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.     

Synthesis and cytotoxic activity of carboxamide derivatives of benzimidazo[2,1-a]isoquinoline and pyrido[3',2':4,5]imidazo[2,1-a]isoquinoline

A series of benzimidazo[2,1-a]isoquinolines with carboxamide side chains at the 1-, 6-, 9- and 11-positions were prepared, in order to study the biological effects of varying the position of the side chain in this tetracyclic series. The 6-, 9- and 11-analogues were obtained by modifications to published chemistry. The 1-carboxamide analogue was obtained via a one-pot isocoumarin/isoquinolone conversion of 3-methylisocoumarin-8-carboxylic acid with o-phenylenediamine in buffered aqueous acid, which gave the required 1-acid. The compounds were evaluated in a panel of cell lines in culture. The 6-carboxamides, where the side chain is attached to one of the central rings, were not active, but the 1- and 11-carboxamides, where the side chain is attached to one of the terminal rings off the chromophore short axis, were reasonably cytotoxic (IC50s < 1 microM). Overall, the structure-activity relationships are broadly in line with those seen with other tri- and tetracyclic carboxamides, and are consistent with recent crystal structure studies of acridine-4-carboxamides bound to DNA. The most potent 1-carboxamide was highly active in vivo against s.c. colon 38 tumours in mice, providing a growth delay of 12 days.     

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 pharmacological properties of 13H-naphtho[1',2':7,6] [1,4] diazepino[2,3-b] pyridines

The synthesis and properties of 13H-naphtho[1',2':7,6] [1,4] diazepino[2,3-b] pyridines (7a--g) were described. New compounds were studied in rats and in mice in the tests used for preclinical assessment of antidepressant or anxiolytic activity. Compound 7c showed weak antagonism towards the reserpine-induced hypothermia and shortened immobility time in the despair test. None of the tested compounds had an anxiety-relieving action.     

Synthesis and pharmacological evaluation of novel octahydro-1H-pyrido[1,2-a]pyrazine as mu-opioid receptor antagonists

To better understand structural requirements for a mu ligand of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class to interact with the mu opioid receptor, we have described in the previous article (Le Bourdonnec, B. et al. J. Med. Chem. 2006, 25, 7278-7289) new, constrained analogues of the N-phenethyl derivative 3. One of the active constrained analogues, compound 4, exhibited subnanomolar mu-opioid receptor affinity (K(i) = 0.62 nM) and potent mu-opioid antagonist activity (IC(50) = 0.54 nM). On the basis of structure 4, a new series of mu-opioid receptor antagonists were designed. In these compounds the octahydroquinolizine template of 4 was replaced by an octahydro-1H-pyrido[1,2-a]pyrazine scaffold. The new derivatives were tested for their binding affinities and in vitro functional activity against the cloned human mu-, delta-, and kappa-opioid receptors. From this study, we identified compound 36, which displays high affinity toward the mu-opioid receptor (K(i) = 0.47 nM), potent mu in vitro antagonist activity (IC(50) = 1.8 nM) and improved binding selectivity profile mu/kappa and mu/delta, when compared to 4.     

Structure and Spectral Properties of β-Carbolines,I: 13C-NMR and Mass Spectra of Decahydro-5H-pyrido[1′,2′;5,1]-imidazo[3,4-a]-β-carbolines

¹³C-NMR and the electron impact mass spectra of the β-carboline derivatives 1 – 18 were examined. The structure of the possible diastereomers is discussed. A quantitative relationship between the relative intensity of ions a in the mass spectra of 1 – 18 and the structure of substituents R was found.     

Synthesis and antibacterial activity of fused 1, 2, 4-triazolo[4, 3-a]quinoxaline and oxopyrimido[2', 1':5, 1]-1, 2, 4-triazolo[4, 3-a]quinoxaline derivatives

A new series of potential antibacterial agents having tricyclic 1, 2, 4-triazolo-[4, 3-a] quinoxaline fused with one or more heterocyclic rings was synthesized via several routes. The tricyclic 1-amino-4-chloro-1, 2, 4-triazolo[4, 3-a] quinoxaline (2 ) and tetracyclic 1, 6-diamino-bis-1, 2, 4-triazolo[4, 3-a:3, 4-c] quinoxaline (3) were synthesized from 2, 3-dichloroquinoxaline (1) with two or four equivalents of thiosemicarbazide, respectively. Compound 2 was allowed to react with different aldehydes, alkoxides, cyclic amines, phenyl isothiocyanate, and t-butyl isocyanate to afford the corresponding quinoxaline derivatives. Moreover, compound 2 reactedwithhydrazine hydrate to give compound 4 which was cyclized by carbondisulfide inalcoholic potassium hydroxide to give the tetracyclic compound 5. Compound 2 was subjected to another cyclocondensation reaction using diethyl ethoxymethylene malonate (DEMM), dimethyl acetylenedicarboxylate (DMAD), and ethyl cyanoacetate to give the tetracyclic compounds 18, 20, and 21, respectively. All the synthesized compounds were evaluated in vitro for antibacterial activity; compounds 18 and 20 were found to display the greatest antibacterial activities. Structural identification was provided by elemental analyses, IR, and (1)H-NMR spectroscopy.     

Synthesis and in vitro antibacterial evaluation of novel imidazo[2',1':5,1]-1,2,4-triazolo[4,3-c]-quinazoline derivatives of 5-thioxo-1, 2, 4-triazole, 4-oxothiazolidine, and their open-chain counterparts

Two novel series of imidazo[2', 1':5, 1]-1, 2, 4-triazolo[4, 3-c]quinazolines bearing 5-thioxo-1, 2, 4-triazoles, 6a-f, and 4-oxothiazolidines, 7a-f, were synthesized from corresponding thiosemicarbazide derivatives, 5a-f. The stepwise methodology applied to the preparation of compounds 5a-f was initiated with reaction of the parent 3-amino-1, 2, 4-triazolo[4, 3-c]quinazolines, 2, with ethyl 2-chloroacetoacetate resulting in annelation of the imidazole ring to give esters, 3a-c. However, hydrazinolysis of these ester derivatives gave the corresponding acid hydrazides, 4a-c, which on reaction with the appropriate alkyl isothiocyanate yielded compounds 5a-f. In turn, compounds 5, were cyclized with potassium hydroxide or with ethyl bromoacetate to give the corresponding thioxotriazoles 6 and oxothiazolidines 7, respectively. All synthesized compounds were screened for their in vitro antibacterial activity against various Gram-positive and Gram-negative bacteria. Some test compounds were found to possess potent antibacterial activities. Compound, 7f, exhibited much higher potency than the reference standard ciprofloxacin, against both types of bacteria, particularly, Gram-positive organisms.     

Synthesis of imidazo[4,5-d]oxazolo[3,4-a]pyridines. New heterocyclic analogues of lignans.

The preparation of new analogues of lignans carrying an imidazole ring has been achieved. Starting from L-histidinol, cis and trans stereoisomers have been obtained. The synthesized products lack the cytotoxicity displayed by related podophyllotoxins and azatoxin.     

Synthesis of several new isoxazole,imidazo[1,2-a]pyridine,imidazo[1,2-a]pyrimidine,benzoxadiazine and benzothiazine derivatives from hydroximoyl halides

Furoylhydroximoyl chloride3 reacted with 2-aminopyridine, 2-aminopyrimidine,O-aminophenol,O-phenylenediamine and aminothiophenol to afford imidazo[1,2-a]pyridine6, imidazo[1,2-a]pyrimidine8, benzoxadiazine10, nitrosobenzopyrazine13a and nitrosobenzothiazine13b, respectively. Isoxazoline18 and pyrrolidino[3,4-d]isoxazolin-4,6-dione derivatives19a and19b obtained by the reaction of3 with acrylonitrile and N-arylmaleimide. Hydroximoyl chloride3 reacted with thiophenol and sodium benzenesulfinate to yield furylglyoxaloxime16a and16b, respectively. Hydroximoyl chloride3 reacted also with some active methylene compound to give isoxazole derivatives20–23, respectively.     

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.     

Synthesis and pharmacological activity of 2-methoxyphenyl-and 2-oxyphenyl-substituted 1-dialkylaminoalkylimidazo[1,2-a]-benzimidazoles

A series of 2-methoxy-and 2-oxyphenyl-1-dialkylaminoalkylimidazo[1,2-a]benzimidazoles have been synthesized and characterized with respect to pharmacological properties. Some of the synthesized compounds exhibit antioxidant, membranotropic, antiaggregant, hemorheological, anticalmodulin, and hypotensive properties, and behave as antagonists of serotonin (5-HT_2,3) and purine (P2Y₁) receptors. The obtained data show good prospects for the synthesis and screening of biologically active substances in this class of compounds. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 1, pp. 17–23, January, 2006.