Derivatives of 4-(1-piperazinil)benzoic acid, method for their production and pharmaceutical composition

 

(57) Abstract:

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. Compounds according to the invention can be used for the treatment of diabetes, especially insulin-independent forms, due to their hypoglycemic action and lack of toxicity at effective doses. There is also described an farmcampsite on the basis of the claimed compounds and the method of their derivation. 3 c. and 1 C. p. F.-ly, 2 tab.

The present invention relates to new derivatives of 4-(1-piperazinil)benzoic acid, which can find application in the treatment of diabetes.

The object of the present from the symbolic aryl, having from 6 to 14 carbon atoms,

or is a heteroaromatic group selected from a range that includes pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, hinely, indolyl, benzothiazyl, benzofuran, benzopyranyl, benzothiophene, dibenzofuran, carbazole and benzothiazines,

while Ar may have from 1 to 3 substituents selected from the group comprising (C1-C8)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C1-C8)alkoxy,

(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-C14)aryl, (C6-C14)heteroaryl, (C6-C14)heteroaryl(C1-C6)alkyl, (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)alkyloxy or (C6-C14)aryl(C1-C6the, carboxy, (C1-C6)alkoxycarbonyl, carbarnoyl, (C1-C8)alkylthio, (C1-C8)alkylsulfonyl, (C1-C8)alkylsulfonyl, sulfamine, (C1-C8)alkylsulfonyl, sulfamoyl or (C1-C8)alkylcarboxylic or two of these substituents form methylenedioxy,

R1, R2, R3each independently selected from the group comprising a hydrogen atom,

(C1-C8)alkyl or (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 or (C3-C8)cycloalkyl(C1-C6)alkoxy(C1-C6)alkyl, (C6-C14)aryl, (C6-C14)heteroaryl, (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 or (C6-C14)aryloxy(C1-C6)alkyl, or in another embodiment, R1together with the nitrogen atom to which he Eerikainen,

R4, R5, R6each independently selected from the group comprising a hydrogen atom,

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

(C6-C14)aryl, (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 or (C6-C14)aryl(C1-C6)alkyloxy(C1-C6)alkyl, halogen, trifluoromethyl, triptoreline, cyano, carboxy, hydroxy, nitro, amino, (C1-C6)alkoxycarbonyl, carbarnoyl, (C1-C8)alkylthio, (C1-C8)alkylsulfonyl, (C1-C8)alkylsulfonyl, sulfamine, (C1-C8)alkylsulfonyl, sulfamoyl or (C1-C8)alkylarylsulfonate, which is selected from the group comprising (C1-C8)alkyl, (C1-C8)alkoxy, halogen, trifluoromethyl, triptoreline, hydroxy, nitro, amino,

their solvate and a pharmaceutically acceptable salt.

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

(C1-C8)alkyl groups may be linear or branched. As examples of such groups can be called methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl.

(C1-C8)alkoxygroup can also be linear or branched. As examples of such groups can be called methoxy-, ethoxy-, propoxy-, isopropoxy, butoxy and isobutoxy.

The halogen may be fluorine, chlorine, bromine and iodine.

The invention also relates to the tautomeric, enantiomeric, diastereoisomeric and epimeres forms of the compounds of General formula (I).

Compounds of General formula (I) have a carboxyl functional group and therefore can be obtained in the form of salts with various bases.

Examples of salts with various bases of compounds of General formula (I) include pharmaceutically acceptable salts, t is acceptable salts can also be obtained salts of compounds of General formula (I) with amines. As examples of such salts can be called the salt of the compounds of formula (I) with glucamine, N-methylglucamine, N, N-dimethylglycine, ethanolamine, morpholine, N-methylmorpholine or lysine.

Compounds of General formula (I) have a nitrogen atom having basic properties and can form mono - and dibasic salts with inorganic and organic acids. Examples of such salts of compounds of General formula (I) include pharmaceutically acceptable salts of (but not limited to), as the hydrochloride, hydrobromide, sulfate, succinate, maleate, fumarate, malate, tartrate and sulfonates such as methanesulfonate, benzoylphenyl, toluensulfonate.

Among the compounds of General formula (I) according to the invention, the preferred 4-{ 4-[2-(N-isopropyl-N-phenylamino)-2-oxoethyl] -1-piperazinil} benzoic acid, 4-{ 4-[2-(N-[2,6-dimetilfenil] amino)-2-oxoethyl] -1-piperazinil} benzoic acid and 4-{ 4-[2-(N-[2,6-diisopropylphenyl] amino)-2-oxoethyl] -1-piperazinil} benzoic acid.

The invention also relates to a method of obtaining compounds of General formula (I). According to the invention this method of obtaining includes the interaction of aromatic amine of General formula (II):

< / BR>
where Ar and R1have knowledge chlorine or bromine, a R2and R3have the meanings stated above, with the formation of compounds of General formula (IV):

< / BR>
where Ar, R1R2, R3and Hal have the meanings indicated above, and the interaction of the compounds of General formula (IV) with a compound of General formula (V):

< / BR>
where R4, R5, R6have the meanings indicated above, and R7denotes a hydrogen atom or a C1-C6alkyl in the presence of a base, such as triethylamine, to form compounds of General formula (VI):

< / BR>
where Ar, R1, R2, R3, R4, R5, R6and R7have the values specified above.

In the case when R7represents an alkyl group, the compound of General formula (VI) may be hydrolyzed in the usual acid or base with the formation of compounds of General formula (I):

< / BR>
where Ar, R1, R2, R3, R4, R5and R6have the values specified above.

The compounds of formula (V) are known substances. They can be synthesized according to the method described by V. Prelog and Z. Blazek in Collection Czechoslov. Chem. Communications 6, 211-24 (1934), for example, synthesis of ethyl 4-(1-piperazinil)benzoate[ethyl ester of 4-(1-piperazinil)benzoic acid] .

Naprimer diluted sodium hydroxide.

The enantiomers of the compounds of General formula (I) is shared by successive recrystallization of the salt of the acid (I) with an optically active base solvents such as acetone, ethyl acetate or isopropanol, followed by salt of the optically active acid in the presence of inorganic or organic acids by known methods.

Compounds according to the invention can be used for the treatment of diabetes, especially insulin-independent forms, due to their hypoglycemic action and lack of toxicity at effective doses.

In addition, the object of the present invention are pharmaceutical compositions comprising as an active ingredient the compound according to the invention.

The pharmaceutical compositions according to the invention can be produced in forms that are intended for parenteral, oral, rectal, percutaneous injection or through the mucous.

Therefore, these compositions can be prepared in the form of injectable solutions, suspensions or capsules with multiple doses, in the form of flat tablets or pellets in the shell, tablets sugar shell, capsules, gelatin capsules, pills, starch wafers, paraskovia insertion through the mucous in the polar solvent.

Suitable excipients are derivatives of cellulose or microcrystalline cellulose, carbonates of alkali and alkaline-earth metals, magnesium phosphate, starches, modified starches, and solid form lactose.

In a rectal preferred excipients are coconut oil or glycol stearate.

When parenteral introduction of the most suitable solvents are water, aqueous solutions, physiological saline or isotonic solutions.

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

Obtaining compounds of formula (I) are illustrated by the following examples.

Example 1

Getting 4-{ 4-[2-(4-chlorpheniramine)-2-oxoethyl] -1-piperazinil} benzoic acid (compound No. 5)

A. Obtain 2-chloro-N-(4-chlorophenyl)-ndimethylacetamide

34,5 ml chloroacetanilide added dropwise to 50 g of 4-Chloroaniline and 108 g of potassium carbonate in 400 ml of chloroform. Then the reaction mixture is filtered and the solid residue is suspended in 1500 ml of water. After stirring for 1 h, the aqueous suspension is filtered and p the CSO solids with tPL= 169-170oC.

IR (KBr): 1669 cm-1(C= O amide bond).

1H-NMR: (DMSO-d6, 200 MHz) in common. /million: of 4.25 (2H, s, CH2), 7,30 (2H, d, protons of phenyl group), 7,60 (2H, d, protons of phenyl group), the 10.40 (1H, s, NH).

B. Obtaining ethyl ester 4-{ 4-[2-(4-chlorpheniramine)-2-oxoethyl] -1-piperazinil} benzoic acid

25 g of 2-chloro-N-(4-chlorophenyl)ndimethylacetamide, 35 g of ethyl 4-(1-piperazinil)benzoate[ethyl ester of 4-(1-piperazinil)benzoic acid] and 80 g of potassium carbonate is stirred in 300 ml of DMF overnight at room temperature. Nerastvorim the precipitate was separated by filtration and the resulting filtrate was poured into 1000 ml of water. Precipitated crystalline precipitate was separated by filtration and washed with water. This way obtain 39 g of ethyl ester 4-{ 4-[2-(4-chlorpheniramine)-2-oxoethyl] -1-piperazinil} benzoic acid with tPL= 172-174oC.

IR (KBr): 1686 cm-1(C= O ester bond).

1H-NMR: (DMSO-d6, 200 MHz) in common. /million: of 1.20 (3H, t, CH3), of 2.50 (4H, s, 2CH2), was 3.05 (2H, s, CH2), 3,20 (N, s, 2CH2), of 4.05 (2H, q, CH2), to 6.80 (2H, d, protons of phenyl group), 7,20 (2H, d, protons of phenyl group), 7,60 (4H, m, protons of phenyl group), 9,80 (1H, s, NH).

C. Obtain 4-{is Ino)-2-oxoethyl] -1-piperazinil] benzoic acid, 165 ml of 1N. an aqueous solution of sodium hydroxide and 150 ml of ethanol is refluxed with stirring for 1 h the Reaction mixture was acidified with concentrated hydrochloric acid to pH 5. Precipitated crystalline precipitate was separated by filtration and washed with ethanol. In this way gain of 16.4 g of the crude product by recrystallization from a mixture of DMF/acetonitrile (1: 1 ratio) gain of 13.6 g 4-{ 4-[2-(4-chlorpheniramine)-2-oxoethyl] -1-piperazinil} benzoic acid as a white solid with tPL= 263-265oC.

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

1H-NMR: (DMSO-d6, 200 MHz) in common. /million: or 2.7 (4H, s, 2CH2), 3,20 (2H, s, CH2), 3,40 (4H, s, CH2), a 7.0 (2H, d, protons of phenyl group), 7,40 (2H, d, protons of phenyl group), of 7.75 (4H, m, protons of phenyl group), to 9.90 (1H, s, NH), 12,40 (1H, broadening s, acid IT).

Patterns and characteristics of the compounds according to the invention are presented in table 1.

Below are the results of pharmacological studies.

The study of antidiabetic activity in rats NOSTZ

Antidiabetic activity of compounds of the formula (I) were determined in oral introduction to experimental diabetes caused in rats by injection of streptozotocin in the neonatal period (birth).

In the experiment used rats with induced diabetes at the age of 8 weeks. Animals from birth to the beginning of the experiment were kept in a cage with controlled temperature (21-22oC) when a fixed cycle shifts the light/dark (light regime from 7 h to 19 h, the dark mode from 19 h to 7 h). Animals were kept on a maintenance diet, water and food were given on request, except prior to the start of the experiment, 2 h, when the feeders with food removed (postreformation period).

The test product was administered orally during the day. Two hours after administration of the product and subsequent 30-minute anesthesia pentobarbital sodium (Nembutalfrom the tip of the tail took blood samples with a volume of 300 μl.

The results are shown in table 2. These results suggest that the effectiveness of compounds of the formula I in lowering blood glucose levels in animals with experimental diabetes. The results of the experiment are presented as the change in glycemia in percent on the fourth day (D4) after injection compared with the day before the introduction of the (D0).

1. Derivatives of 4-(1-piperazinil)benzoic acid of General formula I

< / BR>
in which Ar represents a mono-, di - or critic the dust, includes (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;

or in another embodiment, R1together with the nitrogen atom to which it is attached, and the Ar-group forms a cycle, which is chosen from the group comprising tetrahydroquinolin;

R4, R5, R6each independently selected from the group including a hydrogen atom,

their solvate and a pharmaceutically acceptable salt.

2. Connection on p. 1, namely 4-{ 4-[2(N-isopropyl-N-phenylamino)-2-oxoethyl] -1-piperazinil} benzoic acid, 4-{ 4-[2-N-[2,6-dimetilfenil] amino)-2-oxoethyl] -1-piperazinil} benzoic acid and 4-{ 4-[2-N-[2,6-diisopropylphenyl] amino)-2-oxoethyl] -1-piperazinil} benzoic acid.

3. The method of obtaining compounds on p. 1, including the interaction of aromatic amine of General formula II

< / BR>
where Ar and R1have the meanings specified above,

with halogenosilanes General formula III

< / BR>
where Hal represents a chlorine atom illy IV

< / BR>
where Ar, R1, R2, R3and Hal have the meanings indicated above,

and the interaction of the compounds of General formula IV with a compound of General formula V

< / BR>
where R4, R5, R6have the values specified above;

R7denotes a hydrogen atom or a C1-C6alkyl,

in the presence of a base, such as triethylamine, to form compounds of General formula VI

< / BR>
where Ar, R1, R2, R3, R4, R5, R6and R7have the meanings specified above,

in the case when R7denotes alkyl group, the hydrolysis of compounds of General formula VI to form compounds of General formula I.

4. Pharmaceutical composition having hypoglycemic effect, characterized in that it contains as an active ingredient the compound under item 1 or 2.

 

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