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Cyclic amine derivatives and their uses

A technology of compounds and oxides, which is used in the treatment of diseases mediated by M3 muscarinic receptors, such as respiratory diseases, can solve problems such as lung indications without antimuscarinic compounds

Inactive Publication Date: 2009-02-25
ARGENTA DISCOVERY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Few antimuscarinic compounds are currently available in the clinic for pulmonary indications despite substantial evidence supporting the use of antimuscarinic receptor therapy for the treatment of airway disease states

Method used

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  • Cyclic amine derivatives and their uses
  • Cyclic amine derivatives and their uses
  • Cyclic amine derivatives and their uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0273] Trans(±)-Biphenyl-2-yl-carbamic acid 2-dimethylamino-bicyclo[2.2.1]heptan-7-yl ester (II): R a , R b =CH 3 , R 4 = Biphenyl-2-ylcarbamoyl

[0274]

[0275] a.(±)-7-Benzyloxy-5-bromo-bicyclo[2.2.1]heptan-2-one (XI)

[0276] In N 2Next, to a suspension of NaH (60% dispersion in oil; 433 mg, 10.8 mmol) in anhydrous THF (7 mL), benzyl alcohol (1.07 mL, 10.4 mmol) was added dropwise. The mixture was stirred for 30 minutes, then cooled to -30°C, and (±)-2,3-dibromo-bicyclo[3.2.0]heptane-6-one (1.32g, 4.9mmol) in dry THF The solution in (6mL) was treated dropwise, and the reaction mixture was warmed to 0°C over 2 hours. The brown heterogeneous mixture was diluted with ethyl acetate, then washed with 10% aqueous citric acid, water and brine, dried over magnesium sulfate, and evaporated. The crude product was purified by silica gel chromatography, eluting with 15% ether / pentane, to give the title compound as a colorless syrup (609 mg). 1 H NMR(CDCl 3 , 400MHz): δ 1.79 (1H, ddd, ...

Embodiment 2

[0290] a. Trans (1S, 2S) hydroxy-di-thiophen-2-yl-acetic acid 2-[methyl-(3-phenyl-propyl)-amino]-bicyclo[2.2.1]hept-7- Base ester (II): R a =CH 3 ; R b =3-phenyl-1-propyl; R 4 = Hydroxy-dithiophen-2-ylcarbonyl

[0291]

[0292] b. Trans (1S, 2S) 2-[methyl-(3-phenyl-propyl)-amino]-bicyclo[2.2.1]heptane-7-ol (IV): R a =CH 3 ；R b = 3-phenyl-1-propyl

[0293] Using methods similar to those in Example 1, the title compound was obtained from (1S, 2R, 3R)-2,3-dibromo-bicyclo[3.2.0]heptane-6-one and methyl-(3-benzene Propyl)-amine preparation. 1 H NMR(CDCl 3 , 400MHz): δ 0.91-0.95 (1H, m), 1.32-1.38 (1H, m), 1.54-1.62 (2H, m), 1.68-1.89 (6H, m), 1.98 (1H, m), 2.08 ( 3H, m), 2.26-2.29 (3H, m), 2.59-2.63 (2H, m), 3.97 (1H, m), 7.15-7.19 (3H, m), 7.25-7.29 (2H, m).

[0294]

[0295] c. Trans (1S, 2S) hydroxy-di-thiophen-2-yl-acetic acid 2-[methyl-(3-phenyl-propyl)-amino]-di Cyclo[2.2.1]heptan-7-yl ester (II): R a =CH 3 ；R b =3-phenyl-1-propyl; R 4 = Hydroxy-dithiophene-2-...

Embodiment 3

[0298] Trans(1S,2S)[7-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-2-yl]-dimethyl- (3-Phenyl-propyl)-ammonium bromide (I): R a , R b =CH 3 ; R b =3-phenyl-1-propyl; R 4 = Hydroxy-dithiophen-2-ylcarbonyl

[0299]

[0300] In a sealed tube, add trans (1S, 2S) hydroxy-di-thiophen-2-yl-acetic acid 2-[methyl-(3-phenyl-propyl)-amino]-bicyclo[2.2.1] A solution of hept-7-yl ester (33 mg, 0.069 mmol) in 30% w / w methyl bromide in acetonitrile (1 mL) was heated at 50°C for 2 days. Remove the solvent and purify by chromatography, using 0-10% methanol-CH 2 Cl 2 As an eluent, the title compound was obtained as a foamy substance (33 mg). LC-MS (Method 2): Rt 7.45 minutes, m / z 496[M]+; 1 H NMR(CDCl 3 , 400MHz) δ 1.33-1.41 (1H, m), 1.45-1.56 (1H, m), 1.57-1.67 (2H, m), 1.69-1.79 (1H, m), 2.04-2.21 (3H, m), 2.43 (1H, m), 2.64-2.79 (3H, m), 3.23 (3H, s), 3.25 (3H, s), 3.43-3.55 (1H, m), 3.56-3.68 (1H, m), 4.31 (1H) , M), 4.89-4.92 (1H, m), 5.02-5.05 (1H, m), 6.93-6.99 (2H, m), 7.10-7...

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Abstract

Compounds of formula (I) have muscarinic M3 receptor modulating activity; formula (I) wherein R<1> is C1-C6-alkyl or a hydrogen atom; and R<2> is a hydrogen atom or a group -R<5>, or a group, -Z-Y-R<5>, or a group -Z-NR<9>R<10>, or a group -Z-N(R<9>)C(O)R<11>; and R<3> is a lone pair, or C1-C6-alkyl; R<4> is selected from one of the groups of formula (a), (b), (c) or (d); formulae (a), (b), (c), (d), Z is a C1-C16-alkylene, C2-C16-alkenylene or C2-C16-alkynylene group; Y is a bond or oxygen atom; R<5> is an C1-C6-alkyl, aryl, arylalkyl; aryl-fused-cycloalkyl, aryl-fused- heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, cycloalkyl or heterocycloalkyl group; R<6> is C1-C6-alkyl or a hydrogen atom; R<7a> and R<7b> are a C1-C6- alkyl group or halogen; n and m are independently 0, 1 , 2 or 3; R<8a> and R<8b> are independently selected from the group consisting of aryl, aryl-fused-heterocycloalkyl, heteroaryl, C1-C6-alkyl, cycloalkyl and hydrogen; R<8c> is -OH, C1-C6-alkyl, hydroxy-C1-C6-alkyl, or a hydrogen atom; R<8d> is C1-C6-alkyl or a hydrogen atom; R<9> and R<10> are independently a hydrogen atom, C1-C6-alkyl, aryl, aryl-fused-heterocycloalkyl, aryl- fused-cycloalkyl, heteroaryl, aryl(C1-C6-alkyl)-, or heteroaryl(C1-C6-alkyl)- group; or R<9> and R<10> together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom; R<11> is C1-C6-alkyl or a hydrogen atom; Ar<1> is aryl, heteroaryl or cycloalkyl; Ar<2> are independently aryl, heteroaryl or cycloalkyl; and Q is an oxygen atom, -CH2-, -CH2CH2- or a bond.

Description

Invention field [0001] The present invention relates to bicyclo[2.2.1]heptan-2-ylamine derivatives, pharmaceutical compositions, their preparation methods and their use in the treatment of diseases mediated by M3 muscarinic receptors, such as respiratory diseases. Background of the invention [0002] Anticholinergic drugs prevent the passage through various stimuli of the parasympathetic nerve or the various effects caused by the passage. This is also the result of these compounds being able to inhibit the activity of acetylcholine (Ach) by blocking the binding to muscarinic cholinergic receptors. [0003] There are five subtypes of muscarinic acetylcholine receptors (mAChRs) called M1-M5, which are the products of different genes, and each show its unique pharmacological properties. mAChRs are widely distributed in vertebrate organs, and these receptors can simultaneously regulate inhibition and stimulation. For example, in the smooth muscles found in the airways, bladder, and g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/38C07C217/52C07C219/24C07D311/86C07D333/24A61K31/27A61K31/381A61K31/14A61K31/216A61K31/352A61P11/00
Inventor 哈里·芬奇尼古拉斯·C·雷莫尼克·B·范尼尔菲利普·史密斯
Owner ARGENTA DISCOVERY LTD