Novel inhibitors of meprin alpha and beta
A technology of crystal form and solvate, applied in the field of novel hydroxamic acid derivatives, can solve the problems of lack of acceptable drug-like properties and low inhibition
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[0056] Preparation and separation of stereoisomers:
[0057]When the processes for the preparation of the compounds of the present invention result in mixtures of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. Compounds may be prepared in racemic form, or individual enantiomers may be prepared by enantiospecific synthesis or by resolution. Compounds can be resolved, for example, into their component enantiomers by standard techniques, such as by reaction with optically active acids such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l -tartaric acid) to form diastereoisomeric pairs followed by fractional crystallization and regeneration of the free base, or by reacting with optically active bases (e.g., quinoline, quinidine, quinixine, cinchotoxin, (S)-benzene Diethylamine, (1R,2S)-ephedrine, (R)-phenylglycinol, (S)-2-aminobutanol) to form diastereoisomeric pairs, followed by fractional crystallization...
Embodiment
[0183] Specific description of the synthesis method
[0184] plan 1
[0185]
[0186] Method A:
[0187] The corresponding Fmoc-amino acid (1 equivalent) was dissolved in DMF (1 ml / mmol). Tritylhydroxylamine (1 eq), TBTU (1 eq) and DIPEA (2 eq) were added and the mixture was stirred at room temperature for 1.5 h. The reaction was quenched with water. The resulting precipitate was collected by filtration and washed with diethyl ether and a small amount of saturated NaHCO 3 Wash with aqueous solution. The residue was redissolved in THF (2ml / mmol) and treated with DBU (1.5eq). The mixture was stirred at room temperature until completion (TLC monitoring, usually about 30 min). The solvent was evaporated and flash chromatography (silica gel, CHCl 3 / MeOH gradient) to purify the residue.
[0188] Method B:
[0189] The corresponding trityl-protected hydroxamic acid (1 equiv) obtained by method A was dissolved in DMF (5 ml / mmol). Triethylamine (2.2 equiv) and the correspon...
Synthetic example 2
[0193] 3-[[(3-carboxyphenyl)methyl-[2-(hydroxyamino)-2-oxo-ethyl]amino]methyl]benzoic acid
[0194] Step 1: 2-Amino-N-trityloxy-acetamide
[0195] According to method A from Fmoc-Gly-OH (2.97g, 10mmol, 1 equiv), trityl hydroxylamine (2.8g, 10mmol, 1 equiv), TBTU (3.21g, 10mmol, 1 equiv), DIPEA (3.5ml , 20mmol, 2eq) and DBU (2.2ml, 15mmol, 1.5eq) to synthesize the compound. Yield: 1.4 g (42.1%), ESI-MS: m / z 243.2 [trityl] + , 333.3[M+H] + ; HPLC (gradient 2): 12.24 min at room temperature (100%).
[0196] Step 2: 3-[[(3-Carboxyphenyl)methyl-[2-(hydroxyamino)-2-oxo-ethyl]amino]methyl]benzoic acid
[0197] From 2-amino-N-trityloxy-acetamide (332 mg, 1 mmol, 1 eq), tert-butyl 3-(chloromethyl)benzoate (499 mg, 2.2 mmol, 2.2 equiv. ) and TEA (305 μl, 2.2 mmol, 2.2 eq) to synthesize the compound, followed by acid deprotection and purification by semi-preparative HPLC. Yield: 43 mg (12%, TFA salt); ESI-MS: m / z 359.1 [M+H] + ; HPLC (gradient 2): room temperature 7.73min (97.4%);...
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