4-(1-benzoylindol-3-yl)butyric acids and FK143: novel nonsteroidal inhibitors of steroid 5 alpha-reductase (II).

A novel series of indolebutyric acids with varying benzoyl substituents were synthesized to develop nonsteroidal inhibitors of steroid 5 alpha-reductase. We previously reported the discovery of a novel nonsteroidal 5 alpha-reductase inhibitor, FR119680, which had an IC50 value of 5.0 nM against the rat prostatic enzyme. However, this compound was not strongly active against the human prostatic enzyme. By further study of the structure-activity relationships we succeeded in producing the strongly active compound, FK143, 4-[3-[3-[bis(4-isobutylphenyl)-methylamino]benzoyl]-1H-indol-1-yl] butyric acid, with an IC50 value of 1.9 nM against the human enzyme. FK143 also has in vivo inhibitory activity against the castrated young rat model and it should therefore be an extremely useful agent for the treatment of benign prostatic hyperplasia.     

A novel class of inhibitors for human steroid 5 alpha-reductase: phenoxybenzoic acid derivatives. I.

In a search for novel nonsteroidal inhibitors of human prostatic 5 alpha-reductase, we found a new series of phenoxybenzoic acid derivatives to be potent human prostatic 5 alpha-reductase inhibitors. Among them, 4-(biphenyl-4-yloxy)benzoic acid derivatives (2n, YM-31758), 2o and 2s showed more potent inhibitory activities than finasteride with IC50 values of 0.87, 0.67 and 0.56 nM, respectively. The optimized structures for the phenoxybenzoic acid derivatives 2d-2i were calculated by molecular modeling analysis, and the favorable distance between the carbon of the carboxyl group and the centroid of the phenyl group (benzene ring C) was found to be in the 9-11 A range.     

Synthesis of tricyclic compounds as steroid 5alpha-reductase inhibitors

A series of 4-phenoxybutyric acid derivatives attached to a tricyclic skeleton were prepared and evaluated as 5alpha-reductase inhibitors. Structure activity relationships for these compounds in terms of rat epididymis (type 2) 5alpha-reductase inhibitory activities reveal that 1) the substitution pattern at the 11-position of dibenz[b,e]oxepin influenced potency, 2) higher lipophilicity of the tricyclic skeleton improved potency, whereas the existence of a basic nitrogen atom in this skeleton was detrimental to potency, and 3) isobutyl substitution at the 8 positon of the azepine skeleton was tolerated. Among the tricyclic compounds studied, 4-[3-[5-benzyl-8-(2-methyl)propyl-10,11-dihydrodibenz[b,f]azepine- 2-carboxamido]phenoxy]butyric acid (26) was the most potent inhibitor of rat type 2 5alpha-reductase at 0.1 microM.     

A novel class of inhibitors for human steroid 5alpha-reductase: synthesis and biological evaluation of indole derivatives. II

In a search for novel nonsteroidal inhibitors of human prostatic 5alpha-reductase, we found a new series of indole derivatives that showed potent inhibitory activities for the human enzyme. Among them, 4-[(1-benzyl-1H-indol-5-yl)oxyl-3-chlorobenzoic acid (2d, YM-32906) showed more potent inhibitory activity than finasteride with an IC50 value of 0.44 nM. 3-Chloro-4-[[1-(4-phenoxybenzyl)-1H-indol-5-yl]oxy]benzoic acid (2m) showed inhibitory activities for both human and rat prostatic 5alpha-reductase with IC50 values of 2.1 and 73 nM, respectively. The synthesis and structure-activity relationships of these indole derivatives are presented.     

Functionalization of 5-(4-alkoxybenzyl)-4-R-4<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazole-3-thiols. Synthesis of novel DNA methylation inhibitors

Aminomethylation and cyanoethylation reactions of 5-(4-alkoxybenzyl)-4-methyl(phenyl, allyl)-4H-1,2,4-triazole-3-thiols have been investigated. According to NMR spectroscopy data, the reactions occur at the nitrogen atom Ν². The effect of the synthesized compounds on cancer DNA methylation has been evaluated.     

Preparation of 4-(azol-1-yl)butyric acids by the interaction of azoles with γ-butyrolactone

The interaction of salts of imidazole, 1,2,4-triazole, benzimidazole, and 2-benzylbenzimidazole with γ-butyrolactone has been studied. Ab initio quantum-chemical calculations showed a preference for N-alkylation on interaction of azolates with γ-butyrolactone. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6. pp. 910–916, June, 2007.     

N1-Substitution in 2-methyl-4(5)nitroimidazole. III. New syntheses of 1-(2′-(ethylsulfonyl)ethyl)-2-methyl-5-nitroimidazole

Some new syntheses of 1-[2′-(ethylsulfonyl)ethyl]-2-methyl-5-nitroimidazole (IV), a new antitrichomonal agent are described. The most successful method proved to be alkylation of sodium ethanesulfinate (XXI) with 1-(2′-haloethyl)-2-methyl-5-nitroimidazoles (1a,b) in dimethylformamide.     

Spectral Response to Protonation of 4-(4-(4-(Didodecylamino)phenylazo)phenyl)butyric Acid in Its Langmuir-Blodgett Monolayer

4-(4-(4-(Didodecylamino)phenylazo)phenyl)butyric acid is synthesized, and its Langmuir-Blodgett (LB) monolayer is successfully fabricated. The drastic changes in electronic spectra of this compound are found in acidic solution and in LB monolayer upon exposure to HCl vapor (mainly the decrease in absorption at 416 nm and great increase at 540 nm). The UV-visible and infrared spectra reveal a mechanism of protonation to either azo group or amino group. This phenomenon has been suggested to have its prospective application in fundamental interfacial materials for pH sensors. Copyright 2000 Academic Press.     

A novel synthesis of 2-(disubstituted amino)-5(4)phenylimidazoles

The reaction of 1-phenyl-1,2-propanedione with 1,1-disubstituted guanidines in methanol yielded 2-(disubstituted amino)-4-hydroxy-4-methyl-4H-imidazoles (III). Compound III produced 5(4)methylimidazoles by catalytic hydrogenation and 5(4)chloromethylimidazoles (IV) by concentrated hydrochloric acid treatment. Solvolysis of IV in water and alcohols gave 5(4)hydroxymethyl- and 5(4)alkoxymethylimidazoles, respectively.     

Electropolymerization of aminophthalic acids. II. Polymerization of 4-(4′-aminobenzamido)-, 4-(2′-aminobenzoyl)-, and 4-(3′-aminobenzoyl) phthalic acid

The electrochemical polymerization of the amino phthalic acid series has been extended to the following derivatives: 4-(4′-aminobenzamido), 4-(2′-aminobenzoyl), and 4-(3′-aminobenzoyl)phthalic acid. Reactions were performed in both dimethylacetamide and ethanol. Both systems produced a film deposit at the anode which was identified as the amide acid of the starting material. Conversion by heat to the imide produced a brittle coating. Inherent viscosity measurements indicate that only low molecular weight material was formed.     

Synthesis of 3-keto-4-diazo-5-α-dihydrosteroids as potential irreversible inhibitors of steroid 5-α-reductase

3-Keto-4-diazo-5-α-dihydrosteroids are prepared using the Hendrickson diazo transfer reaction on the corresponding β-diketones, which are available from 3-ketoΔ-4-steroids $\text{via}$ Li/NH₃ reduction and acylation of the kinetic enolate.     

Synthesis of novel 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines as potential protein kinase inhibitors

Abstract  A short and efficient sequence for the synthesis of a series of 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines was developed. 1-Phenyl-2-(6-pyrimidinyl)-ethanones, obtained via Weinreb’s methodology, were used in a Hantzsch thiazole cyclization reaction, followed by introduction of the aniline moieties via nucleophilic substitution. Graphical abstract        

Synthesis of 1-(4-methylsulfone-phenyl)-5-(4-fluoro-phenyl)-5-[14C]-1,2,3-triazole and 1-(4-sulfonamide-phenyl)-5-(4-fluoro-phenyl)-5-[14C]-1,2,3-triazole as novel carbon-14 anticonvulsant

Summary Two 1,2,3-triazole anticonvulsants, 1-(4-methylsulfone-phenyl)-5-(4-fluoro-phenyl)-5-[¹⁴C]-1,2,3-triazole and 1-(4-sulfonamide-phenyl)-5-(4-fluoro-phenyl)-5-[¹⁴C]-1,2,3-triazole, both labeled with carbon-14 in the 5-position were prepared from para-fluoro-benzonitrile-[cyano-¹⁴C].     

Efficient Synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric Acid

3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric acid (9) was obtained from L-methionine in six steps with a total yield of 32%. The α-amino acid segment of L-methionine was transferred to chiral aziridine by amino protection, reduction, hydroxyl derivation, and cyclization. After ring opening of 2,4,5-trifluoro-phenyl magnesium bromide, the methylthiomethyl group was then hydrolyzed to β-amino alcohol and oxidized to the target β-amino acid.     

Ortho effects in 3-methyl-5-(o-r-styryl)-4-aminoisoxazoles on electron impact. III

Electron impact mass spectra of eight of the title compounds are discussed. Based on our data a mechanism for the formation of the m/e 91 ion is proposed. Fragmentation pathways have been confirmed by measurement of the metastable peaks.