RU2205826C2 - (±)-cis-3-(2'-benzimidazolyl)-1,2,2-trimethylcyclo- pentane carboxylic acid eliciting sugar-reducing and antidiabetogenic effect - Google Patents

Abstract

FIELD: organic chemistry, medicine, endocrinology. SUBSTANCE: invention relates to the novel biologically active compound (±)-cis-3-(2'-benzimidazolyl)-1,2,2-tri- methylcyclopentane carboxylic acid eliciting sugar-reducing and anti- diabetogenic effect. EFFECT: valuable medicinal properties of compound. 4 tbl, 6 ex

Description

Приведенное соединение проявляет высокую сахароснижающую и антидиабетогенную активность и может быть использовано как сахароснижающее средство при манифестных формах сахарного диабета I и II типа, а также как антидиабетогенное средство, которое предупреждает и/или ослабляет развитие инсулиновой недостаточности на ранних стадиях заболевания.The invention relates to the chemical-pharmaceutical field, in particular to new biologically active compounds, and in particular to (±) -cis-3- (2'-benzimidazolyl) -1,2,2-trimethylcyclopentanecarboxylic acid of the formula

The compound shown exhibits high hypoglycemic and antidiabetogenic activity and can be used as a hypoglycemic agent in the manifest forms of type I and type II diabetes mellitus, as well as an antidiabetogenic agent that prevents and / or reduces the development of insulin deficiency in the early stages of the disease.

 There are no analogues in structure. The closest analogue in biological action for the claimed compound is glibenclamide [1], as one of the most active sulfa-lowering drugs.

 Despite the effectiveness of the action of the comparison drug, experimental and clinical data on its diabetogenic (damaging pancreatic beta cells) action with prolonged administration are known [2].

 The objective of the invention is the creation of a new biologically active compound (±) -cis-3- (2'-benzimidazolyl) -1,2,2-trimethylcyclopentanecarboxylic acid, which exhibits a hypoglycemic and antidiabetogenic effect, and can be used as a substance for obtaining a medicinal product , which will make it possible to expand the arsenal of antidiabetic agents, which, along with a high hypoglycemic effect, have antidiabetic activity and lower toxicity.

проявляющей сахароснижающее и антидиабетогенное действие (в дальнейшем соединение формулы I).The essence of the invention consists in the creation of (±) -cis-3- (2'-benzimidazolyl) -1,2,2-trimethylcyclopentanecarboxylic acid of the formula

exhibiting a hypoglycemic and antidiabetogenic effect (hereinafter the compound of formula I).

 The claimed compound of formula I is obtained by acylation of orthophenylenediamine with (±) camphor anhydride.

The compound of formula I is a white crystalline powder, with a melting point of 252-256 ^o C; gross formula C ₁₆ H ₂₀ N ₂ O ₂ .

 Found: C, 70.40; H 7.50; N, 10.20.

 Calculated: C 70.56; H, 7.40; N, 10.28.

PMR spectrum (СД 3) 2 СО, δ _gd : 0.75 (3 Н, С., 1-Ме); 1.27 and 1.35 (6 H, C., 2.2-Me); 3.51 (1 H, tr., J = 9.9 Hz, 3-CH); 2.56 and 1.59 (2 N, g, 5-CH ₂ ); 7.11 (2H, g, Ar).

Mass spectrum, m / e: 272 [M ⁺ ] (32); 254 (11); 228 (13); 227 (100); 186 (23); 185 (41); 183 (11); 171 (17); 158 (12); 157 (15); 145 (73); 132 (22).

IR spectrum, cm ^-1 : 1559 (δ _NH ); 1609 (ν _Ar ); 1700 (ν _{C = O} ); 3200 (ν _OH ); 3653 (ν _NH ).
UV spectrum, λ, nm (ε • 10 ^-3 ): 246 (7.7); 276 (9.5); 282 (8.6).

TLC: chloroform-ethanol-hexane (1: 1: 1); R _f = 0.53;
chloroform-acetone (2: 1); R _f = 0.24.

 The invention is illustrated by the following examples.

Example 1. Synthesis of a compound of formula I. 5.46 g (0.03 mol) of (±) camphor anhydride and 3.24 g (0.03 mol) of ortho-phenylenediamine are placed in a flask. The reaction mixture is heated in an oil bath to 150 ^o C and maintained at this temperature for 10 minutes The melt is poured into cold water. The thickened alloy is crushed, dried and crystallized from methanol. Obtain 3.2 g (45%) of the compound of formula I.

Example 2. The study of the acute toxicity of the compounds of formula 1. The acute toxicity of the compounds of formula I was studied on outbred white mice of both sexes weighing 17-18 g with a single oral administration in various doses. Observation of animals was carried out for 7 days. The dose that caused the death of 50% of the animals, that is, the LD _{50 of the} compound of formula I, is 12000 mg / kg body weight, which corresponds to the class of practically non-toxic substances [3, 4]. LD ₅₀ comparison drug glibenclamide in a similar experiment corresponds to 2000 mg / kg of animal body weight.

The study of the hypoglycemic action of the compounds of formula I
Sugar-lowering activity of the compounds of formula I was evaluated on heterogeneous models of absolute and relative insulin deficiency, reproducing non-insulin-dependent and non-insulin-dependent diabetes mellitus (IDDM and NIDDM, respectively).

 Example 3. The sugar-lowering effect of the compounds of formula I was evaluated on the NIDDM model (stage of relative insulin deficiency) in mutant C57BL / KsJY-db / db mice [5] at the most effective dose - 25 mg / kg of animal body weight.

 It was found that the sugar-lowering effect of a compound of formula I after a single administration over an 8-hour observation period in mice with genetically determined NIDDM is comparable to the similar effect of glibenclamide, also used in the most effective dose - 5 mg / kg of animal body weight (Table 1).

 Example 4. A study of the sugar-lowering activity of a compound of formula l was also performed on DBA / 2J mice with chemically induced absolute insulin deficiency in the model of IDDM (low-dose streptozotocin diabetes induced by intraperitoneal administration of streptozotocin at a dose of 50 mg / kg body weight / day for 5 days).

 It was established that a single oral administration of a compound of formula l caused a significant decrease in glycemia 2 hours after administration and which persisted for an 8-hour study (Table 2). Moreover, the integral decrease in glycemia in animals that received the compound of formula l did not significantly differ from the decrease in glycemia in animals that received glibenclamide.

The study of the antidiabetogenic effect of the compounds of formula l
A study of the antidiabetogenic effect of a compound of formula l was carried out in rats with neonatally induced streptozotocin NIDDM.

 Example 5. Newborn rat pups received intraperitoneal streptozotocin on their birthday, which caused 50% death during the first postnatal week. In animals that survived to the time of slaughter (14 days), basal hyperglycemia was detected. In the study group, pre-postnatal treatment of rat pups with a compound of formula l, by oral administration to mothers at a dose of 25 mg / kg body weight during the last week of pregnancy and one week after childbirth, there was no death of pups during the 14-day observation period. Basal glycemia was within the boundaries of physiological fluctuations (there were no cases of manifest diabetes) (Table 3). Comparison drug glibenclamide at a dose of 5 mg / kg body weight, exhibiting a sugar-lowering effect comparable to the compound of formula l in the above examples, did not prevent the diabetic effect of streptozotocin on the development of absolute deficiency.

 Example 6. Streptozotocin was intraperitoneally administered to newborn rats, and after 8 days at the stage of severe hyperglycemia, some of them orally received a compound of formula l at a dose of 25 mg / kg body weight for 30 days. The second group of animals received glibenclamide at a dose of 5 mg / kg body weight in parallel.

 It was found that long-term treatment of animals with a compound of formula l does not change the nature of the glycemic reaction during the intraperitoneal glucose tolerance test (VBTG), which was observed in animals of the control group studied simultaneously (Table 4). In animals treated with glibenclamide, a delay in the reversal of glucose intolerance was noted, which indicates pathological changes that occurred in the pancreas.

 Thus, as a result of studies, it was found that the compound of formula l has a sugar-lowering effect comparable to glibenclamide, and also exhibits an antidiabetogenic effect and that, unlike glibenclamide, it does not induce pathological changes in the pancreas, prevents the development of absolute and relative insulin deficiency and has lower toxicity .

LITERATURE
1. Mashkovsky M. D. // Medicines. - M., 1984. - T.1. - S. 560.

 2. Poltorak V.V., Gladkikh A.I., Bloch K.O. et al. Effect of glibenclamide on the spontaneous evolution of genetically determined diabetes mellitus in C57BJ / KsJY db / db mice / Pharmacology and toxicology. - 1991. - T.54, 1. - S.34-37.

 3. Gatsura VV Methods of the primary pharmacological study of biologically active substances. - M .: Medicine, 1974. - 114 p.

 4. Sidorov K.K. On the classification of toxic poisons with parenteral routes of administration. In: Toxicology of New Industrial Chemicals. - M., 1973. - 13. - S. 47-51.

 5. A.S. 1439658 USSR. A method for modeling diabetes mellitus / Poltorak V.V., Brindak O.I., Bloch K.O. et al. // Discoveries. - 1988.2. 43. - S. 244.

Claims (1)

(±) Cis-3- (2-benzimidazolyl) -1,2,2-trimethylcyclopentanecarboxylic acid of the formula

exhibiting a hypoglycemic and antidiabetogenic effect.

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