Synthese und Eigenschaften 6-substituierter 4-Alkoxy-5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-one

Synthesis and Properties of 6-Substituted 4-Alkoxy-5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-ones Reactions of the N-alkoxy-2-(2-thienyl)glycolamides 1B with dicyclohexylcarbodiimide yield the 4-alkoxy-5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-ones 2b . Acid catalyzed methanolysis of the tetrahydropyranyl group in 2B, Bk results in the formation of the bicyclic lactams 5 .     

Design and synthesis of some oxadiazolyl, thiadiazolyl, thiazolidinyl, and thiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents

Four series of 1H-pyrazole derivatives have been synthesized. The first series was prepared by cyclization of the intermediate 3-(5-bromo-2-thienyl)-1-phenyl-1H-pyrazole-4-carbaldehyde aroyl-hydrazone 4a-c with acetic anhydride to afford the corresponding oxadiazoline derivatives 5a-c. The other series were prepared by the cyclization of the intermediate 3-(5-bromo-2-thienyl)-1-phenyl-4-substituted thiocarbamoylhydrazonomethyl-1H-pyrazole 6a-c with acetic anhydride, ethyl bromoacetate or phenacyl bromide giving rise to 3-(5-bromo-2-thienyl)-1-phenyl-4-[3-acetyl-5-(N-substituted acetamido)-2,3-dihydro-1,3,4-thiadiazol-2-yl]-1H-pyrazoles 7a-c, 3-(5-bromo-2-thienyl)-1-phenyl-4-(3-substituted- 4-oxothiazolidin-2-ylidenehydrazonomethyl)-1H-pyrazoles 8a-c, or 3-(5-bromo-2-thienyl)-1-phenyl-4-(3-substituted-4- phenyl-2,3-dihydrothiazol-2-ylidenehydrazonomethyl)-1H-pyraz oles 9a-c respectively. Some of these compounds showed anti-inflammatory, antibacterial or antifungal activities comparable to that of Proquazone, Ampicillin, or Clotrimazole respectively.     

Newer substituted benzoxazepinyl-quinazolinones as potent antipsychotic and anticonvulsant agents

3-Amino-[2'-substitutedaryl-3'-substitutedarylaminomethylene-2',3'- dihydro-1',5'-benzoxazepin-4'-yl]-2-methyl-quinazolin-4(3H)-ones 11-18 and 3-amino-[2'-substituted aryl-3'-substitutedaryl-azo-2',3'- dihydro-1',5'-benzoxazepin-4'-yl]-2-methyl-quinazolin-4(3H)-ones 19-26 were synthesized from 3-amino-[2'-substitutedaryl-2',3'-dihydro-1',5'- benzoxazepin-4'-yl]-2-methyl-quinazolin-4(3H)-ones 7-10 by Mannich's reaction and by diazotisation, respectively, on the 3rd position of the benzoxazepine ring of the compounds 7-10. The newly synthesized compounds showed potent antipsychotic and anticonvulsant activities.     

Design and synthesis of poly ADP-ribose polymerase-1 inhibitors. 2. Biological evaluation of aza-5[H]-phenanthridin-6-ones as potent,aqueous-soluble compounds for the treatment of ischemic injuries

A series of aza-5[H]-phenanthridin-6-ones were synthesized and evaluated as inhibitors of poly ADP-ribose polymerase-1 (PARP-1). Inhibitory potency of the unsubstituted aza-5[H]-phenanthridin-6-ones (i.e., benzonaphthyridones) was dependent on the position of the nitrogen atom within the core structure. The A ring nitrogen analogues (7-, 8-, and 10-aza-5[H]-phenanthridin-6-ones) were an order of magnitude less potent than C ring nitrogen analogues (1-, 2-, 3-, and 4-aza-5[H]-phenanthridin-6-ones). Preliminary stroke results from 1- and 2-aza-5[H]-phenanthridin-6-one prompted structure-activity relationships to be established for several 2- and 3-substituted 1-aza-5[H]-phenanthridin-6-ones. The 2-substituted 1-aza-5[H]-phenanthridin-6-ones were designed to improve the solubility and pharmacokinetic profiles for this series of PARP-1 inhibitors. Most importantly, three compounds from this series demonstrated statistically significant protective effects in rat models of stroke and heart ischemia.     

Synthesis and antifungal activity of 9-aryl-8-(2-thienyl)-4,9-dihydrotetrazolo-[1′,5′-1,2]pyrimido[4,5-d]pyridazin-5(6 h)-ones

A series of 9-aryl-8-(2-thienyl)-4,9-dihydrotetrazolo[1′,5′-1,2]pyrimido[4,5-d]pyridazin-5(6H)-ones have been obtained by reaction of equivalent amounts of methyl esters of 7-aryl-6-(2-thienyl)-4,7-dihydrotetrazolo[1, 5-a]pyrimidine-5-carboxylic acids and hydrazine hydrate at 180–190°C in the absence of solvents. The structures of the synthesized compounds have been determined based on spectral data (PMR, IR, high-resolution mass spectrometry). The synthesized compounds were tested for antimicrobial activity.     

5-Nitroimidazole derivatives as possible antibacterial and antifungal agents

Some novel 1-[2-[[5-(2-furanyl)-4-substituted 4H-1,2,4-triazol-3-yl[thio[ethyl[-2-methyl-5-nitro-1H-imidazoles (3), 1-[3-[[5-(2-furanyl/2-thienyl)-4-substituted 4H-1,2,4-triazol-3-yl[-thio]-2-hydroxypropyl[-2-methyl-5-nitro-1H- imidazoles (5) and 1-[3-[(N,N-disubstituted thiocarbamoyl)-thio[-2-hydroxypropyl]-2-methyl-5-nitro-1H-imidazoles (7) were synthesized and evaluated for in vitro antibacterial and antifungal activity. Some of 5 were found to be effective against bacteria and fungi (minimum inhibitory concentration (MIC) 7.3-125 micrograms/ml), whereas 7 were found to be effective against fungi (MIC 3-25 micrograms/ml).     

Design,synthesis, and biological evaluation of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as new A2A and A3 adenosine receptors antagonists

In the past few years, our group has been involved in the development of A(2A) and A(3) adenosine receptor antagonists which led to the synthesis of SCH58261 (5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, 61), potent and very selective at the A(2A) receptor subtype, and N(8)-substituted-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines-N(5)-urea or amide (MRE series, b), very selective at the human A(3) adenosine receptor subtype. We now describe a large series of C(9)- and C(2)-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines to represent an extension of structure-activity relationship work on this class of tricyclic compounds. The introduction of a substituent at 9 position of the tricyclic antagonistic structure led to retention of receptor affinity but a loss of selectivity in respect to the lead compounds b, N(8)-substituted-pirazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines-N(5)-urea or -amide. The substitution of the furanyl moiety of compound 61, necessary for receptor binding, with a phenyl or a substituted aromatic ring (compounds 5a-d, 6-8), caused a complete loss of the affinity at all the adenosine receptor subtypes, demonstrating that the furanyl ring is a necessary structural element to guarantee interaction with the adenosine receptor surface. The introduction of an ethoxy group at the ortho position of the aromatic ring to mimic the oxygen of the furan (compound 5c, 5-amino-7-(2-phenylethyl)-2-(2-ethoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) did not enhance affinity. The introduction of the cycloaminomethyl function by Mannich reaction at the 5' position of the furanyl ring of 61 and the C(9)-substituted compound 41 (5-amino-8-methyl-9-methylsulfanyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) resulted in complete water solubility but a loss of receptor affinity. We can conclude that modifications or substitutions at the furanyl ring are not allowed and the introduction of a substituent at the 9-position of the core pyrazolo-triazolo-pyrimidine structure caused a severe loss of selectivity, probably due to an increased steric hindrance of the radical introduced.     

Synthesis of some novel quinoline-3-carboxylic acids and pyrimidoquinoline derivatives as potential antimicrobial agents

The synthesis and in vitro antimicrobial evaluation of several quinoline and pyrimidoquinoline derivatives are described. Treatment of 7-substituted quinolin-2(1H)-one-3-carboxylic acids 2a-c with phosphoryl chloride or thionyl chloride gave rise to the 7-substituted 2-chloroquinoline-3-carboxylic acids 3a-c and 7-substituted 2-chloro-3-chlorocarbonylquinolines 5a-c respectively. The 2-chloro function in compounds 3a-c was replaced by 2-aminothiazole or 2-aminopyridine to give 2-(thiazol-2-yl)aminoquinoline-3-carboxylic acids 4a-c or 2-(pyrid-2-yl)aminoquinoline-3-carboxylic acids 4d-f. Treatment of 5a-c with the same heterocyclic amines at room temperature furnished the corresponding 7-substituted 2-chloro-3-heteryl-aminocarbonylquinolines 6a-f. The tetracyclic 9-substituted thiazolo[3', 2':1, 2]-pyrimido[4, 5-b]quinolin-5-ones 7a-c and 10-substituted pyrido[1', 2':1, 2]-pyrimido[4, 5-b]quinolin-6-ones 7d-f were synthesized by heating 5a-c with the heterocyclic amines in toluene or by heating 6a-f under reflux in dimethylformamide. The products were evaluated in vitro for potential antimicrobial activity.     

Synthesis and benzodiazepine receptor affinity of pyrazolo[1,5-a]pyrimidine derivatives. 3. New 6-(3-thienyl) series as alpha 1 selective ligands

New 3-aryl-6-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-ones (2a-j) are synthesized and evaluated in vitro on Bz/GABA(A) receptors and on recombinant benzodiazepine receptors (alpha x beta 2/3 gamma 2; x = 1-3, 5) expressed in HEK293 cells. SAR studies on the new compounds are conducted and molecular modeling is accomplished to better investigate requirements leading to subtype selectivity. Some of the synthesized compounds are tested in vivo to explore their pharmacological effect as a consequence of their high alpha 1 beta 2 gamma 2 subtype selectivity observed in vitro.     

Synthesis of 2,3,5,6-tetrahydro-3H-imidazo[2,1-b] [1,3,5]benzotriazepines and their oxidative ring contraction into 1-(4,5-dihydro-1H-imidazol-2-yl)-1H-benzimidazoles

Syntheses of novel 5-aryl-2,3,5,6-tetrahydro-3H-imidazo[2,1-b] [1,3,5]benzotriazepine derivatives 3a-g were performed by reacting 2-(2-aminoarylimino)imidazolidines 1a-b with corresponding aryl aldehydes. The compounds 3 incorporating aminal group upon treatment with 2,3-dichloro-5,6-dicyano-1,2-benzoqinone (DDQ) underwent the oxidative ring contraction to give 1-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-benzimidazoles 4a-g. Reactions of the compounds 1a-c with carbonyldiimidazole (CDI) afforded novel 2,3,5,6-tetrahydro-1H-imidazo[2,1-b] [1,3,5]benzotriazepin-5-ones 5a-c which when heated in boiling methanol gave the corresponding 1-(4,5-dihydro-1H-imidazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-ones 6a-c. Radioligand binding studies using rat central imidazoline I2 receptors and alpha2-adrenoceptors demonstrated that benzimidazoles 4a-g display a low affinity (microM) for these receptors while benzimidazol-2-ones 6a-b elicited a moderate affinity for I2 receptor with Ki values of 490 and 220 nM, respectively.     

Synthesis and antitumor activity of 1-[[(dialkylamino)alkyl]amino]-4-methyl-5H-pyrido[4,3-b]benzo[e]- and -benzo[g])indoles. A new class of antineoplastic agents

The thermal Fischer indolization of hydrazones resulting from 4-hydrazino-5-methyl-1H-pyridin-2-one and various beta- and alpha-tetralones led to 4-methyl-6,7-dihydro-2H,5H-pyrido[4,3- b]benzo[e]indol-1-ones and 4-methyl-11-dihydro-2H,5H-pyrido[4,3- b]benzo[g]indol-1-ones, respectively. After aromatization, these compounds were transformed by phosphorus oxychloride, giving 1-chloro-4-methyl-5H-pyrido[4,3- b]benzo[e]- and -benzo[g]indoles which were substituted by [(dialkylamino)alkyl]amines. The resulting 1-[[(dialkylamino)alkyl]amino]-4-methyl-5H-pyrido- [4,3-b]benzo[e]- and -benzo[g]indoles, as well as hydroxy derivatives obtained by demethylation of methoxylated compounds with hydrobromic acid, were tested for antitumor activity in vitro (leukemic and solid tumor cells) and in vivo on various experimental tumor models using the standard NCI protocols. 1-[[3-(Dialkylamino)propyl]-amino]-4-methyl-9-hydroxy-5H-pyrido[4,3- b]benzo[e]indoles appeared as a promising new class of antineoplastic agents.     

Design and synthesis of some substituted 1H-pyrazolyl-oxazolidines or 1H-pyrazolyl-thiazolidines as anti-inflammatory-antimicrobial agents

Four series of 1 H-pyrazole derivatives have been synthesized. The first series was synthesized starting with the reaction of 3-(5-bromo-2-thienyl)-1-phenyl-1 H-pyrazole-4-carboxaldehyde 1 with L-serine, L-cysteine, or L-penicillamine, followed by N-protection using (Boc)(2)O to provide compounds 2. The latter compounds could be N-deprotected by 4N HCl/dioxane to afford the second series 3 or reacted with NH(4)OH in the presence of DCC/HOBt to give the corresponding amides 4 followed by N-deprotection giving rise to compounds 5. The newly synthesized compounds were evaluated for their anti-inflammatory-antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compound 5b (2RS, 4R)-2-[3-(5-bromo-2-thienyl)-1-phenyl-1H-pyrazol-4-yl]-5-methylthiazolidine-4-carboxamide, proved to be the most active anti-inflammatory-antimicrobial agent in the present study with a good safety margin and no ulcerogenic effect.     

Synthesis of 11-aryl-5H-imidazo[2,1-c][1,4]benzodiazepines and their benzodiazepine and A1 adenosine binding activity.

In the context of a research program aimed at elucidating the properties of the 5H-imidazo[2,1-c][1.4]benzodiazepine system, a series of 11-aryl-5H-imidazo[2,1-c][1,4]benzodiazepines (3a-i) and their 10,11-dihydro-derivatives (4a-i) has been synthesized. The synthetic strategy includes the preparation of the aryl-[1-(2-nitrobenzyl)-1H-imidazol-2-yl]methanones (5a-i) followed by their reduction and subsequent cyclization. Affinities of compounds 3a-i and 4a-i for central benzodiazepine as well as for adenosine A1-receptors were determined by radioligand binding assays. Among the unsaturated analogues, the highest activity at both receptors is displayed by 1H-(2-thienyl) derivative 3e. The hydrogenated analogues 4a-i do not exhibit considerable binding affinity either for central benzodiazepine or for adenosine A1-receptors.     

Reactions with Heterocyclic Arylazo Compounds: Synthesis of New 1-Azoloylimidazolones

Several new carboxamide derivatives of 1-azoloylimidazolones and 1-aryl-1,2,4-triazolones were synthesised by reaction of 2-alkoxy-4-benzylidene-2-thiazolin-5-ones and 2-alkoxy-4-phenylhydrazone-2-thiazolin-5-ones with heterocyclic amines.     

Studies on the synthesis andin vitro antitumor activity of the isoquinolone derivatives

3-Arylisoquinolin-1(2H)-ones (2) are possible bioisosteres of the 5-[4'-(piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,1-a]iso quinoline (1) which is in clinical evaluation for the treatment of cancer. Structure-activity relationship studies of 3-arylisoquinolin-1(2H)-ones (2) led to the synthesis of 3-arylquinolin-2(1H)-ones (3). A number of 3-phenyl substituted quinolin-2(1H)-ones were synthesized and tested for their in vitro antitumor activity against four different human tumor cell lines and 3-phenyl-N-benzyl-3,4-dihydroquinolin-2(1H)-one (12) showed the most potent activity.     

Synthesis, anti-HIV and anticancer activities of new 4-(2-mercaptobenzenesulfonyl)perhydro-1,2,4-triazin-3-ones

Syntheses of N-(6-chloro-1,1-dioxo-7-R1-1,4,2-benzodithiazyn-3-yl)-N'-(2- hydroxyethyl)hydrazines (IIa-d], N-(6-chloro-1,1-dioxo-7-methyl-1,4,2-benzodithiazyn-3-yl)-N'-(2- chloroethyl)hydrazine [IV], 4-(4-chloro-5-R1-2-mercaptobenzenesulfonyl)perhydro-1,2,4-triaz in-3-ones [IIIa-d] and 5-chloro-4-methyl-2-(3-oxoperhydro-1,2,4-triazin-4- ylsulfonyl)phenylthioacetic acid [V] have been described. Preliminary screening data have indicated that compounds [IIIa-d] exhibit either a moderate or a high anti-HIV activity and a moderate anticancer activity in some human tumor cell lines.     

Synthesis and biological properties of thiophene ring analogues of mianserin

The synthesis of two thiophene-containing analogues of mianserin, i.e., 1,2,3,4,10,13b-hexahydro-2-methylpiperazino[1,2-a]thieno[2, 3-c][1]benzazepine (2), and the corresponding [3,2-c] isomer (12) is described. The key step in the synthesis is the nucleophilic aromatic substitution reaction of the N-lithio derivative of 1-methyl-3-(2-thienyl)piperazine (4) with the oxazoline derivative of o-anisic acid (7) to give the N-phenylpiperazine 8. This substance was converted via ethyl ester 10 to 1-[2-(hydroxymethyl)phenyl]-4-methyl-2-(2-thienyl)piperazine (3), which was cyclized with polyphosphate ester to a 5:1 mixture of 2 and 12. The antidepressant potential of 2 maleate (CGS 11049A) and 12 fumarate (CGS 15413A) were compared with that of mianserin hydrochloride in a variety of biochemical and pharmacological test systems. The three substances exhibited generally similar profiles. However, the results suggest that 2 and 12 bind more strongly to central presynaptic alpha-receptors than does mianserin.     

Synthesis and hypnotic activity of new 4-thiazolidinone and 2-thioxo-4,5-imidazolidinedione derivatives

Conveniently accessible 4-[(2-(3,4-dimethoxyphenyl)ethyl]-3-thiosemicarbazide (2) was converted to new 1-substituted benzylidene/furfurylidene-4- [2-(3,4-dimethoxyphenyl)ethyl]-3-thiosemicarbazides (3) which furnished 2-(substituted benzylidene/furfurylidene) hydrazono-3-[2-(3,4-dimethoxyphenyl)ethyl]thiazolidin-4-ones (4) and 1-(substituted benzylidene/furfurylidene)-amino -3-[2-(3,4-dimethoxyphenyl)ethyl]-2-thioxo-4,5-imidazolidinedio nes (5) on reaction with chloroacetic acid and oxalyl chloride, respectively. The structure of 5 was confirmed by X-ray diffraction studies performed on 5a. 4 and 5 were evaluated for their potentiating effects on pentobarbital induced hypnosis. Most of the compounds caused remarkable increases in pentobarbital sleeping time.     

3-Alkoxy-1.2.3-oxathiazolidin-4-on-2-oxide und 1-Alkoxy-indolin-2-one aus N-Alkoxyglykolamiden und Thionylchlorid oder 1.1′-Thionyldiimidazol

3-Alkoxy-1.2.3-oxathiazolidin-4-one-2-oxides and 1-Alkoxyindolin-2-ones from N-Alkoxyglycolamides and Thionyl Chloride or 1.1′-Thionyldiimidazole The reaction of N-alkoxyglycolamides 1 with thionyl chloride or 1.1′-thionyldiimidazole is shown to produce, dependending on the substituents at C-2 in 1 , either 3-alkoxy-1.2.3-oxathiazolidin-4-one-2-oxides 4 or 1-alkoxy-3-arylindolin-2-ones 6 .     

Photolyse von 4-Amino-, 4-Alkoxy- und 4-Hydroxy-2,3-dimethyl-1-phenyl-3-pyrazolin-5-onen

Photolysis of 4-Amino-, 4-Alkoxy- and 4-Hydroxy-2,3-dimethyl-1-phenyl-3-pyrazolin-5-ones After the splitting of the amino-group the photolysis of 4-amino-3-pyrazolin-5-ones (type 1) leads to 2 and 3 . 4-Hydroxy-3-pyrazolin-5-one 4 , which was formed as an intermediate, fragments to 2 and 3 in basic medium but in neutral medium 5 is obtained. In methanolic solution the 4-alkoxy-3-pyrazolin-ones 6 and 7 yield, respectively, 8 and 9 .