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Cathepsin K inhibitor and application thereof

A compound and alkyl technology, applied in the field of medicine, can solve the problems of unsatisfactory selective inhibition of various cathepsins, disturbing side effects, etc.

Active Publication Date: 2017-07-07
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, Odanacatib of Merck & Co. is progressing rapidly. However, because it also has a good inhibitory effect on cathepsin S, its selective inhibitory effect on various cathepsins is not ideal, so there have also been some surprising results in clinical research. disturbing side effects signs

Method used

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  • Cathepsin K inhibitor and application thereof
  • Cathepsin K inhibitor and application thereof
  • Cathepsin K inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0188] N-(1-((1-cyanocyclopropyl)carbamoyl)cyclohexyl)-4'-(2-oxopyrrolidin-1-yl)-[1,1'-biphenyl]- 4-formamide

[0189]

[0190] Step 1: 1-(4-Bromophenyl)pyrrolidin-2-one

[0191] Add 1-bromo-4-iodobenzene (1.10g, 3.77mmol), 2-pyrrolidone (488mg, 5.74mmol), potassium carbonate (1.05g, 7.52mmol), cuprous iodide (0.072g, 0.38 mmol), N,N'-dimethylethylenediamine (0.068g, 0.76mmol) and anhydrous toluene (20mL), the mixed system was heated to reflux for 6 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL), stirred, extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / dichloromethane (V / V)=1 / 7) to obtain the title compound (0.73 g, 80%) as a pale yellow oil.

[0192] MS(ESI,pos.ion)m / z:242.0(M+2).

[0193] Step 2: N-(1-((1-cyanocyclopropyl)car...

Embodiment 2

[0198] N-(1-((1-cyanocyclopropyl)carbamoyl)cycloheptyl)-4'-(2-oxopyrrolidin-1-yl)-[1,1'-biphenyl] -4-formamide

[0199]

[0200] Referring to the synthetic method of step 2 of Example 1, 1-(4-bromophenyl)pyrrolidin-2-one (240mg, 1.00mmol) and N-(1-cyanocyclopropyl)-1-(4- Starting from (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamidoamino)cycloheptylcarboxamide (437mg, 1.00mmol), prepared The title compound as a white solid (39 mg, 49.2%).

[0201] MS(ESI,pos.ion)m / z:485.2(M+1);

[0202] 1 H NMR (600MHz, CDCl 3 )δ (ppm): 8.08 (s, 1H), 7.81 (d, J = 8.4Hz, 2H), 7.73 (d, J = 8.7Hz, 2H), 7.67 (d, J = 8.4Hz, 2H), 7.62 (d, J=8.7Hz, 2H), 6.19(s, 1H), 3.92(t, J=7.0Hz, 2H), 2.65(t, J=8.1Hz, 2H), 2.39-2.25(m, 2H) ,2.24-2.18(m,2H),2.14(dd,J=14.8,7.4Hz,2H),1.71(dd,J=14.2,7.1Hz,2H),1.65-1.60(m,4H),1.52(dd ,J=8.2,5.7Hz,2H),1.31-1.18(m,4H).

Embodiment 3

[0204] N-(1-((1-cyanocyclopropyl)carbamoyl)cycloheptyl)-4'-(2-oxoazetidin-1-yl)-[1,1'-biphenyl base]-4-carboxamide

[0205]

[0206] Step 1: 1-(4-Bromophenyl)azetidin-2-one

[0207] Referring to the synthesis method in Step 1 of Example 1, using azetidin-2-one (267mg, 3.77mmol) and 1-bromo-4-iodobenzene (1.10g, 3.77mmol) as raw materials, the yellow oily title compound was prepared (700 mg, 82%).

[0208] Step 2: N-(1-((1-cyanocyclopropyl)carbamoyl)cycloheptyl)-4'-(2-oxoazetidin-1-yl)-[1,1' -Biphenyl]-4-carboxamide

[0209] Referring to the synthetic method of step 2 of Example 1, 1-(4-bromophenyl)azetidin-2-one (38mg, 0.166mmol) and N-(1-cyanocyclopropyl)-1-( 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzamidoamino)cycloheptylcarboxamide (75mg, 0.166mmol) as starting material, The title compound was prepared as a white solid (43 mg, 55%).

[0210] MS(ESI,pos.ion)m / z:471.2(M+1);

[0211] 1 H NMR (600MHz, CDCl 3 )δ (ppm): 8.05 (s, 1H), 7.80 (d, J = 8.0Hz, 2H), ...

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PUM

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Abstract

The invention relates to a cathepsin K inhibitor and an application thereof, and specifically, relates to a compound and a drug composition thereof used for treating or preventing cathepsin dependence diseases, and the compound and the composition containing the compound can be used as a bone resorption inhibitor to treat relevant diseases. The cathepsin includes but is not limited to cathepsin K.

Description

[0001] field of invention [0002] The invention belongs to the field of medicine. The present invention relates to a class of compounds and pharmaceutical compositions thereof for treating or preventing cathepsin-dependent disorders. These compounds and compositions containing these compounds can be used as bone resorption inhibitors to treat related diseases. Background technique [0003] Osteoporosis is a common and frequently-occurring disease among the elderly, especially menopausal and postmenopausal women. With the changes in the spectrum of contemporary diseases, WHO has listed osteoporosis as one of the three major diseases of middle-aged and elderly people, ranking seventh among common diseases. About 50% of women and 20% of men over the age of 50 suffer a fracture caused by osteoporosis. At present, the common drugs for osteoporosis include anti-resorptive drugs, drugs that promote bone formation, dual-action drugs of the former two, biological drugs or other dru...

Claims

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Application Information

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IPC IPC(8): C07D205/08C07D233/34C07D207/27C07D211/76C07D249/08C07C317/44A61K31/397A61K31/402A61K31/445A61K31/4196A61K31/277A61P19/10A61P19/08A61P1/02A61P19/02A61P29/00A61P35/00A61P3/14
CPCC07C317/44C07D205/08C07D207/27C07D211/76C07D233/34C07D249/08
Inventor 周平健王晓军阳传文林继华曹生田杨新业张英俊
Owner SUNSHINE LAKE PHARM CO LTD
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