Aminoacid derivatives containing a disulfanyl group in the form of mixed disulfanyl and aminopeptidase n inhibitors

A compound and composition technology, applied in the field of new mixed inhibitors, can solve the problems of low bioavailability, no solubility, etc.

Active Publication Date: 2008-12-03
智腾大中华区有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, even if one of the compounds belonging to the amino acid derivative series was shown to be relatively water soluble (Pain, 73, (1997), 383-391), none of the previously disclosed molecules exhibited Solubility and sufficient bioavailability for oral administration and sufficiently low doses in animals to be adapted for humans provide a favorable analgesic response
Likewise, none of the previously described molecules can be administered intravenously because in animal testing they would need to be dissolved in mixtures incompatible with administration to humans by this route

Method used

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  • Aminoacid derivatives containing a disulfanyl group in the form of mixed disulfanyl and aminopeptidase n inhibitors
  • Aminoacid derivatives containing a disulfanyl group in the form of mixed disulfanyl and aminopeptidase n inhibitors
  • Aminoacid derivatives containing a disulfanyl group in the form of mixed disulfanyl and aminopeptidase n inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] Embodiment 1: the synthesis of Boc methionine thiol (methioninethiol) (compound 1)

[0168] This compound was prepared according to the scheme described in J. Med. Chem., 35, 1992, 2473 . White solid: mp: 37 °C; Rf (cyclohexane (CHex): ethyl acetate (AcOEt) = 1.1) 0.73; α D 20℃ : -21.1° (c=1.0CHCl 3 ).

Embodiment 2

[0169] Embodiment 2: Synthesis of (2S)-2-mercaptomethyl-3-phenylpropionic acid (compound 2)

[0170] Step 1. According to (Ber., 57, 1924, 1116), obtain 2-acetylthiomethyl-3-phenylpropionic acid methyl ester through the effect of thioacetic acid on the methyl ester of corresponding acrylate, and according to (Bioor. The general protocol described in Med. Chem. Let., 3, 1993, 2681) treats methyl 2-acetylthiomethyl-3-phenylpropionate with α-chymotrypsin.

[0171] Yield: 71.4%; enantiomeric excess (ee): 88%, α D 20℃ : -42.7°.

[0172] Step 2. (2S)-Mercaptomethyl-3-phenylpropanoic acid. The compound from Step 1 was dissolved in degassed methanol (MeOH) at 0 °C. Under an inert atmosphere, 3 equivalents (eq) of 1 N soda ash (NaOH) were added. The mixture was stirred at room temperature (RT) for 30 minutes. The mixture was acidified by adding 6N hydrochloric acid (HCl) (25ml) and MeOH was evaporated under reduced pressure. The aqueous phase was extracted with 2 x 125 ml AcOEt....

Embodiment 3

[0174] Example 3: Synthesis of (2RS) 2-mercaptomethyl-3-thiophen-3-yl propionic acid (compound 3)

[0175] step 1 : Dimethylmalonate (392mmol, 45ml, 1eq), thiophen-3-ylaldehyde (0.357mmol), piperidine (1.87ml; 0.05eq) and benzoic acid were refluxed in 270ml of toluene using a Dean-Stark apparatus (4.58 g; 0.05 equiv) of the mixture 12h. With 2×140ml of 1N HCl, 2×140ml of 10% sodium carbonate (NaHCO 3 ) and 140ml saturated NaCl to wash the organic phase. use Na 2 SO 4 The organic phase was dried and evaporated to dryness. get oil.

[0176] The yield is 100%. Kromasil C18 HPLC CH 3 CN / H 2 O(0.5% TFA) 60-40: 5.97 minutes.

[0177] Step 2: The compound from Step 1 (340mmol) was dissolved in MeOH (540ml). The mixture was cooled to 0 °C and sodium borohydride (NaBH 4 ). The mixture was stirred at room temperature for 15 minutes. The reaction was quenched by adding 450ml 1N HCl. Evaporate methanol and wash with 2×500ml chloroform (CHCl 3 ) to extract the reaction mix...

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Abstract

The invention relates to novel compounds of formula (I): H2N-CH(R1)-CH2-S-S- CH2-CH(R2)-CONH-R5, wherein R1 is a hydrocarbon chain, phenyl or benzyl radical, methylene radical substituted by a 5 or 6 atom heterocycle; R2 is a phenyl or benzyl radical, a 5 or 6 atom aromatic heterocycle, methylene group substituted by a 5 or 6 atom heterocycle; R5 is a CH(R3)-COOR4 radical, wherein R3 is hydrogen, an OH or OR group, a saturated hydrocarbon group, a phenyl or benzyl radical and OR4 is hydrophile ester, or 5 or 6 membered heterocycle comprising several heteroatoms selected from a group consisting of nitrogen, sulphur and oxygen, with at least two nitrogene atoms, wherein said heterocycle is substitutable by an alkyl C1-C6, phenyl or benzyl radical.; The use of the inventive compounds in the form of drugs, a pharmaceutical composition comprising said compounds, a pharmaceutically acceptable excipient, the use in conjunction of at least one type of cannabinoid derivative for potentiating the analgesic and antidepressant effect of the novel compounds of formula (I) and/or morphine or the derivatives thereof are also disclosed.

Description

technical field [0001] The present invention relates to novel mixed inhibitors of neprilysin and aminopeptidase N. Background technique [0002] Naturally occurring opioid peptides or enkephalins—(Tyr-Gly-Gly-Phe-Met or Tyr-Gly-Gly-Phe-Leu)—are known to be degraded primarily by two zinc metallopeptidases that cleave Enkephalinase (EC 3.4.24.11) (Nature 276 (1978) 523) of the Gly3-Phe4 bond and aminopeptidase N (EC 3.4.11.2) (Eur.J.Pharmacol. 117 (1985) 233; reviewed in Pharmacological review., 1993, 45, 87-146). Mixed inhibitors of these two enzymes are known to completely protect endogenous enkephalins from enzymatic degradation, and they display the pharmacological activities of enkephalins, especially analgesic and antidepressant activities. Mixed inhibitors of these two enzyme activities described in the prior art are compounds with hydroxamate functional groups (FR 2 518 088 and FR 2 605 004), aminophosphinic acid compounds (FR 2 755 135 and FR 2 777 780) and amino a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/24C07H3/02C07C323/65A61K31/381A61P29/00A61P25/00C07C323/60
CPCC07D333/24C07C323/60A61P25/00A61P25/04A61P25/24A61P29/00
Inventor 贝纳德·罗克马里-克洛德·富尼耶-扎武斯基
Owner 智腾大中华区有限公司
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