A novel method for the efficient synthesis of 1,8-diazabicyclo[4.3.0]non-3-ene-7,9-diones 5 (bicy... more A novel method for the efficient synthesis of 1,8-diazabicyclo[4.3.0]non-3-ene-7,9-diones 5 (bicyclic hydantoins) starting from ureas or Z-protected aminoacids has been developed. The key step is a ring-closing metathesis (RCM) reaction of diallyl substituted hydantoins 3 catalyzed by the ruthenium-carbene complex bis(tricyclohexylphosphine)benzilidine ruthenium dichloride (4).
ABSTRACT The Sonogashira reaction of a resin-bound iodobenzoic acid with trimethylsilyl acetylene... more ABSTRACT The Sonogashira reaction of a resin-bound iodobenzoic acid with trimethylsilyl acetylene followed by TBAF desilylation provided a polymer-supported aryl acetylene, 3. Treatment of 3 with an aldehyde and a secondary amine in dioxane in the presence of CuCl catalyst results in the generation of resin-bound propargylamines. The final products (4) were cleaved from the resin and obtained in excellent yields and purity.
A small set of acyclic analogs 5 were prepared to explore their structure-activity relationships ... more A small set of acyclic analogs 5 were prepared to explore their structure-activity relationships (SARs) relative to heterocyclic core, opioid receptor (OR) agonists 4. Compound 5l was found to have very favorable OR binding affinities at the δ and μ ORs (r K(i) δ=1.3 nM; r K(i) μ=0.9 nM; h K(i) μ=1.7 nM), with less affinity for the κ OR (gp K(i) κ=55 nM). The OR functional profile for 5l varied from the previously described dual δ/μ OR agonists 4, with 5l being a potent, mixed dual δ OR antagonist/μ OR agonist [δ IC(50)=89 nM (HVD); μ EC(50)=1 nM (GPI); κ EC(50)=1.6 μM (GPC)]. Compound 5l has progressed through a clinical Phase II Proof of Concept study on 800 patients suffering from diarrhea-predominant Irritable Bowel Syndrome (IBS-d). This Phase II study was recently completed successfully, with 5l demonstrating statistically significant efficacy over placebo.
The synthesis, resolution, and stereochemical characterization of novel piperazino-, thiazino-, a... more The synthesis, resolution, and stereochemical characterization of novel piperazino-, thiazino-, and oxazinobenzodiazepines are described. The absolute stereochemistry of the heterotricycles was determined by using X-ray crystallography and the enantiomeric purity was determined by using Pirkle-solvent NMR techniques and chiral HPLC.
Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science, May 1, 1991
A synthesis of propargyl diazoacetate (I) was carried out and its chemical transformations were s... more A synthesis of propargyl diazoacetate (I) was carried out and its chemical transformations were studied. The reaction of (I) in the presence of Rh(OAc)2 at 25‡C with 1-pentyne gives the propargyl ester of l-propylcyclopropene-3-carboxylic acid in 80% yield, while reaction with 2,3-dimethyl-2-butene at 60‡C results in the propargyl ester of tetramethylcyclopropanecarboxylic acid in 10% yield. Compound (I) reacts under the same conditions (35–60‡C) with ether, CH2Cl2 and water, with the formation of propargyl esters of ethoxyacetic, 2,3-dichloropropionic, and a mixture of glycols and 2-[(propyn-2-yl)-oxycarbonyl]methoxy acetic acids in yields of up to 35%. A spontaneous oligomerization of (I) was observed as a result of a dipolar [1, 3]-cycloaddition of the CH=N2 fragment of one molecule of (I) to the terminal triple bond of the second molecule with the formation of oligomers of 3-hydroxymethylpyrazole-5-carboxylic acid.
A novel method for the efficient synthesis of 1,8-diazabicyclo[4.3.0]non-3-ene-7,9-diones 5 (bicy... more A novel method for the efficient synthesis of 1,8-diazabicyclo[4.3.0]non-3-ene-7,9-diones 5 (bicyclic hydantoins) starting from ureas or Z-protected aminoacids has been developed. The key step is a ring-closing metathesis (RCM) reaction of diallyl substituted hydantoins 3 catalyzed by the ruthenium-carbene complex bis(tricyclohexylphosphine)benzilidine ruthenium dichloride (4).
ABSTRACT The Sonogashira reaction of a resin-bound iodobenzoic acid with trimethylsilyl acetylene... more ABSTRACT The Sonogashira reaction of a resin-bound iodobenzoic acid with trimethylsilyl acetylene followed by TBAF desilylation provided a polymer-supported aryl acetylene, 3. Treatment of 3 with an aldehyde and a secondary amine in dioxane in the presence of CuCl catalyst results in the generation of resin-bound propargylamines. The final products (4) were cleaved from the resin and obtained in excellent yields and purity.
A small set of acyclic analogs 5 were prepared to explore their structure-activity relationships ... more A small set of acyclic analogs 5 were prepared to explore their structure-activity relationships (SARs) relative to heterocyclic core, opioid receptor (OR) agonists 4. Compound 5l was found to have very favorable OR binding affinities at the δ and μ ORs (r K(i) δ=1.3 nM; r K(i) μ=0.9 nM; h K(i) μ=1.7 nM), with less affinity for the κ OR (gp K(i) κ=55 nM). The OR functional profile for 5l varied from the previously described dual δ/μ OR agonists 4, with 5l being a potent, mixed dual δ OR antagonist/μ OR agonist [δ IC(50)=89 nM (HVD); μ EC(50)=1 nM (GPI); κ EC(50)=1.6 μM (GPC)]. Compound 5l has progressed through a clinical Phase II Proof of Concept study on 800 patients suffering from diarrhea-predominant Irritable Bowel Syndrome (IBS-d). This Phase II study was recently completed successfully, with 5l demonstrating statistically significant efficacy over placebo.
The synthesis, resolution, and stereochemical characterization of novel piperazino-, thiazino-, a... more The synthesis, resolution, and stereochemical characterization of novel piperazino-, thiazino-, and oxazinobenzodiazepines are described. The absolute stereochemistry of the heterotricycles was determined by using X-ray crystallography and the enantiomeric purity was determined by using Pirkle-solvent NMR techniques and chiral HPLC.
Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science, May 1, 1991
A synthesis of propargyl diazoacetate (I) was carried out and its chemical transformations were s... more A synthesis of propargyl diazoacetate (I) was carried out and its chemical transformations were studied. The reaction of (I) in the presence of Rh(OAc)2 at 25‡C with 1-pentyne gives the propargyl ester of l-propylcyclopropene-3-carboxylic acid in 80% yield, while reaction with 2,3-dimethyl-2-butene at 60‡C results in the propargyl ester of tetramethylcyclopropanecarboxylic acid in 10% yield. Compound (I) reacts under the same conditions (35–60‡C) with ether, CH2Cl2 and water, with the formation of propargyl esters of ethoxyacetic, 2,3-dichloropropionic, and a mixture of glycols and 2-[(propyn-2-yl)-oxycarbonyl]methoxy acetic acids in yields of up to 35%. A spontaneous oligomerization of (I) was observed as a result of a dipolar [1, 3]-cycloaddition of the CH=N2 fragment of one molecule of (I) to the terminal triple bond of the second molecule with the formation of oligomers of 3-hydroxymethylpyrazole-5-carboxylic acid.
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