted twice with ethyl acetate. Allow the aqueous phase to cool with NH ₄ OH solution. 0.5 g of a white solid is precipitated, which is filtered off with suction and dried (F1). The combined organic phases are evaporated under reduced pressure. Treat the residue with water. The aqueous phase is filtered, made alkaline with NH ₄ OH solution while cooling again and extracted twice with ethyl acetate. The combined organic phases are dried and evaporated under reduced pressure (F2-0.9 g). F1 and F2 are refluxed together in 20 ml of methanol. After 5 hours, the solvent is distilled off under reduced pressure. Two bromine isomers are separated by chromatography (silica gel, eluent: methylene chloride / methanol / ammonia (9/1/1%)). 0.15 g of 6'-bromo-3'-isopropyl-2'-methyl-phen-1'-2-iminoimidazolidine is obtained as a hygroscopic white powder. 0.45 g of 4'-bromo-3'-isopropyl-2'-methyl-1'-phen-yl-2-iminoimidazolidine is obtained as a white powder having a melting point of 178 to 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 are dissolved in 75 ml of dimethyl formamide. A solution of 6.7 g of N-chloro-succinimide in 50 mL DMF is slowly added dropwise. The reaction is somewhat exothermic. After overnight at room temperature, the solution is diluted with water and extracted with ethyl acetate. The combined organic phases are dried and evaporated under reduced pressure. Two chlorine isomers are separated by chromatography (silica gel, eluent: petroleum ether / ethyl acetate (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 in oil form.

Step 2

For 6'-chloro-3'-isopropyl-2'-methylaniline regioisomer, iminoimidazolidine for compound (1) of step 7 is prepared. 3.03 g of 6'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (3) was added to 6'-chloro-3'-isopropyl-2'- Obtained as hygroscopic brown powder from 3.95 g of methylaniline. For 4'-chloro-3'-isopropyl-2'-methylaniline active isomer, iminoimidazolidine is prepared analogously to compound (5) and compound (7) of step 2. 1.45 g of 4'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (4) was added to 4'-chloro-3'-isopropyl-2'- Obtained as hygroscopic brown powder from 2.16 g of methylaniline.

3'-tert-butyl-6'-methoxy-phen-1'-yl-2-iminoimidazolidine (2)

Step 1

2.04 g of potassium isothiocyanate is dissolved in 60 ml of acetone at 10 ° C. 2.38 ml of benzoyl chloride is carefully added dropwise. The white suspension is refluxed for 10 minutes and cooled at 10 ° C. Then a solution of 40 ml of acetone and 3.63 ml of 5-tert-butyl-2-methoxyaniline is added dropwise. The solution is then refluxed. After 3 hours, 100 ml of ice water is added and the mixture is extracted with 3 x 80 ml of ethyl acetate. The combined organic phases are dried and evaporated under reduced pressure. About 9 g of brown material is obtained, which is refluxed with 11.1 mL of a 50% aqueous KOH solution in 43 mL of ethanol. After 1 hour the solution is cooled and combined with 40 ml of water. The alcohol is distilled off under reduced pressure. The brown solution is buffered with 40 ml of saturated NH ₄ Cl solution. The precipitated product is suction filtered and dried. 9.5 g of (3-tert-butyl-6-methoxy-phenyl) -thiourea are obtained as a brown powder.

Step 2

9.5 g of (5-tert-butyl-2-methoxy-phenyl) -thiourea are dissolved in 130 ml of methanol. 1.9 ml of methyl iodide are added and the mixture is stirred at room temperature. After 2 hours the solvent is distilled off under reduced pressure. The oily residue is dissolved in 1.48 mL of ethylenediamine and 100 mL of acetonitrile and the solution is heated at 105 ° C. After 12 hours, the solvent is distilled off under pressure. The residue is dissolved in 20 ml of HCl (1M) and 20 ml of water and extracted with 2 x 40 ml of ethyl acetate. The organic phase is separated off. The aqueous phase is neutralized with 12 mL NaOH (1M) and extracted with 2 x 40 mL ethyl acetate. The organic phase is separated again. The aqueous phase is made basic with 10 mL of NaOH (1M) and extracted with 2 x 40 mL of ethyl acetate. All three organic phases are combined, dried and evaporated under reduced pressure. The product is separated 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 is obtained as a white powder having a melting point of 172 to 174 ° C.

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

Step 1

0.85 g of 3'-tert-butyl-phen-1'-yl-2-iminoimidazolidine was converted to 3'-3 using the same synthesis as described for compound (2) (steps 1 and 2). Obtained as a white powder from 2.5 g of tert-butylaniline.

Step 2

0.85 g of 3'-tert-butyl-phen-1'-yl-2-iminoimidazolidine is dissolved in 20 ml of methylene chloride and acidified with a few drops of glacial acetic acid. Then 0.2 ml of bromine is added dropwise carefully while cooling in an ice bath. The solution is discolored. It is stirred at 0-5 ° C. for 1 hour. The reaction mixture is then made alkaline with concentrated NH ₄ OH solution. The organic phase is separated, dried and evaporated under reduced pressure. The product is separated 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 is obtained as a white powder having a melting point of 152 to 154 占 폚.

5'-Chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazoline (27)

Step 1

14.9 g of 3-isopropyl-2-methyl-aniline are dissolved in 100 ml of tetrahydrofuran. 9.55 mL acetic anhydride is added with stirring. After refluxing for 1 hour, the reaction mixture is cooled and petroleum ether is added to the mixture. The precipitated solid material is suction filtered, washed with petroleum ether and dried. 17.5 g of 3-isopropyl-2-methyl-acetanilide are obtained in the form of white crystals.

Step 2

17.5 g of 3-isopropyl-2-methyl-acetanilide are dissolved in 90 mL of concentrated sulfuric acid while slowly cooling with ice at 20 to 25 ° C. 10.64 g of 1,3-dichloro-5,5-dimethylhydantoin are added in a batch manner with stirring. The reaction mixture is stirred at rt for 24 h and then added to 500 g of ice / water. The mixture is extracted twice with ethyl acetate and the combined organic phases are evaporated under reduced pressure. The residual oil is dissolved in 90 ml of methanol, 90 ml of tetrahydrofuran and 90 ml of concentrated hydrochloric acid and refluxed for 4 hours. After cooling, the mixture is alkylated with a concentrated ammonia solution. The mixture is extracted twice with ethyl acetate and the combined organic phases are evaporated under reduced pressure. The residual oil is purified by chromatography (silica gel, eluent: petroleum ether / ethyl acetate 9/1) to give 2.34 g of 5-chloro-3-isopropyl-2-methyl-aniline in oil form.

Steps 3 to 4

1.8 g of 5-chloro-3-isopropyl-2-methyl-aniline was reacted similarly to Example 2 via the corresponding thiourea to give 5'-chloro-3'-isopropyl-2'-methyl-phen-1 1.4 g of '-yl-2-iminoimidazoline are obtained. The product is a solid material having a melting point of 141 to 143 ° C.

The other compounds mentioned may be prepared according to the prior art and / or analogous to the prior art.

Claims (14)

Tautomers and / or pharmacologically acceptable salts thereof of the compounds of formula (I) or formula (II) and the corresponding tautomeric forms and / or pharmacologically acceptable salts of the compounds according to formula (II). Formula I Formula II In the above formula, R ₁ or R ₅ are independently of each other H, F, Cl, Br, CH ₂ F, CHF ₂ , CF ₃ , Me or OMe, R ₂ or R ₄ are each, independently of each other, H, branched C _3-6 -alkyl, F, Cl, Br, CH ₂ F, CHF ₂ , CF ₃ or Me, and at least one of the groups R ₂ or R ₄ is branched C _3-6 -alkyl, R ₃ is H, F, Cl, Br, CH ₂ F, CHF ₂ , CF ₃ or Me. The method of claim 1, R ₁ or R ₅ are independently of each other H, F, Cl, Br, CF ₃ , Me or OMe, R ₂ or R ₄ are each independently of each other H, iPr, tert. Bu, F, Cl, Br, CF ₃ or Me, and at least one of the groups R ₂ or R ₄ is iPr or tert.Bu, And / or a pharmacologically acceptable salt thereof, wherein R ₃ is H, F, Cl, Br, CF ₃ or Me. The method according to claim 1 or 2, R ₁ or R ₅ are independently of each other H, F, Cl, Br, CF ₃ , Me or OMe, R ₂ or R ₄ are each independently of each other H, iPr, tert.Bu or Me, and at least one of the groups R ₂ or R ₄ is iPr or tert.Bu, And / or a pharmacologically acceptable salt thereof, wherein R ₃ is H, F, Cl, Br or Me. The method according to any one of claims 1 to 3, R ₁ is H, Cl, Br or Me, R ₂ is iPr or tert.Bu, R ₃ is H, Br or Cl, R ₄ is H, A compound and / or pharmacologically acceptable salt thereof, wherein R ₅ is H, Cl, Br or OMe. The method according to any one of claims 1 to 4, R ₁ is H or Me, R ₂ is iPr or tert.Bu, R ₃ is H, Cl or Br, R ₄ is H, Compounds and / or pharmacologically acceptable salts thereof, wherein R ₅ is H or OMe. The compound and / or pharmacologically acceptable according to any one of claims 1 to 5, wherein R ₂ is iPr or tet.Bu, R ₄ is H and R ₁ is different from OMe. Salts thereof. The method according to any one of claims 1 to 6, 3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (1), Tertiary 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) and 4'-bromo-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (7) and / or pharmaceutically acceptable salts thereof Or tautomers. 8. The compound according to any one of claims 1 to 7, characterized in that it is 5'-chloro-3'-isopropyl-2'-methyl-phen-1'-yl-2-iminoimidazolidine (27). Compounds and / or pharmacologically acceptable salts and / or tautomers thereof. The compound and / or pharmacologically acceptable salt thereof according to any one of claims 1 to 8, characterized in that the compound according to formula (I) occurs as imino-imidazolidine. The compound and / or pharmacologically acceptable salt thereof according to any one of claims 1 to 9, characterized in that the compound according to formula (II) occurs as amino-imidazoline. The compound and / or pharmacologically acceptable salt thereof according to any one of claims 1 to 10 as a pharmaceutical composition for the treatment of bladder disease. A pharmaceutical formulation containing a compound according to any one of claims 1 to 10 and / or pharmacologically acceptable salts thereof. Use of a compound according to any one of claims 1 to 10 and / or pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical composition for the treatment of bladder disease. A method for treating bladder disease, in particular urinary incontinence, using a compound according to claim 1 and / or a pharmacologically acceptable salt thereof.