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Azole and thiazole derivatives and their use

一种化合物、药用盐的技术，应用在噁唑和噻唑衍生物领域，能够解决很少抗毒蕈碱化合物等问题

Inactive Publication Date: 2008-10-08
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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  • Azole and thiazole derivatives and their use
  • Azole and thiazole derivatives and their use
  • Azole and thiazole derivatives and their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0619]

[0620] (5-Dimethylaminomethyl-oxazol-2-yl)-diphenyl-methanol (I-a): R a , R b = Ph, R c , R d =CH 3

[0621] Phenylmagnesium bromide (0.75ml in 1M THF, 0.75mmol) was added dropwise to (5-dimethylaminomethyl-oxazol-2-yl)-phenyl-methanone (Intermediate 4) ( 0.15 g, 0.65 mmol) in cold (0° C.) solution in anhydrous THF (1.5 ml). The mixture was stirred and cooled for 1.5 hours, then additional phenylmagnesium bromide (0.4ml of a 1M solution in THF, 0.4mmol) was added dropwise. The mixture was stirred at 0°C for 0.5 h, then treated with excess saturated aqueous ammonium chloride solution. The mixture was extracted with DCM (x2), the combined organic phases were washed with brine and dried (Na 2 SO 4 ) and removal of the solvent gave the crude product. Purified by HPLC using 5-70% acetonitrile / water with 0.1% TFA over 18.5 minutes.

[0622] Yield: 0.19g (69%, as its TFA salt)

[0623] LC-MS (Method 1): Rt 5.56 min, m / z 309 [MH + ].

[0624] LC-MS (Method 3):...

Embodiment 2

[0630]

[0631] [2-(Hydroxy-diphenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium formate (I-b): R a = R b = Ph, R c , R d =CH 3 , R e = 3-phenoxypropyl

[0632] A solution of (5-dimethylaminomethyl-oxazol-2-yl)-diphenyl-methanol (Example 1) (24 mg, 0.078 mmol) in acetonitrile (0.3 mL) and chloroform (0.5 mL) Treated with 3-phenoxybromopropane (37 μL, 0.23 mmol), the reaction mixture was stirred at room temperature overnight and then at 50° C. for 42 hours. The volatiles were removed by evaporation and the crude product was purified by preparative HPLC using 25-75% acetonitrile / water containing 0.1% formic acid over 30 minutes to give the product as a colorless gum.

[0633] Yield 24mg, 63%

[0634] LC-MS (Method 1): Rt 7.56 min m / z 443 [M + ]

[0635] 1 H NMR (MeOD): δ2.29(m, 2H), 3.11(s, 6H), 3.45(m, 2H), 3.98(t, 2H), 4.79(s, 2H), 6.85-6.90(m, 2H ), 6.93-6.98 (m, 1H), 7.24-7.38 (m, 12H), 7.56 (s, 1H), 8.51 (br s, 1H).

[0636] The following ...

Embodiment 4

[0642]

[0643] Cyclohexyl-(5-dimethylaminomethyl-oxazol-2-yl)-phenyl-methanol (I-a): R a ,=Ph,R b = cyclohexyl, R c , R d =CH 3

[0644] A solution of (5-bromomethyl-oxazol-2-yl)-cyclohexyl-phenyl-methanol (Intermediate 9) (3.2 g, 9.2 mmol) in 40 mL THF was treated with 2M dimethylamine in THF (40 mL, 80 mmol ) solution treatment. A suspension formed after stirring for several minutes. The reaction mixture was allowed to stand overnight at room temperature, then the solid was filtered and discarded. After the filtrate was concentrated under reduced pressure, the residue was partitioned between DCM and saturated sodium bicarbonate solution. The organic layer was dried (Na 2 SO 4 ) to afford the title compound as a solid.

[0645] Yield: 2.74g (95%)

[0646] LC-MS (Method 1): Rt 6.57 min, m / z 315 [MH + ].

[0647] 1 H NMR (DMSO-d 6 ): δ0.92-1.29(m, 6H), 1.42-1.74(m, 4H), 2.10(s, 6H), 2.22(m, 1H), 3.45(s, 2H), 5.90(s, 1H), 6.98 (s, 1H), 7.18-7.22 (m, 1H), 7.27...

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Abstract

Compounds of formula (I) are useful in the treatment of diseases where enhanced M3 receptor activation is implicated, such as respiratory tract diseases: wherein (i) R<1> is C1-C6-alkyl or hydrogen; and R<2> is hydrogen or a group -R<7>, -Z-Y-R<7>, -Z-NR<9>R<10>; -Z-CO-NR<9>R<10>, -Z-NR<9>-[AE11]C(O)O-R<7>, or -Z-C(O)-R<7>; and R<3> is a lone pair, or C1C6-alkyl; or (ii) R<1> and R<3> together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R<2> is a lone pair or a group -R<7>, -Z-Y-R<7>, -Z-NR<9>R<10>, -Z-CO-NR<9>R<10>, -Z-NR<9>-[AE12]C(O)O-R<7>; or; -Z-C(O)-R<7>; or (iii) R<1> and R<2> together with the nitrogen to which they are attached form a heterocycloalkyl ring, the ring being substituted by a group -Y-R<7>, -Z-Y-R<7>, -Z-NR<9>R<10>; -Z-CO-NR<9>R<10>; -Z-NR<9>-[AE13]C(O)O-R<7>; or; -Z-C(O)-R<7>; and R<3> is a lone pair, or C1-C6-aIkyl; R<4> and R<5> are independently selected from the group consisting of aryl, arylfused-heterocycloalkyl, heteroaryl, C1-C6-alkyl, cycloalkyl; R<6> is -OH, C1-C6-alkyl, C1-C6-alkoxy, hydroxy-C1-C6-alkyl, nitrile, a group CONR<8>2 or hydrogen; A is oxygen or sulfur; X is alkylidene, alkenylene or alkynylene; R<7> is C1-C6-alkyl, aryl, arylfused-cycloalkyl, arylfused-heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl (C1-C8-alkyl)-, cycloalkyl or heterocycloalkyl; R8 is C1-C6-alkyl or hydrogen; Z is C1-C16- alkylidene, C2-C16- alkenylene or C2-C16- alkynylene; Y is chemical bond or hydrogen; R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6-alkyl, aryl, arylfused-heterocycloalkyl, arylfused-cycloalkyl, heteroaryl, aryl(C1-C6-alkyl)-or heteroaryl (C1-C6-alkyl)-group; or R9 and R10 together with the nitrogen to which they are attached form a heterocyclic ring having 4-8 ring atoms and any of nitrogen or oxygen.

Description

field of invention [0001] The present invention relates to oxazole and thiazole derivatives, pharmaceutical compositions, processes for their preparation and use in the treatment of diseases in which enhanced activity of the M3 receptor is involved. Background of the invention [0002] Anticholinergic drugs block the pathways through which various stimuli pass through the parasympathetic nerves or the effects caused by this pathway. This is also a result of the ability of this class of compounds 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), termed M1-M5, which are each the product of different genes, each displaying its own unique pharmacological properties. mAChRs are widely distributed in vertebrate organs, and these receptors can regulate both inhibitory and stimulatory effects. For example, in smooth muscle found in the airways,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/32C07D277/30A61K31/421A61K31/426C07D277/28C07D413/06C07D413/12
CPCC07D413/12C07D277/28C07D263/32C07D413/06A61P1/04A61P1/08A61P11/00A61P11/02A61P11/06A61P11/08A61P11/16A61P13/00A61P13/02A61P13/10A61P25/04A61P25/08A61P37/08A61P43/00A61P9/00A61K31/426A61K31/421C07D277/30
Inventor 尼古拉斯·C·雷理查德·J·布尔哈里·芬奇马科·范登霍伊维尔乔斯·A·布拉沃
Owner ARGENTA DISCOVERY LTD
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