SU1611216A3 - Method of producing derivatives of thiazolidinedion or their pharmaceutically acceptable salts with alkali metals - Google Patents

Abstract

The invention relates to heterocyclic substances, in particular the preparation of thiazolidinedione derivatives of general formula CH ₂ -CH ₂ -CHR-XC = C-CH-CK-CH = CH, where K = CH ₂ -CH-C / O / -NH-C [O ] -S

R = H, phenyl, benzyl

X = ΣН ₂

Σ / O /

* 98NR

R = CH ₃ , benzyl, phenethyl, or their pharmaceutically acceptable alkali metal salts, which can be used in medicine to treat hyperglycemia. The goal is to create new, more active and less toxic substances of the specified class. The synthesis is carried out by the reaction of a compound of the formula CH ₂ -CH ₂ -CHR-XC = C-CH = CK-CH = CH, where X = ΣH ₂

* 98NR ₁

Σ-O- [CH ₂ ] ₂ -O, with thiazolidine-2,4-dione in the presence of sodium acetate at 140 ° C, followed by reduction of hydrogen in the presence of a palladium catalyst (preferably in acetic acid), or sodium amalgam (better in methanol environment). Wherein when X ₁ = XO- / CH _2/2 -O, then the compound is treated with perchloric acid. The desired product is isolated either in free form or in the form of the desired salt. The novel compounds are less toxic and more active than cyclitazone. 2 hp f-ly, 1 tab.

Description

The present invention relates to a method for producing new chemical compounds, namely, derivatives of thiazolidinone dione of their pharmaceutically acceptable salts with alkali metals, which have hypoglycetic properties and can be used in medicine for the treatment of hyperglycemia.

The purpose of the invention is to obtain new thiazolidinedione derivatives possessing higher hypoglycemic activity at lower respiratory rates; toxicity

PRI me R -K 6-Benzyl-5,6,7,8-tetrahydro-2-naphthacenecarbaldehyde „

2-Benzyl-6-bromo-1,2,3,4-tetrahydronaphthalene (1.5 g, 0.005 mol) is dissolved in 30 ml of tetrahydrofuran and cooled to -78 ° C under dry N ,. Butyl lithium (2.32 ml, 2.14 M, in hexane, 0.005 mol) is added and the mixture is stirred at -70 ° C for 1 hour. Then dimethylformamide (0.39 W1, 0.005 mol) is added dropwise and the mixture is stirred at -70 ° C for 2 hours, allowing ei i to reach room temperature in 0.5 hours,

N5

05

s

Add MejvtCHHO in 38 ml of ohmuid from about 1 I, solution of PS1 and extract with x50 ml of ethyl acetate ,. The combined organic layers were coated with a COJIRHMM slurry, dried (MgSO4), and spun into an Akum to form an oil, 1.26 g, thin layer, 1: R (0.6: 4, 1, hexa: ethyl acetate). ten

Example 2 5- (6-Benzyl-5,6, 7, 8-tetrahydro-2-naphthyl) methi. zolidin-2,4-dione with

The product obtained in Example 1 (1.26 g, 0.005 mol), sodium acetate 15 (1.02 g, 0.0125 mol) and thiazol-gadim-2,4-dione (0.73 g, 0.0062 mol) are , t; inset, mixed thoroughly and stored in a preheated oil bath at 140 ° C for 20 minutes, 20 during which the mixture otlodates, the solid is cooled to room temperature, crushed., mixed in 15 ml in 15 minutes , filtered off and hard)

solid); parts 1C51 were dried under high vacuum at 60 ° C for 45 M1P to obtain a product, 1.4 g, thin layer chromatography Rf 0.7 (1 h1, ethyl acetate: hexane),

Example Zo 5 - (6-Benzsh1-5,6 ,, 7, 8-tetrahydro-2-} aftsh1methyl) -thiaoolidin-2,4-dione

The product obtained in Example 2 (1.2 g, 0.0034 mol) is dissolved by heating in 150 MJE glacial acetic acid. 10% Pd / C (1.2 g) is added and the mixture is hydrogenated at 4 atm for 2 days. The mixture is naturated, the catalyst is reduced by filtration in the presence of diatomaceous earth and the fugrate is evaporated to parts by weight.h. The oil is re-evaporated from 100 t-vi of toluene and then 100 ml of ether, and finally subjected to g slash chromatography on a short column of silica gel using ether as eluant and removing less polar lines; Pure fractions of the product are combined and evaporated to obtain a product in the form of a gummy solid, 0.9 g, thin layer) 1a chromium; 1 -tograph Rf 0.3 (2: 1, geasan: ether)

Example 4, 5- (6-Benzyl-5,6,7, 8-tetrag1 DR 2-onOylmethyl) -thiazol-din-2,4-dione, sodium salt with

The product obtained in Example 3 (0.9 g, 0.0026 mol) is dissolved in 40 ml of methanol. Methyl added: at

thirty

35

40

45

0

five

0

five

sodium (0.318 g, 0.0026 mol) and the mixtures are stirred for 5 hours at room temperature. The solvent is evaporated under a stream of N. The obtained solid parts; white resuspendirunet in 25 ml of ether and filtered with the product, 0.84 g (87%), melting point more than 285 ° C, the mass spectrum includes peaks at 351, 291, 276, 235, 200, 143, 128 and 92.

Example 5 1-Benzyl-1,2, 3,4-tetrahydro-6-quinolinecarb; shdegid „

K / |, imetsch) pho;) mamide (1.7 ml, 0.022 mol) at 0 ° C is added dropwise POCl3 (2.0 W, 0.022 mol) and the mixture is heated and, at an ambient temperature, for 20 min, then diluted with 1,2-dichloroethane (5 1 t) with 1-Bepzil-1, 2, 3, 4-tetrahydroquinol (4.5 g 0.020 mol) is dissolved in 5 ml of 1,2-; is added to the mixture, which is then stirred for 1 h with the addition of sodium acetate (9.0 g, 0.11 mol) of the dissolved) minimal amount of water, and stirring is continued for 15 minutes. water layer is washed with 2x10 ml of ether „

The combined organic layers were thoroughly rinsed (gas evolution) to pH 8} 1%; (IJallCO ,, washed (K CO,) and evaporated in vacuo to give 4.83 g of product ,.

Twice recrystallized from, - mixture of ethyl acetate - cyclohepsy has t „pLo 74-75 C.

Calculated,%: C 81j 24; N 5.57.

С „П„ 1Ю Found, N 5.40.

P 1 m e

en product H 6.82;

C, 80.86; H 6.76;

R

50

55

6. 5- (1-Benzyl-1,2, 3, 4-tetrahydro-6-quinolium) methylene - thiazo4 Shdin-2,4-dione o

The product obtained in Example 5 (1.76 g, 0.0070 mol), thiazolchl-2,4-dione (1.02 g, 0.0088 mol) and sodium acetate (1.435 g, 0.01775 mol) carefully mix and heat in an oil bath at 140 ° C for 0.5 h. The resulting solid mass is cooled to room temperature and triturated in three 10 ml portions. Solids: Supat II (1D vacuum., then triturated with 25 ml SIZO}) to obtain the product, 0,69 g, t „pl ,.

516

230 C (agglomerate) ,. 242-250 C (generation time) o4i-- and

Calculated,%: C 68.55; H 5 18- N 7.99 „

Found,%: C 68.94; H 5.02; N 7.62.

Example 7 „5- (1-Benzyl-1,2,3,

4-tetrahydro-6-quinol-1methyl) -thiazolidine-2,4-dione „

The product obtained in Example 6 (0.60 g) is suspended in methanol (25 br) under Ngo. Milled 3% -Na1 Na-Hg of aluminum ry (12.7 g) is added and the mixture is stirred for 3 hours. The suspension is decanted from a sufficient gray precipitate and a sufficient amount of glacial acetic acid is added to the sink to dissolve all the remaining suspended material. The resulting solution is concentrated to dryness and the residue is subjected to flash chromatography: a 5 cm x 50 mm column using 1:39 CH ONGHSHS as eluant Eloant evaporated to a powder, 0.48 g, which is recrystallized from ethyladetate and cyclohexane to obtain a purified product, 0.31 g, t „pl„ 155-157,5 ° С

Calculated,%: C 68.15; P 5 72- N7.95.

GoNO2 go2

Found,%: C 68.39; H 5.83; N 7.72 „

Example 8, 5- (1-Benzyl-1,2,3 4-tetrahydroquinolylmethyl) -thiazolidine-2,4-dione, sodium salt ,.

To the product obtained in Example 7 (0.27 g, 0.0077 mol) sodium ethyl hexanoate (0.14 g, 0.0084 mol) o is added in ethyl acetate (5 mp). The mixture is stirred for 1 hour and the resulting product restored by filtration with washing with ethyl acetate, 0.19 g t "Topl ... above 250 ° C

Calculated,%: C 64.15; H 5.12; N 7.48 „

C, oH, gN20zSNa

Found,%: C 63.81; H 4.91; Y 7.33,

Example 9 „1- (2-Feni. 1ethsh1) 1, 2,3,4-tetrahydro-b-quinolinecarbaldego

According to the method of Example 5, 1- (2-phenylztil) 1, 2,3,4-tetrahydroquinoline (4.99 g, O, 020 mol) is converted into the indicated product in the form of an oil, 5.6 g.

five

l

c

166

Example 10, (2-Fenrsh-ethyl) -1 2,3,4-tetragon vdpo-6-xynolJlp-methyl) J thiazolidin-2,4-dione “I Semi-string in example 9 product (2.52 g, 0 , 0095 mol), thiazolidin-2,4-dione (1.45 g, 0.0124 mol) and sodium acetate (2.03 g, 0.0247 mol) are carefully mixed and heated in an oil bath at 140 ° C in flow

40 OIH, then cooled to room temperature, and the resulting solids are triturated with 50 ml, stirred for 30 minutes and dried in air to obtain 3, 7 g of solid particles. The latter is triturated with 20 ml of hot oil and filtered with a half-life of 1e} 1 purified product 2.43 g, t „pl„ 211-213 ° С (decomposition) Calculated,%: s 69.20; H 5.53- N 7.69.

Found,%: from 68.95; H 5.39; N 7.42 „

Example 1b (2-Feshch-ethyl) - 1, 2,3,4-tetragne; ro-o-quinol1 and 1-methyl-J-thiazo-120-2,4-dione „

In accordance with the method of Example 7, in the title of Example 10, the product (1.0 g) is converted into a crude product. Subsequent purification is not done by chromatography, but by irrigation with 75 g of ethyl acetate for 10 nos, purification of the filter and evaporation of the obtained mixture with the addition of the indicated product in the form of oil, 0.75 g

 P "meper 12" (2-Phenyl-ethyl) -1, 2, 3,4-tetrahydro-6-Xiraoyl-mitshIJ-thiazolidin-2, 4-dione, sodium salt

In the method of example 8, the product obtained in example 11 (0.55 g) is converted into the indicated compound, 0.37 g of ToplO are 250 ° Co.

Vych Sleno, Z: C 64.93; H 5 45 N 7.21.,

C2, H2, i 02SNa

By day,%: C 63.84; H 5.22; N 7.06.

Example 13, 1,2-Dtgbenzyl1, 2,3,4-tetrahydro-6-hnolyncarbal-eguid,

By the method of Example 5, 1.2 dibenz-1, 2,3,4-tetrahydrochilol (0.89 g, 0028 mol) transform the indicated compound into B1 more than oil, 0.93 g is subsequently subjected to liter per gram cleavage ( on thick plates of silica gel ,, elyuschtu CHCIj. Basics

A strip gives a fine product, 0.54 g, as an oil, thin layer chromatography Rf 0.25 (CHCl;))

Example 14 „5- (1,2 - Dibenzsh1-1,2,3, A-tetrahydro-6-quinolyl) -methylene1-thiazolidin-2,4-dioHc

The product obtained in Example 13 (30.52 g, 0.0015 mol), thiazolidin-2,4-dione (0.23 g, 0.0020 mol) and sodium acetate (0.32 Gs 0.0039 mol) are thoroughly mixed. is heated in an oil bath at 140 ° C for 2.5 h and cooled to room temperature; the resulting solids are suspended in 25 ml of H2.0., filtered and the solid parts are dried under high vacuum with a 0.52 g s Recrystallized; methanol from methanol gives a very good product, 0.27 g, Toplo 199-2014 :.

Example 15c, 5- (1,2-Dibapsh11, 2,3,4-tetrahydro-6-chiylyl) metsch1 - thiazolidin-2,4-dione o

The product obtained in Example 14 (0.215 g) is reduced with sodium amalgam according to the method of Example 7o. Following evaporation of the methanol, the residue is taken up in 25 ml and the resulting solution is acidified to pH 4 with POM1TC 6 of the P1 solution and extracted with 3x25 ml of CH2Cl2. The organic layers are combined. are dried (MgSO ,,.) and evaporated to obtain the indicated product in B1, more than 180 mg of sucky foam, used directly in the following

stages about

Example 16c 5- (1,2-Dibenzyl 1,2,3,4-tetrahydro-6-quinolsch1) -methyl1 thiazolidin-2.4 dioneJ sodium salt B and, according to the method of Example 4, the product of example 15 (0.14 g) transmuted into a specified product, 51 mg ,.

Example 17 2-Benzyl-1 methyl 1, 2,3,4-tetrahydro-6-quinol. Incarbl1ceride.

According to method 5, 2-benzyl-1-methyl-1,2,3,4-tetrahydroquinoline (1.5 g, 0.0063 mol) is converted into the indicated product in the form, 1.66 g, which is purified by chromatography in accordance with Example 13, to obtain a purified product, 1, 29

EXAMPLE 18c, 5 - | (2-Benzyl-1-methyl-1, 2,3,4-tetrag1gcr-6-quinol1, 1) - methyleneP thiazolidin-2,4-dione „

In accordance with the method of example 6, the product of example 15 (1.24 g, 0.0047 mol) is converted into

product.

1.14 g, mp, 214-217 ° C.

five

five

,

d5

with

55

0

Example 19: 5- (2-Benzyl-1-methiot-1, 2,3, 4-tetrahydro-6-quinolyl) -; metshi thiazolidin-2,4-dione with

B In accordance with the method of Example 15, the product of Example 18 (1.0 g) is converted into an indicated product in the form of an oil, 1.03 g

PRI me R 20c. 5- (2-Benzyl-1-methyl-1,2,3,4-tetrahydro-6-quinolyl) - methylptiazolidin-, 4-dione, sodium salt o

In accordance with the method of example 8, the specified product of example 19 (0.81 g. 0.0022 mol) is converted into the specified product, 0.60 g, TopPLo is higher than 280 ° C „

Example 21 „1-Methyl-1,2,3,4-tetrahydro-b-quinolinecarbaldehydes,

B in accordance with the method of Example 5, 1-methyl-1,2,3,4-tetrahydroquinoline (2.27 g, 0.015 mol) is converted into the indicated product in the form of an oil, which is purified by flash chromatography on a silica gel column 4 cm x 40 mm s as eluant, 1.84 g „

Example 22o 5- (1-Methyl-1,2,3, 4-tetrahydro-6-quinolyl) methylene 1-thiazole ;; in-2,4-dione „

B in accordance with the method of Example 6, the specified product of Example 21 (1.40 g, 0.008 mol) is converted into the indicated product, 1.50 g, Tog1Lo254-257 C „

EXAMPLE 23: 5- (1-Methyl-1, 2, 3,4-tetrahydro-6-quinolyl) methyl 1-thiazolidine-2.4-; 1, iOH

In accordance with the method of Example 15, the product of Example 22 (1.0 g) is converted into the indicated product in the form of a solid, 0.67 g, which is recrystallized from a mixture of ethyl acetate - cyutohexane with the reduction of the purified product indicated in the title , 42 g, t, silt, 122-125 ° C,

Example 24; 5- (1-Methyl-1, 2, 3 54-tetrahydro-6-quinolyl) -methyl | thiazolidin-2, 4-dione, sodium salt

B In accordance with the method of Example 8, the product of Example 23 (0.38 g, 0.0014 mol) is converted into a specified product of 0.31 g, Tspl over 250 CoPmeper 25, 2-Benzyl-1- (2-phenylethyl ) -1,2,3,4-tetrahydroquinolin-6-carbal-Hegid.o

In accordance with the method of Example 5, 2-benzyl-1- (2-phenylstil) quinoline (1.05 g, 0.0032 mol) is converted into a crude product, 1.30 g as an oil „

516

The latter is chromatographed on a single layer plate of silica gel, eluting. The third fraction gives a purified compound, 1.14 g in oil, thin layer chromatography Rf 0.25 (CHCl3)

Example 26 of 5- (2-Benzyl-1- (2-phenylethyl) -1,2,3,4-tetrahydro-6-quinolyl) methylene thiazolidin-2,4-dione

In accordance with the method of example 14, without recrystallization, the product of example 25 (0.98 g, 0.0028 mol is converted into the indicated product, 1.36 g

Example 27c 5- (2-Benzsh1-1- (2-phenylethyl) -1,2,3,4-tetrahydro-6-quinolylT methyl (-thiazolidin-2,4-dione)

In accordance with the method of Example 7, using CHCla as eluant on chromatography, the product of Example 27 (1.2 g, 0.0026 mol) was converted to the indicated product, the second component for the elution, 0.47 g, as a foam.

Example 28 5- 2-Benzyl-1- (2-phenylethyl) -1,2,3,4-tetrahydro-6-quinolyl methyl thiazolidin-2,4-dione, sodium salt

In accordance with the method of Example 4, the product of Example 27 (0.30 g, 0.00066 mol) is converted into the indicated product, 0.22 G

Example 29 of 1-Methyl-2-phenyl-1,2,3,4-tetrahydro-6-quinolincarb-aldehyD

In accordance with the method of example 13, 1-methyl-2-phenylquinoline (1.5 g, 0.0067 mol) is converted into the indicated product, 1.48 g, TopPLo 86-89 ° Co

Example 30 of 5- (1-Methyl-2-phenyl-1,2,3,4-tetrahydro-6-quinolsh1) - methylene thiazolidin-2,4-dione 5

In accordance with the method of Example 14, without recrystallization, but by rubbing the product with methanol, the product of Example 29 (1.38 g, (0.0055 mol) is converted into the indicated product, 1.49 g, ToPLo 244-246 C

Example 31 5- (1-Methyl-2-phenyl-1,2,3,4-tetrahydro-6-quinolyl) methyl-thiazolidine-2,4-dione

In accordance with the method of Example 7, without chromatography, the product of Example 30 (1, 43 g, 0.0041 mol) is converted into the indicated product, 1.27 g, as a foam

Example 32 5- (1-Methyl-2-phenyl-1,2,3,4-tetrahydro-6-quinolyl) me21610

THnJ-thiazolidine-2,4-dione, sodium

with OL about.

In accordance with the method of example. 8 product of example 31 (1.20 g,

0.0034 mol) is converted into the specified product 0.86: g, Toplo above 280 C.

Example 33o 2-Benzyl-6-form} chl-1,2,3,4-tetrahydronaphthalen-1-spiro-2-0 (1,3-dioxolane)

Ethylene glycol 2-benzyl-3,4-dihydro-1 (2H) -naphthalenone.,

According to the method of Example 1, 2-benzyl-6-bromo-1,2,3,4-tetrahydro-5 naphthalene-1-spiro-2 - (1, 3-dioxolane) (1.09 g, 0.003 mol) was converted into the indicated product, purified by column chromatography on 100 g of silica gel, using 1: 1 hexane: ether in 20 as eluant, 0.29 g, thin layer chromatography Rf 0.4 - (1: 1, hexane: ether) o

Example 34 5-β-Benzyl-1,2, 3,4-tetrahydronaphthalen-1-spiro-2-5 (1, 3-dioxolane) J-6-yl J metschlenl thiazo-. Lead-2,4-DioNo.

In accordance with the method of Example 2, the product of Example 33 (0.29 g, 0.00094 mol) was converted into the indicated 0 product, 0.38 g, thin-layer chromatography Rf 0.6 (9: 1, CH2Cl2: CH3OH) o

Example 35o 5- (2-Benzyl-1,2,. 3,4-tetrahydronaphthalen-1-spiro-2 - (1, 3 -dioxolane) -6-1b | methyl thiazolidin-2, 4-dione o

In accordance with Method 7, without recrystallization, the product of Example 34 (0.38 g, 0.00093 mol) is converted into the indicated product, 0.4 g, as a d foam, thin-layer chromatography Rf (9: 1, CH2Cl2: CH} OH), contents of unrestored starting material (at Rf 0.6) o

Example 36o 5- | 2-Benzyl-3,4- 5 Dihydronaphthalen-1 (2H) -on-6-yl methylenJ-thiazolidin-2,4-dione of

5-2-Benzyl-3,4-dihydronaphthalen-1 (2H) -one-6-Sh1 methyl-thiazolidin-2,4 DIONO

0 The entire product of example 35 (0.4 g, contaminated with unreduced olefin) is combined with 15 ml of tetrahydrofuran and 10 ml of 3.5% perchloric acid, stirred for 16 hours, 5 is diluted with 50 ml of ethyl acetate and the layers are separated. - The organic layer is washed with 1x50 ml and 1x50 ml of saturated JHoro brine, dried () - and evaporated to a foam. The latter at the beginning of the test, after the test, according to the following procedure,

Mythia B aged six-armed C57 BL / K-about / about (semi-: nn1lh pz Yakekson laboratory, 1: ar Xap6oji, Mei) placed ps; P1 Wasps: Obi to Kjr-crku under the conditions of standardization, and for animals, Io fic Te-iciinn od he :: del () of the native accryse of gizapia / IP.NUGNAh

vCH2-, -C- or

оRI

where R. is methyl, benzyl i-um phenethyl, their pharmaceutically acceptable salts with alkali metals, excl 1D and with non-Hire of formula II

what connect

where R has the indicated meanings, XI is a group of the formula

-CH, -, -С- or О О

T

HI

where R (has the indicated 3%), is reacted with thiazolidine-2,4-dione in the presence of sodium acetate at 140 ° C, a compound of formula III

, R i

where K and X, have the indicated meanings, are subjected to reduction with hydrogen in the presence of a palladium catalyst or sodium amalgam to obtain H1;

R-x;

where R and X, have the indicated meanings, if necessary, a compound of formula IV,

where X, is a group

about

treated with chlorophenol acid to obtain the desired product, where X is a group of the formula

 -cII

about

and the product is isolated in free form or in the form of a pharmaceutically acceptable salt with a hemi metal

2 o- The method according to claim 1, wherein the compound of formula III is subjected to reduction with hydrogen in the presence of a palladium catalyst in a glacial acetic acid medium.

3. The method according to claim 1, characterized in that the compound of formula III is subjected to reduction with sodium amalgam in methanol

Results of testing for glucose normalizing activity

compounds of the formula

Claims (1)

<claim-text> <table border = "1"> <tbody> <tr> <td> Example </ td> <td> X </ td> <td> to </ td> <td> % normalization of glucose, mg / kg </ td> </ tr> <tr> <td> 3/4 (salt) </ td> <td> CH <sub> 2 </ sub> </ td> <td> CH <sub> g </ sub> C <sub> 6 </ sub> H <sub> 3 </ sub> </ td> <td> 81 (25) </ td> </ tr> <tr> <td> 7/8 (salt) </ td> <td> HCH <sub> g </ sub> C <sub> b </ sub> H5 - </ td> <td> n </ td> <td> 50 (25) </ td> </ tr> <tr> <td> 11/12 (salt) </ td> <td> PSN, C11 <sub>? </ Sub> C <sub> p </ sub> H <sub>? </ Sub> </ td> <td> n </ td> <td> 75 (25) </ td> </ tr> <tr> <td> 19/20 (salt) </ td> <td> HCH, </ td> <td> CH <sub> g </ sub> C <sub> 6 </ sub> H ^ - </ td> <td> 50 (25) </ td> </ tr> <tr> <td> 23/24 (salt) </ td> <td> MSN s </ td> <td> n </ td> <td> 75 (25) </ td> </ tr> <tr> <td> 31/32 (salt) </ td> <td> YN, </ td> <td> C <sub> 6 </ sub> Well </ td> <td> 20 (25) </ td> </ tr> <tr> <td> 36 </ td> <td> co </ td> <td> CH <sub> 2 </ sub> C <sub> 6 </ sub> H <sub> 5 </ sub> </ td> <td> 55 (10) </ td> </ tr> <tr> <td> Ziglitazone </ td> <td> - </ td> <td> - </ td> <td> 100 (50) </ td> </ tr> </ tbody> </ table>