Sandor Batori

A novel orally active inhibitor of HLE.

Human leukocyte elastase (HLE) is a serine proteinase, capable of degrading a variety of structural matrix proteins. SSR69071 2-[(4-isopropyl-6-methoxy-1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methoxy]-9-(2-piperidin-1-ylethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one was selected as a novel orally active HLE inhibitor for treatment of chronic obstructive pulmonary diseases, asthma, emphysema, cystic fibrosis and several inflammatory diseases (WO 01/44245 A1) (J. Pharm. Exp. Ther., submitted for publication).

Stability and Chemical Reactivity of 7-Isopropoxyisoflavone (Ipriflavone)

The stability (hydrolysis and oxidation) of ipriflavone (7-isopropoxyisoflavone, 1) was studied under basic and acidic conditions in different solvents; the effects of irradiation were investigated in methanol. Identification of the isolated products enabled suggestions to be made concerning the mechanisms of decomposition.

Reactions of 2-dialkylamino-3H-azepines with oxidants and electrophiles

Abstract 2-n-Butoxy-3H-azepine (2) reacts with amines, anthranilic add and active methylene compounds to afford 2-aminoazepines 3 and 13, quinazolinoazepine 4 and 2-methylene-1,2-dihydro-3H-azepines 6,7, 9 and 10 respectively. The reaction of 3 with trityl tetrafluoroborate provides 3-amino-7-trityl-2-aza-1H+-norcaradienium salts 22 which on deprotonation gives 7-amino-3-trityl-3H-azepines 20. Azepines 20 on heating are converted to 2-amino-6-trityl-3H-azepines 19; they react with trialkyl oxonium salts, diazonium salts and 2-methyfthio-1 ,3-dithiolium methylsulfate to give 2-alkyl-7-trityl-2-aza-norcaradienium salts 23, azepine-3-one arylhydrazones 32 and dihydro-azadithiasesquifulvalene 34, respectively. The reaction of 3 with dimetnylmethyltrtiosuflonitim tetrafluorobrate produces sahs 24 of 2-amino-6-mthyithio-3H-azepines 25. TCNQ reacts with 25 to yield 2-amino-6-methylthio-1H+,3H-azepinium tetracyanoquinodimethanide 29. 24 is used as a starting material for the synthesis of 2,6-bis-methylthio-3H-azepine 31.

Prolyl Oligopeptidase Inhibition by N-Acyl-pro-pyrrolidine-type Molecules †

Three novel, N-acyl-pro-pyrrolidine-type, inhibitors of prolyl oligopeptidase (POP) with nanomolar activities were synthesized and their binding analyzed to the host enzyme in the light of X-ray diffraction and molecular modeling studies. We were interested in the alteration in the binding affinity at the S3 site as a function of the properties of the N-terminal group of the inhibitors. Our studies revealed that, for inhibitors with flat aromatic terminal groups, the optimal length of the linker chain is three C-C bonds, but this increases to four C-C bonds if there is a bulky group in the terminal position. Molecular dynamics calculations indicate that this is due to the better fit into the binding pocket. A 4-fold enhancement of the inhibitor activity upon replacement of the 4-CH2 group of the proline ring by CF2 is a consequence of a weak hydrogen bond formed between the fluorine atom and the hydroxy group of Tyr473 of the host enzyme. There is notably good agreement between the calculated and experimental free energies of binding; the average error in the IC50 values is around 1 order of magnitude.

Chemical reactivity of [1,2,3]triazolo[1,5-a]- and [1,5-c]-pyrimidinium salts

The chemical reactivity of the [1,2,3]triazolo[1,5-a]- and [1,5-c]-pyrimidinium salts towards morpholine, water and sodium methoxide have been studied. Among others, new 1-aza and 2-azabutadienes substituted by a [1,2,3]-triazole ring were obtained in the course of the opening of the positively charged pyrimidine ring.

Photoinduced ring transformation of pyrido-[1,2-b]pyridazinium-4-olate

Abstract The photolytic behaviour of the zwitterionic pyrido[1,2-b]pyridazinium-4-olate (1) was studied. A marked difference was observed depending on the wavelength used: irradiation with a light of λ>280 nm resulted in 3-pheny]-5-(2-pyridyl)isoxazole (2) and 2-phenyl-3-(2-pyridylcarbonyl)azirine (3) as main products, while the use of light of λ

Synthesis and biological evaluation of N-(1-aziridino)-6-fluoro- quinolone-3-carboxylic acids

New racemic N-(1-aziridino)-6-fluoro-7-(4-methylpiperazin-1-yl)-4(1H)-quinolone-3-carboxylic acids (9a-i) were synthesized and their antibacterial activities were tested against Gram-positive and Gram-negative micro-organisms. According to the MIC, all compounds studied are less active than Ciprofloxacin; two of them (9a,b) have similar activity as Nalidixic acid (1).

Reactivity of Substituted N-Aminopyridinium Salts and Their Benzologues. A Novel Approach to s-Triazolo[1,5-a]quinolinium and s-Triazolo[5,1-a]isoquinolinium Derivatives

The reaction of 1-amino-2-cyanopyridinium perchlorate with triethyl orthoformate gave an ethyl iminoformate derivative which resulted in formation of a 1-iminopyrido-as-triazinium salt in reaction with primary amine, and a formamidino derivative with secondary amine. The reaction of the latter compound with morpholine gave 2,3-diaza-1,3,5,7-octatetraene. The two benzologues of 1, N-aminoquinolinium and N-aminoisoquinolinium gave ethyl iminoformates and formamidines. In reactions with primary amines these compounds led to s-triazolo [1,5-a] quinolinium and [5,1-a] isoquinolinium salts, respectively

STUDIES ON SYNTHESIS OF 3(2H)-BENZOFURANONE DERIVATIVES

ABSTRACT Two known methods were used for synthesis of 2,6-disubstituted-3(2H)-benzofuranone derivatives. It was found that depending on the reaction conditions, degradation products or the products of oxidation were isolated. This latter reaction became the main process when the ring closure was performed starting from methoxy- or 2-propoxy-desoxybenzoin and diethyl bromo-(or chloro-)-malonate to give d,l- and meso-dimers of the substituted 3(2H)-benzofuranones.

I. Discovery of a novel series of CXCR3 antagonists. Multiparametric optimization of N,N-disubstituted benzylamines.

N,N-Disubstituted benzylamine derivatives have been identified as CXCR3 antagonists. Compounds were optimized to improve affinity and selectivity, to increase metabolic stability in human and mouse liver microsomes, to increase Caco-2 permeability. Optimization was supported by monitoring physico-chemical properties using both experimental and computational means. Several compounds with double-digit nanomolar CXCR3 affinity, favorable selectivity, microsomal stability, Caco-2 permeability and human hepatocyte clearance have been identified.