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4,5-dihydro-(1h)-pyrazole derivatives as cannabinoid CB1 receptor modulators

A technology of derivatives and compounds, applied in the fields of medicine and organic chemistry

Inactive Publication Date: 2011-01-05
SOLVAY PHARMA GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

act as a pair of CB 1 Pyrazoline derivatives of receptor agonists or partial agonists have not been reported, but certain pyrazoline derivatives have been claimed as pest control agents (JP 61189270) and as mitotic kinesin inhibitors (WO2006 / 068933, WO2003079973)

Method used

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  • 4,5-dihydro-(1h)-pyrazole derivatives as cannabinoid CB1 receptor modulators
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  • 4,5-dihydro-(1h)-pyrazole derivatives as cannabinoid CB1 receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Example 1: Materials and methods

[0117] On Varian 300MHz instrument, Varian UN400 instrument (400MHz), use DMSO-d 6 or CDCl 3 As a solvent, using tetramethylsilane as an internal standard, record 1 H NMR spectrum. Using CDCl on a Varian UN400 instrument 3 As a solvent, record 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). Using Supelco equipment, VersaFLASH TM Column, VersaPak TM Silica cartridges, Büchi UV Monitor C-630, Büchi Pump Module C-605, Büchi Fraction Collector C-660 and Büchi Pump Manipulator C-615 were used for Sepacore chromatographic separation. Melting points were recorded on a Büchi B-545 melting point apparatus or determined by DSC method. The optical rotation ([α] D ). Optical rotati...

Embodiment 2

[0118] Example 2: General aspects of synthesis

[0119] Pyrazoline derivatives can be prepared by published methods (Barluenga, 1999 (and references cited therein); Wang, 2003). In Scheme 1 the synthesis of compounds of general formula (I) is outlined. Ketone derivatives of general formula (II) can be prepared by various methods known to those skilled in the art. An example is the Weinreb amide RC(=O)N(OCH 3 )CH 3 application, which can be used with the Grignard reagent R 2 CH 2 MgCl or R 2 CH 2 MgBr reacts, or RMgBr or RMgCl with the general formula R 2 CH 2 C(=O)N(OCH 3 )CH 3 The Weinreb amide reaction. Alternatively, Grignard reagent R 2 CH 2 MgCl or R 2 CH 2 MgBr can be reacted with HCN followed by acidic hydrolysis, for example by using hydrochloric acid. where R and R 2 The ketone derivative of the general formula (II) having the above-mentioned meaning can be in the presence of a base, such as sodium methylate, with the general formula R 5 R 6 The hal...

Embodiment 3

[0134] Example 3: Synthesis and Spectral Data of Intermediates

[0135] Intermediate II-1

[0136]

[0137] Part A: To a magnetically stirred solution of valeric acid (10.9ml, 0.1mol) in dichloromethane (200ml) was added sequentially: N-methyl-N-methoxy-amine.hydrochloride (10.14g, 0.104mol), N-methylmorpholine (22.9ml, 0.208mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDCl) (19.92 grams, 0.104mol ) and HOBt (14.04 g, 0.104 mol) and the resulting mixture was reacted at room temperature for 20 hours. Water, citric acid aqueous solution (24 grams of citric acid in 250ml H 2 solution in O) and 5% NaHCO 3 The obtained suspension was washed with aqueous solution. in Na 2 SO 4 The organic layer was dried on top, filtered and concentrated to afford methoxy-methyl-valeric acid (12.31 g, 85% yield) as a colorless oil. 1 H-NMR (400MHz, CDCl 3 )δ0.93(t, J=7, 3H), 1.31-1.43(m, 2H), 1.57-1.66(m, 2H), 2.42(br t, J=7, 2H), 3.18(s, 3H) , 3.69(s, 3H).

[0138] Part B: ...

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Abstract

This invention relates to 4,5-dihydro-(1 H)-pyrazole (pyrazoline) derivatives as cannabinoid CB1 receptor modulators, to pharmaceutical compositions containing these compounds, to methods for their syntheses, methods for preparing novel intermediates useful for their syntheses, and methods for preparing compositions. The invention also relates to the uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in disorders in which CB1 receptors are involved, or that can be treated via manipulation of those receptors. The compounds have formula (I) wherein the symbols have the meanings given in the specification.

Description

technical field [0001] The present invention relates to the fields of medicine and organic chemistry and provides the cannabinoid CB 1 4,5-Dihydro-(1H)-pyrazole (pyrazoline) derivatives of receptor modulators, as well as their intermediates and formulations, and methods of using these compounds. Background technique [0002] Cannabinoid (CB) receptors are part of the endocannabinoid system, which has been implicated in neurology, psychiatry, cardiovascular, gastrointestinal, reproductive and eating disorders, and cancer (De Petrocellis, 2004; Di Marzo, 2004; Lambert, 2005; Vandevoorde, 2005). [0003] CB 2 Receptors are present mainly in the immune system (spleen, tonsil, immune cells), but also in astrocytes, microglia and to some extent in the central nervous system. CB 2 Receptor modulation has been implicated in the perception of inflammatory and neuropathic pain, as well as in allergies, asthma, multiple sclerosis, osteoporosis and (neuro)inflammatory conditions (Va...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/06C07D401/12C07D409/04A61K31/415A61P25/28
CPCC07D401/12C07D409/04C07D231/06
Inventor M·伊尔迪利姆H·C·瓦尔斯B·J·梵维利特J·H·M·兰格
Owner SOLVAY PHARMA GMBH
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