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Cathepsin cysteine protease inhibitors

A compound, alkyl technology, applied in the field of cathepsin cysteine ​​protease inhibitors, can solve problems such as inactivity

Inactive Publication Date: 2007-02-28
MERCK FROSST CANADA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

All mutations identified to date in the cathepsin K gene are known to result in an inactive protein

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0218] N 1 -(2-oxotetrahydrofuran-3-yl)-N 2 -{(1S)-2,2,2-Trifluoro-1-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide

[0219]

[0220] Under stirring at room temperature within 30 minutes, to N-{(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L - Leucine (30 mg, 68 μmol), benzotriazol-1-yl-oxotripyrrophosphine hexafluorophosphate (40 mg, 77 μmol) and α-amino-γ-butyrolactone (26 mg, 140 μmol) in DMF (0.20ml) was added triethylamine (30μl, 220μmol). The mixture was partitioned between ethyl acetate and water and the layers were separated. The organic phase was washed with brine, dried (sodium sulfate) and concentrated, and purified by flash chromatography on silica gel eluting with ethyl acetate to afford the title compound as a colorless solid. MS(+ESI):527.2(M+1) + .

[0221] h 1 NMR (acetone-d 6 , 500MHz) δ8.06 (4H, d), 8.00-7.95 (4H, m), 7.90 (1H, m), 7.83 (1H, overlapping m), 7.80 (4H, d), 7.67 (4H, t), 4.58(2H,m), 4.45(2H,m), 4.37(2H,m),...

Embodiment 2

[0223] N 1 -[2-Oxo-1-(phenylsulfonyl)pyrrolidin-3-yl]-N2 -{(1S)-2,2,2-Trifluoro-1-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide

[0224]

[0225] Under stirring at room temperature within 2.5 hours, to N-{(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L -Leucine (40 mg, 90 μmol), benzotriazol-1-yl-oxotripyrrophosphine hexafluorophosphate (55 mg, 110 μmol) and (54 mg, 220 μmol) in DMF (0.2ml) were added tris Ethylamine (30 μl, 220 μmol). The mixture was partitioned between ethyl acetate and water and the layers were separated. The organic phase was washed with brine, dried (sodium sulfate) and concentrated, and purified by flash chromatography on silica gel eluting with 3 / 2 ethyl acetate / hexanes to give the title compound as a colorless thick syrup. MS(+ESI):666.3(M+1) + .

[0226] h 1 NMR (acetone-d 6 , 500MHz) δ8.07-7.97 (8H, d), 7.96-7.92 (4H, m), 7.86-7.70 (8H, m), 7.65-7.57 (8H, m), 4.54 (2H, m), 4.40 ( 2H, m), 3.93 (2H, m), 3.80 (2H, ...

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Abstract

The present invention relates to a novel class of compounds mainly, substituted leucinamide-carboxylate derivatives of formula (I) wherein X is O or NR<9>, Y is CR<1>R<2>, -SO<2>, C=O or NR<9>; Z is CR<1>R<2>, O, S, -SO2 or NR<9> and each G is independently a CR<1>CR<2> and pharmaceutical compositions thereof. Said compounds are cathepsin cysteine protease inhibitors, including but not limited to, inhibitors of cathepsin K, L, S and B. These compounds are useful for treating and preventing cathpesin dependent conditions in which inhibition of bone resorption is indicated, such as osteoporosis.

Description

Background of the invention [0001] A number of disorders in humans and other mammals involve or are associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, atherosclerosis, obesity, parasites Infection, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, malignant hypercalcemia, and multiple myeloma. One of the most common of these diseases is osteoporosis, which most commonly occurs in postmenopausal women. Osteoporosis is a systemic skeletal disorder characterized by low bone mass and deterioration of the microarchitecture of bone tissue, with consequent increased bone fragility and susceptibility to fracture. Osteoporotic fractures are the leading cause of morbidity and mortality in the elderly population. Because osteoporosi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P19/08C07D207/26C07D307/33C07D207/273
CPCC07D307/33C07D207/273A61P1/02A61P19/02A61P19/08A61P19/10A61P29/00A61P3/04A61P3/06A61P43/00A61P9/10
Inventor C·贝利S·N·克兰S·莱格尔
Owner MERCK FROSST CANADA INC
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