Derivatives of substituted benzamidine

 

(57) Abstract:

The proposed substituted derivatives of benzamidine General formula I, where a represents-O-CmH2m-X1group or a group of formula IV; m = 2-6; X1group of the formula III, X3group-O-CnH2n-; X2group-CnH2n-O-; n = 1 or 2; R1HE, COR7or COOR7; R2- (C1- C6)-alkyl, -CR5R6is aryl or hydrogen if a is a residue of formula IV, or if X1- the remainder of the formula (III), (C1- C6)-alkoxy (if a is-OSmH2mX1group and X1group of the formula (III); R3is hydrogen, (C1- C6)-alkyl, (C1- C6)-alkoxy (provided that R2- -CR5R6-aryl or if X1group of the formula (III); R4- N or (C1- C6)-alkyl; R5and R6- (C1- C4)-alkyl; R7- (C1- C6)-alkyl, (C5- C7-cycloalkyl, aryl, heteroaryl with a nitrogen atom as a heteroatom, which has antagonistic action on leukotriene receptors IN4provided that if A - group-OCmH2mX1-; m = 2, 3 or 4, X1is a group of formula III; R2- H or (C1- C6)-alkyl; RKil, R1't mean IT. 9 C.p. f-crystals.

The invention relates to substituted derivative of amidine possessing biological activity, in particular to new substituted derivative of benzamidine possessing biological activity, in particular antagonistic action on leukotriene receptors B4.

Known derivatives of substituted benzamidine, which has antagonistic action on leukotriene receptors B4(see application WO 93/16036, class C 07 C 257/18, A 61 K 31/35, 19.08.1993).

The objective of the invention is the expansion of the Arsenal substituted derivatives of benzamidine, which has antagonistic action on leukotriene receptors B4.

The problem is solved proposed substituted derivatives of benzamidine General formula I

< / BR>
where A represents 1) a group of the formula

-O-CmH2m-X1- (II)

where m denotes 2-6, and

X1means a group of the formula

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or 2) a group of the formula

< / BR>
where X2means the group-CnH2n-O-, where n is 1 or 2;

X3means the group-O-CnH2n-;

R1means hydroxyl, COR7, COOR7;

R2means al is no residue of the formula (III), and alkoxy with 1-6 carbon atoms (if A denotes a group of formula II, m have the above significance and X1means a group of formula (III);

R3denotes hydrogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms (provided that R2means-CR5R6-aryl or if X1means a group of formula (III);

R4means hydrogen or alkyl with 1-6 carbon atoms;

R5and R6denote alkyl with 1-4 carbon atoms;

R7means alkyl with 1-6 carbon atoms, cycloalkyl with 5-7 carbon atoms, aryl, heteroaryl with a nitrogen atom as a heteroatom, aralkyl;

provided that if

A denotes the group-O-CmH2m-X1-, where m = 2, 3, or 4

X1means a group of the formula

< / BR>
R2denotes hydrogen, alkyl with 1-6 carbon atoms;

R3denotes hydrogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms;

R4denotes hydrogen, alkyl with 1-6 carbon atoms,

R1does not mean hydroxyl.

The above-mentioned aryl means preferably phenyl, substituted hydroxide, and heteroaryl - pyridyl, pyridazinyl, pyrimidyl or pyrazinyl.

The first group preferred the X2X3and R1have a specified value,

X1means a group of formula III;

R2means alkyl with 1-6 carbon atoms, -CR5R6-aryl or alkoxy with 1-6 carbon atoms (if X1means a group of formula (III);

R3denotes hydrogen, alkyl with 1-6 carbon atoms or alkoxy with 1-6 carbon atoms (if R2means-CR5R6-aryl);

R4means hydrogen;

R5and R6denote alkyl with 1-3 carbon atoms.

The second group of preferred substituted derivatives of benzamidine the above General formula I includes compounds that have

X1means a group of formula III;

R1means a group COOR7;

R2means alkyl with 1-6 carbon atoms or-CR5R6-aryl;

R3denotes hydrogen, alkyl with 1-6 carbon atoms or alkoxy with 1-6 carbon atoms (if R2means-CR5R6-aryl);

R4means hydrogen;

R5, R6denote alkyl with 1-3 carbon atoms;

R7means alkyl with 1-6 carbon atoms, aralkyl or cycloalkyl with 5-7 carbon atoms.

Particularly preferred substituted derivatives of benzamidine is ethoxy] -biphenyl-4 - yl}methyl)-amine, (benzyloxycarbonyl-imino-{4'-[2-(2-propylenoxide)-ethoxy]-biphenyl-4 - yl} methyl)-amine, [hydroxy-imino-(4-{3-[4-(1-methyl-1-phenylethyl)- phenoxymethyl] -benzyloxy}phenyl)-methyl]-amine, (etoxycarbonyl-imino-(4-{3-[4-(1-methyl-1-phenylethyl)-phenoxymethyl] - benzyloxy}phenyl)-methyl]-amine, [3'-pyridylcarbonyl-imino-(4-{ 3-[4-(1- methyl-1-phenylethyl)-phenoxymethyl] -benzyloxy} phenyl)-methyl] -amine and (etoxycarbonyl-imino-(4-{3-[4-(1-methyl-(4'-hydroxy)phenylethyl)- phenoxymethyl]-benzyloxy}phenyl)-methyl]amine.

The new compounds may contain one or more chiral centers. Therefore, the invention also relates to racemates, pure enantiomers or enriched enantiomers forms, if necessary in the form of pairs of diastereomers. The invention also covers the possible tautomers (with residue-C(NH)-other1).

New connections can be obtained by known methods, such as the following.

1. The interaction of amidine formula

< / BR>
where A, R2, R3and R4have the above significance, with a compound of the formula

L-R'1(VI)

where R'1has the same meaning as R1with the exception of hydroxyl, and L means nucleophilic delete the group, such as halogen atom (napic, for example, tetrahydrofuran, methylene chloride, chloroform or dimethylformamide, preferably in the presence of a base, such as, for example, sodium carbonate, potassium carbonate or sodium lye, or in the presence of tertiary organic bases, such as, for example, triethylamine, N-ethyl-Diisopropylamine, N-methylmorpholine or pyridine, which may simultaneously serve as solvent, at temperatures between -30 and +100oC, preferably however at temperatures between -10 and +80oC.

2. The interaction of compounds of the formula

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where R2, R3and R4have the above meaning,

with a derivative of benzamidine formula

< / BR>
or

< / BR>
where L, m, n, X1X3and R1have the above meaning.

3. The interaction of compounds of the formula

< / BR>
where X1, R1and R2have the above meaning,

with the compound of the formula

< / BR>
or

< / BR>
where L, m, n, R2, R3, R4, R8, R9and X2have the above meaning.

Methods 2 and 3 are expediently carried out in an environment aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide, acetonitrile, or an alcohol what are you metal the metal hydroxides, metal hydrides, at temperatures between about 0 and 140oC or the boiling temperature of the reaction mixture.

4. To obtain the compounds of formula I, where R1means hydroxyl:

the interaction of NITRILES of the formula

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where A, R2, R3and R4have the above meaning,

with hydroxylamine.

Method 4 expediently carried out by heating in alcohol, such as, for example, methanol, ethanol or propanol, or in the environment aprotic solvent, such as, for example, dimethylsulfoxide, dimethylformamide or acetonitrile, if necessary in a mixture with water. Hydroxylamine is used, for example, in the form of hydrochloride or methanesulfonate with the addition of a suitable base, for example sodium carbonate.

The initial substance can be synthesized by standard methods.

The new compounds of formula I differ in numerous therapeutic applications. It should be emphasized features such application, in which case a role play antagonistic action on leukotriene receptors B4. In particular, it is necessary to include the following areas of application: arthritis, asthma, chronic obronie anti-inflammatory drug gastropathy or disease, Alzheimer's disease, shock, damage associated with reperfusion/ischemia, atherosclerosis, multiple sclerosis.

In addition, the new compounds can be cured of the disease or condition in which the passage of cells from the blood through the vascular endothelium into the tissue has a certain value (for example in the case of metastasis), or diseases and conditions under which the combination of leukotriene B4or other molecules (for example, 12-oxyacetylene acid) receptor leukotriene B4has an effect on cell proliferation (for example chronic malificence leukemia).

The new compounds can also be used in combination with other active principles, such as those used in the case of the same evidence, or, for example, with a non-allergenic means, secretolytic means2-adrenergic drugs, steroids for inhalation, anti-histamine drugs and/or antagonists of platelet activating factor. The administration can be topical, oral, transdermal, through the nose, parenterally or by inhalation.

The new compounds are characterized by good tolerability and a favorable bioavailability.

1. Tablets

Composition in weight.h.:

The active principle according to the invention - 20

Stearic acid - 6

Grape sugar - 474

The ingredients in the standard manner processed into tablets weighing 500 mg. If you want you can increase or decrease the content of active principle and accordingly to increase or decrease the amount of grape sugar.

2. Suppositories

Composition in weight.h.:

The active principle according to the invention - 100

Powder lactose - 45

Cocoa butter - 1555

Ingredients processed in the standard manner in suppositories weight of 1.7 g

Derivatives of benzamidine according to the invention show better tolerability compared with the derivative of benzamidine on the above closest analogue, for example with the compound of the formula

< / BR>
as evidenced by the results of experience, in which daily for 5 days to rats orally gave the compound of example 2 of this application and the above-mentioned known compound at doses of 30, 100 and 300 mg/kg Each day the animals were examined for signs and symptoms and the last day was determined action on the gastrointestinal tract. It was found that when the country is known compounds at a dose of 300 mg/kg died one of the ten animals, and eight animals had to wordplays because of the presence of symptoms of dyspnea. During the subsequent autopsy were observed in the lungs of bleeding. Even when the country is known compounds at a dose of 100 mg/kg died two animals.

In contrast to the known connection example 2 of this application was postponed animals without problems, i.e., the condition of the experimental animals is no different to the examples Below explain the acquisition of new connections.

Example 1. (Methoxycarbonyl-imino-{4'-[2-(2-propylenoxide)- ethoxy]-biphenyl-4-yl}-methyl)-amine

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3.8 g amidnogo compounds of the above formula where R = NH (which can be obtained by standard methods described, for example, in the above nearest equivalent), suspended in 200 ml of chloroform. To a mixture of 1.6 ml of triethylamine and at room temperature was added dropwise 0.8 ml complicated methyl ether of Harborview acid. After the dissolution of the components is stirred for 3 hours, three times extracted with water, evaporated, the residue is stirred with diethyl ether and sucked off. The output of the compounds of the above formula where R = NCOOCH3: 3,7,

Etc.: 170-176oC.

Example 2. (Benzyloxycarbonyl-imino-{4'-[2-(2-propylenoxide)- ethoxy]-biphenyl-4-yl}-methyl)-amine

< / BR>
2.6 g amidnogo compounds of the above formula where R = NH, served in 200 ml of chloroform. To the mixture is added 1.3 ml of triethylamine and at room temperature was added dropwise 1 ml of a complex benzyl ether of Harborview acid. After the dissolution of the components is stirred for 3 hours, three times extracted with water, evaporated, the residue is stirred with diethyl ether and sucked off. The product is recrystallized the ASS="ptx2">

Accordingly, the compounds with other residues R:

R = NCOOC2H5; Etc.: 120-123oC

R = NCOO-n-C3H7; Etc.: 113-114oC

R = NCOO-ISO-C3H7: T. p.: 110-117oC

R = NCOO-n-C4H9: T. p.: 135-138oC

R = NCOO-ISO-C4H9; Etc.: 103oC

R = NCOO-tert-C4H9: T. p.: 129-132oC

R = NCOO-n-C6H13: T. p.: 117-121oC

Example 3. 3.5 g amidnogo compounds of the above formula where R = NH, served in 150 ml of chloroform. To the mixture is added 2 ml of triethylamine and at room temperature was added dropwise 1 ml of di-tert-BUTYLCARBAMATE. After the dissolution of the components is stirred for 3 hours, three times extracted with water, evaporated, the residue is stirred with diethyl ether and sucked off. The product is recrystallized from 20 ml of ethanol. The output of the compounds of the above formula where R = NCOO-tert-butyl: 3,

Etc.: 129-132oC.

Example 4. a) [Hydroxy-imino-(4-{3-[4-(1-methyl-1-phenylethyl)- phenoxymethyl]-benzyloxy}phenyl)-methyl]-amine

< / BR>
the 5.25 g obtained by standard techniques nitrile above formula, where R = CN, served in 60 ml of ethanol and boiled. Within 30 minutes to the mixture was added dropwise a solution of 2.7 g of sodium carbonate and 3, which after cooling the mixture is thickened, the remainder served in 50 ml of water and extracted three times with ethyl acetate, taken in an amount of 40 ml of the Organic phase is dried over magnesium sulfate, filtered and concentrated. The crystals are served in 20 ml of acetone and acidified with ethereal hydrochloric acid. After a short dissolution is formed of 5.3 g of the hydrochloride amidoxime the above formula, where R = C(NOH)-NH2.

Etc.: 180-181oC.

b) [Imino-(4-{3-[4-(1-methyl-1-phenylethyl)-phenoxymethyl]- benzyloxy}phenyl)-methyl]-amine

< / BR>
5,1 g amidoxime above formula, where R = NOH, dissolved in 120 ml of methanol and hydronaut in the presence of 10 g of hydrated methanol of Raney Nickel at atmospheric pressure and room temperature for 2 hours. Nickel is sucked off and the solution is filtered over diatomaceous earth. The filtrate is acidified with ethanolic hydrochloric acid, the solution is concentrated and recrystallized from ethanol. The output is 3.3 g amidnogo compounds of the above formula where R = NH.

T. p.: 160oC.

in) [Etoxycarbonyl-imino-(4-{ 3-[4-(1-methyl-1-phenylethyl)- phenoxymethyl] -benzyloxy}phenyl)-methyl]-amine

2,44 g obtained in stage b) amidnogo compounds of the above formula where R = NH, served in 150 ml of dichloromethane. To the mixture is added 0.6 g sloneg is to 52.5 ml of 0.2 N. sodium lye. The resulting solution was stirred at room temperature for 2 hours. Then the organic phase is separated, extracted with 100 ml of water and dried over sodium sulfate. The solution is concentrated and the residue will recrystallized from 10 ml of ethanol. Obtain 2.1 g of the target compound, where R = NCOOC2H5.

T. p.: 99oC.

Similarly can be obtained, for example, the following compounds listed in example 4 (b) formula:

R = NCOO-(-)-Menthyl; Etc.: 113oC

R = NCO-C6H5; Etc.: 101-103oC

Example 5. [3'-pyridylcarbonyl-imino-(4-{3-[4-(1-methyl-1-phenylethyl)- phenoxymethyl]-benzyloxy}phenyl)-methyl]-amine

5.0 g amidnogo compounds of the above formula where R = NH (see example 4 (b)), served in 250 ml of dichloromethane. For 10 minutes at room temperature was added dropwise a solution of 3.9 g of nicotinic acid chloride in the form of hydrochloride and 16.3 ml of triethylamine in 50 ml dichloromethane. After 15 hours at room temperature, extracted twice with water, taken in an amount of 300 ml of the Organic phase is dried over sodium sulfate, filtered and the filtrate concentrated. The residue is purified by low pressure chromatography on silica gel grade 60 using ethyl acetate as eluent. Praesidium as hydrochloride. The output is 2.0 g derived nicotinoyl above formula, where R = N-CO-3-pyridyl, etc., 172oC.

Similarly to the above examples we can get the following connections:

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1

1. Derivatives of substituted benzamidine General formula (I)

< / BR>
where A is a:

1) a group of the formula II

-O-CmH2m-X1-

where m = 2 to 6; X1group of the formula

< / BR>
or 2) a group of the formula

< / BR>
where X2group-CnH2n-O-, where n = 1 or 2; X3group-O-CnH2n-;

R1is hydroxyl, COR7, COOR7;

R2is alkyl with 1 to 6 atoms, -CR5R6is aryl or hydrogen if A is a residue of formula (IV) or if X1- the remainder of the formula (III)), as well as alkoxy with 1 to 6 carbon atoms (if A is A group of formula (II), m is the specified value and X1group of the formula (III));

R3is hydrogen, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms (provided that R2- -CR5R6-aryl or if X1group of the formula (III));

R4is hydrogen or alkyl with 1 to 6 carbon atoms;

R5and R6is alkyl with 1 to 4 carbon atoms;

R7is alkyl with 1 to 6 carbon atoms, cycloalkyl is if A - the group-O-CmH2m-X1-, where m = 2, 3 or 4, X1group of the formula

< / BR>
R2is hydrogen, alkyl with 1 to 6 carbon atoms; R3is hydrogen, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms; R4is hydrogen, alkyl with 1 to 6 carbon atoms, R1does not mean hydroxyl.

2. Derivatives of substituted benzamidine under item 1 of General formula (I), where aryl means phenyl or phenyl substituted by hydroxyl, heteroaryl means pyridyl, pyridazinyl, pyrimidyl or pyrazinyl.

3. Derivatives of substituted benzamidine under item 1 or 2 of General formula (I), where A, m, n, X2X3and R1have the specified values, X1group of the formula (III); R2is alkyl with 1 to 6 carbon atoms, -CR5R6-aryl or alkoxy with 1 to 6 carbon atoms (if X1group of the formula (III)); R3is hydrogen, alkyl with 1 to 6 carbon atoms or alkoxy with 1 to 6 carbon atoms (if R2- -CR5R6-aryl); R4is hydrogen; R5and R6is alkyl with 1 to 3 carbon atoms.

4. Derivatives of substituted benzamidine under item 1 or 2 of General formula (I), where X1group of the formula (III); R1group COOR7; R2is alkyl with 1 to 6 carbon atoms or-CR5R6-aryl; R34
is hydrogen; R5and R6is alkyl with 1 to 3 carbon atoms; R7is alkyl with 1 to 6 carbon atoms, aralkyl or cycloalkyl with 5 to 7 carbon atoms.

5. Derivative of substituted benzamidine General formula (I) under item 1, representing (methoxycarbonyl-imino-{4'-[2-(2-propylenoxide)-ethoxy] -biphenyl-4-yl}methyl)-amine.

6. Derivative of substituted benzamidine General formula (I) under item 1, representing (benzyloxycarbonyl-imino-{4'-[2-(2-propylenoxide)-ethoxy]-biphenyl-4-yl}methyl)-amine.

7. Derivative of substituted benzamidine General formula (I) under item 1, representing [hydroxy-imino-(4-{3-[4-(1-methyl-1-phenylethyl)-phenoxymethyl]-benzyloxy}phenyl)-methyl]-amine.

8. Derivative of substituted benzamidine General formula (I) under item 1, representing (etoxycarbonyl-imino-(4-{3-[4-(1-methyl-1-phenylethyl)-phenoxymethyl]-benzyloxy}phenyl)-methyl]-amine.

9. Derivative of substituted benzamidine General formula (I) under item 1, representing [3'-pyridylcarbonyl-imino-(4-{3-[4-(1-methyl-1-phenylethyl)-phenoxymethyl]-benzyloxy}phenyl)-methyl]-amine.

10. Derivative of substituted benzamidine General formula (I) under item 1, representing (etoxycarbonyl-imino-(4-{ 3-[4-(1-methyl-(4'-hydroxy)Fe

 

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