Octahydropyrazino[2',3':3,4]pyrido[1,2-a]indoles. A new class of potent antihypertensive agents

Simplifications and modifications of the vincamine molecule led to the discovery of antihypertensive 1,2,3,4,4a,5,6,12b-octahydro-12-methylpyrazino[2',3':3,4]pyr ido[1,2-a] indoles. Stereoselective syntheses of both 4a,12b-cis and 4a,12b-trans isomers represent new annulation strategies for the construction of fused piperazines. Compounds of the trans series were at least 10 times more potent than the corresponding cis isomers. Antihypertensive activity and alpha 1-adrenoceptor blocking properties peaked with a simultaneous introduction of 4-methylethyl and 1-alkyl substituents. Compound 15j (AY-28,228; atiprosin), (4a, 12b-trans)-1-ethyl-1,2,3,4,4a,5,6, 12b-octahydro-12-methyl-4-(1-methylethyl)pyrazino[2',3':3,4]pyrido [1,2-a]indole, was chosen for a detailed preclinical evaluation.     

3,4-Dihydro-1H-1,4-oxazino[4,3-a]indoles as potential antidepressants.

A series of 3,4-dihydro-1H-1,4-oxazino[4,3-a]indoles bearing basic side chains has been synthesized by a novel chemical process. These compounds have been screened for potential antidepressant activity. One of these derivatives, 3,4-dihydro-1,10-dimethyl-1-(3-methylaminopropyl)-1H-1,4-oxazino[4,3-a]indole (AY-23,673), was particularly potent in the prevention of reserpine ptosis test in mice, with an ED50 of 0.5 mg/kg ip.     

Synthesis of pyrazino (1, 2-a) indoles

Conclusion 1-Aryl-10-methylpyrazino(1,2-a)indoles are prepared by the condensation of ammonium acetate in acetic acid solution and the dibutyl acetals of 2-aroylindolyl-1-acetaldehydes which are formed by the reaction of the sodium derivatives of 2-aroyl-3-methylindoles with bromoacetaldehyde dibutyl acetal. 1-Aryl-1,2,3,4-tetrahydro-10-methylpyrazino(l,2-a)indoles are prepared by the reduction of the 1-aryl-10-methylpyrazinoindoles with sodium in alcohol. Furthermore, the synthesis of N-alkyl-dialkylamino derivatives of the 2-aroyl-3-methylindoles are carried out by the alkylation of the appropriate indoles with bisdiethylaminomethane and alkyldialkylamino chlorides.Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 12, pp. 3–7, December, 1968.     

Synthesis and central nervous system effects of 8.9-dihydro(1)benzazepino(3,2.1-ak)(1,4)benzodiazepin-1(2H)-ones and (1) binzazepino(3,2,1-jk)(1,4)benzodiazepin-1(2H)-ones.

A series of 4-alkyl-8,9-dihydro[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives was synthesized. Two approaches for the synthesis of 4-alkyl[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives are described. All compounds were evaluated for CNS activity. None showed significant activity. The results obtained indicate that in the case of the 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one a phenyl group at the 1 position causes a fall in CNS activity not only when it is free but also when fused to the benzodiazepine system.     

Synthesis of 11-phenyl-2,3,4,5-tetrahydro-1H-(1,4)diazepino(1,2-a)indoles and 1-(3-aminopropyl)-2-hydroxymethyl-3-phenylindoles as 5-hydroxytryptamine antagonists

A series of novel 11-phenyl-2,3,4,5-tetrahydro-1H-(1,4)diazepino(1,2-a) indoles (5a-f) and 1-(3-aminopropyl)-2-hydroxymethyl-3-phenylindoles (6a-f) are reported. The compounds (5a-f) were prepared by the lithium aluminum hydride (LAH) reduction of corresponding 11-phenyl-1H-1-oxo-2,3,4,5-tetrahydro(1,4)diazepino(1,2-a)indoles (4a-f). The precursors (4a-f) were, in turn, prepared by the catalytic reduction of 1-(2-cyanoethyl)-3-phenylindole-2-carboxylates (2a-f) and cyclization of the resulting 1-(3-aminopropyl)-3-phenylindole-2-carboxylates (3a-f) with sodium hydride in xylene. The LAH reduction of 2a-f gave exclusively 1-(3-aminopropyl)-2-hydroxymethyl-3-phenylindoles (6a-f) and not the diazepinoindoles (5a-f) which were expected. The title compounds and the intermediates have been screened for their anti-5-hydroxytryptamine (anti-5-HT) activity. The most potent anti-5-HT compounds of this series, 6a and 6e, were found to be weak compared with cyproheptadiene, a standard anti-5-HT drug.     

Synthesis and anxiolytic activity of a series of pyrazino[1,2-a][1,4]benzodiazepine derivatives

The synthesis and biological evaluation of some derivatives of pyrazino[1,2-a][1,4]benzodiazepines for anxiolytic and antidepressant activity are presented. Significant levels of anxiolytic activity were noted for 7-(o-chlorophenyl)-9-chloro-1,2,3,4,4a,5-hexahydro-3-methylpyrazino[1,2-a];E11,4]benzodiazepine (4b).     

3,4-二氢吡咯[1,2-a]吡嗪-1-酮衍生物的合成及抗炎镇痛作用

目的研究(2H)-2-环己基-3,4-二氢吡咯[1,2-a]吡嗪-1-酮衍生物抗炎镇痛作用的构效关系。方法以2-吡咯甲酸甲酯为原料,经取代、环合,制备(2H)-2-环己基-3,4-二氢吡咯[1,2-a]吡嗪-1-酮(3);通过Friedel-Crafts酰基化反应,制得其6-酰基衍生物4a~4j。用小鼠测试了所合成化合物的抗炎和镇痛活性。结果与结论合成了10个未见文献报道的新化合物4a~4j,其结构经MS1、H-NMR分析确证。抗炎镇痛试验表明,有些化合物具有明显的抗炎和/或镇痛作用,其中化合物4d的活性与对照药布洛芬相当。     

Cyclic guanidines: synthesis and antiplatelet activity of 4,6,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-7-ones and 1,4,6,7,8,9-hexahydropyrazolo [3',4':4,5]pyrimido[2,1-c] [1,2,4]triazin-7-ones

A series of 4,6,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo [3,4-d]pyrimidin-7-ones (1b-n) and 1,4,6,7,8,9-hexahydropyrazolo [3',4':4,5]pyrimido [2,1-c][1,2,4]triazin-7-ones (2a-d) has been synthesized. In view of their potential anti-aggregating activity the compounds were tested in vitro for inhibitory activity towards ADP- and collagen-induced aggregation of human platelets. Among the compounds studied, 8-benzyl-1-(2,5-dichlorophenyl)-4,6,7,8-tetrahydro-1H-imidazo [1,2-a]pyrazolo[3,4-d]pyrimidin-7-one (1n) exhibited the most favorable activity. The 2,5-dichlorophenyl side chain is an important lipophilic and/or steric pharmacophore.     

Synthesis and anti-hIV activity of 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole structurally-related 1,2-substituted benzimidazoles

The synthesis of 1,2-substituted benzimidazoles is reported. These novel derivatives share chemical similarities with 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles, a class of HIV-1 NNRTIs studied widely. All compounds prepared were tested in MT-4 cells to explore their potential anti-HIV activity and were found to be less potent than 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (TBZ).     

Synthesis and antimicrobial activity of new substituted 10-methyl-1,2-dihydro-1-oxo-1,2,4-triazino(4,5-a)indoles

Ten new 4,8-disubstituted 10-methyl-1,2-dihydro-1-oxo-1,2,4-triazino(4,5-a)indoles (5 and 6) were prepared by refluxing various 5-substituted indole-2-carbohydrazides (4) with triethylorthoformate or triethylorthoacetate in dimethylformamide. These derivatives were evaluated for their antimicrobial activity. Some of the title compounds possess fairly potent antimicrobial activity.     

Synthesis and oral antiallergic activity of carboxylic acids derived from imidazo[2,1-c][1,4]benzoxazines, imidazo[1,2-a]quinolines, imidazo[1,2-a]quinoxalines, imidazo[1,2-a]quinoxalinones, pyrrolo[1,2-a]quinoxalinones, pyrrolo[2,3-a]quinoxalinones, and imidazo[2,1-b]benzothiazoles

4H-Imidazo[2,1-c][1,4]benzoxazine-2-carboxylic acid (3) was found to possess potent activity in the IgE-induced rat passive cutaneous anaphylaxis model which may be predictive of clinical antiallergic activity. Compared to disodium cromoglycate (DSCG, 1), 3 was less active following iv administration but unlike DSCG showed very significant oral activity. To explore the structural requirements for this activity, a range of tricyclic compounds was prepared and their activities were measured. Individual 2-carboxylic acids derived from imidazo[1,2-a]quinolines, imidazo[1,2-a]quinoxalines, imidazo[1,2-a]quinoxalinones, pyrrolo[1,2-a]quinoxalinones, pyrrolo[2,3-a]quinoxalinones, and imidazo[2,1-b]benzothiazoles showed iv activities up to 10(3) times as potent as DSCG and many of them showed significant oral activity. From these, imidazo[1,2-a]quinoxaline-2-carboxylic acid 114 has been chosen for further development.     

Synthesis and pharmacological properties of decahydro-5H-pyrido [1',2';5,1] imidazo [3,4-a]-beta-carbolines. Part II

Ten cyclic animals (1-10), including a form of decahydro-5H-pyrido [1',2';5,1] imidazo [3,4-a]-beta-carboline, were obtained by treating erythro 1-(2'-piperidyl)-1,2,3,4-tetrahydro-beta-carboline with aldehydes. The anticonvulsant action of those compounds (1-10) was investigated in mice using a behavioral test. Only 5-(3-chlorophenyl) (2) and 5-(3-pyridyl) (9) derivatives showed an anticonvulsant activity in the electric seizure test, but their therapeutic index was inferior to that of phenytoin.     

Oral hypoglycemic agents. Pyrimido[1,2-a]indoles and related compounds.

A series of pyrimido[1,2-a]indoles were synthesized and studied for their hypoglycemic activity following oral administration at a standard dose of 100 mg/kg to fed rats. The effect of 10-alkoxyalkyl, 10-alkyl, 10-aryl, and 3,3-dialkyl substitution on the activity of 10-hydroxypyrimido[1,2-a]indoles was investigated. Relative potencies of a number of the most active compounds were defined by three-point dose-response studies. The most potent compounds were those with either 3,3-dimethyl substituents, compounds 21, 22, and 38, or 3,3-spirocyclohexane substituents, compounds 39 and 49. 10-Aminopyrimido[1,2-a]indoles were in general less active than the 10-hydroxy analogues, and potency was further decreased by derivatizing the 10-amino group. The most potent 10-amino derivatives were 57 and 58.     

Synthesis of 1-oxo-9-methyl-pyrrolo-(1,2-a)indole (author's transl)]

Synthesis of 1-Oxo-9-methyl-pyrrolo-[1,2-a]indole . The reaction of 3-methyl-indole with acrylonitrile leads to 1-(β-cyano-ethyl)-3-methyl-indole. By treatment with P₂O₅ the corresponding carboxylic acid can be cyclised to 1-oxo-9-methylpyrrolo-[1,2-a]-indole.     

Antiarrhythmic properties of 2-(2'-hydroxy-2')-substituted ethyl-1,2,3,4-octahydropyrrolo[1,2-a]pyrazines

The antiarrhythmic activity and acute toxicity of a series of 2-(2'-hydroxy-2')-substituted ethyloctahydropyrrolo[1,2-a]pyrazines were studied. Two most promising compound (PV-238) is characterized by high antiarrhythmic activity, broad spectrum of action, and low toxicity.     

New heterocyclic ring systems--V synthesis and pharmacological activity of 6H-1,3,4-thiadiazolo [3',2':1,2]-5-oxopyrimido [5,4-b] indole derivatives and of 1-phenyl-6H-1,2,4-triazolo [1',5':1,2]-5-oxopyrimido[5,4-b] indole

As a part of a study on analgesic and antiinflammatory active condensed heterocyclic compounds containing the pyrimidinic ring, a number of 6H-1,3,4-thiadiazolo [3',2':1,2]-5-oxopyrimido [5,4-b]indole and 1-phenyl-6H-1,2,4-triazolo [1',5':1,2]-5-oxopyrimido [5,4-b] indole were synthesized and tested. The results of pharmacological assays are reported and discussed.     

Synthesis of 5-imino-5H-dipyrido[1,2-a; 2',3'-d]pyrimidines as potential antiallergy agents (1)

A novel route to 5-imino-5H-dipyrido[1,2-a; 2',3'-d]pyrimidines is described. The method is based on the Ullmann condensation of 2-chloro-3-cyano-5-nitropyridine with 2-amino-pyridine 1-oxides, followed by intramolecular cyclization of the resulting 2-(3-cyano-5-nitro-2-pyridylamino)pyridine 1-oxides with phosphorous trichloride.     

Tricyclic pyrazoles. 4. Synthesis and biological evaluation of analogues of the robust and selective CB2 cannabinoid ligand 1-(2',4'-dichlorophenyl)-6-methyl-N-piperidin-1-yl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide

New analogues (2a-p) of the previously reported CB(2) ligands 6-methyl- and 6-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamides (1a,b) have been synthesized and evaluated for cannabinoid receptor affinity. One example, 1-(2',4'-dichlorophenyl)-6-methyl-N-cyclohexyilamine-1,4-dihydroindeno[1,2-c] pyrazole-3-carboxamide (2a) was shown to have single digit nanomolar affinity for cannabinoid CB(2) receptors. Furthermore, compounds 2a and 2b, as well as lead structures 1a,b, were also shown to be agonist in an in vitro model based on human promyelocytic leukemia HL-60 cells.     

Synthesis and antiproliferative activity in vitro of new derivatives of 3-aminopyrazolo[3,4-b]pyridine. Part 1. Reaction of 3-aminopyrazolo[3,4-b]pyridine with 1,3-, 1,4-diketones and alpha,beta-unsaturated ketones

The synthesis of several new pyrazolo[3,4-b]pyridine, pyrido[2',3':3,4]-pyrazolo[1,5-a]pyrimidine and imidazo[1',2':1,5]pyrazolo[3,4-b]pyridine derivatives is described. The obtained compounds were tested for their antiproliferative activity in vitro. One of them, 4-phenyl-2-(3,4,5-trimethoxy-beta-styrylo)pyrido- [2',3':3,4]pyrazolo[1,5-a]pyrimidine (9), revealed cytotoxic properties against the cells of all three human cancer cell lines applied. Another one, 2,4-dimethyl-pyrido[2',3':3,4]pyrazolo[1,5-a]-pyrimidine (2), revealed weak cytotoxic activity only against the cells of human bladder cancer cell line HCV29T. All other compounds tested did not reveal any cytotoxic activity.     

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines (2 and 3) and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines (4 and 5) are described. The activity, shown by these compounds in the rat passive cutaneous anaphylaxis (PCA) test, is compared to the PCA data previously reported for a series of 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidines. 10-Oxo-N-1H-tetrazol-5-yl-10H-pyrido[1,2-a]thieno[3,4-d]pyri midine (2b), 10-oxo-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,4-d]py rimidine (4e), and 3,10-dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1,2-a]thieno[3, 4-d] pyrimidine (7e) gave a 100% inhibition in the rat PCA test at a dose of 5 mg/kg. The activity displayed by these compounds is comparable to that of the most active compounds in the 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine series.