Synthesis and hypoglycemic activity of substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines.

A series of alkyl- and halo-substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines were prepared using two approaches, the condensation of alpha-halocarbonyl derivatives with an aminopyrazine or the oxidation-dehydration of a [(beta-hydroxyalkyl)amino]pyrazine. These imidazo[1,2-a]pyrazines were evaluated for their binding affinity to the alpha 1, alpha 2, beta 1, and beta 2 adrenergic receptors as well as their ability to lower blood glucose in insulin resistant hyperglycemic ob/ob mice. Modifications on 8-(1-piperazinyl)imidazo[1,2-a]pyrazine (4) reduced alpha 2 binding, lowered hypoglycemic potency, and showed variations in binding to the alpha 1, beta 1, and beta 2 adrenergic receptors. In addition to 4, the 2-methyl, 3-methyl, and 5-methyl 8-(1-piperazinyl)imidazo[1,2-a]pyrazines (16k, 25m, and 16f, respectively) displayed high affinity for the alpha 2 receptor and were potent hypoglycemic agents when compared to 2-amino-7,8-dihydro-4-(1-piperazinyl)-6H-thiopyrano[3,2- d]pyrimidine (MTP-1403, 2). Receptor binding was modified by use of a 4-methylpiperazine moiety which reduced alpha 1 and beta 1 binding while retaining some hypoglycemic activity. The structure-activity relationship for heterocyclic alkyl and halo substitution on biological activity is discussed.     

(S,S)-2,8-二氮杂双环[4.3.0]壬烷的合成

以吡啶-2,3-二羧酸为原料,经过双酯化、酯羰基还原、醇羟基氯代,与对甲苯磺酰胺环合、吡啶环氢化,用D-酒石酸拆分和脱保护七步反应合成氟喹诺酮类抗菌药盐酸莫西沙星的关键中间体(S,S)-2,8-二氮杂双环[4.3.0]壬烷,总收率32%,光学纯度99.7%。     

Synthesis and biological activity of substituted 2-(4-imidazolyl)ethylamines

The synthesis of 2-(4-imidazolyl)ethylamines with hydrocarbon substituents on the heterocyclic ring or on the side-chain, from 2-acylbutyrrolactones (V) or from similar ester-type open structures (VII) is described in this paper. In particular, the results already obtained, show that the scheme given for the preparation of 2-(5-methyl-4-imidazolyl)ethylamines can be rendered general, by suitable variations correlated more with side-chain branching, than with the nature of the heterocyclic ring substituents. Synthetized imidazolyethylamines have been preliminarily tested for their properties towards H2 receptors and, secondly, towards H1 receptors.     

Synthesis and biological activity of 1-N-[4-(substituted)amidino and guanidino-2-hydroxybutyryl]kanamycins A and B

The synthesis and biological properties of 1-N-[4-(substituted)amidino and guanidino-2-hydroxybutyryl]kanamycins A and B are described. Reaction of 3,3",6'-tri-N-tert-butoxycarbonyl-amikacin with an appropriate amidinating or guanidinating reagent and subsequent deblocking gave a series of amikacin derivatives having an amidino or guanidino group on the 4"'-position. The corresponding kanamycin B analogs were also prepared by a similar procedure. Among these derivatives, 1-N-(4-formamidino- and guanidino-2-hydroxybutyryl)kanamycins A (7a and 7k) and B (11 and 14) exhibited antibacterial activity similar to the corresponding 4-amino analogs. The nephrotoxic potential of selected compounds is also briefly discussed.     

Synthesis and biological activity of dynorphin-(1 - 13) and analogs substituted in positions 8 and 10

Dynorphin-(1–13) (Dyn-(1–13)) and various analogs substituted in positions 8 and 10 were synthesized by the solid-phase technique and analyzed for their ability to inhibit the electrically evoked contraction of the guinea pig ileum (GPI) and to compete with the binding of [³H]-ethylketocyclazocine (EKC, k ligand), [³H]-[D-Ala², MePhe⁴-Gly-ol⁵]-enkephalin (DAGO, μ ligand) and [³H]-[D-Ser², Thr⁶]-Leu-enkephalin (DSLET, δ ligand) to membrane preparations of the guinea pig cerebellum or rat brain. Introduction of Ala in position 8 decreased the activity of the peptide on the GPI by 50% but induced a 2.22-fold increase in its affinity for the k receptor ([³H]-EKC binding displacement from guinea pig cerebellum; Ki of 0.05 nM as compared with 0.11 nM for Dyn-(1–13)). On the other hand, the ability of [Ala⁸]-Dyn-(1–13) to displace the binding of [³H]-DSLET from rat brain membranes was decreased by a factor of 1.7 while its affinity for the μ receptor was not greatly affected ([³H]-DAGO displacement; Ki of 0.44nM as compared with 0.50nM for Dyn-(1–13)). Replacement of position 8 by D-Ala caused similar changes in the activity of the peptide but the increase in its affinity for the k site was somewhat smaller (Ki of 0.08 nM as compared with 0.11 nM). [D-Pro¹⁰]-Dyn-(1–13) was equipotent to [Ala⁸]-Dyn-(1–13) in the GPI but its affinity for the μ binding site was decreased by a factor of 2.7 as compared with Dyn-(1–13). The affinity of [D-Pro¹⁰]-Dyn-(1–13) for the other binding sites (k and δ) was not greatly affected. Replacement of positions 8 or 10 by Trp or D-Trp decreased the activity on the GPI by more than 50% as well as the affinity for most receptor types. These data indicate that the selectivity of Dyn(1–13) for the k opioid receptor can be increased either by increasing its affinity for the K binding site ([Ala⁸]-Dyn-(1–13)) or lowering its potency for other binding sites, [Ala⁸]-Dyn-(1–13) being less potent on δ sites and [D-Pro¹⁰]-Dyn-(1–13) less potent on μ sites.     

Synthesis and biological evaluation of 3,7-diazabicyclo[4.3.0]nonan-8-ones as potential nootropic and analgesic drugs

A series of cis and trans 3,7-diazabicyclo[4.3.0]nonan-8-ones has been synthesized and tested for their ability to revert scopolamine-induced amnesia in the mouse passive-avoidance test. The racemates of the most potent compounds 4 and 7 were separated and tested, but no enantioselectivity was found for the nootropic activity. Compounds 4 and 7 and their enantiomers displayed interesting antihyperalgesic activity in two models of neuropathic pain (streptozotocin-induced and oxalilplatin-induced neuropathy) in comparison with pregabalin.     

Synthesis and antitumor activity of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones

The synthesis of 3-(5-imidazo]2,1-blthiazolylmethylene)-2-indolinones, analogs of compounds recently published, is described. The EIZ isomerism was studied by means of nuclear Overhauser effect experiments and X-ray crystallography. All the compounds were tested as potential antitumor agents. They were also tested as potential inhibitors of cyclin-dependent kinase 1 (CDK1), in order to determine if the antitumor activity was related to this mechanism of action. The results showed that under certain substitution conditions (5-methoxy group for the indole benzene ring and 2-methyl group for the imidazothiazole system), an interesting antitumor activity was found for some compounds. From the analysis of the antitumor data, 3-1(2,6-dimethylimidazo[2,1-bJ-thiazol-5-yl)methylenel-5-methoxy-2-indolinone was the most active of the whole series.     

Synthesis and antiulcer activity of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo [1,5-a]pyrimidine-7-ones

A series of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo-[1,5-a]pyrimidine-7-ones were synthesized and evaluated for the inhibition of stress-induced gastric ulcers in the rat after oral administration. Several molecules were found to be very active. The particularly interesting compound (E)-1-(3-chlorophenyl)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo[1,5-a]- pyrimidine-7-one was chosen for wider pharmacological investigation.     

Synthesis and antiviral activity of bisquaternary salts of 3,12-bis(3'-haloacyl)-3,12-diaza-6,9-diazoniadispiro[5.2.5.2]hexadecane

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 23, No. 3, pp. 307–310, March, 1989.     

Synthesis and biological activity of 1-aryl-2-oxa-5-aza-5r1-6-oxocyclooctano[6,7-b]indoles

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 26, No. 6, pp. 23–26, June, 1992.     

Synthesis and antibronchospastic activity of 8-alkoxy- and 8-(alkylamino)imidazo[1,2-a]pyrazines.

Theophylline still occupies a dominant place in asthma therapy. Unfortunately its adverse central nervous system (CNS) stimulant effects can dramatically limit its use, and adjustments in the dosage are often needed. We have synthesized a new series of imidazo[1,2-alpha]pyrazine derivatives which are much more potent bronchodilators than theophylline in vivo and do not exhibit the CNS stimulatory profile. In vitro studies on isolated rat uterus and guinea pig trachea confirm the high potentialities of these derivatives. 6-Bromo-8-(methylamino)imidazo[1,2-alpha]-pyrazine-3-carbonitrile (23) is identified as the most potent compound of the series. As in the case of theophylline, phosphodiesterase inhibition appears unlikely to be the unique mechanism of action of this series of heterocycles.     

Synthesis and antidepressant activity of some new 8-thiocarbamoyl-7,8-diazabicyclo[4.3.0]non-6-ene derivatives.

Several 8-thiocarbamoyl-7,8-diazabicyclo[4.3.0]non-6-enes were prepared by condensing two alpha,beta-unsaturated ketones (2-benzylidene and 2,6-dibenzylidene cyclohexanones) with hydrazine hydrate and reacting the resulting compounds with various isothiocyanates. The structures of the synthesized compounds were confirmed by spectra (IR, 1H-NMR) and microanalysis; they were tested for antidepressant activity using Porsolt's behavioural despair test.     

Synthesis and biological activity of 5-(4-[2-(Methyl-p-substituted phenylamino)ethoxy]benzyl)thiazolidine-2,4-diones

Thiazolidinedione derivatives are potential antidiabetic drugs that bind and activate peroxisome proliferator activated receptor gamma (PPARgamma), which is a member of the nuclear hormone receptor superfamily and enhances insulin sensitivity. In an effort to develop a novel and effective thiazolidindione derivative, 5-{4-[2-(methyl-p-substituted phenylamino) ethoxy] benzyl} thiazolidine-2,4-diones 7 have been prepared by Mitsunobu reaction of the hydrophobic segment, methyl-p-substituted phenylaminoethanol 4 with hydroxybenzylthiazolidinedione 5 and their ability to activate PPARgamma and inhibit LPS-induced NO production were evaluated.     

Synthesis and anti-HIV activity of N'-nicotinoyl--3-(4'-hydroxy-3'-methylphenyl)-5-[substituted phenyl]-2-pyrazolines

A series of N'-nicotinoyl-3-(4'-hydroxy-3'-methylphenyl)-5-(substituted phenyl)-2-pyrazolines were synthesized by the reaction between isoniazid (INH) and chalcones and were tested for their in vitro anti-HIV activity. Among them, compound (c) showed a promising anti-HIV activity in vitro against used strains (IIIB, ROD), with IC50 of both IIIB 5.7 microM and ROD 7.0 microM.     

Semisynthetic beta-lactam antibiotics. III. Synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)-2-(substituted carbamoylmethoxyimino)acetamido]cephalosporins

Syntheses of cephalosporins modified with a 7 beta-[2-(2-aminothiazol-4-yl)-2-(substituted carbamoylmethoxyimino)acetamido] group at the C-7 position and with various hetero aromatics at the C-3 position are described. The effects of substituents on the carbamoyl group in the 7-side chain were investigated in order to improve antibacterial activity. Some of these compounds exhibited high antibacterial activity against Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa, as well as good resistance to beta-lactamase.