Derivatives of phenylimidazoline and pharmaceutical composition based on them

 

(57) Abstract:

Proposed new derivatives of phenylimidazoline General formula I, where n = I, R1and R2- H, halogen, CN, C1-C6- alkyl, C1-C6- alkoxy, C1-C6- alkylthio, CF3, NO2, R3means a group II or group III, where R4- N or C1-C6alkyl, R5- H, C1-C6- alkyl or azatadine group, or its pharmaceutically acceptable salt. These compounds are used as active ingredients in pharmaceutical compositions, with 5 HT3antagonistic activity. 2 S. and 3 C.p. f-crystals, 2 PL.

The present invention relates to new derivatives of 1-imidazolyl-alkyl-3-phenyl-imidazolidin-1-ones and to the containing pharmaceutical compositions.

Pharmaceutically acceptable salts of compounds of formula (I) include salts of joining inorganic acids, such as nitrogen, chloride-hydrogen, Hydrobromic, sulphuric, perchloric and phosphoric.

New derivatives of phenylimidazoline have the General formula (I):

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where

n = 1;

each of R1and R2that may be the same or different, is>alkylthio, trifluoromethyl or nitro:

R3represents an imidazole group of the formula

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or

< / BR>
where R4represents hydrogen or C1-C6-alkyl,

R5represents hydrogen, C1-C6-alkyl or attitudinal group;

or their pharmaceutically acceptable salts.

The above formula for compounds in accordance with the present invention includes all the possible isomers and their mixtures.

Examples of preferred compounds according to the invention are the following compounds;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-chlorophenyl)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-phenylimidazoline-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-bromophenyl)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-signofevil)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-methylthiophenyl)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-were)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3, 5dimethylphenyl)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3,5-dichlorophenyl)imidazolidin-2-he;

1-(1H-imidazol-4-yl)methyl-3-(3-chlorophenyl)imidazolidin-2-he;

1-(1H-imidazol-4-yl) who yl)methyl-3-(3-tianfeng)imidazolidin-2-he;

1-(1H-imidazol-4-yl)methyl-3-(3-methylthiophenyl)imidazolidin-2-he;

or their pharmaceutically acceptable salts, in particular hydrochloride.

The connection according to the invention and their salts can be obtained by a method comprising:

a) interaction of the compounds of formula (II) or its salt

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where R1and R2have the above significance, with a compound of formula (III)

R3-(CH2)n-Y

where n has the above meaning and Y represents a leaving group and R3that has the above meaning, R5represents a C1-C6-alkyl or attitudinal group, thus obtaining the compounds of formula (I) in which R5has the above value, excluding hydrogen; or

b) removing the protection from the compounds of formula (IV)

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where R1, R2and n have the above significance, and R3represents a group of the formula

< / BR>
or

< / BR>
where R4have the above significance, and R5is astonishing group, thus obtaining a compound of formula (I) in which R5represents a hydrogen: and, if required, converting the compounds of formula (I) into another compound of formula (I), and/or, if n is in loose coupling, and/or, if necessary, separating a mixture of isomers of compounds of formula I into individual isomers.

Salt of the compounds of formula (II) may be, for example, alkali metal salt, preferably a salt of sodium or potassium.

Transformation into a salt of the compounds of formula (II) can be carried out with known methods, for example, by treatment with alkali metal hydride, preferably sodium hydride, or diisopropylamide lithium or alkali metal alkoxides, preferably tert-butyl potassium.

In the compound of formula (III) Y as a leaving group may be, for example, a halogen atom, generally chlorine, iodine or bromine, in particular chlorine: or a reactive residue of ester, typically by a reactive residue of ester alcohol, especially sulfonylacetonitrile, for example, methylsulfonylamino or tolilsulfonil, more preferably by methylsulfonylamino.

The reaction of the compound of formula (II) or its salt with the compound of the formula (III) can be carried out, for example, in an anhydrous aprotic organic solvent, for example dimethylformamide, dimethylacetamide or any other organic solvents, for example toluene, tetrahydrofuran is the for example NaH or of potassium tert-butylate.

Removing protection from the compounds of formula (IV) can be carried out in accordance with known methods, such as hydrolysis, for example, acidic hydrolysis, for example using an aqueous solution galoidvodorodnykh acid, typically HCl or HBr, or diluted sulfuric acid or aqueous acetic acid, at a temperature ranging from room temperature to the temperature of phlegmy.

Alternatively, removing the protection can be implemented by processing triperoxonane acid in an organic aprotic solvent, such as methylene chloride, chloroform or carbon tetrachloride, at temperatures ranging from room temperature to the temperature of phlegmy.

The compound of formula (I) may be converted, if necessary, into another compound of formula (I) in accordance with known methods.

The compound of formula (I) in which R5represents hydrogen, can be converted into another compound of formula (I) in which R5is C1-C6-alkyl, by the following procedures, for example,as described above relative to the reaction of compounds of formula (II) with an alkylating agent of the formula (III).

Prevremeni and isomers on the individual isomers may be carried out by conventional methods.

When in the compounds described above, there are groups that must be protected during the reaction described above, such groups can be protected in the usual way before the reaction occurs, and then the protection can be removed. Examples of protective groups include protective groups commonly used in the chemistry of peptides.

The compounds of formula (II) are either known or can be obtained by known methods, for example as described in J. Med. Chem. 9, 852 (1966).

The compounds of formula (III) are known or can be obtained by known methods.

Compounds according to the invention act on serotoninergicescuu system, in particular as 5HT3 receptor antagonists, as is proved, for example, the fact that was discovered their activity in Anatoliivna of chemoreflex of Bezold-Arisa caused due to 5-HT in rat shot based on the method described by Tsardom j. R., Naunyn Sckmiedeberg''s Arch. Pharmacol. 326, 36 - 44 (1984).

The following table 1 contains data on 5HT3antagonistic activity in vivo, obtained in this test for a representative group of compounds according to the invention.

Affinity for serotonin 5-HT3receptors were determined, nab is-BRL 43694, described by Nelson and Thomas (1989). Nelson D. R. and Thomas, D. R. /3H/-BRL 43694 (granisetron), a specific ligand for 5-HT3binding sites in cortical membranes of the brain of the rat, Biochem Pharmac 38, 1693-1695, 1989.

Data affinity relating to a representative group of compounds according to the invention, shown in the following table 2.

Taking into account the specified activity, for example, in the treatment of disorders of the Central nervous system such as anxiety and psychosis, and/or treatment of disorders of bowel motility and/or vomiting.

Taking into account the above activity, the compounds according to the invention can also be applied, for example, as an anti-migraine or against excessive addiction to drugs, or as activators cognitive abilities.

The dose level of the compounds according to the invention, suitable for administration to adults either for prevention or for treatment can vary from approx. 0,010 up to approx. 20 mg/kg of body weight depending on the chosen route of administration, the particular compound, a particular patient receiving this treatment, and the nature and severity of the disorder. For example, for the second oral medication dosage is within the following limits.

Preferably, the compounds can be, for example, entered as a single or divided doses, so that the total daily dose would be in the range from approx 0.020 approx. 10 mg/kg / day.

Of course, such medication can be adjusted to achieve optimal therapeutic outcomes.

Compounds according to the invention can be administered in different dosage forms, for example orally in the form of pills, capsules, tablets, sugar or film coating, liquid solutions or suspensions.

The invention includes pharmaceutical compositions containing a compound according to the invention in combination with pharmaceutically acceptable auxiliary agent (which may be a carrier or a diluent).

The nature of the pharmaceutical compositions containing compounds according to the present invention, in combination with pharmaceutically acceptable carriers or diluents will, of course, depend upon the desired route of administration of drugs. Compositions can be prepared in the usual way with the usual ingredients. For example, the compounds according to the invention can be administered in the form of water or oil rastv what about the use of the pharmaceutical composition, containing compounds according to the present invention, preferred are tablets, pills or capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, lubricants, for example silica, talc, stearic acid, magnesium stearate or calcium, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatin, methylcellulose, carboxymethylcellulose, gum Arabic, tragakant, polyvinylpyrrolidone; disaggregated agents, such as starches, alginic acid, alginates, sodium starch glycolate; boiling the mixture; the dyestuffs; sweeteners; wetting, such as lecithin, Polysorbate, laurylsulfate; and in General, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations can be prepared in the usual way, for example by mixing, granulating, tabletting, sugar coating or coating film. Liquid dispersions for oral administration can be, for example, syrup, emulsions and suspensions.

The syrups may contain as carrier, Nagot contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections may contain, together with the active compound in pharmaceutically acceptable carrier, e.g. sterile water, olive oil, etiloleat, glycols, such as propylene glycol and, if necessary, a suitable number of ignorance.related. The solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of a sterile aqueous isotonic salt solutions.

Suppositories can contain along with the active compound in pharmaceutically acceptable media, such as cocoa butter, polyethylene glycol, surfactant-based complex polyoxyethylenesorbitan esters of fatty acids or lecithin.

The following examples illustrate but do not limit the present invention.

Example 1

1-(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)-methyl-3-(3 - chlorophenyl)-imidazolidin-2-it.

To a stirred solution of 1-(3-chlorophenyl)-imidazolidin-2-she (1.2 g; 0,0061 mol) in 20 ml of anhydrous dimethyl who eshivot for 1 hour at 60oC; then added at room temperature 4-chloromethyl-5-methyl-1-triphenyl - methyl-1H-imidazol (2.3 g; 0,0061 mol).

The mixture is stirred for 6 hours at 90oC, then cooled, poured into water and extracted with methylene chloride. The organic layer was washed with brine, dried over anhydrous sodium sulfate and after filtration, evaporated to dryness. The residue is purified by instantaneously evaporating chromatography on silica gel (ethyl acetate as eluent) to give 2.1 g of the desired product as a white solid (so pl. 189-191oC; C33H29ClN4O must be = C:74,35; H: 5,48; N: 10,51, Cl: of 6.65; found = C: 74,60; H: 5.55 N: 10,23; Cl: to 6.43).

Similarly, you can obtain the following connections:

1-(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl-3 - phenylimidazoline-2-he; so pl. 196-198oC;

1-(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl-3-(3-bromophenyl)- imidazolidin-2-it, so pl. 215-217oC;

1-(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl-3-(4-chlorophenyl)- imidazolidin-2-he;

1-(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl-3-(2-chlorophenyl)- imidazolidin-2-he;

1-(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl-3-(3 - methylthiophenyl)-imidazolidin-2-it, so pl. 206oC decomp.;

1-(5-methyl-1-Triveni the Il-3-(3, 5dimethylphenyl)-imidazolidin-2-he;

1-(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl-3-(3,5 - dichlorophenyl)-imidazolidin-2-it, so pl. 199-202oC;

1-(1-triphenylmethyl-1H-imidazol-4-yl)methyl-3-(3 - chlorophenyl)-imidazolidin-2-he;

1-(1-triphenylmethyl-1H-imidazol-4-yl)methyl-3-phenyl - imidazolidin-2-it, so pl. 162-166oC;

1-(1-triphenylmethyl-1H-imidazol-4-yl)methyl-3-(3-bromophenyl)- imidazolidin-2-he;

1-(1-triphenylmethyl-1H-imidazol-4-yl)methyl-3-(3-tianfeng)- imidazolidin-2-it; and

1-(1-triphenylmethyl-1H-imidazol-4-yl)methyl-3-(3-methylthiophenyl)- imidazolidin-2-it.

Example 2

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-chlorophenyl)- imidazolidin-2-it.

A solution of 1-(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl-3- (3-chlorophenyl)-imidazolidin-2-she (2 g; 0,0038 mol) in acetic acid (30 ml), water (30 ml) and tetrahydrofuran (30 ml) is heated under reflux for 1 hour. The solution is cooled and evaporated in 1 N. hydrochloric acid (100 ml) and washed with ethyl acetate.

The aqueous layer was slightly alkalinized with potassium carbonate (to pH 9) and extracted with methylene chloride. The organic layer is washed with brine, dried over anhydrous sodium sulfate and after filtration, evaporated to dryness.

The remainder of the grated into powder with dry diethyl ether, receive the ClN4O must be = C: 57,83; H: 5,20; N: 19,27 Cl: 12,20; found = C: 57,65; H: 5,32 N: 19,04; Cl: 12,53).

Similarly, you can obtain the following connections:

1-(5-methyl-1H-imidazol-4-yl)methyl-3-phenyl-imidazolidin-2-it, so pl. 207-210,5oC;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-bromophenyl)-imidazolidin - 2-it, so pl. 233-238,5oC;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-tianfeng)- imidazolidin-2-it, so pl. 221-226oC;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-methylthiophenyl)- imidazolidin-2-it, so pl. 185-190oC;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(4-chlorophenyl)- imidazolidin-2-it, so pl. 230-234oC;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(2-chlorophenyl)- imidazolidin-2-it, so pl. 159,5-167,5oC;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-were - imidazolidin-2-it, so pl. 216-221oC;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3, 5dimethylphenyl)- imidazolidin-2-it, so pl. 246-249oC;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3,5-dichlorophenyl)- imidazolidin-2-it, so pl. 242-249oC;

1-(1H-imidazol-4-yl)methyl-3-(3-chlorophenyl)-imidazolidin-2-he;

1-(1H-imidazol-4-yl)methyl-3-phenyl-imidazolidin-2-it, so pl. 201-203oC;

1-(1H-imidazol-4-yl)methyl-3-(3-bromophenyl)imidazolidin-2-he;

1-(1H-imidazol-4-yl)methyl-3-(3-tianfeng)imidazolidin-2-he;

1-(1H-imidazol-4-yl)DIN-2-it, so pl. 205-209oC;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-nitrophenyl) imidazolidin-2-it, so pl. 227-231oC;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-forfinal) imidazolidin-2-it, so pl. 220,5-223,5oC; and

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-methoxyphenyl) imidazolidin-2-it, so pl. 183-187oC.

Example 3

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-chlorophenyl)imidazolidin-2-he hydrochloride

To a solution of 1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-chlorophenyl) imidazolidin-2-she (0.6 g; 0,00206 mol) in absolute ethanol (10 ml) was added an excess of chloride-hydrogen acid in ethanol. Add diethyl ether. The precipitate is filtered off, getting 0.65 g of the desired product in the form of a solid white color, so pl. 245oC (decomp.).

Similarly, you can obtain the following connections:

1-(5-methyl-1H-imidazol-4-yl)methyl-3-phenylimidazoline-2-he hydrochloride;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-bromophenyl)imidazolidin-2-he hydrochloride;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-tianfeng)imidazolidin-2-he hydrochloride;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-methylthiophenyl)imidazolidin-2-he hydrochloride;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-were)imidazolidin-2-he hydrochloride;

1-(5-methyl-1H-imidazol-4-yl)gazolidon-2-he hydrochloride;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(4-chlorophenyl)-imidazolidin - 2-he hydrochloride;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(2-chlorophenyl)-imidazolidin - 2-he hydrochloride;

1-(1H-imidazol-4-yl)methyl-3-(3-chlorophenyl)-imidazolidin - 2-he hydrochloride;

1-(1H-imidazol-4-yl)methyl-3-phenyl-imidazolidin-2-he hydrochloride;

1-(1H-imidazol-4-yl)methyl-3-(3-bromophenyl)-imidazolidin-2-he hydrochloride;

1-(1H-imidazol-4-yl)methyl-3-(3-tianfeng)-imidazolidin-2-he hydrochloride; and

1-(1H-imidazol-4-yl)methyl-3-(3-methylthiophenyl)-imidazolidin-2-he hydrochloride.

Example 4

1-(1-ethyl-4-methyl-1H-imidazol-5-yl)methyl-3-phenyl)- imidazolidin-2-one-hydrochloride.

To a solution of 1-(5-methyl-1H-imidazol-4-yl)methyl-3-phenyl - imidazolidin-2-it (1 g; to 0.0039 mol) in 20 ml of anhydrous dimethylformamide, supported under a nitrogen atmosphere, add 50% NaH (0,198 g; 0,0041 mol) at 0oC. After 15 minutes, add ethyliodide (0.33 ml; 0,0041 mol) and continue stirring for 1 hour at room temperature. The mixture is cooled to 0oC, poured into water and extracted with methylene chloride.

The organic layer was washed with brine, dried over anhydrous sodium sulfate and, after filtration, evaporated to dryness. The residue is purified by mgnew srabatyvayut excess chloride-hydrogen acid in ethanol. The crude salt is collected by filtration and precrystallization of absolute ethanol, getting 0.21 g of the desired product as a solid white color. so pl. 227-230oC.

Working in a similar way, it is possible to prepare the following compounds:

1-(1-ethyl-4-methyl-1H-imidazol-5-yl)methyl-3-(3-chlorophenyl)- imidazolyl-2-he hydrochloride;

1-(1,4-dimethyl-1H-imidazol-5-yl)methyl-3-(3-chlorophenyl)- imidazolidin-2-he hydrochloride; and

1-(1,4-dimethyl-1H-imidazol-5-yl)methyl-3-phenyl - imidazolidin-2-he hydrochloride, T. pl. 219-223oC.

Example 5

1-(1-ethyl-5-methyl-1H-imidazol-5-yl)methyl-3-phenyl-imidazolidin-2-he hydrochloride.

Instantly evaporating chromatography (flash chromatography) of example 4 gives the second eluate, which is treated with an excess of chloride-hydrogen acid in ethanol. The crude salt is collected by filtration and recrystallized from absolute ethanol, gaining 0.4 g specified in the subtitle of the product in the form of a solid white color, so pl. 225-230oC.

Similarly, you can obtain the following connections:

1-(1-ethyl-5-methyl-1H-imidazol-4-yl)methyl-3-(3-chlorophenyl)- imidazolidin-2-he hydrochloride;

1-(1,5-dimethyl-1H-imidazol-4-yl)methyl-3-(3-chlorophenyl, the.sq. 250-270oC (decomp.).

Example 6

Tablets each weighing 150 mg and containing 80 mg of the active substance, can be obtained by mixing and crushing of the following ingredients:

1-(5-methyl-1H-imidazol-4-yl-methyl-3-(3-chlorophenyl)-imidazolidin-2-he - 60 mg

Starch 50 mg

Microcrystalline cellulose 30 mg

Polyvinylpyrrolidone 5 mg

Natrocarbonatite - 4.5 mg

Magnesium stearate 0.5 mg

Example 7

Capsules, each dose of 200 mg and containing 80 mg of the active substance, can be prepared as follows:

1-(5-methyl-1H-imidazol-4-yl-methyl-3-(3-chlorophenyl)-imidazolidin-2-he - 80 mg

Corn starch 60 mg

Microcrystalline cellulose - 59 mg

Magnesium stearate 1 mg

This composition can be enclosed in gelatin capsules consisting of two parts and dosed at 200 mg per capsule.

1. Derivatives of phenylimidazoline General formula I

< / BR>
where n is 1;

each of R1and R2that may be the same or different, represent hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, trifluoromethyl or nitro;

R3performance is 6-alkyl;

R5is hydrogen, C1-C6-alkyl or azatadine group,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, characterized in that it is:

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-chlorophenyl)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-phenylimidazoline-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-bromophenyl)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-tianfeng)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-methylthiophenyl)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3-were)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3, 5dimethylphenyl)imidazolidin-2-he;

1-(5-methyl-1H-imidazol-4-yl)methyl-3-(3,5-dichlorophenyl)imidazolidin-2-he;

1-(1H-imidazol-4-yl)methyl-3-(3-chlorophenyl)imidazolidin-2-he;

1-(1H-imidazol-4-yl)methyl-3-phenylimidazoline-2-he; ;

1-(1H-imidazol-4-yl)methyl-3-(3-bromophenyl)imidazolidin-2-he;

1-(1H-imidazol-4-yl)methyl-3-(3-tianfeng)imidazolidin-2-he;

1-(1H-imidazol-4-yl)methyl-3-(3-methylthiophenyl)imidazolidin-2-it.

or its pharmaceutically acceptable salt.

3. The salt of the compound according to any one of paragraphs.1 to 3, where this salt is the hydrochloride.

4. Prod CLASS="ptx2">

5. Pharmaceutical composition having NC3antagonistic activity comprising an active ingredient and a suitable carrier and/or diluent, wherein the active substances it contains an effective amount of the compounds of General formula (I) or its pharmaceutically acceptable salt, as defined in paragraph 1.

 

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