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.     

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 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.     

Synthesis and antimicrobial activity of some new 1-alkyl-2-alkylthio-1,2,4-triazolobenzimidazole derivatives

Some new derivatives of 1,2,4-triazolo[2,3-a]benzimidazoles were synthesized through the reaction of 1,2-diaminobenzimidazole with carbon disulfide. The resulting 1,2,4-triazolo-[2,3-a]benzimidazole-2-thione intermediate was reacted with one equivalent of alkyl halides to give the corresponding 2-alkylthio derivatives, which were further alkylated through the reaction with another one equivalent of different alkyl halides to afford the target compounds; 1-alkyl-2-alkylthio-1,2,4-traizolo[2,3-a]benzimidazoles. On the other hand, the 1,2-disubstituted derivatives with two identical alkyl substituents were prepared by the reaction of 1,2,4-triazolo[2,3-a]benzimidazole-2-thione with two equivalents of the alkyl halides. The structures of the new compounds were assigned by spectral and elemental methods of analyses. The synthesized compounds were tested for their antibacterial and antifungal activities. Most of the tested compounds proved comparable results with those of ampicillin and fluconazole reference drugs. The study indicated that, the antibacterial as well as the antifungal activities of the test compounds were improved with increase in the bulkiness of the introduced alkyl groups. Also, some active antibacterial compounds were tested for their antimycobacterial activity. All the test compounds showed equipotent antitubercular activity as that of INH as a reference drug.     

Synthesis and SAR of a new series of COX-2-selective inhibitors: pyrazolo[1,5-a]pyrimidines.

The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.     

Quinoxaline chemistry. Part 16. 4-substituted anilino and 4-substituted phenoxymethyl pyrrolo[1,2-a]quinoxalines and N-[4-(pyrrolo[1,2-a]quinoxalin-4-yl)amino and hydroxymethyl]benzoyl glutamates. Synthesis and evaluation of in vitro biological activity

Twenty eight pyrrolo[1,2-a]quinoxalines bearing at position 4 various substituents related to the moieties present in classical and non classical antifolic agents were prepared and evaluated in vitro for antiproliferative activity. In an in vitro screening performed at NCI, several compounds emerged as potent antiproliferative agents at concentrations ranging between 10 and 100 microM. Interestingly, some of these compounds proved active also against bovine and murine DHFR (Farmaco 53 (1998) 480). More recently, a compound of classical antifolate type has been reported to be a potent inhibitor of hDHFR in vitro (Farmaco 58 (2003) 51). We then synthesized new derivatives that, in our hands, were endowed with in vitro antiproliferative activities as low as 3.4 microM against a panel of cell lines derived from hematological and solid tumours. In addition, a complete screening of cytotoxicity, antiretroviral HIV-1 and antimicrobial activity has been carried out.     

Chemotherapeutically effective nitro compounds. 3rd communication: nitropyridines, nitroimidazopyridines and related compounds (author's transl)

New 2-nitropyridines and 3-nitropyridines, and 3-nitroimidazo-[1,2-a]-pyridines and related compounds (together 106) were synthesized and tested for their chemotherapeutic efficacy against trichomonads, amoebas and other organisms, such as Eimeria tenella, bacteria, fungi, helminths. Several 2-nitropyridines revelaed a detectable systemic effect against Entamoeba histolytica (extraintestinal amoebiasis of the golden hamster) and also a weak activity against Trichomonas fetus in the NMRI-mouse. Only a few 3-nitropyridines showed a marked systemic effect against trichomonads. Of the 3-nitroimidazo-[1,2-a]-pyridines, only the electroneutral carboxylic acid amide group exhibited a pronounced activity, exclusively against trichomonads; however, the activity was nullified again by electronegative, electropositive and other electroneutral substituents. As they were not superior in chemotherapeutic respect compared to the known standard preparation (metronidazole), no further tests were carried out with the most effective compounds.     

Central nervous system activity of a novel class of annelated 1,4-benzodiazepines, aminomethylene-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-ones.

The synthesis and CNS activity of a noval class of annelated 1,4-benzodiazepines, the aminomethylene-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepines, are described. An investigation of the structure--activity relationships in the series derived from 8-chloro-2,4-dihydro-2-dimethylaminomethylene-6-phenyl-1H-imidazo[1,2-a][1,4]-benzodiazepin-1-one (10) led to the synthesis of a group of compounds with potent minor tranquillizer activity.     

Novel bronchodilators: synthesis, transamination reactions, and pharmacology of a series of pyrazino[2,3-c][1,2,6]thiadiazine 2, 2-dioxides

The synthesis, pharmacological evaluation, and structure-activity relationships of a new class of bronchodilator agents, derivatives of pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides are described. The compounds were prepared by reaction of 3,4,5-triamino-1,2, 6-thiadiazine 1,1-dioxide with suitable 1,2-dicarbonyl compounds or alpha-hydroxyiminoketones and subsequent N-alkylation. A transamination procedure for synthesizing derivatives with different substituents at the 4-amino group is reported for the first time. The pyrazino[2,3-c][1,2,6]thiadiazine derivatives were screened for tracheal relaxing activity in vitro, and the active compounds were evaluated in vivo in guinea pigs as bronchodilator agents in comparison to theophylline. Among the compounds studied, the most interesting properties were displayed by the 4-amino-1-ethyl-6-methyl derivative (21). The toxicological evaluation of this derivative is also reported.     

Synthesis of 1-acyl-2-alkylthio-1,2,4-triazolobenzimidazoles with antifungal, anti-inflammatory and analgesic effects

Some new derivatives of 1,2,4-triazolo[2,3-a]benzimidazoles were synthesized through the reaction of 1,2-diaminobenzimidazole with carbon disulfide. The resulting 1,2,4-triazolo[2,3-a]benzimidazole-2-thione intermediate reacted with one equivalent of the alkyl halide to give the corresponding 2-alkylthio derivative 3a-g. The latters were acylated to afford the 1-acyl-2-alkylthio-1,2,4-triazolo[2,3-a]-benzimidazole derivatives 4-10 in good yields. Structures of the new compounds were verified on the basis of spectral and elemental methods of analyses. Fourteen of the prepared compounds were tested for their possible antifungal activities. Most of the tested compounds showed activity against Candida albicans and Fusarium oxysporum comparable to that of fluconazole as a reference drug. Compounds 8a, 9a, and 10d are the most active ones against most of the fungi used. Compounds 3e, 4d, 5d, 6d, 7d, 8c, 8d, 9d, and 10d were tested for their anti-inflammatory and analgesic effects; most of these compounds showed potent and significant results compared to indomethacin. Moreover, ulcerogenicity and the median lethal dose (LD(50)) of the most active compound 8d were determined in mice; LD(50) was found to be 275 mg kg(-1) (i.p.).     

Synthesis of 1,10-trimethylenepyrazino [1,2-a]indoles

A new class of heterocylic compounds, the 1,10-trimethylenepyrazino[1,2-a]indoles have been synthesized by condensing the dibutyl acetals of 1-keto-1,2,3,4-tetrahydrocarbazolyl-9-acetaldehyde with ammonium acetate in acetic acid solution. The 3-aryl-1,10-trimethylenepyrazino[1,2-a]indoles were synthesized in the same way from the 9-phenacyl derivatives of ketotetrahydrocarbazole.Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 3, pp. 25–30, March, 1967.     

Cationic antiprotozoal drugs. Trypanocidal activity of 2-(4'-formylphenyl)imidazo[1,2-a]pyridinium guanylhydrazones and related derivatives of quaternary heteroaromatic compounds

A series of quaternary 2-phenylimidazo[1,2-a]pyridinum salts has been prepared and evaluated for antiparasitic activity. Primary attention was focused on derivatives with amido, substituted hydrazone, and heterocyclic functionality at the para position of the phenyl substituent. Guanylhydrazones and N-substituted guanylhydrazones of the 4'-formyl-substituted compounds are very active against the blood state Trypanosoma rhodesiense in mice by subcutaneous or oral administration. The most potent compounds attain 100% survival for 30 days at doses of less than 1.0 mg/kg (sc) and greater than 5.0 mg/kg (po). Weaker activity is noted for certain other 4'-substituents such as carboxamidines and carboxamide oximes. Considerable variation in structure, including replacing of the imidazo [1,2-a]pyridinium ring by other cationic heterocyclic rings and insertion of linking groups between the heterocyclic ring and phenyl group, can be done, and a high level of activity is maintained. Relationships between these structural changes and biological activity are discussed.     

Structure-activity relationship of 4(5)-aryl-2-amino-1H-imidazoles, N1-substituted 2-aminoimidazoles and imidazo[1,2-a]pyrimidinium salts as inhibitors of biofilm formation by Salmonella typhimurium and Pseudomonas aeruginosa

A library of 112 4(5)-aryl-2-amino-1H-imidazoles, 4,5-diphenyl-2-amino-1H-imidazoles, and N1-substituted 4(5)-phenyl-2-aminoimidazoles was synthesized and tested for the antagonistic effect against biofilm formation by Salmonella Typhimurium and Pseudomonas aeruginosa. The substitution pattern of the 4(5)-phenyl group and the nature of the N1-substituent were found to have a major effect on the biofilm inhibitory activity. The most active compounds of this series were shown to inhibit the biofilm formation at low micromolar concentrations. Furthermore, the influence of 6 imidazo[1,2-a]pyrimidines and 18 imidazo[1,2-a]pyrimidinium salts on the biofilm formation was tested. These compounds are the chemical precursors of the 2-aminoimidazoles in our synthesis pathway. A good correlation was found between the activity of the imidazo[1,2-a]pyrimidinium salts and their corresponding 2-aminoimidazoles, supporting the hypothesis that the imidazo[1,2-a]pyrimidinium salts are possibly cleaved by cellular nucleophiles to form the active 2-aminoimidazoles. However, the imidazo[1,2-a]pyrimidines did not show any biofilm inhibitory activity, indicating that these molecules are not susceptible to in situ degradation to 2-aminoimidazoles. Finally, we demonstrated the lack of biofilm inhibitory activity of an array of 37 2N-substituted 2-aminopyrimidines, which are the chemical precursors of the imidazo[1,2-a]pyrimidinium salts in our synthesis pathway.     

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.     

(Imidazo[1,2-a]pyrimidin-2-yl)phenylmethanones and related compounds as potential nonsedative anxiolytics

Several series of heterocyclic carboxylic esters were found to be active in the benzodiazepine receptor binding assay, a typical example being ethyl 7-ethyl-5-methoxyimidazo[1,2-a]quinoline-2-carboxylate (4b) with an IC50 of 150 nM. The corresponding phenylmethanone 5d was more potent with an IC50 of 14 nM and was orally active in animal models thought to predict anxiolytic effects. The synthesis of a large number of compounds resulted in the optimization of this activity in a series of (imidazo[1,2-a]pyrimidin-2-yl)phenylmethanones of which compounds 7e, 8b, 8h, 8j, and 8k were equipotent with chlordiazepoxide while exhibiting reduced anticonvulsant activity, little or no muscle relaxation, and negligible sedative effects.     

Studies on condensed-heterocyclic azolium cephalosporins. II. Synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]-3-(condensed- heterocyclic azolium)methyl-3-cephem-4-carboxylates.

From our series of studies on cephalosporins bearing condensed-heterocyclic azolium methyl groups at the 3 position in the cephalosporin nucleus, we describe here the synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]ceph alosporins containing imidazo[1,5-a]pyridinium, imidazo[1,2-b]pyridazinium, imidazo[1,2-a]pyrimidinium, imidazo[1,2-c]pyrimidinium, and pyrazolo[1,5-a]pyridinium methyl groups at the 3 position. Among the cephalosporins tested, 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3- (imidazo[1,5-a]pyridinium-2-yl) (1), (imidazo[1,2-b]pyridazinium-1-yl) (2), and (pyrazolo[1,5-a]-pyridinium-1-yl) (3)methyl-3-cephem-4-carboxylates showed potent antibacterial activity and broad antibacterial spectrum. The antibacterial activity of these cephalosporins (1 approximately 3) was superior to that of ceftazidime (CAZ). These results imply that the delocalization of the positive charge of the imidazo[1,5-a]pyridinium, pyrazolo[1,5-a]pyridinium and imidazo[1,2-b]pyridazinium groups leads to an expanded antibacterial spectrum and increased activity and that these condensed-heterocyclic compounds as well as imidazo[1,2-a]pyridine are effective moieties for improving antibacterial activity and spectrum.     

Synthesis and anti-inflammatory activity of 3,3a-dihydro-2H,9H-isoxazolo [3,2-b] [1,3]benzoxazin-9-ones and related compounds.

A series of 3,3a-dihydro-2H,9H-isoxazolo[3,2-b]-[1,3]benzoxazin-9-ones was synthesized and evaluated for anti-inflammatory, antipyretic and analgesic activity. Since many of these compounds exhibited promising activity, particularly in the anti-inflammatory tests, a number of homologous 2,3,4,4a-tetrahydro-10H-1,2-oxazino[3,2-b]-[1,3]benzoxazin-10-ones and one 3,4,5,5a-tetrahydro-2H, 11H,-1,2-oxazepino [3,2-b][1,3]benzoxazin-11-one, the 9-chloro analog, were also prepared and evaluated. The expanded ring members were generally less active than the tricyclic compounds containing the isoxazolidine ring.     

Novel cyano- and amidino-substituted derivatives of styryl-2-benzimidazoles and benzimidazo[1,2-a]quinolines. Synthesis, photochemical synthesis, DNA binding, and antitumor evaluation, part 3

Synthesis of novel cyano- and amidino-substituted styryl-2-benzimidazoles and benzimidazo[1,2-a]quinolines by condensation reactions and photochemical dehydrocyclization and dehydrohalogenation cyclization is described. Thermal denaturation experiments reveal that cyclic derivatives considerably stabilize DNA double helix, while the effect of their acyclic analogues is negligible. According to the spectroscopic study of the interaction of cyclic derivative 19, we propose intercalation of benzimidazo[1,2-a]quinoline moiety into ct-DNA as a dominant interaction underlying biologically relevant effects of this compound, whereas for its acyclic derivative 11, we propose binding into the minor groove of DNA. All compounds show noticeable antiproliferative effect. Morpholino- and chloro-substituted compound 9 is the most active among all acyclic derivatives. All cyclic compounds were 2- to 10-fold more potent, which is correlated with their property to intercalate into DNA. The most active imidazolyl-substituted compound 19 inhibits topoisomerase II and induces strong G2/M cell cycle arrest, pointing to the impairment in mitotic progression. Its pronounced selectivity toward colon carcinoma cells encourages further development of this compound as a lead.     

Mapping the melatonin receptor. 6. Melatonin agonists and antagonists derived from 6H-isoindolo[2,1-a]indoles, 5,6-dihydroindolo[2,1-a]isoquinolines, and 6,7-dihydro-5H-benzo[c]azepino[2,1-a]indoles

6H-Isoindolo[2,1-a]indoles (5, 7, 10, 13), 5,6-dihydroindolo[2, 1-a]isoquinolines (20, 21), and 6,7-dihydro-5H-benzo[c]azepino[2, 1-a]indoles (23, 25, 27, 30) have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human mt(1) and MT(2) receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores. The 2-methoxyisoindolo[2, 1-a]indoles (7a-d) showed much higher binding affinities than the parent isoindoles (5a-e), and whereas 7a-c were agonists in the functional assay, 7d and 5a-e were antagonists. The 2-ethoxyisoindolo[2,1-a]indoles (10a-d) showed reduced binding affinities compared to their methoxy analogues, while the 5-chloro derivative 13 showed a considerable reduction in binding affinity and potency compared to 7a. The 10-methoxy-5,6-dihydroindolo[2, 1-a]isoquinolines (21a-c) had higher binding affinities than the corresponding parent indoloisoquinolines (20a-c) in the human receptor subtypes, and the parent compounds were antagonists whereas the 10-methoxy derivatives were agonists in the functional assay. The N-cyclobutanecarbonyl derivatives of both the parent (20d) and 10-methoxyl (21d) series had similar binding affinities and were both antagonists with similar potencies. The 11-methoxy-6, 7-5H-benzo[c]azepino[2,1-a]indoles (25a-d) had higher binding affinities than the corresponding parent compounds (23a-d) at the MT(2) receptor but similar affinities at the mt(1) site; all of the compounds were antagonists in the functional assay. Changing 11-methoxy for 11-ethoxy decreased the binding affinity slightly, and this was more evident at the MT(2) receptor. All of the derivatives investigated had either the same or a greater affinity for the human MT(2) receptor compared to the mt(1) receptor (range 1:1-1:132). This suggests that the mt(1) and MT(2) receptor pockets differ in their ability to accommodate alkyl groups in the indole nitrogen region of the melatonin molecule. Two compounds (7c and 25c) were tested in functional assays on recombinant mt(1) and MT(2) melatonin receptors. Compound 7c is a potent agonist with some selectivity (44-fold) for the MT(2) receptor, while 25c is an MT(2)-preferring antagonist. Increasing the carbon chain length between N-1 of indole and the 2-phenyl group from n = 1 through n = 3 leads to a fairly regular decrease in the binding affinity, but, remarkably, when n = 3, it converts the methoxy compounds from melatonin agonists to antagonists. The Xenopus melatonin receptor thus cannot accommodate an N-n-alkyl chain attached to a 2-phenyl substituent with n > 2 in the required orientation to induce or stabilize the active receptor conformation.     

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.