Tetrasubstituted imidazole derivatives as cannabinoid cb1 receptor modulators with a high CB1/CB2 receptor subtype selectivity

A technology for stereoisomers and drugs, applied in the field of imidazole derivatives, can solve problems such as no disclosure

Inactive Publication Date: 2011-03-23
SOLVAY PHARMA GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no CB disclosed in the above patent applications and papers regarding the compounds disclosed therein 1 / CB 2 Receptor subtype selectivity data

Method used

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  • Tetrasubstituted imidazole derivatives as cannabinoid cb1 receptor modulators with a high CB1/CB2 receptor subtype selectivity
  • Tetrasubstituted imidazole derivatives as cannabinoid cb1 receptor modulators with a high CB1/CB2 receptor subtype selectivity
  • Tetrasubstituted imidazole derivatives as cannabinoid cb1 receptor modulators with a high CB1/CB2 receptor subtype selectivity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1: Materials and methods

[0052] On Bruker Avance DRX600 instrument (600MHz), Varian UN400 instrument (400MHz) or Varian VXR200 instrument (200MHz), use DMSO-d 6 or CDCl 3 As solvent and tetramethylsilane as internal standard, record 1 H and 13 C NMR spectrum. Chemical shifts are given in ppm (delta scale) downfield from tetramethylsilane. Coupling constants (J) are expressed in Hz. Flash chromatography was performed using silica gel 60 (0.040-0.063 mm, Merck). Column chromatography was performed using silica gel 60 (0.063-0.200 mm, Merck). Melting points were recorded using a Büchi B-545 melting point apparatus. Mass spectra were recorded on a Micromass QTOF-2 instrument with MassLynx application software for data acquisition and reconstruction. Perform quasi-molecular ions [M+H] + exact mass determination.

Embodiment 2

[0053] Embodiment 2: the synthesis of concrete compound

[0054] Compound 1-3

[0055] 1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid

[0056] To magnetically stirred ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (18.44 g, 0.0466 mol) in THF (240 ml) LiOH (2.24g, 0.0932mol) and H were added to the solution 2 O (240ml). The resulting mixture was stirred at 50 °C for 16 hours to give a clear solution. After cooling to room temperature, HCl (1N solution, 95ml) and H 2 O (240ml) gave a precipitate which was collected by filtration, washed with water and dried in vacuo to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole- 4-Formic acid (16.83 g, 98% yield), mp 138-142°C (decomposition); 1 H-NMR (600MHz, DMSO-d 6 )δ7.08(br d, J=8Hz, 2H), 7.31-7.37(m, 4H), 7.45(d, J=8Hz, 1H), 7.96(s, 1H); 13 C-NMR (150MHz, DMSO-d 6 )δ 126.87, 127.85, 127.91, 128.47, 129.36, 129.66, 133.56, 133.99, 134.44, 134.49, 135.54, 135.99...

Embodiment 4

[0093] Example 4: Formulations for Animal Studies

[0094] Oral (p.o.) administration: To the desired amount (0.5-5 mg) of solid Compound 1 in a glass tube was added a certain amount of glass beads and the solid was triturated by vortexing for 2 minutes. After adding 1 ml of a solution of 1% methylcellulose in water and 2% (v / v) poloxamer 188 (Lutrol F68), the compound was suspended by vortexing for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1 N). The remaining particles in suspension were further suspended by using an ultrasonic bath.

[0095] Intraperitoneal (i.p.) administration: To the desired amount (0.5-15 mg) of solid Compound 1 in a glass tube was added a certain amount of glass beads and the solid was triturated by vortexing for 2 minutes. After adding 1 ml of a solution of 1% methylcellulose and 5% mannitol in water, the compound was suspended by vortexing for 10 minutes. Finally the pH was adjusted to 7.

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Abstract

The present invention relates to 1,2,4,5-tetrasubstituted imidazole derivatives as selective cannabinoid CB1 receptor modulators, in particular CB1 receptor antagonists or inverse agonists having a high CB1 / CB2 receptor subtype selectivity, to methods for the preparation of these compounds and to novel intermediates useful for the synthesis of said imidazole derivatives. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament giving a beneficial effect. A beneficial effect is disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition. More particularly, the invention relates to a new use for the treatment of a disease or condition disclosed herein or apparent to a person skilled in the art from the specification and general knowledge in the art. In embodiments of the invention specific compounds disclosed herein are used for the manufacture of a medicament useful in the treatment of psychiatric and neurological disorders. The compounds have the general formula (I) wherein the symbols have the meanings given in the specification.

Description

field of invention [0001] The present invention relates to as selective cannabinoid (cannabinoid) CB 1 Receptor modulators, especially those with high CB 1 / CB 2 Receptor subtype-selective CB 1 1,2,4,5-tetrasubstituted imidazole derivatives of receptor antagonists or inverse agonists, the present invention relates to processes for the preparation of these compounds and to new intermediates for the synthesis of said imidazole derivatives . The invention also relates to the use of the compounds disclosed herein for the preparation of medicaments having beneficial effects. Beneficial effects are disclosed herein or may be apparent to those skilled in the art from this specification and general knowledge in the art. The present invention also relates to the use of the compounds of the present invention in the manufacture of medicaments for the treatment or prevention of diseases or disorders. More particularly, the present invention relates to novel uses for the treatment of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61P25/00A61K31/454A61K31/4164C07D233/90
Inventor J·H·M·朗格H·C·瓦尔斯C·G·克鲁瑟
Owner SOLVAY PHARMA GMBH
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