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Peptidyl heterocyclic ketones useful as tryptase inhibitors

Technology of a compound, alkyl, in the field of peptidyl heterocyclic ketones as tryptase inhibitors

Inactive Publication Date: 2002-06-12
ORTHO MCNEIL PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In contrast to drugs such as steroids that cause multiple effects, tryptase inhibitors may cause fewer side effects due to selective inhibition of a specific inflammatory mediator (tryptase) that belongs only to mast cells

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1 (2S, 4R)-1-acetyl-N-[(1S)-4-[(aminoiminomethyl)amino]-1-(2-benzene

[0068] (Thiazolylcarbonyl)butyl]-4-hydroxy-2-pyrrolidinecarboxamide

[0069] step a

[0070] At 5°C under an argon atmosphere, add benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent; 113.5 g, 0.256 mol) to N-α- t-Boc-N G -(p-toluenesulfonyl)-L-arginine (Boc-Arg(Ts)-OH; 100g, 0.233mol), N,O-dimethylhydroxylamine hydrochloride (34.2g, 0.350mol), three In a stirred solution of ethylamine (97 mL, 0.696 mol) in anhydrous N,N-dimethylformamide (2.5 L). The reaction mixture was slowly warmed to room temperature over 1 hour, filtered through celite, and concentrated in vacuo at 60 °C. The residue was dissolved in dichloromethane (1 L), washed sequentially with water, saturated aqueous sodium bicarbonate (2×), 1 N HCl (2×), brine, and dried (Na 2 SO 4 ), and concentrated in vacuo to obtain a thick syrup. The sy...

Embodiment 2

[0085] (2S, 4R)-1-acetyl-N-[4-[(aminoiminomethyl)amino]-1-(2-benzothiazolylcarbonyl)butyl]-4-hydroxy-2-pyrrolidine Formamide

[0086] Compound 2

[0087] Compound 2 was prepared in the same manner as Example 1 except that the L- and D-arginine epimers were collected during reverse phase HPLC purification to obtain a 1.1:1 epimer Construct mixture. The trifluoroacetic acid salt of 2 was converted to its hydrochloride salt by dissolving in 0.1N aqueous hydrochloric acid solution and concentrating in vacuo 3 times. The resulting glass was dissolved in water and lyophilized to give the hydrochloride salt of 2 as a pale yellow solid; MS (ES) m / z 447 (MH + ).

Embodiment 3

[0089] cis-2-acetylamino-N-[(1S)-4-[(aminoiminomethyl)amino]-1-(2-benzothiazolylcarbonyl)butyl]-1-cyclopentane Amide

[0090] step a

[0091] At 0°C under an argon atmosphere, add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent; 25.0 g, 56 mmol) to N-α-t- Boc-N G -(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginine (Boc-Arg(Mtr)-OH; 24.96g, 51.3mmol), N,O dimethyl In a stirred solution of hydroxylamine hydrochloride (7.6 g, 56 mmol), triethylamine (22 mL, 154 mmol) in anhydrous N,N dimethylformamide (100 mL). The reaction mixture was slowly warmed to room temperature over 2 hours, filtered through celite, and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate, water (3x), 1M KHSO 4 aqueous solution, saturated aqueous sodium bicarbonate solution, brine, and dried (Na 2 SO 4 ) and concentrated in vacuo. Purification of the residue by chromatography on silica gel, eluting with ethyl ac...

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PUM

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Abstract

The present invention relates to a series of peptidyl heterocyclic ketones which are inflammatory cell serine protease inhibitors and their compositions and methods for the prevention and treatment of a variety of immunomediated inflammatory disorders. More particularly, these compounds are potent and selective inhibitors of tryptase and are therefore effective for the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis.

Description

[0001] Related Application Cross Reference [0002] This application claims priority from US Provisional Application No. 60 / 117,602, filed January 27, 1999, the contents of which are incorporated herein by reference. field of invention [0003] The present invention relates to a series of compounds as peptidyl heterocyclic ketone inflammatory cell serine protease inhibitors, and their compositions, and the prevention and treatment of various immune-mediated inflammatory diseases, skin hyperpigmentation, and trypsin-mediated method of causing disease. More specifically, the compounds of the present invention are potent and selective tryptase inhibitors and are therefore effective in the prevention and treatment of respiratory-related inflammatory diseases such as asthma and allergic rhinitis, as well as other immune-mediated Inflammatory diseases such as rheumatoid arthritis, conjunctivitis, psoriasis, inflammatory bowel disease, various...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/55A61P1/04A61P1/16A61P1/18A61P9/10A61P11/00A61P11/06A61P13/12A61P17/00A61P17/06A61P19/00A61P19/02A61P27/00A61P27/02A61P29/00A61P37/00A61P37/08C07D277/64C07D417/12C07K5/062C07K5/065C07K5/072C07K5/078
CPCC07D417/12C07K5/06139C07K5/06026C07D277/64A61P1/04A61P1/16A61P1/18A61P11/00A61P11/06A61P13/12A61P17/00A61P17/06A61P19/00A61P19/02A61P27/00A61P27/02A61P29/00A61P37/00A61P37/08A61P9/10
Inventor M·J·科斯坦佐B·E·马亚诺夫S·C·雅布特
Owner ORTHO MCNEIL PHARM INC
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