Abstract

Imidazoline derivatives have been reported to show antihyperglycemic activity in vivo. In the present study, we first showed that there was no correlation between the in vivo antidiabetic activity and the in vitro affinities for the I₁/I₂ binding sites for several substituted aryl imidazolines. Among these compounds, 2-(α-cyclohexyl-benzyl)-4,5-dihydro-1H-imidazole 2 exhibited potent antihyperglycemic properties. It was then chosen as lead compound. Thirty-six new derivatives were synthesized by replacing the cyclohexyl/benzyl group by various cyclic systems or the imidazoline ring by isosteric heterocycles. These compounds were evaluated in vivo for their antihyperglycemic activity using an oral glucose tolerance test (OGTT) in a rat model of type-2 diabetes obtained by giving a single intravenous (iv) injection of a low dose of streptozotocin to rats (STZ rats) and in normal rats. Nine compounds with an imidazoline moiety, possibly substituted by a methyl group, had a potent effect on the glucose tolerance in normal or STZ-diabetic rats, after an oral (po) administration of the test compound at a dose of 30 or 10 mg kg⁻¹, without any hypoglycemia. Replacement of the imidazoline ring by isosteric heterocycles resulted in a total loss of activity.

Graphical abstract

Two series of imidazolines derived of 2-(α-cyclohexyl-benzyl)-4,5-dihydro-1H-imidazole were synthesized and evaluated for their in vivo antidiabetic activity in a rat model of type-2 diabetes.

Full-size image (12K)

Keywords: Imidazoline; Imidazoline receptors; Type 2 diabetes mellitus; Glucose tolerance

Article Outline

1. Introduction

2. Chemistry

3. Biological activity

4. Results and discussion

4.1. Activity of imidazolines 1–11

4.2. Effect of chemical modifications of the imidazoline group

5. Conclusion

6. Experimental section

6.1. Preparation of imidazoline derivatives 1, 2, 4 and 11 (Method A)

6.1.1. 2-Cycloheptyl-4,5-dihydro-1H-imidazole (1)

6.1.2. 2-(α-Cyclohexyl-benzyl)-4,5-dihydro-1H-imidazole (2)

6.1.3. 2-(1-Phenyl-cyclohex-1-yl)-4,5-dihydro-1H-imidazole (4)

6.1.4. 2-[2-Phenyl-2-(pyridin-2-yl)-cyclopropyl]-4,5-dihydro-1H-imidazole (11)

6.2. Preparation of imidazoline derivatives 3, 5, 6, 7, 8, 9 and 10 (Method B)

6.2.1. Synthesis of ester derivatives 3′, 5′–10′

6.2.1.1. Dicyclohexyl acetic acid, methyl ester (3′)

6.2.1.2. 1-(4-Chlorophenyl)-1-cyclohexanecarboxylic acid, methyl ester (5′)

6.2.1.3. 1-Phenyl-1-cyclopentanecarboxylic acid, methyl ester (6′)

6.2.1.4. 1-(4-Chlorophenyl)-1-cyclopentane carboxylic acid, methyl ester (7′)

6.2.1.5. 1-Phenyl-1-cyclopropane carboxylic acid, methyl ester (8′)

6.2.1.6. 1-Methyl-1-cyclohexane carboxylic acid, methyl ester (9′)

6.2.1.7. 4-Methyl-1-cyclohexane carboxylic acid, methyl ester (10′)

6.2.2. Synthesis of imidazoline derivatives 3, 5–10

6.2.2.1. 2-(α-Dicyclohexylmethyl)-4,5-dihydro-1H-imidazole (3)

6.2.2.2. 2-[1-(4-Chlorophenyl)-cyclohex-1-yl]-4,5-dihydro-1H-imidazole (5)

6.2.2.3. 2-(1-Phenyl-cyclopent-1-yl)-4,5-dihydro-1H-imidazole (6)

6.2.2.4. 2-[1-(4-Chlorophenyl)-cyclopent-1-yl]-4,5-dihydro-1H-imidazole (7)

6.2.2.5. 2-(1-Phenyl-cycloprop-1-yl)-4,5-dihydro-1H-imidazole (8)

6.2.2.6. 2-(1-Methyl-cyclohex-1-yl)-4,5-dihydro-1H-imidazole (9)

6.2.2.7. 2-(Trans-4-methyl-cyclohexyl)-4,5-dihydro-1H-imidazole (10)

6.3. Preparation of compound 2a

6.3.1. α-Cyclohexyl phenyl thioacetamide

6.3.2. 2-(α-Cyclohexyl-benzyl)-4-methyl-4,5-dihydro-1H-imidazole (2a)

6.4. Preparation of derivatives 4a and 9a

6.4.1. 2-(1-Phenyl-cyclohex-1-yl)-4-methyl-4,5-dihydro-1H-imidazole (4a)

6.4.2. 2-[(1-Methyl-cyclohex-1-yl)-4-methyl-4,5-dihydro-1H-imidazole (9a)

6.5. Preparation of 1H-benzimidazole derivatives 2b, 4b and 9b

6.5.1. Preparation of amide derivatives 2b′, 2b″, 4b′, 4b″, 9b′, 9b″

6.5.1.1. N-(2′-aminophenyl)-2-cyclohexyl-2-phenyl-acetamide (2b′)

6.5.1.2. 1,2-N,N′-phenyl-bis-(2-cyclohexyl-2-phenyl-acetamide) (2b″)

6.5.1.3. N-(2′-aminophenyl)-1-phenyl-cyclohex-1-yl-carboxamide (4b′)

6.5.1.4. 1,2-N,N′-phenyl-bis-(1-phenyl-cyclohex-1-yl-carboxamide) (4b″)

6.5.1.5. N-(2′-aminophenyl)-1-methyl-cyclohexane-1-carboxamide (9b′)

6.5.1.6. 1,2-N,N′-Phenyl-bis-(1-methyl-cyclohexane-1-carboxamide) (9b″)

6.5.2. Preparation of 1H-benzimidazole derivatives 2b, 4b and 9b

6.5.2.1. 2-(α-Cyclohexyl-benzyl)-1H-benzimidazole (2b)

6.5.2.2. 2-(1-Phenyl-cyclohex-1-yl)-1H-benzimidazole (4b)

6.5.2.3. 2-(1-Methyl-cyclohex-1-yl)-1H-benzimidazole (9b)

6.6. Preparation of Δ-2-oxazoline derivatives 2c, 4c and 11c

6.6.1. 2-(α-Cyclohexyl-benzyl)-Δ-2-oxazoline (2c)

6.6.2. 2-(1-Phenyl-cyclohex-1-yl)-Δ-2-oxazoline (4c)

6.6.3. 2-[2-Phenyl-2-(pyridin-2-yl)-cyclopropyl]-Δ-2-oxazoline (11c)

6.7. Preparation of Δ-2-thiazolines derivatives 2d, 4d and 11d

6.7.1. 2-(α-Cyclohexyl-benzyl)-Δ-2-thiazoline (2d)

6.7.2. 2-(1-Phenyl-cyclohex-1-yl)-Δ-2-thiazoline (4d)

6.7.3. 2-[2-Phenyl-2-(pyridin-2-yl)-cyclopropyl]-Δ-2-thiazoline (11d)

6.8. Preparation of 1,4,5,6-tetrahydropyrimidine derivatives 2e, 4e and 9e

6.8.1. 2-(α-Cyclohexyl-benzyl)-1,4,5,6-tetrahydropyrimidine (2e)

6.8.2. 2-(1-Phenyl-cyclohex-1-yl)-1,4,5,6-tetrahydropyrimidine (4e)

6.8.3. 2-(1-Methyl-cyclohex-1-yl)-1,4,5,6-tetrahydropyrimidine (9e)

6.9. Preparation of 1H-tetrazole derivatives 2f, 4f and 11f

6.9.1. 5-(α-Cyclohexyl-benzyl)-1H-tetrazole (2f)

6.9.2. 2-(1-Phenyl-cyclohex-1-yl)-1H-tetrazole (4f)

6.9.3. 5-[2-Phenyl-2-(pyridin-2-yl)-cyclopropyl]-1H-tetrazole (11f)

6.10. Preparation of 1N and 2N-methyl-tetrazoles 2g–h, 4g–h and 11g–h

6.10.1. 5-(α-Cyclohexyl-benzyl)-1N-methyl-tetrazole (2g)

6.10.2. 5-(α-Cyclohexyl-benzyl)-2N-methyl-tetrazole (2h)

6.10.3. 5-(1-Phenyl-cyclohex-1-yl)-1N-methyl-tetrazole (4g)

6.10.4. 5-(1-Phenyl-cyclohex-1-yl)-2N-methyl-tetrazole (4h)

6.10.5. 5-[2-Phenyl-2-(pyridin-2-yl)-cyclopropyl]-1N-methyl-tetrazole (11g)

6.10.6. 5-[2-Phenyl-2-(pyridin-2-yl)-cyclopropyl]-2N-methyl-tetrazole (11h)

6.11. Preparation of carboxamidine derivative 2i

6.11.1. 1-Cyclohexyl-1-phenyl acetamidine, hydrochloride (2i)

6.12. X-ray analysis of compound 11h

6.13. Pharmacology, animals and treatments

6.13.1. Glucose tolerance tests

6.13.2. Analytical methods

6.13.3. Calculations and statistical methods

Acknowledgements

References