-(1-piperazinil)acetaminophenodeine aringarosa acid, the method of production thereof, pharmaceutical compositions, methods of treatment

 

(57) Abstract:

The invention relates to new -(1-piperazinil)acetamidophenyl Aringarosa acid of General formula I, in which Ar is selected from mono-, bi - or tricyclic aryl group having from 6 to 14 carbon atoms, possibly substituted WITH1-C6alkoxy, halogen or CF3; R1, R2, R3independently selected from H, C1-C8of alkyl, C3-C8cycloalkyl (C1-C6) alkyl; a, b,C and D are= CH-; R4, R5and R6independently H, C1-8alkoxy, C3-C8cycloalkane, halogen, C1-C6alkylthio or two of these radicals may form a phenyl condensed with the ring to which they are attached; or Alfacam, pharmaceutically acceptable salts. The compounds I are suitable for the treatment of non-insulin-dependent diabetes. 6 C. and 1 C.p. f-crystals, 4 PL.

The invention relates to new -(1-piperazinil)-acetamidophenyl Aringarosa acid, suitable for the treatment of diabetes.

The object of the present invention are therefore compounds of General formula (I)

< / BR>
in which Ar is selected from mono-, bi - or tricyclic aryl group, who olila, Furie, teinila, chinoline, indolyl, benzothiazyl, benzofuran, benzopyranyl, benzothiophene, dibenzofuran, carbazole and benzothiazine,

the remaining AG may have from 1 to 3 substituents selected from the group comprising FROM1-C8alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, C1-C8alkoxy,

(C3-C8)cycloalkane(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkoxy(C1-C6)alkyl, (C3-C8)cycloalkane,

(C3-C8-cycloalkyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, C6-C14aryl, C6-C14heteroaryl, (C6-C14)heteroaryl (C1-C6)alkyl, (C6-C14)aryl(C1-C6)alkyl,

(C6-C14)aryl (C1-C6)alkyl(C6-C14)aryl, C6-C14aryloxy, (C6-C14)aryloxy(C1-C6)alkyl, (C6-C14)aryl(C1-C6)alkyloxy, (C6-C14)-aryl(C1-C6)alkyloxy(C1-C6)alkyl, halogen, trifluoromethyl, triptoreline, cyano, hydroxy, nitro, amino, carboxy, (C1-C6)alkoxycarbonyl, is sulfolane, (C1-C8)alkylsulfonyl, sulfamoyl and (C1-C8)alkylcarboxylic or two of these substituents form methylenedioxy, with the exception of the values for the remainder of AG 4-carboxyaniline and substituted 4-carboxyphenyl group,

R1, R2and R3independently from each other selected from the group comprising a hydrogen atom,

WITH1-C8alkyl, (C1-C6)alkoxy (C1-C6)alkyl, cycloalkyl containing from 3 to 8 carbon atoms, (C3-C8)cycloalkyl (C1-C6)alkyl, (C3-C8)cycloalkane (C1-C6)alkyl, (C3-C8)cycloalkyl (C1-C6)alkoxy (C1-C6)alkyl, C6-C14aryl,

WITH6-C14heteroaryl, (C6-C14-heteroaryl (C1-C6)alkyl, (C6-C14)aryl (C1-C6)alkyl, (C6-C14)aryl (C1-C6)alkyl (C6-C14)aryl, (C6-C14)aryl (C1-C6)alkoxy (C1-C6)alkyl and (C6-C14)aryloxy (C1-C6)alkyl,

A, b, C and D represent the group =CH-, and one or two of these residues can also be a nitrogen atom,

R46alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, C1-C8alkoxy, (C3-C8)cycloalkane(C1-C6)alkyl, (C3-C8)cycloalkane, (C3-C8)cycloalkyl(C1-C6)alkoxy, (C3-C8)cycloalkyl(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl,

WITH6-C14aryl, (C6-C14)aryl(C1-C6)alkyl, (C6-C14)-aryl(C1-C6)alkyl(C6-C14)aryl, (C6-C14)aryloxy, (C6-C14)aryloxy(C1-C6)alkyl, (C6-C14)aryl(C1-C6)alkoxy, (C6-C14)aryl(C1-C6)alkyloxy(C1-C6)alkyl, halogen, trifluoromethyl, triptoreline, cyano, carboxy, hydroxy, nitro, amino, (C1-C6)alkoxycarbonyl, carbarnoyl, (C1-C6)alkylthio, (C1-C8)alkylsulfonyl, (C1-C8) alkylsulfonyl, sulfolane, (C1-C8)alkylsulfonyl, sulfamoyl and (C1-C8)alkylcarboxylic,

two of these groups can form methylenedioxy or phenyl ring condensed with calzavarini from the group include1-C8alkyl, C1-C8alkoxy, halogen, trifluoromethyl, triptoreline, hydroxy, nitro and amino, and their solvate and a pharmaceutically acceptable salt.

As an example, aryl groups can be called phenyl, -naphthyl, -naphthyl or fluorenyl.

WITH1-C8alkyl groups can be linear or branched. As examples of such groups can be called methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl.

WITH1-C8alkoxygroup can also be linear or branched. As examples of such groups can be called methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy.

The halides can be selected from fluorine, chlorine, bromine and iodine. Heteroaryl groups as values for R1, R2and R3may constitute, in particular, those same groups and heteroaryl groups specified as values for AG.

The invention also relates to the tautomeric forms and enatiomers, diastereoisomers and epimers compounds of General formula (I).

Compounds of General formula (I) have functional carboxypropyl and can form salts with bases.

Compounds of General formula (I) can be converted into the salt form by reacting with amines to obtain pharmaceutically acceptable salts. So, for example, compounds of General formula (I) can form salts with glucamine, N-methylglucamine, N, N-dimethylglycine, ethanolamine, morpholine, N-methylmorpholine or lysine.

Compounds of General formula (I) contain basic nitrogen atoms and may form a mono - or dibasic salts with inorganic or organic acids. Examples of salts of compounds of General formula (I) with acids include, but are not limited to) such pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, sulfate, succinate, maleate, fumarate, malate or tartrate, and sulfonates such as methanesulfonate, bansilalpet or toluensulfonate.

The invention also relates to a method of obtaining compounds of General formula (I). This method according to the invention provides for the interaction of aromatic amine of General formula (II):

< / BR>
in which a, b, C, D, R1, R4, R5and R6have the above values, a R7means atom vodovody General formula (III):

< / BR>
in which R2and R3have the above values, a, Hal denotes a chlorine atom or bromine, to obtain the compounds of General formula (IV):

< / BR>
in which a, b, C, D, R1, R2, R3, R4, R5, R6, R7and Hl have the above values, and the interaction of the compounds of General formula (IV) with a compound of General formula (V):

< / BR>
in which AG has the above meaning, in the presence of a basic agent such as triethylamine, to obtain the compounds of General formula (VI):

< / BR>
in which Ar, a, b, C, D, R1, R2, R3, R4, R5, R6and R7have the above values.

In that case, if R7denotes alkyl group, the compound of General formula (VI) may be subjected to hydrolysis using conventional acids or bases with obtaining compounds of General formula (I).

In that case, if R7denotes a benzyl group, the compound of General formula (VI) may be subjected to hydrogenolysis in the presence of a catalyst such as palladium on charcoal, to obtain the compounds of General formula (I).

Compounds of formulas (II) and (V) are known or can be obtained by known methods.

For example, the compound (VI) in which R7denotes an alkyl group, may be subjected to hydrolysis in the presence of a basic agent, such as dilute sodium hydroxide solution.

The enantiomers of compounds of formula (I) can be isolated by successive recrystallization of the salt of the acid (I) with an optically active base in solvents such as acetone, ethyl acetate or isopropanol, followed by displacement of the salt of the optically active inorganic acid or organic acid in the usual method.

Thanks to their hypoglycemic action and nontoxicity in active doses of the compounds according to the invention can be used in the treatment of diabetes, particularly non-insulin dependent diabetes.

Thus, another object of the present invention are pharmaceutical compositions containing an effective amount of the compounds according to the invention.

The pharmaceutical compositions according to the invention can be presented in a form intended for parenteral, oral, rectal, percutaneous introduction and insertion through slithis the state of preparations in their respective containers, containing multiple doses of a medicinal product, in the form of tablets (uncoated or coated tablets, sugar coating, capsules, including hard gelatin capsules, pills, starch wafers, powders, suppositories or rectal capsules, solutions or suspensions for percutaneous use in a polar solvent or in the form of means for applying through the mucous.

Acceptable fillers for such applications are derivatives of cellulose or microcrystalline cellulose, carbonates of alkaline-earth metals, magnesium phosphate, starches, modified starches or lactose for solid forms.

Preferred fillers for rectal injection are cocoa butter or polyethylene glycol stearates.

The most preferred fillers for parenteral administration include water, aqueous solutions, physiological saline or isotonic solutions.

The dose can vary within wide limits depending on therapeutic indications and routes of administration of medicines, and the age and weight of the patient.

The following examples illustrate the formation of compounds of formula (I) and p is methyl-2-cyclohexylethylamine-5-methoxybenzoate

to 17.6 g of methyl-5-methoxyaniline, and 11.8 ml of cyclohexanecarboxaldehyde and 2 g of 10% palladium on charcoal (50% water) is introduced into 200 ml of methanol in a 1-liter hydrogenation apparatus. In this unit, create an atmosphere of nitrogen and the contents stirred at room temperature for 3 hours then add 300 ml of dichloromethane, palladium on activated carbon was separated by filtration and the resulting filtrate concentrated under vacuum. The oil obtained is crystallized from a mixture of ethanol (200 ml) and water (50 ml) to give 25.4 g of yellow solids with tPL58-60oC.

IR (KBR): 1683 cm-1(C=O), 1528-1(C=O).

1H-NMR (Dl3, 200 MHz): ppm million 1,06-of 1.64 (1H, m, cyclohexyl), with 2.93 (2H, t, CH2), 3,68 (3H, s, och3), of 3.78 (3H, s, och3), 6,56 (1H, d, phenyl proton), of 6.96 (1H, dd, phenyl proton), 7,34 (2H, d+s, the proton of the phenyl + NH).

The structure and characteristics of the compounds of the formula (II) are given in table I.

B. the Example of obtaining the compounds of formula (IV)

Getting 4-chloro-2-(chloroacetamido)benzoic acid

of 25.5 ml chloroacetanilide added dropwise with stirring to 50 g of 2-amino-4-chlorbenzoyl acid in 600 ml of dioxane, maintaining the temperature of the reaction of Mesut 1200 ml of water. The desired product precipitated, the mixture is stirred for 1 h, filtered, and then the obtained solid is washed with water. After drying receive a total of 60.7 g of 4-chloro-2-(chloroacetamido)benzoic acid with tPL194-196oC.

IR: 1676 cm-1(C=O).

1H-NMR (d6-DMSO, 200 MHz): ppm million 4,30 (2H, s, CH2), and 7.1 (1H, d, phenyl proton), and 7.7 (1H, d, phenyl proton), and 8.5 (1H, s, phenyl proton), 11,75 (1H, s, NH), 13,90 (1H, broad s, COOH).

The structure and characteristics of the compounds of the formula (IV) are given in table II.

Century is an Example of obtaining the compounds of formula (II)

Getting 4-chloro-2- {[4-(2-methoxyphenyl)-1-piperazinyl]-acetamido} benzoic acid

15 g of 4-chloro-2-(chloroacetamido) benzoic acid are added under stirring and at room temperature to 11.6 g of 1-(2-methoxyphenyl)piperazine and 17 ml of triethylamine in 120 ml of dimethylformamide (DMF). The reaction mixture continued to stir for 48 h at room temperature and then it was added 500 ml of water. Extracted with dichloromethane (3 times portions 300 ml). The solvent is evaporated under vacuum and the resulting solid is again dissolved in 300 ml of 2n. an aqueous solution of sodium hydroxide. The solution was washed with diethyl ether (3 times with portions of 300 ml) and water the crude product. After recrystallization from dioxane obtain 21.1 g of 4-chloro-2-{ [4-(2-methoxyphenyl)-1-piperazinil] acetamido} benzoic acid as a white solid with tPL218-220oC.

IR: 1699 cm-1(C=O), 1673 cm-1(C=O).

1H-NMR (CF3Soul): frequent./million of 4.25 (3H, s, och3) and 4.65 (8H, broad s, 4 CH2), of 4.95 (2H, s, CH2), and 7.5 (2H, m, phenyl protons), and 7.6 (1H, d, phenyl proton), of 7.90 (2H, m, phenyl protons), and 8.50 (1H, d, phenyl proton), is 8.75 (1H, s, phenyl proton).

, Another option for obtaining compounds of formula (I)

Getting 2- {[4-(4-forfinal)-1-piperazinil]acetamido} -4,5-(methylenedioxy) benzoic acid

15 g of 2-(chloroacetamido)-4,5-(methylenedioxy)benzoic acid are added under stirring and at room temperature to 10.5 g of 1-(4 - forfinal)piperazine and 16.2 ml of triethylamine in 150 ml of DMF. The reaction mixture continued to stir for 48 h at room temperature. Add 3.5 ml of acetic acid and slowly add 150 ml of water. The acid crystallizes, and diluted with 300 ml of water. The mixture is stirred for 30 min, filtered and the obtained solid is washed with water. After recrystallization from a mixture of dioxane with DMF obtain 14.9 g of 2- {[4-(4-forfinal) -1-piperazinyl] acetamido} -4,5 - (the1H-NMR (CF3D, 200 MHz): ppm million and 4.40 (8H, s, piperazinil), of 4.67 (2H, s, CH2), equal to 6.05 (2H, s, O-CH2-Oh), 7,30 (2H, t, phenyl proton), the 7.65 (3H, m, phenyl proton), of 7.90 (1H, s, phenyl proton).

The structure and characteristics of the compounds of formula (I) are shown in table III.

Below are the results of pharmacological studies. The study of antidiabetic activity in rats NOSTZ

Antidiabeticheskoe activity of the compounds of formula (I) when oral administration was determined in an experimental model of non-insulin-dependent diabetes induced in rats by streptozotocin.

Non-insulin-dependent diabetes model in rats by injection of streptozotocin newborn (day of birth).

Age diabetic rats, in which the research was conducted, was eight weeks. Starting from the day of their birth to the day of the experiment animals were kept in a vivarium at a temperature in the range from 21 to 22oWith and at a fixed cycle day/night (duration of the light phase from 7 to 19 hours; the duration of the dark phase from 19 to 7 hours). Animals were kept on a maintenance diet, with water and feed were provided on request, but for 2 h before food experience UX is cut to two hours after the last injection and after 30 min after anesthesia, the animals pentobarbital sodium (Nembutal) from the tip of the tail took blood samples in the amount of 300 μl.

The obtained main results are presented in table IV. These results indicate that the compounds of formula (I) are effective in reducing glycemia in animals with diabetes.

The results are expressed in percentage changes of glycemia in day D4 (4 days of treatment) in comparison with the first day of D0 (before treatment).

1. -(1-Piperazinil)acetaminophenodeine Aringarosa acid of the formula (I)

< / BR>
in which AG is selected from mono-, bi - or tricyclic aryl group having from 6 to 14 carbon atoms, optionally having one to three substituents selected from the group comprising (C1-C6)alkoxy, halogen and trifluoromethyl;

R1, R2and R3independently from each other selected from the group comprising a hydrogen atom, (C1-C8)alkyl and (C3-C8)cycloalkyl(C1-C6)alkyl;

A, b, C and D represent the group =CH-;

R4, R5and R6independently from each other selected from the group comprising a hydrogen atom, (C1-C8)alkoxy, (C3-C8)cycloalkane, halogen and (C1-C6)alkylthio, with two of these groups may form a phenyl ring condensed with the ring to which they are porom at least one of the groups R4, R5and R6represents a C1-C6alkoxygroup.

3. A method of obtaining a connection on p. 1, including the interaction of aromatic amine of General formula (II)

< / BR>
in which a, b, C, D, R1, R4, R5and R6have the above meanings;

R7selected from the group comprising a hydrogen atom, a C1-C6alkyl and benzyl, with halogenerator halogen-substituted carboxylic acid of formula (III)

< / BR>
in which R2and R8have the above meanings;

Hal denotes chlorine or bromine,

obtaining the compounds of formula (IV)

< / BR>
in which a, b, C, D, R1, R2, R3, R4, R5, R6, R7and Hl have the above values,

and the interaction of the compounds of formula (IV) with the compound of the formula (V)

< / BR>
in which AG has the above value,

in the presence of a basic agent to obtain compounds of formula (VI)

< / BR>
in which Ar, a, b, C, D, R1, R2, R3, R4, R5, R6and R7have the above values,

and if R7denotes alkyl, hydrolysis of this compound with obtaining the compounds of formula (I), and if R7denotes the position intended for the treatment of non-insulin-dependent diabetes, comprising an effective amount of the compounds under item 1.

5. The pharmaceutical composition intended for the treatment of non-insulin-dependent diabetes, comprising an effective amount of the compounds on p. 2.

6. A method of treating non-insulin dependent diabetes, including the introduction of a person suffering from diabetes, the effective number of connections on p. 1.

7. A method of treating non-insulin dependent diabetes, including the introduction of a person suffering from diabetes, the effective number of connections on p. 2.

 

Same patents:

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The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to new derivatives of 4-(1-piperazinil)benzoic acid of formula I in which Ar represents a mono-, di - or tricyclic aryl having from 6 to 14 carbon atoms, while Ar may have from 1 to 3 substituents selected from the group comprising (C1-C8)alkyl, (C1-C8)alkoxy, halogen, trifluoromethyl; R1selected from the group comprising a hydrogen atom, cycloalkyl containing from 3 to 8 carbon atoms, (C6-C14)aryl, heteroaryl(C1-C6)alkyl, and heteroaryl selected from the group comprising furyl; R2and R3is hydrogen, a solvate and a pharmaceutically acceptable salt

The invention relates to new derivatives of 4-(1-piperazinil)benzoic acid of formula I in which Ar represents a mono-, di - or tricyclic aryl having from 6 to 14 carbon atoms, while Ar may have from 1 to 3 substituents selected from the group comprising (C1-C8)alkyl, (C1-C8)alkoxy, halogen, trifluoromethyl; R1selected from the group comprising a hydrogen atom, cycloalkyl containing from 3 to 8 carbon atoms, (C6-C14)aryl, heteroaryl(C1-C6)alkyl, and heteroaryl selected from the group comprising furyl; R2and R3is hydrogen, a solvate and a pharmaceutically acceptable salt

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The invention relates to medicine, specifically to means of therapy dementia

The invention relates to compounds of the formula I

< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

Het denotes a single or dual core unsubstituted or one - or multi-substituted by a group of Hal, A, Ar', COOR6, CN, N(R6)2, NO2, Ar-CONH-CH2and/or carbonyl oxygen saturated or unsaturated heterocyclic ring system containing one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen or sulphur,

Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

and their salts

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FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

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EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

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12 cl, 2 ex

FIELD: pharmaceutics.

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EFFECT: higher efficiency of therapy.

4 cl, 1 ex

Endoparasitic agent // 2250779

FIELD: medicine.

SUBSTANCE: invention relates to endoparasitic agent containing cyclic depsipeptide of general formula 1 and piperazine of formula 2 .

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6 cl, 7 ex, 7 tbl

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