Hydrochloride 8-amino-7-(2-hydroxypropyl-1)-1,3-dimethylxanthine derivatives displaying haemorheological activity

FIELD: chemistry.

SUBSTANCE: invention refers to new derivatives of hydrochloride 8-amino-7-(2-hydroxypropyl-1)-1,3-dimethylxanthine of general formula: where . Compounds under this invention display haemorheological activity surpassing that of common pentoxifylline compound. Compounds represent hydrochloride 1,3-dimethy-7-(2-hydroxy-3- piperidinopropyl-1)-8-phenylaminoxanthine or hydrochloride 1,3- dimethy-7-[2-hydroxy-3-(2- chlorophenoxy)-propyl-1]-8- piperazinoxanthine.

EFFECT: production of compounds displaying haemorheological activity.

4 cl, 2 tbl, 4 ex

 

The present invention relates to medicine, namely to pharmaceutical chemistry and pharmacology, and can be used to create new offsets hemorheological disorders.

The objective of the invention - expanding Arsenal of biologically active substances with hemorheological properties.

The technical result - obtaining compounds having hemorheological activity.

Prototype and product comparison is pentoxifylline(3,7-dimethyl-1-(5-oxohexyl)xanthine, Aventis, Germany), which for a long time used in the clinic as a corrector of rheological disorders (Zudin A.M. Violation of rheological properties of blood and their correction with postthrombotic syndrome / Aminudin, Gastronomski, Ahemtov etc. // Surgery. - 2004, No. 2. - Pp.33-36).

The essence of the invention: derivatives of 8-amino-7-(2-hydroxypropyl-1)-1,3-dimethylxanthine hydrochloride (1A, b), General formula

where

showing hemorheological activity.

As the comparison drug used pentoxifylline ((1-(5-oxohexyl)was 3.7-dimethylxanthine) Aventis, Germany), which had long been used in the clinic as a corrector of rheological disorders (Nam, H.Goto, N.Sekiya et al. // Phytomedicine - 2003 - Vol.10, No. 6-7. - P.459-466).

p> The claimed compounds are synthesized as follows.

Compound 1A was synthesized by the interaction of 1,3-dimethyl-8-phenylenediamine (Sasse F., Masirone R. Derivati della 8-aminoteofillina // Ann. di Chim. (Roma) - 1957. - V.47, No. 4. - P.362-365) and 2.8 g (0.02 mol) of 1-piperidino-2,3-epoxypropane (pacen A.M. Epoxy compounds and epoxy resins. / Aimpact. TRANS. with it. - L.: Goskomizdat, 1962, 693 S.) in n-propanol boiling for 3 hours and then receive hydrochloride.

Compound 1b was synthesized in 3 stages. Initially the interaction of 8-bromo-1,3-dimethylxanthine (Eckstein M,. gorczyca M, Zeic A. Pozukiwania nowych lekow w grupie pochodnych ksanthyny. Cz XXL. Produktu przu lazania kwasow podchlorowcawych do 7-allilo-pochodnych 8-chloro-i 8-bromoteofiliny // Dissert. Pharm - 1964. - V.26. No. 1. - R-66), 1-(2-chlorophenoxy)-2,3-epoxypropane (pacen A.M. Epoxy compounds and epoxy resins. / Aimpact; TRANS. with it. - L.: Goskomizdat, 1962, 693 C.) in the presence of pyridine in ethanol medium at boiling for 3 hours got 1,3-dimethyl-7-[2-hydroxy-3-(2-chlorophenoxy)-propyl-1]-8-brocantes. Then heat the resulting compound with piperazine with uranyl in ethanol medium at 170°autoclave and receive 1,3-dimethyl-7-[2-hydroxy-3-(2-chlorophenoxy)propyl-] 8-piperazinediones and translate it into hydrochloride.

Example 1. The synthesis of compounds 1A.

The mixture 4,07 g (0.015 mol) of 1,3-dimethyl-8-phenylimidazoline and 2.8 g (0.02 mol) of 1-piperidino-2,3-epoxypropane in 50 ml of n-propanol Ki is att 3 hours, cooled to 5-8°C, the precipitation is filtered off, washed with n-propanol and dried.

Obtain 3.7 g (59.9 per cent) of 1,3-dimethyl-7-(2-hydroxy-3-piperidinomethyl-1)-8-phenylimidazoline.

Purify by crystallization from n-propanol. TPL227-228°C.

Elemental analysis:

Found, %: C 60,7; N 6,9; N 20,4. - C21H28N6O3.

Calculated, %: From 61.1; H 6,8; N 20,4.

IR-spectrum (in vases. oil), cm-1:

1696, 1672 (C=O); 1584 (C=N); 3275 (-NH-); 3380 (OH).

In a solution of 2.9 g (to 0.007 mol) of 1,3-dimethyl-7-(2-hydroxy-3-piperidinomethyl-1)-8-phenylenediamine in 30 ml of chloroform is added dropwise a 5% solution of hydrogen chloride in ethanol to pH 1-2, cooled to 5-8°C, after 24 hours, the precipitation is filtered off, washed with chloroform and dried. Obtain 3.0 g (95%)

1,3-dimethyl-7-(2-hydroxy-3-piperidinomethyl-1)-8-phenylenediamine hydrochloride.

Purify by crystallization from ethanol. TPL272-274°C.

Elemental analysis.

Found, %: C 56,87; N 6,1; Cl 8,03; N 18,47. - C21H28N6O3·HCl.

Calculated, %: C 56,27; N. Of 6.5; Cl 7,9; N 18,7.

The inventive compound is a white powder, soluble in water, when heated, soluble in ethanol, insoluble in ether and chloroform.

Example 2. The synthesis of compounds 1b

Mix at 2.59 g (0.01 mol) of 8-bromo-1,3-dimethylxanthine, 2,03 g (to 0.011 mol) of 1-(2-chlorophenoxy)-2,3-epoxypropane and 0.2 ml su is th pyridine in 50 ml of ethanol is boiled for 3 hours, cooled to 5-8°C, the precipitation is filtered off, washed with ethanol and dried. Receive 3.58 g (81%) of 8-bromo-7-[2-hydroxy-3-(2-chlorophenoxy)propyl-1]-1,3-dimethylxanthine. Purify by crystallization from ethanol. TPL162-164°C.

Elemental analysis:

Found, %: From 42.9; H 3,7; N 12.7mm. - C16H16, BrClN4O4.

Calculated, %: C To 43.3; H 3,6; N 12,6.

IR-spectrum (in vases. oil), cm-1:

1700, 1645 (C=O); 1590 (C=N); 3450-3440 (HE).

The mixture 4,43 g (0.01 mol) of 8-bromo-7-[2-hydroxy-3-(2-chlorophenoxy)propyl-1]1,3-dimethylxanthine and 14.6 g (0,075 mol) of piperazine of uranyl in 100 ml of ethanol is heated in an autoclave at 170°C for 6 hours, cooled to 18-20°C, the precipitation is filtered off, washed with water, dried. Get of 3.78 g (84%) of 1,3-dimethyl-7-[2-hydroxy-3-(2-chlorophenoxy)propyl-1] 8-piperazinoazepine. Purify by crystallization from ethanol. TPL134-136°C.

Elemental analysis:

Found, %: From 53.4; H 5,3; Cl 7,9; N 18,74. - C20H25ClN6O4.

Calculated, %: From 53.5; H 5,6; C1 7,9; N 18,7.

IR-spectrum (in vases. oil), cm-1:

1695, 1675 (C=O); 1615 (C=N); 3280 (NH); 3340 (HE).

Into a solution of 2.3 g (0,005 mol) of 1,3-dimethyl-7-[2-hydroxy-3-(2-chlorophenoxy)propyl-1]-8-piperazinoazepine in 100 ml of ethyl acetate is added dropwise a 5% solution of hydrogen chloride in ethanol to pH 1-2, cooled to 5-8°C, after 24 hours, the precipitation is filtered off, washed with ethyl acetate, su is at. Gain of 2.08 g (86%) of 1,3-dimethyl-7-[2-hydroxy-3-(2-chlorophenoxy)propyl-1]-8-piperazinone hydrochloride.

Purify by crystallization from ethanol. TPL243-245°C.

Elemental analysis:

Found, %: C And 49.2; H 5,6; Cl 14,2; N 17,8. - C20H25ClN6O4·HCl.

Calculated, %: 49,51; H 5,4; Cl 14,6; N 17,3.

The inventive compound is a crystalline white powder, soluble in water, when heated, soluble in ethanol, insoluble in ether, chloroform, acetone.

Example 3. Acute toxicity of the claimed compounds.

Acute toxicity was determined on rats when administered intravenously. The death of animals were recorded for two weeks. The calculation of LD50produced according to the method of Prozorovsky (Prozorovsky V.B. have been et al. // Pharmacol. and toxicol. - 1978. No. 4. - S-502). The results are presented in table 1.

As can be seen from the table, the inventive compounds are malotoksicnam compounds (Sidorov, K.K. Toxicology of new industrial chemical substances // CEO. - L.: Medicine, 1973).

Example 4. Hemorheological activity.

Hemorheological activity of the claimed compounds was studied using playback violations of rheological properties of blood in vitro. The syndrome of increased blood viscosity was modeled using hyperthermia (MB carpenters Koltunov, A., Alawai // Bull. Exp. Biol. and the honey. - 1996. No. 9. - S-275), using the blood of rabbits. Compounds 1a, 1b and pentoxifylline at concentrations of 10, 50, 100 μmol/l was added to 10 μl of warm (37° (C) saline solution. The viscosity of the blood samples was measured in centipoise (SP) before and after incubation in the viscometer ACRE-2 (N. A. Dobrovolsky, Humopehy, Astafiev etc. // Rheological studies in medicine: collected scientific articles. Tr. - M.: NCH Russian Academy of medical Sciences, 1998. - C.45-51). Effects of substances on the erythrocyte aggregation was assessed by the index of aggregation, calculated as the ratio of blood viscosity at the shear rate of 3-1to blood viscosity at 100 C-1(Dinten L. // Aging. - 1989. No. 1. - R-125). The calculation of the inhibition effect of the inventive compounds on aggregation of red blood cells produced by the formula

INAA=100-(V/a)·100%,

where Inae - the index of inhibition of aggregation of erythrocytes;

A - index of aggregation of erythrocytes without the studied compounds;

In the index of aggregation of the erythrocytes after incubation of the suspension with the target connection.

The claimed compounds in the tested concentrations caused statistically significant compared to control reduction of the index of inhibition of aggregation of erythrocytes (table 2). As can be seen from the table, hemorheological activity of the claimed substances exceeds that of pentoxifylline. The greatest magnitude of effect observed in connection 1b is a concentration of 100 µmol/L.

When determining the value of the effective concentration (EC20), which causes a decrease in the aggregation of erythrocytes by 20% (table 2), (Dukhanin A.S., Gubaev FR // Experimental. and clinically. pharmacology. - 1998. No. 4. - P.66-71), it is established that the claimed compounds 1A, 1b superior in hemorheological activity pentoxifylline in 8,81 and 9,86 times, respectively.

As an indicator of conditional breadth of therapeutic action used conventional therapeutic index (UTI), which is calculated by dividing the index of acute toxicity LD50to measure the effective concentration EC20. OOTY compounds 1A equal 23,27, compounds 1b - 12,45, and pentoxifylline - 1,92. Largest OOTY claimed compounds 1A, 1b exceed pentoxifylline 12.1 and 6,48 times, respectively.

Accordingly, the chemical compounds (1A, 1b) have hemorheological activity, significantly exceed pentoxifylline therapeutic breadth and compares favorably to more low toxicity.

Table 1
Derivatives of 8-amino-7-(2-hydroxypropyl-1)-1,3-dimethylxanthine hydrochloride, showing hemorheological activity
ConnectionThe rate of acute toxic the spine of LD 50rats/
mmol/kgmg/kg
1A0,512229,8
1b0,249120,6
Pentoxifylline0,79105,4

Table 2
Hemorheological activity (M± (m) the claimed compounds and the comparison drug
The number of connectionsThe concentration, µmol/lEC20µmol/l
1050100500
1A-16,12±2,44**-22,46±3,57***-34,78±to 2.06***-22,40
1b-16,66±3,19**-23,16±3,37**-37,98±3,19**-20,02
Comparator drug (M±m)
Pentoxifylline-6,00±1,54**-14,56±3,71**-18,59±3,66**-28,13±2,84***197,40
** data is significant in relation to control (p<0.01), and t - student test.

*** - data is significant in relation to control (p<0,001) t - student test.

1. Derivatives of 8-amino-7-(2-hydroxypropyl-1)-1,3-dimethylxanthine hydrochloride General formula

where

2. The compound according to claim 1, which represents a 1,3-dimethyl-7-(2-hydroxy-3-piperidinomethyl-1)-8-phenylenediamine hydrochloride.

3. The compound according to claim 1, which represents a 1,3-dimethyl-7-[2-hydroxy-3-(2-chlorophenoxy)-propyl-1]-8-piperazinone hydrochloride.

4. Derivative according to claim 1, exhibiting hemorheological activity.



 

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2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to producing the novel compounds with dipeptidyl peptidase IV (DPP-IV) inhibiting activity and particularly, it relates to the compounds with the condensed 1,3-dihydroimidazole cycle. The invention relates to the compounds represented by the common formula (II), or their pharmaceutically acceptable salts, where, Z3a means nitrogen atom or the group with formula -CR2a=; X3a means oxygen atom or sulfur atom; T1a means piperazine-1-yl group, 3-amino-piperidine-1-yl group, 3-methylamino-piperidine-1-yl group; X1a means oxygen atom hydrogen, C2-6-alkenyl group, C2-6-alkynyl group or benzyl group; each of R1a and R2a independently means hydrogen atom, halogenatom, C1-6-alkyl group, cyanogroup or group, represented with formula-A0a-A1a; A0a means oxygen atom, sulfur atom or group, represented with formula-NA2a-; Ala means hydrogen atom, C1-6-alkyl group, C1-6-alkenyl group, C2-6-alkynyl group, phenyl group, cyanophenyl group, carbamoylphenyl group, benzyl group; A2a means hydrogen atom or C1-6-alkyl group; X2a means hydrogen atom, C2-6-alkenyl group, C2-6-alkynyl group, 1H-piridine-2-onyl group, 1-methyl-1H-piridine-2-onyl group, C1-6-alkyl group, which can have a group, selected from the substitutes group specified below B, phenyl group, which can have a group, selected from the substitutes group specified below B, 5- or 6-membered heteroarylgroup, containing one or two nitrogen atoms, oxygen or sulfur, which can have a group, selected from the substitutes group specified below B, phenylC1-6-alkyl group, which can have a group, selected from the substitutes group specified below B: <Substitutes group B> substitutes group B is group, including chlorine atom, bromine atom; cyanogroup, C1-b-alkyl group, C2-b-alkenyl group, C2-6-alkynyl group, C3-8-cycloalkyl group, C1-6alcoxigroup, carbamoyl groupcarboxyl group and C1-6-alcoxicarbonyl group.

EFFECT: research and revealing compounds with DPP-IV inhibiting activity, useful as pharmaceutical agents which can be used as therapeutic and preventing medicines in such diseases as diabetes, obesity and hyperlipidemia.

12 cl, 84 ex, 2 tbl

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