UA56324C2 - DERIVATIVES OF a-(1-PIPERAZINYL)ACETAMIDOAREN CARBOXYLIC ACIDS, A PROCESS FOR PREPARING THEREOF AND A PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

The invention relates to compounds of general formula (I). These compounds are useful in the treatment of diabetes. (I)

Description

Description of the invention

The present invention relates to new "-(1-piperazinyl)-acetamidoderivatives of arenecarboxylic acid, suitable for the treatment of diabetes.

The object of this invention is, thus, compounds of the general formula (I)

Sov in, V

And skh e

KE F in which

Ag is selected from a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms, a heteroaromatic group selected from pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl , carbazolyl and benzothiazinyl, and the Ag residue can have from 1 to 3 substituents selected from the group consisting of C.-Cv alkyl, (C3-Cv) cycloalkyl(C1-Cv)alkyl, C svaloxy, (C3-Cv) cycloalkyloxy (C.4-Cv)alkyl, (C3-Cv)cycloalkyl(C-C )alkyl (C,-Cv)alkyl, (C3-Cv)cycloalkyloxy, (C3-Cv)-cycloalkyl(C.4-Cv) Alkoxy, (C1-Cv)Alkoxy(C1-Cv)Alkyl, Cv-Sidaryl, Cv-Sidheteroaryl, (Cv-C44)Heteroaryl(Ci-Cv)Alkyl, (Cv-Ci4)aryl (C4-Cv)Alkyl, ( Св-С44)aryl(С1-Св)alkyl(Св-С-4)aryl, (Св-С.4,5)aryloxy, (Св-С14)aryloxy(Св-Св)alkyl, (Св-С44) aryl (С4-Св)alkyloxy, (Св-С14)aryl(С1-Св)alkyloxy(С1-Св)alkyl, halide, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (С4-Св) alkoxycarbonyl, carbamoyl, (С4-Св)alkylthio o (C1-C) alkylsulfinyl, (C4-C) alkylsulfonyl, sulfoamino, (C4-C) alkylsulfonylamino, sulfamoyl («| and (C4-C) alkylcarbonylamino, or two of these substituents form a methylenedioxy group, except for the values for the residue Ag of 4-carboxyphenyl and substituted 4-carboxyphenyl group, "

Ku EK" and Kz independently of each other are selected from the group that includes the hydrogen atom, p

C.i-Cvalkyl, (C1-Cv)Alkoxy(C4-Cv)alkyl, cycloalkyl containing from 3 to 8 carbon atoms, (C3-Cv)cycloalkyl(C 4-Cv)alkyl, o (C3-Cv) cycloalkyloxy(C 4-Cv)alkyl, (C3-Cv)cycloalkyl(C4-Cv)alkyloxy(C.4-Cv)alkyl, "o

Cev-C:aryl, Cev-C.lheteroaryl, (Cv-C44)heteroaryl(C1-Cv)alkyl, (Cv-C14)aryl(C4-Cv)alkyl, (Cv-Ci))aryl(C1-Cv )alkyl(Cv-Cv)aryl, (Cv-Cv)aryl(C1-Cv)alkyl(C4-Cv)alkyl and (Cv-C14)aryloxy(C4-Cv)alkyl, it)

A, B, C and O are -CH- groups, and one or two of these residues can also be a nitrogen atom,

Ku, Kb and Kv independently of each other are selected from the group, which includes: "a hydrogen atom,

C.i-Cvalkyl, (C3-Cv)cycloalkyl(C 1-Cv)alkyl, C-Cvlkoxy, (C3-Cv)cycloalkyloxy(C 1-Cv)alkyl, o) c (C3-Cv)cycloalkyloxy, (C3 -Cv)cycloalkyl(C 4-Cv)alkyl, (C3-Cv)cycloalkyl(C 1-Cv)alkyl(C.4-Cv)alkyl, Св-Silaryl, (Св-Си4)aryl(Си-Св)alkyl, (Св-Си4)aryl(С1-Св)alkyl(Св-Си4)aryl, " (Св-С.4,5)aryloxy, (Св -C14)aryloxy(C.4-Cv)alkyl, (Cv-C14)aryl(C4-Cv)alkyl, (Cv-Ci4)aryl(C1-Cv)alkyloxy(C.4-Cv)alkyl, halide, trifluoromethyl , trifluoromethoxy, cyano, carboxy, hydroxy, nitro, amino, (C41-Cv)alkoxycarbonyl, carbamoyl, (C4-Cv)alkylthio, (C41-Cv)alkylsulfinyl, (C4-Cv)alkylsulfonyl, o sulfoamino, (C1-Cv) )alkylsulfonylamino, sulfamoyl and (C--C)alkylcarbonylamino, while two of these groups

FOs can form a methylenedioxy group or a phenyl ring fused to the ring to which they are attached, while the various neat aryl groups themselves can be substituted with 1-3 substituents selected from the group consisting of C-Cylalkyl, C-Cyloxy, halide , trifluoromethyl, trifluoromethoxy, hydroxy, nitro and amino, as well as their

He 50 solvates and pharmaceutically acceptable salts.

An example of an aryl group is phenyl, d-naphthyl, r-naphthyl or fluorenyl.

T» S.-Landfill groups can be linear or branched. Examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl.

C.-Svaloxy groups can also be linear or branched. Examples of such groups include 2-methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy.

F! Halides can be selected from fluorine, chlorine, bromine and iodine.

Heteroaryl groups as values for K 4 Ko and Kz can represent, in particular, the same groups as and where heteroaryl groups are indicated as values for Ag.

The invention also relates to tautomeric forms and enantiomers, diastereoisomers and epimers of compounds 60 of the general formula (1).

Compounds of the general formula (I) have a functional carboxy group and can form salts with bases.

Examples of salts formed by compounds of general formula (I) with bases include pharmacologically acceptable salts such as sodium salts, potassium salts, calcium salts and other salts of the same type.

Compounds of the general formula (I) can be converted into salt form by reacting with amines to obtain pharmaceutically acceptable salts. So, for example, compounds of general formula (I) can form salts with glucamines, M-methylglucamine, M,M-dimethylglucamine, ethanolamine, morpholine,

M-methylmorpholine or lysine.

The compounds of the general formula (I) contain basic nitrogen atoms and can form 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) pharmaceutically acceptable salts such as hydrochloride, hydrobromide, sulfate, succinate, maleate, fumarate, malate, or tartrate, and sulfonates such as methanesulfonate, benzenesulfonate, or toluenesulfonate .

The invention also relates to a method of obtaining compounds of the general formula (I). This method according to the invention 70 involves the interaction of an aromatic amine of the general formula (II): sleep; 28,

M pk ten pet ho h

C in yo (And in which A, B, C, O, КК. Ку, Кб and Кв have the above values, and К7 denotes a hydrogen atom, C--Salkyl or benzyl group, with a halogen anhydride of a halogen-substituted carboxylic acid of the general formula (1) :

Vo. Az 2

On! On! (IP) in which K" and Kz have the above values, and Na! denotes a chlorine or bromine atom, resulting in a compound with the general formula (IM):

In Nv so to (Se) in which A, B, C, O, K., Ko, Kz, K4 K Ke K;7 and Na! have the above values, and the interaction of the compound of the general ! and | of the formula (IM) with the compound of the general formula (M): n i mu "

See

M - s DA in which Ag has the above value, in the presence of a basic agent such as triethylamine, to give . and?" compounds of the general formula (MI): juice,

In Vo A po Kiya (in It

F o ny sh TA (95) K5 i Y ko 20 in which Ag, A, B, C, 0, Ku, K", Kz, Ku, Kv, Kv and K7 have the above values.

In that case, if K 7 denotes an alkyl group, the compound of the general formula (MI) can be subjected

T" hydrolysis using common acids or bases to obtain a compound of the general formula (1).

In the case where K7 represents a benzyl group, the compound of general formula (MI) can be subjected to hydrogenolysis in the presence of a catalyst such as palladium on activated carbon to give compound 22 of general formula (1).

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

Thus, in particular, compounds of formula (II) are described in Ogdapis Rgeragayop apa Rgosedigez Ipiegpaiopai, 13, 189, 1981. where Compounds of formula (M) can be obtained by the method described in K. Kaitsiv et al. (). Honey. Spet., 8, 104, 1965) or in Rgoiod et al. (SoPesiop Sgespovioum. Spet. Sottipisaiiopv, 6, 211, 1934). 6o For example, a compound (MI) in which K 7 represents an alkyl group can be subjected to hydrolysis in the presence of a basic agent, such as a dilute solution of sodium hydroxide.

Enantiomers of compounds of formula (I) can be isolated by successive recrystallization of the salt of acid (I) with an optically active base in solvents such as acetone, ethyl acetate or isopropanol, followed by displacement from the salt into the optically active acid with an inorganic or organic acid by a conventional method. because Due to their hypoglycemic action and non-toxicity in active doses, the compounds according to the invention can be used in the treatment of diabetes, in particular non-insulin-dependent diabetes.

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

Pharmaceutical compositions according to the invention can be presented in a form intended for parenteral, oral, rectal, transdermal and mucosal administration.

They can be presented in the form of injectable solutions or suspensions or in the form of medicinal preparations in appropriate containers containing several doses of the medicinal product, in the form of uncoated or coated tablets, sugar-coated tablets, capsules, including hard gelatin capsules , pills, 7/0 starch wafers, powders, suppositories or rectal capsules, solutions or suspensions for transdermal use in a polar solvent or in the form of means for administration through the mucosa.

Acceptable excipients for such applications are cellulose or microcrystalline cellulose derivatives, alkaline earth metal carbonates, magnesium phosphate, starches, modified starches, or lactose for solid forms.

Preferred excipients for rectal administration are cocoa butter or polyethylene glycol stearates.

The most preferred excipients for parenteral administration are water, aqueous solutions, saline or isotonic solutions.

The dose can vary widely depending on the therapeutic indications and the route of administration of the drug, as well as on the age and weight of the patient.

The following examples illustrate the preparation of compounds of the formula (I) and intermediate compounds of the formulas (Bi(M.

A. Example of obtaining a compound of formula (II)

Production of methyl-2-cyclohexylmethylamino-5-methoxybenzoate 17.6g. methyl-5-methoxyanthranilate, 11.8 ml of cyclohexanecarboxaldehyde and 2 g of 10956 palladium on activated carbon (5096 water) are introduced into 200 ml of methanol in a 1-liter hydrogenation apparatus. In this apparatus, a nitrogen atmosphere is created and its contents are stirred at room temperature for three hours. After i) add 300 ml of dichloromethane, palladium on activated carbon is separated by filtration and the resulting filtrate is concentrated under vacuum. The obtained oil was crystallized from a mixture of ethanol (200 ml) and water (5 ml), obtaining 25.4 g of a yellow solid with (dl 58-60". -0). 1H-NMR (SOCI3, 200 MHz): 5 ppm 1.06-1.64 (1H, t, cyclohexyl), 2.93 (2H, i, CH"), 3.68 (ZH , 5, OSN"), sch 3.78 (ZN, 5, OSN"), 6.56 (1H, 4, phenyl proton), 6.96 (1H, ad, phenyl proton), 7.34 (2H, av, proton of phenyl i- MH). (ze)

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

Table I

IS c) osva sweater 0010172 2 2 2 2 2 2 2 1 Xia according to Kefler) 58-602 С sozhsn | | | (according to Kefler; " syuk ! Z s no ;" 1 2

Fo | oil, ! H-NMR (200 MGy,

OO sleep SOSIz,): 6 parts./ml 1.28 (i, sleep and 7 50 | M. ZN), 3.20 (a, 2H), 3.77 (8, ZN), n 3.88 ( 5, ZN), 6.71 (4, 18), 7.09 t" - (44, IN), 7.8 (5, IN), 7.50 and 18)

AND

55 . --- 3 dl

F) dream (according to Kefler) 147-1492 C name) V, C" because To

B. Example of obtaining a compound of the formula (IM) in 5 Preparation of 4-chloro-2-(chloroacetamido)benzoic acid 25.5 ml of chloroacetyl chloride is added dropwise with stirring to 50 g of 2-amino-4-chlorobenzoic acid in bOOml of dioxane, maintaining the temperature of the reaction mixture at level of 207"C. Stirring is continued for 2 hours at room temperature and after that 1200 ml of water is added. The target product is precipitated, the mixture is stirred for 1 hour, filtered and then the resulting solid is washed with water. After drying, 60.7 g of 4-chloro-2 is obtained -(chloroacetamido)benzoic acid from IUD 194-196.

IR: 1676cm7 (C-0). 1 NA-NMR (io5-DMSO, 200 MHz): 5 ppm 4.30 (2H, 8, CH"), 7.1 (1H, d, phenyl proton), 7.7 (1H, a, proton phenyl), 8.5 (1H, in, phenyl proton), 11.75 (1H, 5, MH), 13.90 (1H, wide with, COOH).

The structure and characteristics of compounds of the formula (IM) are given in Table II.

Table HER according to Kefler 194-196 in she ko y

Si 2. 182-184 oon duty" (v; oo p (8) 3. 236-235 son "

МН ра с 9) but | and

Osn (Se)

IC c)

Compound Structure in C (according to Kefler) 4 180-182 "un - s MN si i t i"? Nov 5 , 155-157 s soon

Mn SI and su (95) du o va 70 83-85

Y" 7 sooivg

ZoshN (c) no

GF) 71 soon 211-219 t s Mne . (c) 60 and b5

Table II (continued) parts per million oil; 0.99 (6 ZN), 3.35 (t, 1H), 2 KI stasis 3.63 (0, 2), 3.89 (zt, 78), 7.12 nso o (t, 2H), 7 .40 (0.18) 9 oil; 1.05 (i, 3NI), 1.57 (t, 6H), soy» and 2.81 (44, 18), 3.66 (5, 2H), 3.81 (in,

M si b), 3.88 (44, IN), 7.13 (t, 2H), shku by 7.38 (40, 18)

B. An example of obtaining a compound of formula (II)

Preparation of 4-chloro-2-1|4-(2-methoxyphenyl)-1-piperazinyl)-acetamido)benzoic acid 15g of 4-chloro-2-(chloroacetamido)benzoic acid is added with stirring and at room temperature to 11.6g of 1- -2-methoxyphenyl) piperazine and 17 ml of triethylamine in 120 ml of dimethylformamide (DMF). The reaction mixture is continued to be stirred for 48 hours at room temperature, and then 500 ml of water is added to it.

Extracted with dichloromethane (3 times in portions of 30 ml). The solvent is evaporated under vacuum and the resulting solid is redissolved in ZOOml 2N. aqueous solution of sodium hydroxide. The solution is washed with diethyl ether (3 times in 30 ml portions) and the aqueous phase is then acidified with acetic acid. The solid substance is crystallized and after filtration, 22.5 g of crude product is obtained. After recrystallization from dioxane i) 21.1 g of 4-chloro-2-C4-(2-methoxyphenyl)-1-piperazinylacetamido)benzoic acid is obtained as a white solid with (Pl 218-22076.

IR: 1699cm7! (С-О), 16737 (С-0). "E 1 H-NMR (SEZSOO0b): 5 ppm 4.25 (ZH, z, OSN"), 4.65 (8H, (broad) c, 4 CH»o), 4.95 (2H, 85, CH"), 7.5 cm (2H, t, phenyl protons), 7.6 (IN, y, phenyl proton), 7.90 (2H, t, phenyl protons), 8.50 (1H, a , phenyl proton), 8.75 (1H, 5, phenyl proton). (ze)

D. Another option for obtaining the compound of formula (I) p

Preparation of 2-14-(4-fluorophenyl)-1-piperazinyl|iacetamido)-4,5-(methylenedioxy)benzoic acid 15g of 2-(chloroacetamido)-4,5-(methylenedioxy)benzoic acid are added with stirring and room temperature M to 10.5g of 1-(4-fluorophenyl)piperazine and 16b.2ml of triethylamine in 150ml of DMF. The reaction mixture is continued to be stirred for 48 hours at room temperature. Add 3.5 ml of acetic acid and slowly add 150 ml of water. The acid crystallizes, and it is dissolved in ZOO ml of water. The mixture is stirred for 30 minutes, filtered and the resulting solid is washed with water. After recrystallization, 14.9 g of 2-14-(4-fluorophenyl)-1-piperazinyl is obtained from a mixture of dioxane and DMF. acetamido)-4,5-(methylenedioxy)benzoic acid with (dl 254-25676. "» IR(KVh): 1654 cm"! (С-О). " 1 H-NMR (SEZSOOO, 200 MHz): 5 parts ./million 4.40 (8H, 5, piperazinil), 4.67 (2H, 5, CH"), 6.05 (2H, in, 0-

CH.-O), 7.30 (2H, i, phenyl proton), 7.65 (ZH, t, phenyl proton), 7.90 (1H, 5, phenyl proton). page 15 The structure and characteristics of the compounds of formula (I) are given in table II. (22) (95) with 50 s"

F) name) 60 b5

Table PI.

Spolu-| Structure by C SI H-NMR (200 MHz): ka (according to Kefler) | b parts/million 185-187 4,-DMSO: 2.60 b, soon YAN, 3.10 (5, 48), 3.20 mn (v, 28), 3.70 (v, Z),

STILL IN 6.80 "4, 48), 7.10 (, h o M f 19), 7554.18),8 (4,

C 1, 8.7 (4.18) osn, 10 . 2 233-235 SEzSOOO: 4.25 b, soon 8H), 4.65 (5, 2H), 7.30

Mn (1), 7.55 5, 58),

M T.O (a, 1H), 8.25 (t, stro, 1 m ! and with 248-250 SEZSOOYU: 4.25 (v,

ZNO, 4.55 (5, 2H), 7.10 soon "4.180, 7.50 5, 5),

Shan vo (0.180, 8.30 b,

GT

4 son 241-243 SE,SOO0: 4 b, ZV), with mn 4.5 (5.88), 4.8 b, "d- M 29), 7.2 (0.28), 74 and I m F (8.180, 7.65 (0, 2), o

B: We, 8.25 (4, IN), 8.60 5,

HER 18) a cha osn, « 305 5 265 SEZSOOO: 4.20 6, toon 8H), 4.62 (5, 2), 7.20 s

Mn "a, 18), 7.55 (5, 48)

M, 1H), 7.55 (5, 48),

WE are 8.10 (4, 18), 8.35 s, p

With Sk IV si (se)

IF) - . and" 1

Ge") (95) ko

I" ko bo b5

Spolu- | The structure of the SI H-NMR (200 MHz): ka (according to Kefler) | b parts/million 6 son 199-201 SEZSOOO: 3.8 (5, ZYU), mn 4.25 (v, VN), 4 .60 (v, 7", 7.20 (t, 48), 7.5 ! 7.20 (t, 48), 7,

NI «t, IN), 8.15 (4, I), about M вn осн, 8.40 (5, 1)

I II

7 238-240 SEZSOOO: 4.60 (4 n with "00 (ad, bro chn 8), 4.90 (5, 28), 7.50 7 "shsh, ЗН), 7.85 (in, 2H) 7-x ' PI , z i Set e 8,354, 18), 8,65 (5, x o M z I

I. in dream 7244-7246 SSO: 40 (5,

ZO, 4.45 (5, 28), 7.05

МН "a, Z, 7.45 (t, 28), t 1.954, 18), 8.20 5, o C, 19

It is not 9 191-193 SEzSOOO: 4.25 (8,

And ZNO, 4,60 5, 2), 715

Mn (4.180), 7.75 (t, 48), z 8.104, 110), 8.30 (v, o M lm se, 1 s 2 J o 218-220 SEZSOOO: 4.25 (5, seon ZN) , 4.65 (5, 8), 4.95

Mn 5.20, 7.5 (t, 29),

Yatrooosn, 7.6 (8.189, 7.9 (t, " zo o S lm 28)", 8.5 (4, 18), 8.15 8.15 se se

Go) (Se)

IS o) - . and" 1

Ge") (95) ko

I" ko bo b5

Spolu- spolu Structure a S NYMRObo Mghts (according to Kefler) | 5 parts/ml and 260-262 SEzSOOYU: 4.3 (5, 8), cOon 4.7 (5, 29), 7.25 "I,

Mn IN), 7.55 (in, 48), 7.70 5th "F, IN), 8.25 (t, 2H) gi ma more

Z o S m o ts

I2 soon I 249-251 SESOO0: 42 (5, 88),

Mn 4.6 (5, 2H), 7.2 (t,

ZYU, 7.6 (in, ZK), 8.15 and "her, » o, also st, ZV) x o Km

Fe

IS

IZ soon 174-156 SOS: 2.65 (5, 49), sh 3.10 (5, 28), 3.20 (5, d M 48), 7.00 (sh, 78), that SHI se 8 .65 (4, 1H), 10.00 (5, x se

IF with 189), 11.8 5, IN) sovn 190-192 SErzSOOP: 3.85 (5, mn ZN), 4.30 (5, 8H), 4.15 sch b, 2, 7.5 (t .

Mn 2 28), 6.80 (t, 50), 7.5

Kt e (NU, 775.1), sch (in) C in 8.80 (9, 1), 11.45 5, 19),12.00 5.1) so (Se)

IC o)

Spolu- | The structure of the C H-NMR (200 MHz): ka (according to Kefler) | b parts./ml 217-219 Ssrow 3.5 (8, Z), le 3.75 (5, 88), 4.29 (v, « 2), 6.65 (0, 28), 6.85 - your basic FIN), 7,10 ssh, ZY), Z s ko o S, m ti5 av) . i» n 190-192 SEZSOO: 3.75 b, 1 soon 8), 4.15 (5, 28), 6.715

Mn: (sh, IN), 7.00 "t, 5), o Su g 1.60 (t, 29) o M si

FS and IV soon »265 SEZSOOO: 3.65 (v, t 50 6), 4.15 (5, 88), 4.5

Mn 5.2), 7.55 (5, 58),

Z 7.655, 18), 7.85 b, o m miz» no o s I) osn, 19 . » 265 СсЕзСООр: 3.75 (5, sleep, 6Н), 4.15 (5, ВН), 4.50

Mich (5.280, 7.05 p, 28),

F! your 7.42 (sh, 2), 7.55 65, o Sm IN), 7.855, 1H) ko nu, s Y osn, a 60 soon » 265 SEzSOOO: 3.80 5, 6H), 4.15 "5, ZNO, 4.50 mn (5, ZNO, 7.40 (in, 4), in total 7.60 (8, 18), 7.90 (5, o m no i: d i 19) asn, x s b5

Spolu- | Structure ah ("SI NAMR (200 MHz): ka (according to Keffler) | 5 ppm

M 246-248 SEZSOOO: 3.75 (5, | soon Z), 3.85 (8, 68), 415 ma (in, 80, 4.50 (5, 2),

KE 6.90 (a, 28), 7.40 (4, o M zh 2H", 7.60 (5, 18), 7.95 neo 5IN) op, osn

WITH

10. » 244-246 SEzSOOO: 3.80 b, son ' 9H), 4.25 (z, 8), 4.50 mn (in, 2H), 7.00 «y, 2H),

Lu osv, 7.40 "4, 28), 7.60 (5, c) Yum IN, 7.95 5, 18) nudso with osn, Mo 23 245-741 SEZSOOP: 3.80 (5, oon mn 6H ), 4.20 44.35 05,

ZNO), 4.50 (5, 28), 7.20

I Y (a, 2H), 7.50 (t, Z), iv) M no 7.95 8.18) osn, /Й 255-251 SEZSOOYU: 3.15 (5, soon , 6H), 4, 0 4.20 05,

Mn 8), 4.50 (5, 20), 7.60 g (t, 58), 7.85 (5, 15) s

But I am still, Go) 25 »265 SEzSOOO: 3.80 (in,

Y kn bH), 4.15 (5, VN), 4.50 "5, 2H), 7.35 (t, 48), chI z o go 7.55 (8, 18), 8.85 5,

M si 15) no se osn,

Go)

Spolu- | Structure of tn SI NYMRObO Mgts: (Se) ka (according to Kefler) | b parts/million 35 I c) 26 255-257 SEzSOOP: 3.70 (5, ooo kn ZNO, 3.85 (5, 6), 4.22 "5, 8), 4.50 (5.28 ), ge 6.95 (5; ZNO, 7.35 M, o Sm base, 1), 7.55 (5, 18), 7.88 « neo with IF in, 19 base. 40; - and 251-259 SEZSOOYU: 4155417 "with sobn. O5, 8), 4.50 (5.7), mn TLO (4.18), 7.40 (t, also B 4H), 8.00 (0 .

ZN), 4.10 (5, 88), 4.50 2) and shk she (5, 2), 6.90 (4.28), yu GO to s in 8, 9, ko a If (1

T» osn, 729 015265 SEZSOOO: 4.15 v, rya ooon 8H), 4.55 (5, 2H), 7.40

Mn (zna, 58), 8.00 (5, pa IV, 8.15 4, 18) o s i o u ko si 199-201 SEZSOOr: 3.85 (in, 60 | son Z), 4.30 (5 . 18)

AND

! b5

Spolu-| Its structure. SS H-NMR (200 MHz): ka and . |According to Kefler) | b parts./ml

EY 262-264 SEUSOOO: 4.30 out of 4.50 sleep O5, 8), 4.67 (5, 28), mn 7.30 (sh, 2H), 7.65 (t, uk mV ZNO), 8 ...

Mn' (, 2, 7.40 (4, Z), su I 7.90 (5, IN), 8.05 (8, o m a I s 19)

IS

33 213-215 SEzSOOO: 4.25 24.40 t son 5.80), 4.70 5.2),

Mn 7.558, 1), 7.50 (w, r 48), 8.15 5, 1H), 8.25 o S zh se, "Iv si p i 20. 1m 203-205 SEzSOOO: 3.80 b, dream ZN), 4.20 "5, 8H), 4.45 mn s, 2), 6.95 (4.28),

I'm in elementary school, 7.42 "in, ZNU, 8.05

I r v) shchi a, 2 si t x s |5 soon 224-226 SESOYU: 4.10 b, Ge) chn 8H), 4.45 (5, 28), 7.40 d (t, 5), 7.95 (5, 18),

Su IC Vy (a, 18) al p « 5 soon 238-240 SRzSOOO: 4.20 5, Ha

Mn | YAN), 4.50 (5, 2), 5.85 m 5.28), 7.45 (5.68), 7 SHCHI TO 5.18) i) o x IF (Se) s-0

IS o) - . and 1

Ge") (95) ko

I" ko bo b5

Spolu- | The structure of the | SI H-NMR (200 MHz): ka (according to Kefler) | b parts./min 31 254-256 SEZSOOYU: 4.40 b, oon. ZNO, 4.67 8, 29), 6.05 9 She m shk b,28), 7.30 (0.28), 7.65 (sh, ZN), 7.90 (5, o M 15) about S. and E

GE » 265 SEZSOOO: 4.22 (from, son. . 88), 4.57 (5, 29), 5.92

M 6.2), 7.52 (5, 5), higher TO in, 18) shcha: o and - s 39 236-238 СезСООО: 3.83 b, soon ЗН), 4.25 (5, 8Н) , 4.59

Mn 6.28), 6.0 5.20, ke TZ (8, 7H), 7.49 ", about M in Z), 7.82 5.18)

Mo osn, t 257-259 SEzSOOYU: 3.97 (5, sosn ZN), 4.29 (5, 88), 4.59

Mn (5.2), 6.06 (5.28),

ШЧХ th usn, TA5 (8,28), 7,55 8, s x. o M m ZNO), 782 5.18) guilty 6) ho soon 236-238 SEzSOOYU: 4.23 5 4.38 in O5, 88), 4.56 (5, 2Yu), « m 5.97 5, 2H), 7.3 (t, zome i 28), 7.55 (w, Z), o M un 7.16 8.15) s (o)

M-oh co

Spolu- | Structure t C NMR (200 MHz): yu ka (according to Keffler) | 5 parts/million about | 228-230 SEzZSOOO: 4.05 54.15 oon O5, 8), 4.35 (5.2), mn 5.15 (3, ZNU, 7.30 b, a she 19), 7.60 (in , 58) « o what m sv, o - s -9 .

R. 43 240-242 SEzSOOR: 4.00 (5, " ooon , VN), 4.37 (5, 2H), 5.15 mn ' (8, 2H), 7.35 (4.5, at tlo в, о I M. dyn s o -o s (o) : y 198-200 СезСОО: 3.55 (5, с оон ЗН), 4.00 (z, 88), 4.30 mn v,2Н) , 5 b, 2u, mo chm 6.85 (5. ZNO, 7.25 5,

Gei S m os 289), 7.60 (5.1H) o / iz" Ho If 45 (188-190 SEzSOOYU: 4.05 (5, soon ZNO, 4.42 (in, VN), 4.78

AK tn b,zN), 7.45 (0, IV), ! in 7.72 (v, 50), 7.93 (5, (F. x o S m IN), 8.30 "4, 1) no t ! t sh 46 197-199 SESOOO: 3.75 5, 60 oo ZNO), 4.20 "5, JAN), 4.50

Mn 5,2), 70th century, ZYU),

KE 7.50 (p, 280, 7.70 sv, o S m IN, 8.054, 18) and and

Oh b5!

Spolu-| Structure of them SI H-NMR (200 MHz): ka (according to Kefler) | b parts./ml 47 221-223 СЕ,СООО: 3.80 (5, OSN ZNO, 4.20 (5, 8Н), 4.55 8.2), 7.154, 19),

M 71.40 (from, 48), 7.70 (in,

Z IN), 8.00 (a, 18) a

Shchi IF 70 a 48 I ' 198-200 SEZSOOO: 3.85 (4, oson bH), 4.25 (5, VN), 4.75 kn (8.2), 7.22 (8.2), m 7.40 (5.18), 7.58 (5, и ШЧИ 28), 7.82 5.18), 8.20 в в, и ш осн, 49 171-173 SEUSOOr: 3.15 5, ro ZN), 4.15 (5, 8), 4.50

Mn (5, 2). 7.15 (5. 18). x I Y 7.70 (4, 5H), 8.05 (5, x o C z SE. 1 with poo IF 50 200-202 SEZSOOO: 3.65 (5,

ZN). 3.70 5, 30), 412 toson (5, VN), 4.42 (5, 2H), s chn - y 7.00 (a, 280, 7.10 "a, she pt ooosn, IN), 7.40 (l, 28), Ge) sx o S zh 7.65 (5, 18), 8.00 (a, no 1 "I zo z 179-181 SEzSOOO: 3.72 (v, soon Z) , 4.25 (а, 88), 4.50 Ha

MN (5.2), 7.15 (t, ZYU), 1.50 (a, 2), 7.65 (6,

M E m More IN, 8.00 (4, 1) o

With but Ge

IS o) - . a 1 (e)) (95) ko "g" ko bo b5

Spolu-| Structure of fir (SI H-NMR (200 MHz): ka (according to Keffler) | 5 ppm 52 171-179 SEZSOOO: 3.88 5, soon ZN), 3.96 (5, ZN), 4, 34 (8.8, 4.72 (5.2), 7.20 "t, 18), 7.39 (ad,

IN, 7.62 (w, IN), (in S m son, 71.88 8.18, 8.22 (0, but IF zyu 53 . 182-184 SEZSOOO: 3.95 (5,

And soon ZN), 4.40 (5, VN), 4.70! kn (8.29), 7.30 (4.18),

In 7.60 (sh, ZN), 7.85 (5, that IN), 8.25 (4, 18) o M SI neo s 54 210-212 a6-DMSO: 2.42 (a, soon sn, AN), 2.90 (5, 29), 310 ! schi (8, 4), 3,18 5, ZYU),

It is more than 6.80 (i, 18), 6.93 (a,

C, 29), 7.25 p, 28), 7.50 o M (t, 28), 7.70 p, 1H), another 8.00 "4, 18) c 55 226-227 a5-DMSO: 2.34 (4, s soon sn 4H), 2.81 (5, 2H),

From 3,003.10 05.78), | o sh Shi ak 6.93 (0, 2H), 7.22 (a. 2H), 7.47 (t, 28), not ko 7.70 (0, 18), 7.95 "8, g IN ) oi "I zo 15 193-195 4,-DMSO: 2.55 (i, soon CH, 4H), 3.03 5, 2), 3.25 s i, "0, 7), 7.25 ( t, ZYU), 1.60 (t, ZN), 7.82 Ch, your 18), 8.12 18) Shk (in M m and se, s

IC o)

Spolu-| Structure t (2 SI H-NMR (200 MHz): ka (according to Keffler) | b parts./million 51 sn 208-210 a,-DMSO: 2.55 5, « son uz 40), 3.00 (a , 69), 325

M (5, ZN), 3.80 (5, Z), - pu 1.00 (5, 48), 7.65 (t, s o K m 28), 7824, 15), 8.10 and "a, 1) a osn, sl 58: 196-198 45-DMSO: 215 b, soon CH 48), 2.65 (5.2), 2.80

F pc (5, 4), 2.90 (5, Z),

M 3.55 (5, ZN), 6.20 (,

Sg has Z), 6.85 1, 18), 7.25

Ge) M zh osn (t, 250), 7.50 (40.19), about IF and tl5 vi ko

GT" 59 144-145 a,-DMSO: 72.55 (5, soon CH, 4H), 2.95 (z, 6), 3.20

Y (5, Z), 3.90 5, Z),

BE M 7.00 (a, 48), 7.60 (t, your osn, 28), 7.0 (4.15), 8.10

F! Go) o (a, 18) ko 189-191 SEZSOOO: 2.38 (5, 60 son 3), 3.77 (5, 3), 4.22

I kn (8. 8), 4.60 (5, 2), and M 7.05 (a, 28), 7.50 (4, ro GO ZN), 8.07 (5, 18), 8, 15 x o M «a, 18) and 9 osn, b5

Spolu- | Their structure "SI NMR (200 MHz): ka (according to Kefler) | 5 ppm bi 214-216 4,-DMSO: 2.50 (5,

ZNO, 2.83 (5, 4H), 3.39 | won 5, 68), 7.05 (4, 2H),

Mn 7.43 sa, 2), 7.66 (ad o x z z Ty z u not IN), 7.96 "3, IN), 8.79 niv Z o C z "8, 280, 12.20 (5, 1), 13.80 5, 18)

SI gu | 167-169 4,-DMSO: 0.75 (, von Z, 1.24 (t, 2),

Mn 1.58 (94, 28), 2.52 (5,

HO 4H), 2.94 (5, 6H), 3.50 rt o M (5, Z, 3.81 and, 28), ns o 6.71 (a, 48), 7.05 (ad, 18 ), 7.28 (85, 18), 8.45 sn, (8.18), 11.77 5.18), 13.43 (5, 19) 53 159-161 45-DMSO: 0.83 « I, ah Z), 1.32 (w, 29), mn 1.58 (FON), 2.60 (5, s4 M

S GO Yavni yo IF (a, ZNO, 7.10 "v, ZU), shch 7.35 (4, 18), 8.60 (4, ia IN), 1.81 8.18), 13.50 "5, 18) 64 187-189" a5-DMSO: 1.62 (t, won 880, 2.64 (5, 4), sch ma 3.20 3.28 (25.68), o 7 | Z 4775 (5, 1), 6.86 (0, o - and 29), 7.13 (t, Z), tach o SA, 7.39 (5, 18), 8.56 (4,

SK ID, 10155.18) and « 65 17-73 a5-DMSO: 1.51 (t, 8H), 2.52 (5.4), 2.98 son n H y, zn (5, 6), 3.50 (5, ZYU), c 2 4.60 (5, 1H), 6.60 "4, also IF IC 4H), 6.98 (44, 1B), c aa U M m 7.28 (8, 18) , 8.45 "4,

I, 11.77 8.18), (Se) 13.43 5, 18) he, yu - . and" 1

Ge") (95) ko

I" ko bo b5

Spolu- | Structure of il 2 SI N-YAMER (200 MHz): ka (according to Kefler) | b parts/million 236-238 4,-DMSO: 1.35 (t,

Mon), 2.56 (5, 48), 2 2.84 (t, Z, 3.12 5, 4), 4.90 (from «t, 48), soon 6.92 (9, 28), 7.28 (t, m 4), 746 (a, 1H) 170 si 67 Г 209-211 a;-DMSO: 1.00 (t,

ZI), 1.66 (in, 6), t 2.49 (in, 48), 2.90 (t, ; 7), 3.73 (5, ZN), 3.85 sasn (vzht, 4) , 6.83 (4, m and 4H), 7.24 (4.2), 7.40 uey in v.19)

With n.so 4! x osn, 218-220 a5-DMSO: 1.54 (in, sosn 6), 3.00 (5, 48), 3.50 s, 6), 4.67 (t, 18), sn ports, 7 ...

Iii s s | 132-134 45-DMSO: 1.20 (a, : tya 6), 2.79 (v, 48), 3.13 Go)

Mych (5, 4), 3.20 5, 2), sn, in those 3.62 "8, ZNO, 4.37 (t, bach o MI I), 4.94 (5, 110), 6 ,60 i p with "What IF (8, 29), 6.79 (a, 28), x 7.00 (ad, 19), 7.43 5, osn, IN), 8.56 (0, 15), in 11.88 5.1) p

Spolu- | H-NMR structure (200 MHz): s ka (according to Kefler) | b parts./million 70 161-163 a6-DMSO: 1.05 "I, ise) sn, ZNO, 2.50 (in, 4NU, 3.00 soon g (in, 280, 3.20 (in, 58 ), and)

M 3.902 (p -5, 4H), 6.94 your (I, ZNO, 7.28 (w, 48), and C, 1.47 (h, 18), 13.62 m (wide 5, IN) no « a - s l - I 150-152 sEUSOO0: sn 3.58 (5,

WITH

"from pine | 3.79 5.118 V), " m 3.92 (shi vash 6.83 (4, 28), TO in, o Km 28), 7.28 (4, 2NU, 7.58 but IF in s asn , (o) t | 261-263 SEzSOOr: 3.905, o soon ZN), 4.41 (in, ZNU, 475 kn (in, 28), 7.13 (d, 28), m 7.45 (t, 48), 7 ... 77 (5, 2), 767

MN (5zht, NI), 7.92 (t, (FI "me 20, 8.68 (5, 18), 8.92 th M zh vi o; Ff Fe si 60

Below are the results of pharmacological studies.

Study of antidiabetic activity in rats of the MO5T7 line

The antidiabetic activity of the compounds of formula (I) upon oral administration was determined on the experimental 65 Model of non-insulin-dependent diabetes caused in rats by streptozotocin.

Non-insulin-dependent diabetes is modeled on rats by streptozotocin injection to newborns (on the day of birth).

The diabetic rats studied were eight weeks old. Starting from the day of their birth until the day of the experiment, the animals were kept in a vivarium at a temperature ranging from 21 to 22"C and with a fixed day/night cycle (the duration of the light phase from 7 to 19 hours; the duration of the tempo phase from 19 to 7 hours). The animals were on a maintenance diet, while water and food were given ad libitum, but food was taken 2 hours before the experiment (postabsorptive state).

Rats were orally administered the tested product during the day. Two hours after the last injection and after the end of 30 minutes after anesthesia with sodium pentabarbital (nembutal), 7/o blood samples in the amount of ZOOmcl were taken from the tip of the tail.

The obtained main results are presented in the IM table. These results indicate that compounds of formula (I) effectively lower glycemia in diabetic animals.

The given results are expressed as a percentage of the change in glycemia on the day DA (4 days of treatment) compared to the first day DO (before treatment). 2 1781 181 sch o

Claims (1)

The formula of the invention - Art 1. A compound selected from the compounds of formula (1): c ; (I сОоОоНна () (Се) и М 8 и ою ох и ВВ А " in which - Аг is selected from ц mono-, bi- or tricyclic aryl group having from b to 14 carbon atoms, heteroaromatic group, , » selected from pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazinyl, and the Ag residue may have from 1 to 3 substituents selected from the group consisting of C. --Cv alkyl, 1 (C3-Cv)cycloalkyl(C 1-Cv)alkyl, C.-Svalkoxy, (C3-Cv)cycloalkyloxy(C 1-Cv)alkyl, b" (C3-Cv)cycloalkyl(C 1 -C 4 -C 4 -alkyl, (C 3 -C )cycloalkyloxy, (C 3 -C 4 -cycloalkyl (C 4 -C )alkyl, (C 1 -C )alkyl (C 1 -C )alkyl, Cev-Si4aryl, Cev-Ci4heteroaryl, (Cv-C44)heteroaryl(C1-Cv)alkyl, (95) (Cv-C44)aryl(C.-Cv)alkyl, (Cv-C14)aryl(C4-Cv) alkyl(Cv-C-4)aryl, (Cv-C4,4)aryloxy, 50. (Св-С44)aryloxy(С4-Св)alkyl, (Св-С14)aryl(С4-Св)alkyloxy, (Св-С14)aryl(С4-Св)alkyloxy(С1-Св)alkyl, o halide , trifluoromethyl, "z" trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (C.i-Cv)alkoxycarbonyl, carbamoyl, (Ci-Cv)alkylthio, (C--Cv)alkylsulfinyl, (C4-Cv)alkylsulfonyl , sulfoamino, (C.--Cv)alkylsulfonylamino, sulfamoyl and (C4-Cv)alkylcarbonylamino, or two of these substituents form a methylenedioxy group, with the exception of the values for the Ag residue of the 4-carboxyphenyl and substituted 4-carboxyphenyl groups, o Ku, ER » and Kz independently of each other are selected from the group that includes a hydrogen atom, namely) C1-Alkyl, (C4-Cv)Alkoxy(C4-Cv)alkyl, cycloalkyl containing from C to 8 carbon atoms, (C3-Cv )cycloalkyl(C 4-Cv)alkyl, 60o "C3-Cv)cycloalkyloxy(C 4-Cv)alkyl, (C3-Cv)cycloalkyl(C1-Cv)alkyl (C.-Cv)alkyl, Cv-C:laryl , Cev-C.lheteroaryl, (Cv-C44)heteroaryl(C1-Cv)alkyl, (Cv-C14)aryl(C4-Cv)alkyl, (Cv-C44)aryl(C4-Cv)alkyl (Cv-C .4)aryl, (Cv-C45)aryl(C.-Cv)alkoxy(C.-Cv)alkyl and (Cv-C44)ary oxy(C.-Cv)alkyl, A, B, C and O represent the groups "CH-, and one or two of these residues may also represent a nitrogen atom, 65 Ku, Kb and Kv are independently selected from the group , which includes: a hydrogen atom, C.i-Cvalkyl, (C3-Cv)cycloalkyl(C 1-Cv)alkyl, C-Cvalkyloxy, (C3-Cv)cycloalkyloxy(C 1-Cv)alkyl, (C3-Cv)cycloalkyloxy, (C3-Cv) cycloalkyl(C 4-Cv)alkyl, (C3-Cv)cycloalkyl(C 1-Cv)alkyl(C.4-Cv)alkyl, (C1-Cv)alkyl(Ci-Cv)alkyl, Cev-Silaryl, (Cv -Ci/))aryl(C--Cv)alkyl, (Cv-C4,4)aryl(C4-Cv)alkyl(Cv-C-4)aryl, 50 "Cv-Cd)aryloxy, (Cv-C14) aryloxy(C.4-Cv)alkyl, (Cv-C14)aryl(C4-Cv)alkoxy, (Cv-Ci4)aryl(C1-Cv)alkyloxy(C.4-Cv)alkyl, halide, trifluoromethyl, trifluoromethoxy, cyano, carboxy, hydroxy, nitro, amino, (C--C) alkoxycarbonyl, carbamoyl, (C4-C) alkylthio, (C4-C) alkylsulfinyl, (C--C) alkylsulfonyl, sulfoamino, (C1-C) alkylsulfonylamino, sulfamoyl, and (C--C)alkylcarbonylamino, wherein two of these groups may form a methylenedioxy group or a phenyl ring fused to the ring to which they are attached, 70 while the various aryl groups may themselves be substituted with 1-3 substituents selected from the group consisting of C-Cylalkyl, C-Cyloxy, halide, trifluoromethyl, trifluoromethoxy, hydroxy , nitro and amino, as well as their solvates and pharmaceutically acceptable salts. 2. The compound according to claim 1, which differs in that the main component of the ring system is a phenyl ring. Z. The compound according to claim 2, which differs in that at least one of the groups K/, Kb and Ko is C.-Svaloxy group or two of these groups form a methylenedioxy group. 4. The method of obtaining the compound according to claim 1, which includes the interaction of an aromatic amine of the general formula (I): ; (I! SOOV. work sch - Ka IV, icons B- 7 B « in which A, B, C, O, K., Ku, K5 and Ko have the above values, and K7 is selected from the group that includes a hydrogen atom, SU S.-Svalkylin and benzyl, with halogen anhydride of halogen-substituted carboxylic acid of formula (III): p VE. Ia ; (1) Nai o a Na yu (o; in which K" and Kz have the above values, and Nai means chlorine or bromine, with the formation of a compound of the formula (IM): " СОоОоКк ; (M) KE Ka В shi vo che na " » 4 IV (o; p Kk Er i-y in which A, B, C, O, K.4, Ko, Kz, Ka, Kv, Kv, K;7 and NaY have the above values, and the interaction of the compound of the formula Ge") (IM) with the compound of the formula (M): what about NU k (M) in their iz» At in which Ag has the above value, in the presence of the main agent with the preparation of the compound general MI): formula (MI) Sov. SM o Via YAZ o) M SHE KE. because in Stv At i b in which Ag, A, B, C, O, K., Ko, Kz, Ku, Kv, Kv, and K7 have the above values, and in the case that K7 means alkyl, hydrolysis of this compound to obtain a compound of formula (I), and in the case where K 7 means benzyl, b5 hydrogenolysis of this compound to obtain compound (1). 5. A pharmaceutical composition for the treatment of diabetes, characterized in that it includes an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. 6. Pharmaceutical composition according to claim 5, which is characterized by the fact that it includes an effective amount of the compound according to claim 2. 7. Pharmaceutical composition according to item b, which is characterized by the fact that it includes an effective amount of the compound according to item Z. 5. Kk K-4. . . new Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2003, M 5, 15.05.2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s schi 6) « s (ze) (Se) IS c) - with . and? 1 (o) (95) with 50 s» ime) 60 b5