Linear basic compounds having nk-2 antagonist activity and formulations thereof

A compound, alkaline technology, applied in the field of tachykinins, which can solve problems such as excretion and low bioavailability

Inactive Publication Date: 2005-02-09
梅尔西药品生物化学研究公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the problems arising from the pharmacological use of high molecular weight peptides (multiple sites for enzymatic hydrolytic attack, low bioavailability, acute hepatic and renal excretion) have led to the investigation of peptidomimetic fragments with antagonistic activity

Method used

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  • Linear basic compounds having nk-2 antagonist activity and formulations thereof
  • Linear basic compounds having nk-2 antagonist activity and formulations thereof
  • Linear basic compounds having nk-2 antagonist activity and formulations thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] N α [N α (Benzo[b]thiophen-2-ylcarbonyl)-1-aminocyclopentane-1-carbonyl]-D-phenylalanine-N-[3-(morpholin-4-yl)propyl] Amide

[0139] 1a) To a solution of 1-amino-cyclopentane-1-carboxylic acid (1 g, 7.66 mmol) in 30 ml of anhydrous dichloromethane (DCM) was added N,O-bis(trimethylsilyl) under magnetic stirring ) acetamide (BSA) (3.8ml, 15.4mmol); after 15 minutes, trimethylchlorosylane (TMSCl) (0.38ml, 10% by volume of BSA) was added. The amino acid was completely sylanised (the solution became clear after the addition was complete), and after stirring for about 2 hours at room temperature, benzo[b]thiophene-2-carbonyl chloride (7.66 mmol) dissolved in 10 ml of DCM was added to the reaction in the mixture. The reaction was continued for 12 hours at room temperature with stirring.

[0140] The solution was concentrated under reduced pressure, then 50 ml of 1M NaHCO was added 3 aqueous solution and stirred for 30 minutes. All was transferred to a separatory funnel,...

Embodiment 2

[0152] (1R, 3S)-N γ {N α [N α (Benzo[b]thiophen-2-yl-carbonyl)-1-aminocyclopentane-1-carboxy]-D-phenylalanyl (alanil)}-3-aminocyclopentane-1-carboxylic acid- N-[(1S,2S)-2-Aminocyclohexyl]amide

[0153] 2a) To a solution of (1S,2S)-diaminocyclohexane (1.14g, 10mmol) in 50ml of DCM was added dibenzyl dicarbonate (2g, 7mmol) dissolved in 20ml of DCM dropwise. After the addition was complete, the resulting precipitate was filtered and dried to afford 0.55 g of a white solid, the starting material diaminecyclohexane. The organic filtrate (80ml) was extracted with 1N HCl (3x10ml) and the aqueous extracts were collected, basified to pH=10 and extracted with DCM (3x10ml). The collected organic extracts were washed with anhydrous Na 2 SO 4 Dry, then filter and dry. The residue was dissolved in 3ml of methanol and then added to ethyl acetate saturated hydrochloric acid (EtOAc / HCl) (2ml) followed by diethyl ether (20ml) to give a suspension with a white precipitate. The precipita...

Embodiment 3

[0172] N γ N γ [N α (Biphenyl-4-ylcarboxy)-1-aminocyclopentane-1-carboxy]-D-phenylalanyl)-(1R,3S)-3-aminocyclopentane-1-carboxylic acid-N- ((1S,2S)-2-aminocyclohexyl)amide trifluoroacetate

[0173] MS-FAB: 664.32(M+H) +

[0174] HPLC (Method E): Rt = 10.5 min.

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PUM

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Abstract

Described herein are compounds of formula (I) useful as antagonists of tachykinins in general, and in particular of neurokinin A; and the pharmaceutical formulations comprising the compounds of formula (I).

Description

field of invention [0001] In general, the present invention relates to tachykinin, in particular neurokinin A antagonist compounds and their use in pharmaceutical formulations. Background of the invention [0002] Tachykinins are a family comprising at least three peptides, known as substance P, neurokinin A (NKA) and neurokinin B (NKB). [0003] Research in the field of tachykinin antagonists is mainly based on the single and multiple substitutions of amino acids in the sequence of peptide antagonists of substance P and other tachykinins, thus discovering nonapeptides comprising one or more D-triptophan units ( Regoli et al., Pharmacol. 28, 301 (1984)). However, the problems arising from the pharmacological use of high molecular weight peptides (multiple sites for enzymatic hydrolytic attack, low bioavailability, acute hepatic and renal excretion) have led to the investigation of peptidomimetic fragments with antagonistic activity. As a result of these studies the discove...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61K31/38A61K31/425A61K38/05A61P1/00A61P1/04A61P9/00A61P11/06A61P13/02A61P15/10A61P17/00A61P17/06A61P19/02A61P25/00A61P25/02A61P25/04A61P25/18A61P25/22A61P25/24A61P27/02A61P27/14A61P27/16A61P29/00A61P31/18A61P35/00A61P37/00A61P37/06A61P37/08A61P43/00C07D333/38C07D333/70C07D409/12C07D413/12C07D417/12C07K5/06C07K5/062C07K5/065
CPCC07D409/12C07K5/06078C07D333/70A61K38/00C07K5/06026C07K5/06034A61P1/00A61P1/04A61P11/00A61P11/06A61P13/00A61P13/02A61P15/00A61P15/10A61P17/00A61P17/06A61P19/00A61P19/02A61P19/10A61P25/00A61P25/02A61P25/04A61P25/18A61P25/22A61P25/24A61P27/00A61P27/02A61P27/14A61P27/16A61P29/00A61P31/18A61P35/00A61P37/00A61P37/06A61P37/08A61P43/00A61P9/00C07K5/06017C07K5/0821
Inventor A·西斯托V·卡恰利M·阿尔塔穆拉A·焦利蒂V·费迪A·圭迪D·詹诺蒂N·哈马特R·南尼奇尼F·帕斯奎C·A·马吉
Owner 梅尔西药品生物化学研究公司
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