Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. I. Synthesis of 4H-s-triazolo[3,4-c]-1,4-benzothiazine and derivatives with potential CNS activity

As a part of a program toward the synthesis and the pharmacological studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines, a number of 4H-s-triazolo[3,4-c]-1,4-benzothiazine derivatives were prepared and tested for their CNS activity. The syntheses of the new tricyclic compounds (VII) were performed via the 2H-1,4-benzothiazine-3(4H)-thiones (II) which were obtained by Lawesson's thiation of lactams (I). Compounds (II) and their S-methyl-thioethers (III), quantitatively obtained by PTC method, were reacted with acylhydrazines to give the title compounds. Some triazolobenzothiazines (VII) were also prepared from 3-hydrazinoderivatives (IV) by cyclization with either an aliphatic acid or the corresponding orthoesther.     

Preparation of potentially bioactive aza and thiaza polycyclic compounds containing a bridgehead nitrogen atom synthesis and antimicrobial activity of some pyrrolo[1,2,3-de]-1,4-benzothiazines.

The synthesis of the 2,3-dihydro-pyrrolo[1,2,3-de]-1,4-benzothiazine 1a and 11b, 12-dihydro-isoquino[1,2-c]-1,4-benzothiazine 8 has been accomplished by using a Bischler type cyclization of the N-(2,2-diethoxyethyl)-3,4-dihydro-2H-1,4-benzothiazines 3a and 3d, respectively. The new compounds 1a and 8 together with the known pyrrolobenzothiazines 1b,c and some their derivatives and intermediates of preparation were tested in vitro for their antimicrobial activity. Compound 1b was the most active against the Gram-positive Bacillus subtilis. Compound 7b showed interesting antifungal activity when tested against Saccharomyces cerevisiae.     

6-(Substituted-amino)-4H-s-triazolo[4,3-a][1,4]benzodiazepines and 4-(substituted-amino)-6H-s-triazolo[4,3-a][1,4]benzodiazepines with potential antianxiety activity

A series of 6-(substituted-amino)-4H-s-triazolo[4,3-a][1,4]benzodiazepines was prepared for pharmacological evaluation, and, because of an interesting chemical isomerization, a similar series of 4-(substituted-amino)-6H-s-triazolo[4,3-alpha][1,4]benzodiazepines was also obtained. Pharmacological evaluation of these compounds demonstrated that8-choloro-1-methyl-6-piperidino-4H-s-triazolo[4,3-a][1,4]benzodiazpin e (10) had interesting activity in tests useful for detecting antianxiety activity, while the corresponding 4-piperidino derivative (15) had little activity in these tests. A brief discussion of a possible mechanism for the isomerization is also included.     

Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H- 1,4-benzothiazines

As an extension of the previous investigation (J. Med. Chem. 1988, 31, 919), we synthesized a series of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H- 1,4-benzothiazines (3) and evaluated their Ca2+ antagonistic activities. Ca2+ antagonistic activity was measured with isolated depolarized guinea pig taenia cecum. On the basis of their potent Ca2+ antagonistic activity, six benzothiazines were selected and further evaluated for their vasocardioselectivity. Among these six compounds, the key compound 15 [3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[3,4- (methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo- 2H-1,4-benzothiazine hydrogen fumarate] was recognized as having the lowest cardioselectivity. Following optical resolution, the absolute configuration of the compound's optically active enantiomer was determined by means of X-ray crystallography of a synthetic precursor (+)-4a. The Ca2+ antagonistic activity of 15 was found to reside primarily in (+)-15 (which was about 7 times more potent than (-)-15). The in vitro study showed that (+)-15 had a low cardioselectivity compared to verapamil and diltiazem. This result suggests that (+)-15 would exhibit less adverse effects due to cardiac inhibition than diltiazem and verapamil in therapeutic use.     

Synthesis and Antimicrobial Activity of Some Pyrrolo[1,2,3-de]-1,4-benzothiazines,Part 2

Acid catalyzed cyclization reactions of both 3-alkyl- and 3-aryl-substituted N-/2,2-dialkoxyethyl)-3,4-dihydro-2H-1,4-benzothiazines ( 2 ) lead to 2,3-dihydro-pyrrolo[1,2,3-de]-1,4-benzothiazines ( 3 ). The pyrrolobenzothiazine structure was deduced on the basis of 2D ¹H NMR-NOESY experiments and fully determined by X-ray data. Compounds 3a-c showed poor antibacterial activity. However, the 3-phenyl-N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-1,4-benzothiazine ( 2b′ ) showed antifungal activity against Aspergillus niger 16-fold greater than miconazole.     

Indeno[1,2-c]pyrazolone acetic acids as semirigid analogues of the nonsteroidal anti-inflammatory drugs

A series of 3-substituted indeno[1,2-c]pyrazol-4(1H)-one-2-acetic acids (3a-e) and 3-substituted indeno[1,2-c]pyrazol-4(1H)-one-1-acetic acids (4a-e) were synthesized as semirigid analogues of tolmetin (1). These compounds were evaluated for their anti-inflammatory action by investigating their ability to block arachidonic acid metabolism in vitro as well as the ability to block carrageenan-induced rat foot edema in vivo. No consistent pattern of biological activity was noted.     

Pharmacological properties of 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e] [1,4]diazepine (Y-7131), a new anti-anxiety drug.

6-(o-Chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thienol[2,3-e][1,4]diazepine (Y-7131), a new derivative of the thienodiazepines, had marked activities in antipentylenetetrazole effect in mice, attenuation of conflict behavior in rats, inhibition of aggressive behavior induced by hypothalamic stimulation in cats and muscle relaxant effects in normal and decerebrate cats. Y-7131 had weak activities in anti-MES effect in mice and loss of righting reflex in mice. The acute toxicity of Y-7131 was considerably lower than that of diazepam. No significant autonomic or neuroleptic effects were noted. Y-7131 appears to be a characteristic and potent anti-anxiety agent different from the benzodiazepines.     

6-Aryl-4H-s-triazolo[4,3-a][1,4]benzodiazepines. Influence of 1-substitution on pharmacological activity.

A series of 1-substituted 6-aryl-4H-s-triazolo[4,3-a][1,4]benzodiazepines was prepared and evaluated for central nervous system activity. It was found that electronegative substituents, such as trifluoromethyl, were detrimental to activity in this series. On the other hand, many compounds with electron-donating substituents at C-1 had interesting activity. In addition to showing anxiolytic potential, some were also active in tests useful for detecting antidepressant and antipsychotic activity. Several analogues with 4-methyl-1-piperazinyl and 4-morpholinyl substituents at C-1 were of particular interest.     

1-(Aminoalkyl)-6-aryl-4-H-s-triazolo[4,3-a][1,4]benzodiazepines with antianxiety and antidepressant activity

A series of 1-(aminoalkyl)-6-aryl-4H-s-triazolo[4,3-a][1,4]benzodiazepines has been prepared and evaluated for central nervous system activity. We have found that members of this series have activity in pharmacological test systems designed to detect both anxiolytic and antidepressant activity. Each type of activity could be varied independently by appropriate substituent selections.     

Synthesis and hypoglycemic activity of some substituted flavonyl thiazolidinedione derivatives--fifth communication: flavonyl benzyl substituted 2,4-thiazolidinediones

A new series of 3-benzyl(p-substituted benzyl)-5-[3'-(4H-4-oxo-1-benzopyran-2-yl)-benzylidene]-2,4-thiazolidinediones (8a-e) were synthesized. These products were prepared by Knoevenagel reaction from 3'-flavone carboxaldehyde and 3-substituted 2,4-thiazolidinediones. In vitro insulinotropic activity was determined for compounds 6a-e, 7a-e, 8b and 8c.     

Possible psychopharmacological agents. Part 3: Synthesis and CNS activity of some new fluorine-containing pyrazolo[3,4-e][1,4]thiazepines

A series of new fluorine-containing pyrazolo [3,4-e][1,4]thiazepines has been synthesized by the condensation of 5-amino-3/1, 3-substituted pyrazole with appropriate arylaldehydes or ketones and mercaptoacetic acid in dry toluene. All synthesized compounds have been characterized by their m.p.'s elemental analysis, IR, H-NMR and F-NMR. A representative number of compounds has also been screened for their CNS activity and found to act as mild stimulants.     

Pyrazolo[4,5-c]quinolines. 2. Synthesis and specific inhibition of benzodiazepine receptor binding

A series of 1-aryl-3,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,5-c]quinolin-4-ones (2a-e) and 1-aryl-3-methyl-1H-pyrazolo[4,5-c]quinolines (3-7a-e) bearing different substituents at position 4 were prepared and tested for their ability to displace specific [3H]flunitrazepam binding from bovine brain membranes. The 5-N-methyl derivatives 2a-c,e were the compounds that bound with the highest affinity within this class. The replacement of the carbonyl group with other substituents and the resulting aromatization of the pyridine moiety greatly decreased the binding affinity. From a Lineweaver-Burk analysis on the most active compound 2b, it appears that the inhibition is a competitive one.     

Thiophene systems. 5. Thieno[3,4-b][1,5]benzoxazepines, thieno[3,4-b][1,5]benzothiazepines, and thieno[3,4-b][1,4]benzodiazepines as potential central nervous system agents

10-(Alkylamino)thieno[3,4-b][1,5]benzoxazepines (3) and 10-(alkylamino)thieno[3,4-b][1,5]benzothiazepines (4) were prepared by derivatization of the respective lactams (7 and 8) via phosphorus pentachloride and subsequent condensation with the appropriate alkylamines. 9-(Alkylamino)-4H-thieno[3,4-b][1,4]benzodiazepines (5) were prepared by titanium tetrachloride catalyzed condensation of the lactam 11 with alkylamines. 9-(Alkylamino)-4-methylthieno[3,4-b][1,4]benzodiazepines (6) were prepared by reductive alkylation of 5. The compounds were tested for potential neuroleptic activity by means of the blockade of d-amphetamine lethality in aggregated mice and/or effects on locomotor activity in rats. Antidepressant activity was examined using inhibition of tetrabenazine-induced depression in mice. Most of the title compounds 3-6 were found to have neuroleptic activity. In addition, introduction of a 3-chloro substituent in the oxygen and sulfur systems (3p and 4c), as well as introduction of an N-alkyl in the dinitrogen system (6), was found to produce antidepressant effects. Structure-activity relationships are discussed.     

Synthesis and pharmacology of potential beta-blockers.

Several 1-(4-substituted phenoxyl)-2-hydroxy-3-isopropylaminopropanes and 1-(4-substituted phenoxy)-2-hydroxy-3-[3,4-dimethoxyphenethyl]aminopropanes were synthesized for possible beta-adrenergic receptor blockage. The compounds were synthesized by reaction of the 4-substituted phenol with epichlorohydrin and subsequent opening of the resulting epoxide with either N-isopropylamine or N-3,4-dimethoxyphenethylamine. Preliminary biological testing indicated a decrease in the beta-blocking potency and the duration of action.     

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.     

Novel synthesis of convulsants with a unique ring system: dihydro-1,4-ethano-1H,3H-thieno[3,4-c]thiophene-3,6(4H)-dione

Dihydro-1,4-ethano-1H,3H-thieno[3,4-c]thiophene-3,6(4H)-dione (1) was obtained in 28% yield by an unusual rearrangement reaction on addition of 4 equiv of BBr3 to O,O-diethyl endo,exo-7-oxabicyclo[2.2.1]heptane-2,3-dicarbothioate. The 5-methyl, 1,4-dimethyl, 5-n-butyl, and 5,6-benzo analogues of 1 were synthesized by similar procedures. Dihydro-1,4-ethano-1H,3H-furo[3,4c]furan-3,6(4H)-dione (6) and its 1,4-dimethyl analogue were obtained by acid-catalyzed cyclization of the appropriate endo,exo-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acids. Lawesson's reagent was used to convert 1 and 6 to their monothiono and dithiono derivatives. The exo,exo isomers of several of the starting oxabicycloheptanedicarboxylic acids and their anhydrides are potent vesicants and hepatotoxins interacting with the cantharidin binding site of liver cytosol whereas some of the new bis-thiololactones and their thiono analogues are convulsants that probably act in the brain as GABAA receptor antagonists.     

Synthesis and pharmacological investigation of novel 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones as a new class of H1-antihistamine agents

A series of novel 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones was synthesized by the cyclization of 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4-one with various one-carbon donors. The starting material, 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4-one, was synthesized from 4-substituted aniline by a novel innovative route. When tested for in-vivo H1-antihistamine activity on conscious guinea-pigs, all the test compounds significantly protected the animals against histamine-induced bronchospasm. The compound 1-methyl-4-(4-chloro phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (VII) was more potent (72.71% protection), and 1-methyl-4-(4-methoxy phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) was equipotent (71% protection), when compared with the reference standard, chlorpheniramine maleate (71% protection). Compounds II and VII showed negligible sedation (5% and 8% respectively) when compared with chlorpheniramine maleate (25%). Compounds II and VII could serve as prototype molecules for further development as a new class of H1-antihistamines.     

Activation and detoxication of aminophenols. II. Synthesis and structural elucidation of various thiol addition products of 1,4-benzoquinoneimine and N-acetyl-1,4-benzoquinoneimine

1. Nine thioethers of 4-aminophenol with beta-hydroxyethylmercaptan, ranging from mono- to tetra-substituted thioadducts, were prepared from synthetic 1,4-benzoquinoneimine and characterized by 1H-n.m.r. and u.v. spectroscopy. For each compound, extinction coefficients and pKa values of the amino group were determined. 2. Five thioethers of 4-aminophenol with glutathione (GSH) were prepared and characterized by 1H-n.m.r. and u.v. spectroscopy with their respective extinction coefficients and pKa values. Two further thioadducts were tentatively assigned by their u.v. spectroscopic properties. 3. Reaction products of 1,4-[U-14C]benzoquinoneimine and GSH were studied, indicating formation of 4-amino-2-(glutathione-S-yl)phenol, 4-amino-2,3,6-tris(glutathione-S-yl)phenol as the main products. Formation of glutathione disulphide (GSSG) was not detected. In contrast, N-acetyl-1,4-[U-14C]benzoquinoneimine was partly reduced by GSH and formed only the 2-substituted thioadduct. 4. Investigation of the product orientation in the reductive addition of GSH to 2-(glutathione-S-yl)-1,4-benzoquinoneimine and 3-(glutathione-S-yl)-1,4-benzoquinoneimine, respectively, showed that the 3-substituted derivative formed mainly the 3,5-di-substituted thioadduct, whereas the 2-substituted compound formed mainly the 2,3,6-tri-substituted thioadduct. 5. Formation of thioadducts which autoxidize markedly faster than the parent aminophenol indicates that thioether formation is not an obligatory detoxication process.     

Synthesis and pharmacological evaluation of some 3-substituted octahydropyrido(2,1-c)(1,4)oxazines.

3-Phenyloctahydropyrido[2,1-c][1,4]oxazine hydrochloride and the 10R and 10S diastereomers have been synthesized from (+/-)-, (+)-, and (-)-2-piperidinemethanol. Treatment of 2-piperidinemethanol with alpha-bromoacetophenone gave 3-hydroxy-3-phenyloctahydropyrido[2,1-c][1,4]oxazine which was readily converted to the 3-phenyl derivative by catalytic hydrogenolysis. These compounds were shown to possess a depressant action on the CNS which was quantitated in terms of reduction of locomotor activity in mice. Qualitative differences were noted in the central effects of the 3-phenyl compound and its hemiketal derivative. Further, qualitative differences in the effects of the diastereomers of the 3-phenyl compound on locomotor activity of mice were also noted. The results of this study suggest that the octahydropyrido[2,1-c]1,4]oxazine system may provide a useful molecular framework for the construction of agents exhibiting pharmacologically useful actions in the CNS.     

Synthesis of 2-(4-hydroxyphenyl)benzofurans and their application to β-amyloid aggregation inhibitor

The facile synthesis of a series of 2-(4-hydroxyphenyl)benzofurans (4a-e) is described. The one-pot reaction of 4-substituted phenols with the chloride 1 in the presence of zinc chloride afforded 3-methylthio-2-(4-acetoxyphenyl)benzofurans (2a-e). The compounds 4a-e were obtained from the hydrolysis of 2a-e followed by the desulfurization of the resulting 3-methylthio-2-(4-hydroxyphenyl)benzofurans (3a-e). 5-Methyl-3-p-toluoyl-2-[4-(3-diethylaminopropoxy)phenyl]benzofuran (7), a beta-amyloid aggregation inhibitor, was synthesized by three steps starting from 4a.