Synthesis of 2-aryl-oxazolo[4,5-c]quinoline-4(5H)-ones and 2-aryl-thiazolo[4,5-c]quinoline-4(5H)-ones

[reaction: see text] Novel and highly efficient syntheses of oxazolo[4,5-c]quinoline-4(5H)-ones (1) and thiazolo[4,5-c]quinoline-4(5H)-ones (2) from ethyl 2-chlorooxazole-4-carboxylate (4) and ethyl 2-bromo-5-chlorothiazole-4-carboxylate (13), respectively, are described.     

Solid-phase synthesis of imidazo[4,5-b]pyridin-2-ones and related urea derivatives by cyclative cleavage of a carbamate linkage

A solid-phase synthesis of substituted cyclic urea derivatives as potential heterocyclic library scaffolds is described. 2-Amino-3-nitropyridine is attached to Wang resin via a carbamate linkage. Reduction of the nitro group was achieved with SnCl(2).2H(2)O. Reductive alkylation with a range of substituted benzaldehydes followed by cyclative cleavage afforded a small library of 3-substituted imidazo[4,5-b]pyridine-2-ones in 33-45% yield and 59-88% purity. Subsequently, this methodology was applied to the synthesis of 3-substituted imidazo[4,5-f]quinolin-2-ones.     

Preparation of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction

Representatives of the 3H-imidazo[4,5-c]quinolin-4(5H)-ones have shown interesting biological activity. We have found 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-one as a potent dipeptidyl peptidase 4 inhibitor. However effective synthesis of this nucleus with various substituents at the 6-9-positions has not been reported. We report herein the development of a novel and efficient synthesis of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction. Our optimization of the reaction conditions revealed that the most important factors for this reaction are use of silver carbonate as a base and high reaction temperature.     

4-Hydroxy-2-quinolones. 36. Synthesis of 2-R-oxazolo[4,5-c]quinolin-4(5H)-ones

We consider different variants for synthesis of 2-R-oxazolo[4,5-c]quinolin-4(5H)-ones based on 3-amino-1H-2-oxo-4-hydroxyquinolines and their 3-N-acyl derivatives. We show, that in the latter case, formation of the oxazole ring is possible via two routes, depending on the nature of the substituent on the acyl residue. For Communication 35, see [1]. Ukrainian Pharmaceutical Academy, Kharkov 310002. Translated from Khimiya Geterotsiklicheskikh Soedinenii. No. 11. pp. 1536–1541, November, 1997.     

Dienophilicity of imidazole in inverse electron demand Diels-Alder reactions. 4. Intermolecular reactions with 1,2,4-triazines

Intermolecular inverse electron demand cycloadditions of 2-substituted imidazoles with various 1,2,4-triazines produced both imidazo[4,5-c]pyridines (3-deazapurines) and pyrido[3,2-d]pyrimid-4-ones (8-deazapteridines). The product distribution was controlled by reactant substituents and influenced by reaction temperature. A regioselective method for the preparation of 6-unsubstituted 1,2,4-triazines was also developed. By using this route to 8-deazapteridines, a new 8-deazafolate analogue was prepared.     

Reaction of 4-aminoimadazo[4.5-c]pyridin-2-ones with α-bromomethylketones

The reactions of 4-amino derivatives of imidazo[4.5-c]pyridin-2-ones with -bromomethylketones have been studied. Depending on the nature of the reagents and the reaction conditions, either 5-acylmethyl salts of the starting amine or 2-substituted imidazo[4.5-c]imidazo[1,2-a]pyridin-8-ones can be obtained. The latter compounds are also easily obtained by treatment of the 5-acylmethyl salts with alkali.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 227–232, February, 1986.     

The synthesis of novel 1-hetarylmethylidene-4-sulfanylfuro-[3,4-c]pyridin-3(1H)-ones

Chemistry of Heterocyclic Compounds - 1-Hetarylmethylidene-4-sulfanylfuro[3,4-c]pyridin-3-ones were accessed from 4-thioxo-4,5-dihydrofuro[3,4-c]pyridin-3(1H)-one employing a condensation reaction...     

Chemical and photochemical synthesis of substituted dihydro-thieno[2',3':4,5]thieno[2,3-c]quinolin-6-ones and tetrahydro-dithieno[2,3-b:2',3'-d]thieno[2'',3''c:2'',3''c']diquinolin-6,14-dione

Some new substituted dihydrothieno[2',3':4,5]thieno[2,3-c]quinolin-6-ones 9- 12 and tetrahydrodithieno[2,3-b: 2',3'-d]thieno[2',3'-c:2',3'-c']diquinolin-6,14-dione (17) were prepared from the corresponding new anilides 5-8 and from the corresponding dianilide 15, respectively, by a multistep combination of chemical and photochemical reactions. All the prepared compounds are of particular interest because they might serve as DNA intercalators in anticancer therapy.     

Condensed isoquinolines. 37.* Heterocyclization using 3-(arylamino)- and 3-(hetarylamino)isoquinolin-1(2H)-ones

The reaction of 3-NHR-isoquinolin-1(2H)-ones (R = Ar) with aromatic aldehydes in the presence of Me3SiCl or in acetic acid leads to the formation of derivatives of dibenzo[b,f][1, 8]naphthyridin-5(6H)- one and benzo[f]isoquino[3,4-b][1, 8]naphthyridine-5,9(6H,7H)-dione. The reaction for R = Het in the presence of Me3SiCl gives derivatives of 5H-pyrido[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one, benzo[f]isoquinoline[3,4-b][1,8]naphthyridine-5,9[6H,7H]-dione, and derivatives of new heterocyclic systems, 5H-pyrazino[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one, 5H-[1,3]thiazolo[3',2':1,2]pyrimido- [4,5-c]isoquinolin-5-one, 5-H-benzo[f]pyrazolo[3,4-b][1,8]naphthyridin-5-one, and isoquino[3,4-b]- [1,5]naphthyridin-5(6H)-one. The effect of the structure of substituent R and nature of the substituent in the benzaldehydes on the structure of the reaction products was studied.     

Ibotenic acid analogues. Synthesis and biological testing of two bicyclic 3-isoxazolol amino acids

The bicyclic 3-isoxazolol amino acids (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-4-carboxylic acid (5, 4-HPCA) and (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-6-carboxylic acid (11, 6-HPCA) were synthesized as model compounds for studies of the structural requirements of central excitatory amino acid neurotransmitter receptors. 4-HPCA was synthesized via introduction of a methoxycarbonyl group into the 4-position of the lithiated N-nitroso intermediate 1. The key reaction in the synthesis of 6-HPCA is an intramolecular N-alkylation of the appropriately substituted acetamidomalonate derivative 7 using sodium hydride as a base. On the basis of the pKA values for 4-HPCA the existence of an intramolecular hydrogen bond in the zwitterionic form of this amino acid is proposed. 6-HPCA was shown by 1H NMR spectroscopy to adopt preferentially a conformation with the carboxylate group in an equatorial position. 4- and 6-HPCA were tested as agonists and antagonists at excitatory amino acid receptors on neurones in the cat spinal cord using microelectrophoretic techniques. Neither compound showed significant effects at these receptors.     

Synthesis and pharmacological evaluation of pyrroloazepine derivatives as potent antihypertensive agents with antiplatelet aggregation activity

A series of 1-aminoalkyl-pyrrolo[2,3-c]azepin-8-one derivatives was synthesized and evaluated as alpha 1 adrenergic and serotonin 2 (5-HT2) receptor antagonists, with the aim of finding a novel antihypertensive agent potently exhibiting both activities. Some compounds with a 4-[4-(4-fluorobenzoyl)piperidino]butyl group at the 1-position exhibited both activities, and varied significantly in terms of the substituents at the 4-position of the pyrroloazepine ring. Among the compounds obtained in this study, (E)-1-[4-[4-(4-fluorobenzoyl)piperidino]-butyl]-4-hydroxyimino-7- methyl-1,4,5,6,7,8-hexahydropyrrolo[2,3-c]azepin-8-one (15a, SUN9221) displayed potent alpha 1-adrenergic antagonistic activity (pA2 = 8.89 +/- 0.21) and 5-HT2 antagonistic activity (pA2 = 8.74 +/- 0.22) in isolated guinea pig arteries. This compound exhibited antihypertensive activity and a duration of action equivalent to orally administered prazosin or doxazosin, 3 mg/kg, in conscious spontaneously hypertensive rats, as well as potent antiplatelet aggregation activity.     

Studies on Quinazolines. Part I. Annelation to the Quinazoline Ring Utilizing Amino Acid Esters

The reaction of quinazoline-4(3H)-thiones 2a-d with amino acid ester hydrochlorides in boiling solvents, under the basic catalysis, afforded the corresponding substitution products (3-6)a-e in low yield. The reaction could be improved by carrying it without a solvent yielding imidazo[1,2-c]- and pyrimido[1,2-c]quinazolines (7-10)a-e . The antibacterial and antifungal activities of the prepared compounds were tested.     

Synthesis and evaluation as NOP ligands of some spiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-ones and spiro[piperidine-4,5'(6'H)-[1,2,4]triazolo[1,5-c]quinazolines

Some spiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-ones 3 and spiro[piperidine-4,5'(6'H)-[1,2,4]triazolo[1,5-c]quinazolines] 4 were synthesized and evaluated as ligands of the nociceptin receptor. The examined compounds showed partial agonistic activity, except compounds 3, 4n that proved to be pure antagonists.     

Imidazo[1,2-a]pyridines. I. Synthesis and inotropic activity of new 5-imidazo[1,2-a]pyridinyl-2(1H)-pyridinone derivatives

A series of 1,2-dihydro-5-imidazo[1,2-a]pyridinyl-2(1H)-pyridonones was synthesized and evaluated for positive inotropic activity, 1,2-Dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2- oxo-3-pyridinecarbonitrile (11a) hydrochloride monohydrate (E-1020) was found to be a potent and selective inhibitor of phosphodiesterase III and a long-acting, potent, orally active positive inotropic agent. Additional imidazo[1,2-a]pyridin-2-yl (3a), -3-yl (16), -7-yl (20) and -8-yl (24a) compounds were also prepared. Altering the pyridine substitution from the 2-position to the 6-position produced a 2-fold increase in the i.v. cardiotonic potency (ED50) from 52 to 23 micrograms/kg, while substitution at the 3-, 7- or 8-position reduced potency. In the 2-positional isomers, introduction of halogen groups enhanced the activity and 3-chloro-1,2-dihydro-5-(6-fluoroimidazo[1,2-a] pyridin-2-yl)-6-methyl-2(1H)-pyridinone (3u) was the most potent (i.v. ED50 11 micrograms/kg) in this series. E-1020 is presently under development for the treatment of congestive heart failure.     

Preparation of novel tricyclic ring systems containing the pyridazinone ring

Novel tricyclic ring systems, irmdazo[3,4-d]pyridazino[4,5-b][1,4]thiazines 3 , imidazo[2,1-b]pyridazino[4,5-e][1,3,4]thiadiazines 15 and 18 were prepared by the reaction of 5-amino-4-chloropyridazin-3(2H)-ones 1 and 5(4)-(1-methylhydrazino)-4(5)-chloropyridazin-3(2H)-ones 13 (16) with isothiocyanates 2 and 7 .     

Heterocyclizations with tosylmethyl isocyanide derivatives. A new approach to substituted azolopyrimidines

An efficient synthesis of substituted azolopyrimidines such as pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidines, pyrimido[1,6-a]indoles, benzo[4,5]imidazo-[1,2-c]pyrimidines, an imidazo[1,2-c]pyrimidine, and pyrazolo[1,5-c]pyrimidines is described. The method involves the reaction of N-protected bromomethylazoles and tosylmethyl isocyanide (TosMIC) derivatives in nonanhydrous media. The study of the reaction conditions shows that the method is only successful under phase-transfer conditions (CH2Cl2/30% aq NaOH) using benzyltriethylammonium chloride as a catalyst.     

A synthetic entry to furo[2,3-b]pyridin-4(1H)-ones and related furoquinolinones via iodocyclization

[reaction: see text] N-Methyl-4-alkoxy-3-alkynylpyridin-2(1H)-ones readily undergo iodine-promoted 5-endo-heteroannulation under mild conditions to 3-iodofuropyridinium triiodide salts in moderate to good yields. The latter may be dealkylated in situ upon exposure to an iodide anion to provide the corresponding 3-iodofuro[2,3-b]pyridin-4(1H)-ones. The same strategy applies to the formation of furo[2,3-b]quinolin-4(9H)-ones.     

Synthesis of new heteroaromatic systems: Naphth[2,1-e]imidazo[5,1-c]-1,2,4-triazines and benz[e]imidazo-[5,1-c]-1,2,4-triazines

Cyclization of azo compounds, synthesized from 5-diazoimidazoles and 2-naphthol or p-substituted phenols, into naphth[2,1-e]imidazo[5,1-c]-1,2,4-triazines and benz[e]imidazo[5,1-c]-1,2,4-triazines occurs only in the presence of p-toluenesulfonic acid. Imidazo[4,5-d]-1,2,3-triazines are also formed in this reaction when an amide substituent is present in the imidazole ring.Ural State Technical University, Ekaterinburg 620002, Russia: e-mail: mokr@htf.ustu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 540–546, April, 2000.     

Acetylenchemie. 4 mitt. Synthese von haplophyllin und N-methylflindersin,zwei wege zu N-funktio-nalisierten pyrano[3,2-c]chinolin-alkaloiden

Pyrano[3,2-c]quinoline alkaloids 3 , suitable precursor for photobiomimetic dimerisations, are available by ptc-reactions of 4-hydroxyquinoline-2-ones 1 with 3-chloro-3-methylbut-1-yne, as byproducts uro[3,2-c]-quinoline-2-one is isomeres 5 are found. In the synthesis of flindersine ( 3a ) additionally the oxazolo[3,2-a]quinolin-5-one 4 could be isolated, while in the preparation of N-methylflindersine ( 3b ) a bis-(N-methyal-4′-hydroxyquinolin-2′-one-3′-yl)isopentene ( 7 ) was identified. Alkaloid dimers, which may be formed from the intermediates 6 , were not present. The structure of 7 confirms reaction pathways, discussed previously. Haplophylline ( 3c ) is synthesized for the first time by N-alkylation a of 3a with 3-methylcrotonyal chlormethyl ester.     

Synthesis of imidazo[4,5-c]pyrazoles via copper-catalyzed amidine cyclization

A new synthetic approach to 4-substituted imidazo[4,5-c]pyrazoles is proposed on the basis of the N'-(4-halopyrazol-5-yl)amidine cyclization under the conditions of copper-catalyzed cross-coupling reactions. Using 5-aminopyrazoles and copper catalysts as starting materials, the method is inexpensive and convenient and allows a wide range of substituents at all positions of the imidazo[4,5-c]pyrazole nucleus.