Synthesis of 5S-(1-Oxoalkyl and Aryl)-2-pyrrolidinone Derivatives1

N-Benzyl pyroglutamate esters react with aryllithium reagents and methyllithium to give moderate to good yields of 5-(1-oxoaryl) or 5-(1-oxoalkyl)-2-pyrrolidinone derivatives. The reaction proceeds without racemization, but is accompanied by formation of 5-(1-hydroxy-1-alkyl)-2-pyrrolidinone derivatives. This reaction gives very poor yields of ketone products with most other alkyl organolithium reagents such as n-butyllithium. Grignard reagents react to give primarily the alcohol.     

Cyclization products of N-fluorophenyl-β-alanines and their properties

Interaction of 2-and 4-fluorophenylamines with acrylic and itaconic acids leads to the synthesis of the corresponding N-substituted β-alanines, the cyclization of which leads to derivatives of dihydropyrimidinone, 4-carboxy-2-pyrrolidinone, and tetrahydropyridone. Compounds having benzimidazole, pyrazole, and hydrazine fragments in the molecule have been obtained from 4-carboxy-1-(4-fluorophenyl)-2-pyrrolidinone. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 862–869, June, 2006.     

Synthesis of α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetic acid derivatives

α-(Aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetamide and the ethyl acetate, 3 and 8 , have been synthesized by catalytic hydrogenation of 6-cyanomethylene-9-methoxymethylpurine derivatives 2 and 7 which were obtained by the substitution of 6-chloro-9-(methoxymethyl)purine ( 1 ) with α-cyanoacetamide and ethyl cyanoacetate, respectively. Substitution of 3 and 8 with amines gave the corresponding N-substituted α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetamide and the ethyl acetate 4 and 10 . Reaction of 3 with piperidine gave 9-(methoxymethyl)-9H-purine-6-acetamide ( 5 ).     

Synthesis and biological activity of N-(aminoiminomethyl)-1H-indole carboxamide derivatives as Na+/H+ exchanger inhibitors

A series of N-(aminoiminomethyl)-1H-indole carboxamide derivatives were synthesized and their inhibitory potencies against the Na+/H+ exchanger were measured. Variation of the carbonylguanidine group at the 2- to 7-position of the indole ring system showed that a substitution at the 2-position improved the Na+/H+ exchanger inhibitory activity the most in vitro. This led to the synthesis and evaluation of an extensive series of N-(aminoiminomethyl)-1H-indole-2-carboxamide derivatives. Derivatives having an alkyl or substituted alkyl group at the 1-position of the indole ring system showed higher levels of in vitro activities. N-(aminoiminomethyl)- 1-(2-phenylethyl)-1H-indole-2-carboxamide (49) had the strongest activity.     

First regioselective enzymatic alkoxycarbonylation of primary amines. Synthesis of novel 5'- and 3'-carbamates of pyrimidine 3',5'-diaminonucleoside derivatives including BVDU analogues

The first regioselective enzymatic alkoxycarbonylation of primary amino groups has been achieved in pyrimidine 3',5'-diaminonucleoside derivatives. Thus, Candida antarctica lipase B (CAL-B) catalyzed this reaction with nonactivated homocarbonates allowing the selective synthesis of several N-5' carbamates, including (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) analogues, with moderate-high yields, whereas immobilized Pseudomonas cepacia lipase (PSL-C) afforded mixtures of alkoxycarbonylated regioisomers. To obtain N-3' carbamates selectively, a short and efficient chemoenzymatic route was used employing some of the N-5'-protected derivatives previously synthesized.     

Chiral C2-symmetric 2,3-disubstituted aziridine and 2,6-disubstituted piperidine as chiral ligands in the addition reaction of diethylzinc with arylaldehydes

Chiral C₂-symmetric 2,3-disubstituted aziridines and 2,6-disubstituted piperidines having a β-amino alcohol moiety have been successfully synthesized and their catalytic chiral induction properties have been examined in the asymmetric addition reactions of diethylzinc with arylaldehydes in hexane. When N-(2,2-diphenyl-2-hydroxyethyl)-(S,S)-2,3-bis(methoxymethyl)aziridine 11 was used as a catalytic chiral ligand, sec-alcohols having (S)-configuration formed in high yields of 86–92% but low enantiomeric excesses (ee's) of 11–13%. However, when N-(2,2-diphenyl-2-hydroxyethyl)-(R,R)-2,6-disubstituted piperidine derivatives 16 and 20 were used as the chiral ligands under the same reaction conditions, the ee's of the corresponding sec-alcohols were 20–30 and 5–6%, respectively, along with the inversion of absolute configuration. A plausible mechanism for this inversion is proposed.     

Synthesis of seco-chlorinated derivatives of phenanthroindolizidine precursors via Friedel-Crafts reaction

In the course of synthesizing 3-demethyltylophorine (1) by Lewis acid catalyzed intramolecular Friedel-Crafts reaction starting from N-(3-hydroxy-2,6,7-trimethoxy-phenanthr-9-ylmethyl)-2-chloromethylpyrrolidine, two chlorinated phenanthrene derivatives N-(4,10-dichloro-3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-2-chloromethylpyrrolidine (4) and N-(4-chloro-3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-2-chloromethylpyrrolidine (5) were obtained. The structures of these compounds were determined by spectroscopic analysis.     

Nucleophilic addition of potassium organotrifluoroborates to chiral cyclic N-acyliminium ions: stereoselective synthesis of functionalized N-heterocycles

The stereoselective nucleophilic addition of potassium aryl- and alkynyltrifluoroborates to cyclic N-acyliminium ion derivatives from N-benzyl-3,4,5-triacetoxy-2-pyrrolidinone, affording the respective 5-substituted 2-pyrrolidinone is described. The products were obtained in moderate to good yields and with preference for the syn diastereomer.     

Synthesis and Cyclization of N-(4-Phenoxyphenyl)-β-alanines

We have used the reaction of 4-aminodiphenyl ester with acrylic, methacrylic, crotonic, and itaconic acids to synthesize N-substituted -alanines, which undergo ring closure to form derivatives of dihydropyrimidinedione and 4-carboxy-2-pyrrolidinone. We have studied the reactions of acylation and recyclization of the dihydropyrimidinedione ring, and we have synthesized derivatives of 4-carboxy-1-(4-phenoxyphenyl)-2-pyrrolidinone: arylidene hydrazides, 2[(2-oxo-4-pyrrolidinyl-1-(4-phenoxyphenyl)]benzimidazole.     

Novel benzamides as selective and potent gastrokinetic agents. III. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-methoxy- and 2-ethoxy-N-[(4-substituted 2-morpholinyl)methyl]-benzamides.

A series of 4-amino-5-chloro-2-methoxy- and 2-ethoxy-N-[(4-substituted 2-morpholinyl)methyl]benzamides (11-64) were prepared and evaluated for gastrokinetic activity by determining their effects on the gastric emptying of phenol red semisolid meal in rats. The N-4 substituent includes alkyl, phenoxyalkyl, (4-fluorobenzoyl)alkyl, and heteroarylmethyl groups. The benzamide derivatives, having an isopropyl, isoamyl, neopentyl, 3-(4-chlorophenoxy)-propyl, or pyridylmethyl group at N-4, showed potent in vivo gastric emptying activity. In particular, 4-amino-5-chloro-2-ethoxy-N-[[4-(3-pyridylmethyl)-2- morpholinyl]methyl]benzamide (57b) was equipotent to the 4-fluorobenzyl analogue 1b (AS-4370 as its citrate) in the gastrokinetic activity on phenol red semisolid meal in rats and mice, and on resin pellet solid meal in rats. Moreover, compound 57b was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests. Structure-activity relationships of compounds with various substituents at N-4 are also discussed.     

Some derivatives of 4-(4-aminophenylamino)-2,2,6,6-tetramethylpiperidine

4-(4-Aminophenylamino)-2,2,6,6-tetramethylpiperidine was synthesized by alkylation of 4-aminotriacetoneamine with 4-chloronitrobenzene, followed by hydrogenation of the nitro derivative. Its reactions with acrylic, methacrylic, and itaconic acids were carried out. Transformations of the N-substituted amino acids to derivatives of 2-pyrrolidinone and dihydropyrimidinedione were studied.Kaunas Technological University, Kaunas LT-3028. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 629–631, May, 1997.     

Synthesis of new polyfunctional 2-pyrrolidinones from methyl 2-(carboethoxyhydroxymethyl)acrylate

The synthesis of new polyfunctional 2-pyrrolidinone derivatives from methyl 2-(carboethoxyhydroxymethyl)acrylate is described. These alkenes present an extremely high reactivity upon Michael addition with primary amines leading to a simple, mild, and efficient route to the preparation of new polyfunctional pyrrolidinones.     

Determination of the conformations and relative configurations of exocyclic amines

The conformations and relative configurations of 20 amines, classified according to the following labeling scheme, were analyzed. Series a comprised compounds derived from N-(1-phenylethyl)cyclohexanamine, b comprised derivatives of N-[1-(naphthalen-2-yl)ethyl]cyclohexanamine, c comprised derivatives of N-(diphenylmethyl)cyclohexanamine, and d comprised derivatives of N-(propan-2-yl)cyclohexanamine. The compounds were labeled as follows: 1 indicates cyclohexanamine, 2 indicates 2-methylcyclohexanamines, 3 indicates 3-methylcyclohexanamines, 4 indicates 4-methylcyclohexanamines, and 5 indicates 4-tert-butylcyclohexanamines. These compounds were prepared without the use of stereoselective induction and, therefore, all expected stereoisomers were observed. Structural assignments were established by (1)H, (13)C, and (15)N NMR.     

A novel bis-furan derivative, two new natural furan derivatives from Rehmannia glutinosa and their bioactivity

A novel bis-furan derivative and two new natural furan derivatives were isolated from the CHCl3 extracts of the dried roots of Rehmannia glutinosa (Gaerth) Lilosch. Their structures were identified as 1,5-bis(5-methoxymethyl)furan-2-yl-penta-1,4-dien-3-one 1, (E)-4-(5-(methoxymethyl)furan-2-yl)but-3-en-2-one 2 and (E)-4-(5-(hydroxymethyl)furan-2-yl)but-3-en-2-one 3 on the basis of spectral data. Moreover, biological assay showed that 1 (10 microg/mL) and 3 (10 microg/mL) can promote immune activity, 2 (100 microg/mL) and 3 (100 microg/mL) inhibit immune activity and 1 can inhibit blood platelet aggregation.     

A facile method for the synthesis of polycyclic indole derivatives: the generation and reaction of tungsten-containing azomethine ylides

Treatment of N-(o-alkynylphenyl)imine derivatives with W(CO)(5)(L) induces the 5-endo-mode of cyclization of the imine nitrogen onto the electrophilically activated alkyne moiety to afford a novel reactive species, a metal-containing azomethine ylide. [3 + 2] cycloaddition of this ylide species with various electron-rich alkenes proceeds smoothly to give unstable carbene complexes, which in turn undergo 1,2-hydrogen-, alkyl-, and aryl-migration to afford in good yield 6-5-5 tricyclic indole skeletons having an alkyl or an aryl substituent at the 3-position of the indole nucleus.     

Synthesis of N-[2-(1-piperidinyl)ethyl]benzamides

Novel benzamide derivatives, N-[1-(aminocarbonyl)-2-(1-piperidinyl)ethyl]benzamides (4 and 5), were prepared from the reaction of beta-piperidinoalanine (6) as the starting material.     

Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors IV. A series of new derivatives containing a spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one skeleton

In the course of development of factor Xa (FXa) inhibitor in an investigation involving the synthesis of 1-arylsulfonyl-3-piperazinone derivatives, we found new compounds containing a unique spiro skeleton. Among such compounds, (-)-7-[(6-chloro-2-naphthalenyl)sulfonyl]tetrahydro-8a-(methoxymethyl)-1'-(4-pyridinyl)-spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one (28, M55529) had activity more favorable than those of previously reported compounds. The inhibitory activity of M55529 for FXa is IC(50)=2 nM, with high selectivity for FXa over thrombin and trypsin.     

Synthesis of certain alkenyl purines and purine analogs

Synthesis of alkenyl derivatives of certain purines and purine analogs is described. Direct alkylation of the sodium salt of 6-chloropurine (1) either with 1-bromo-2-pentene or 4-bromo-2-methyl-2-butene in N,N-dimethylformamide furnished N-7, 4a and N-9, 3a , 3b alkenyl derivatives. Similar alkylation of 2-amino-6-chloropurine (2) provided the corresponding N-7, 4c-4e and N-9, 3c-3e alkenyl derivatives. Acid hydrolysis of these chloro derivatives 3a-3e, 4a,c-e furnished the corresponding alkenyl hypoxan-thines 6a, 6b and 7a or alkenyl guanines 6c-6e and 7c-7e. Treatment of 3a-3d with thiourea in absolute ethanol provided the corresponding 6-thio derivatives 5a-5d. Alkylation of the sodium salt of either purine-6-carboxamide (8) or 1,2,4-triazole-3-carboxamide (10) gave mainly one isomer 9a, 9b and 11a, 11b. The direct alkylation of pyrrolo[2,3-d]pyrimidin-4(3H)-one (12) gave N-3 alkenyl derivatives 13a, 13b , and the N-7 alkenyl derivatives 16a, 16b have been prepared starting from the 4-chloro derivative 14 . Synthesis of 2-amino-7-(2-penten-1-yl)pyrrolo[2,3-d]pyrimidin-4(3H)-one (19a) has been accomplished starting from 2-amino-4-methoxypyrrolo[2,3-d]pyrimidine (17) . These alkenyl derivatives were found to be devoid of anti-HCMV activity in vitro.     

1,1,4,4-Tetranitrobutane-2,3-diol and its derivatives. 4. Study of the reaction of 1,1,4,4-tetranitrobutane-2,3-diol with N-(methoxymethyl)-2-fluoro-2,2-dinitroethylamine; synthesis and crystalline structure of 1,12-difluoro-1,1,3,5,5,8,8,10,12,12-decanitro-3,10-diazadodecane-6,7-diol dinitrate

A two-step synthesis has been proposed to obtain 1,12-difluoro-1,1,3,5,5,8,8,10,12,12-decanitro-3,10-diazadodecane-6,7-diol dinitrate, starting from 1,1,4,4-tetranitrobutane-2,3-diol and N-(methoxymethyl)-2-fluoro-2,2-dinitroethyl-amine, followed by nitration of the Mannich base formed. An x-ray-diffraction investigation of the dinitrate obtained was carried out.Insitute of Chemical Physics, Russian Academy of Sciences, 142432 Chernogolovka. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 3, pp. 671–675, March, 1992.     

Synthesis and anti-hyperlipidemic evaluation of N‑(benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide derivatives in Triton WR-1339-induced hyperlipidemic rats

The lipid-lowering activity of a series of novel N-(benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide derivatives has been studied in Triton WR-1339-induced hyperlipidemia in rats. The test animals were divided into four groups: control, hyperlipidemic, compound + 4% DMSO [C1: N-(2-benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide (1), C2: N-(3-benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide (2), C3: N-(4-benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide (3)]-treated and bezafibrate (BF)-treated. At a dose of 15 mg/Kg body weight, compounds 2, 3 and BF significantly reduced elevated plasma triglycerodes levels after 12 h. Moreover, high density lipoprotein-cholesterol levels were significantly increased in all treated groups after 12 h compared to the hyperlipidemic control group, except for C1 which was inactive. In sum, it may be stated that the results of the present study demonstrated new properties of some N-(benzoylphenyl)-5-fluoro-1H-indole-2-carboxamide derivatives as potent lipid lowering agents and these beneficial activities may contribute to their cardioprotective and antiatherosclerotic role.