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Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia

A technology of medicinal salts and enantiomers, which is applied in the field of muscarinic receptor agonists, and can solve the problems that muscarinic agonists and ACHE-Is are not widely used in clinical practice

Inactive Publication Date: 2009-08-05
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Muscarinic agonists and ACHE-Is are not widely used clinically due to their propensity to induce a plethora of adverse events when administered to humans

Method used

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  • Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia
  • Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia
  • Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0264] Example 1: 4-[(cis (+ / -))-2-oxooctahydro-1H-benzimidazol-1-yl]-1,4'-bipiperidine-1'-ethyl carboxylate

[0265]

[0266] To a solution of racemic (cis)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one TFA salt (130 mg, 0.40 mmol) in dichloromethane (4 mL) was added Acetic acid (120 μL), followed by ethyl 4-oxopiperidine-1-carboxylate (120 μL) and NaBH(OAc) 3 (250 mg), and the mixture was stirred overnight at 45°C. Then the mixture was washed with saturated NaHCO 3 The solution was quenched, then diluted in dichloromethane. 1N NaOH was added and the aqueous phase was extracted several times with dichloromethane. The combined organic phases were dried and concentrated in vacuo. The compound was purified by high pH preparative LCMS to afford the title compound (25 mg). 1 H NMR (400MHz, chloroform-D): δ ppm 1.09-1.19(m, 1H), 1.23(t, J=7.16Hz, 3H), 1.29-1.46(m, 3H), 1.45-1.91(m, 12H) , 2.13-2.32(m, 2H), 2.33-2.46(m, 1H), 2.62-2.77(m, 2H), 2.88(d, J=12.69Hz, 1H), 2.93(...

Embodiment 8

[0293] Example 8: (trans (+ / -))-1-{1-[1-(cyclopentylcarbonyl)pyrrolidin-3-yl]piperidin-4-yl}octahydro-2H-benzimidazole -2-one

[0294]

[0295] Step 1: Preparation of 3-{4-[(trans(+ / -))-2-oxooctahydro-1H-benzimidazol-1-yl]piperidin-1-yl}pyrrolidine-1-carboxylic acid tert-butyl ester

[0296]

[0297] Following a procedure similar to that described in Example 1, 3-{4-[(trans(+ / -))-2-oxooctahydro-1H-benzimidazol-1-yl]piperidine-1 was prepared -Yl}pyrrolidine-1-carboxylic acid tert-butyl ester (2.40 g), as a mixture of diastereomers.

[0298] Step 2: Preparation of 3-{4-[(trans(+ / -))-2-oxooctahydro-1H-benzimidazol-1-yl]piperidin-1-yl}pyrrolidine

[0299]

[0300] The crude intermediate from step 1 (2.4 g) was dissolved in dichloromethane (10 mL) and TFA (5 mL) was added. The reaction mixture was stirred overnight at room temperature. Removal of solvent and excess TFA gave the title compound as its TFA salt (4.2 g). Conversion of the TFA salt to its free base by MP ...

preparation Embodiment 9-13

[0305]

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Abstract

Compounds of Formulae I, or pharmaceutically acceptable salts thereof: wherein A, A, G, G, G, R, R, X, Y, Z, m,n and p are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

Description

technical field [0001] The present invention relates to agonists of muscarinic receptors. The invention also provides compositions containing said agonists and methods of using said agonists for treating diseases mediated by muscarinic receptors. In particular, the invention relates to compounds which are effective in the treatment of pain, Alzheimer's disease and / or schizophrenia. Background technique [0002] The neurotransmitter acetylcholine binds two types of cholinergic receptors: the ionotropic family of nicotinic receptors and the metabotropic family of muscarinic receptors. Muscarinic receptors belong to the large superfamily of plasma membrane-bound G protein-coupled receptors (GPCRs) and show a remarkably high degree of homology between species and between receptor subtypes. These M1-M5 muscarinic receptors are predominantly expressed in the parasympathetic nervous system, which exerts stimulatory and inhibitory control of central and peripheral tissues and is i...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/454C07D409/14C07D405/14A61K31/4545A61P25/04A61P25/18A61P25/28
CPCC07D405/14C07D409/14C07D401/14A61P25/00A61P25/04A61P25/18A61P25/22A61P25/28A61P43/00A61K31/454
Inventor 程云兴梅尔纳兹·波拉什拉夫米罗斯劳·托马斯泽夫斯基
Owner ASTRAZENECA AB