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Cathepsin S inhibitors

A compound, selected technology, applied in the direction of anti-inflammatory agents, drug combinations, non-central analgesics, etc., can solve problems such as increased toxicity, non-target enzyme inactivation, etc.

Inactive Publication Date: 2006-04-19
BOEHRINGER INGELHEIM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, irreversible compounds may permanently inactivate non-target enzymes, increasing the potential for toxicity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Example 1: Synthesis of 2-tert-butoxycarbonylamino-4,4,5,5-trimethyl-hexanoic acid

[0095]

[0096]

[0097]

[0098] Lithium diisopropylamide (LDA) (1.5 M solution in cyclohexane / THF / ethylbenzene) (106 mL, 160 mmol, 1.15 equiv) was injected into a 1000 mL round bottom flask under an argon atmosphere. Dry THF (150 mL) was added and the mixture was cooled to -78°C with a dry ice / acetone bath. 3,3-Dimethyl-butyric acid ethyl ester (20 g, 23.3 mL, 139 mmol, 1.0 equiv) was added dropwise via syringe over 10 minutes, followed by stirring at -78°C for 1 hour. Iodomethane (9.5 mL, 152 mmol, 1.1 equiv) was added dropwise by syringe over 10 minutes, and the creamy mixture was stirred at -78°C for 1 hour to give a very thick mixture. The dry ice bath was removed and replaced with a 0 °C ice bath. An additional 150 mL of dry THF was added, followed by additional LDA (106 mL, 160 mmol, 1.15 equiv). The resulting mixture was stirred for 10 minutes, then the round bottom...

Embodiment 2

[0104] Example 2: Synthesis of 2-tert-butoxycarbonylamino-5,5-dimethyl-heptanoic acid

[0105]

[0106]

[0107] 3,3-Dimethyl-pent-4-enoic acid methyl ester (20.0 mL, 126 mmol, 1.00 equiv) was carefully added via pipette to the 4 (3.63 g, 96 mmol, 0.76 equiv) in 500 mL of anhydrous diethyl ether in a 2 L flask (cooled by an ice-water bath). The reaction mixture was allowed to warm to room temperature overnight with stirring, then quenched by the slow addition of saturated potassium sodium tartrate solution (150 mL). The mixture was diluted with ether (200 mL), and the organic layer was separated and dried (MgSO 4 ), concentrated to give 3,3-dimethyl-pent-4-en-1-ol (11.0 g, 76% yield) as a colorless liquid. This material was used without further purification; 1 H NMR (CDCl 3 , 400MHz) δ1.00(s, 6H), 1.58(t, J=7.3Hz, 2H), 2.07(s, 1H), 3.59(t, J=7.3Hz, 2H), 4.89-4.94(m, 2H ), 5.80 (dd, J=17.3, 14.1, 1H).

[0108] Anhydrous DMSO (17.1 mL, 241 mmol, 2.5 eq) was added dro...

Embodiment 3

[0112] Example 3: Synthesis of (S)-2-tert-butoxycarbonylamino-5,5-dimethyl-heptanoic acid

[0113]

[0114] R,R-DIPAMP cyclooctadiene Rh(I) tetrafluoroborate (190 mg, 0.25 mmol, 0.04 equiv) was added to (Z)-2-benzyloxycarbonylamino-5 in a Paar hydrogenation flask, A solution of 5-dimethyl-hept-2,6-dienoic acid methyl ester (2.00 g, 6.30 mmol, 1.00 equiv) in dry methanol (20 mL). The reactor was evacuated and flushed 3 times with hydrogen, then shaken vigorously under 50 psi hydrogen overnight. The reaction mixture was concentrated in vacuo, then filtered through a plug of silica gel using ethyl acetate in hexanes as the gradient eluent to afford (S)-2-benzyloxycarbonylamino-5,5- Dimethyl-heptanoic acid methyl ester (1.63 g, 81% yield); 1 H NMR (CDCl 3 , 400MHz) δ0.74-0.90(m, 9H), 1.10-1.30(m, 4H), 1.58-1.70(m, 1H), 1.75-1.90(m, 1H), 3.75(s, 3H), 4.30- 4.40(m, 1H), 5.14(s, 2H), 5.24-5.33(m, 1H), 7.30-7.37(m, 5H); [α] 20 D =+15.57c=2.00, CHCl 3 .

[0115] In a Paar re...

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Abstract

This invention relates to peptidyl compounds of the formulas (I) and (II) active as cathepsin S, a cysteine protease, inhibitors. The compounds are selective, reversible inhibitors of the cathepsin S are therefore useful in the treatment of autoimmune and other diseases. The invention also relates to processes for preparing such compounds and pharmaceutical compositions comprising them.

Description

[0001] application data [0002] This application claims the benefit of US Provisional Application No. 60 / 454,239, filed March 13,2003. technical field [0003] The present invention relates to peptidyl compounds active as inhibitors of cathepsin S, a cysteine ​​protease. The compounds described are selective reversible inhibitors of cathepsin S. It is therefore used in the treatment of autoimmune and other diseases. The invention also relates to processes for the preparation of these compounds and pharmaceutical compositions containing them. Background technique [0004] Cathepsin S is a member of the papain family, within the papain superfamily of cysteine ​​proteases. The papain family is the largest group of cysteine ​​proteases and includes proteases such as cathepsins B, H, K, L, O and S. (A.J.Barrett et al., 1996, Perspectives in Drug Discovery and Design, 6, 1). Cysteine ​​proteases play an important role in human biology and disease, including atherosclerosis, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/66C07D413/12A61K31/4468A61K31/536A61P37/00
CPCC07D211/66C07D413/12A61P1/04A61P11/06A61P13/12A61P15/08A61P17/00A61P17/06A61P19/02A61P21/04A61P25/00A61P25/28A61P29/00A61P3/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P9/10A61P3/10C07D401/12C07D417/12
Inventor 尤金·R·希基刘为民孙三兴扬西·D·沃德埃里克·R·R·扬
Owner BOEHRINGER INGELHEIM PHARMA INC
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