6,11-Dihydrodibenzo[b,e]thiepin-11-yl 3-quinuclidinyl ethers: New potential intidepressants and antihistamine agents

Reactions of 11-chloro-6,11-dihydrodibenzo[b,e]thiepin and its 2-methyl derivative, and further of the methanesulfonates of 2-chloro- and 2-bromo-6,11-dihydrodibenzo[b,e]thiepin-11-ol with 3-quinuclidinol afforded the title ethers I-IV. The 2-methyl compound II (VÚFB-17 088) showed significant antihistamine activity and the 2-chloro compound III (VÚFB-17 089), having antireserpine and anticataleptic activity, proved a potential antidepressant agent.

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Some 4-Substituted 1-(3-Pyridylmethyl)piperazines with Antihistamine Activity

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19942343 ◽

1994 ◽

Vol 59 (10) ◽

pp. 2343-2350 ◽

Cited By ~ 1

Author(s):

Vojtěch Kmoníček ◽

Martin Valchář ◽

Zdeněk Polívka

Keyword(s):

Acetic Acid ◽

Nicotinic Acid ◽

Addition Reaction ◽

Antidepressant Activity ◽

Structural Resemblance ◽

Antihistamine Activity ◽

Antidepressant Agent ◽

Pharmacological Testing ◽

Substituted 1

Several compounds derived from nicotinic acid were prepared within a more extensive programme aiming at the synthesis of new substances with expected antihistamine and antidepressant activity. Some of these compounds display certain structural resemblance with the antidepressant agent piberaline (EGYT 475, Trelibet®, I) and its analogues. The products were used as intermediates for the synthesis of further compounds and most of them were subjected to pharmacological testing. Substituted nicotinic acid piperazides IIa - IId and IVa - IVe were obtained by reactions of nicotinoyl chloride (prepared in situ) with the correspondingly substituted piperazines. Reduction of the piperazides IIa - IId and IVa - IVd with diborane in situ in tetrahydrofuran afforded corresponding 1-substituted 4-(3-pyridylmethyl)piperazines IIIa - IIId and Va - Vd. Whereas the alkylation of 1-(2-pyrimidinyl)piperazine with 2-(chloromethyl)pyridine in ethanol in the presence of triethylamine resulted in compounds Ve, compound Vf was obtained by the addition reaction of 1-(3-pyridylmethyl)piperazine to acrylamide. The piperazides VIe and VIf were prepared by reactions of 2-(3-pyridyl)acetic acid with 1-(2-pyrimidinyl)piperazine or 3-(1-piperazinyl)propionamide in N,N-dimethylformamide in the presence 1,1'-carbonyldiimidazole. A similar procedure starting from nicotinic acid afforded the piperazide IVf. Compounds Vc and Vd showed significant affinity for the histamine H1-receptors (inhibition of binding of 2 nmol/l [3H]mepyramine in membranes from the rat brain: Vc, IC50 = 28 nmol/l; Vd, IC50 = 148 nmol/l). They also proved active in test of histamine aerosol in guinea pigs (PD50 = 4.1 mg/kg p.o. for compound Vc and 2.4 for compound Vd). Results of a more detailed pharmacological testing of these compounds will be published elsewhere.

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Potential antihistamine agents: 4-(6,11-Dihydrodibenzo[b,e]thiepin-11-ylidene)-1-methyltetrahydrothiopyranium iodide and similar sulfonium salts derived from related tricyclic systems

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19872758 ◽

1987 ◽

Vol 52 (11) ◽

pp. 2758-2774 ◽

Cited By ~ 4

Author(s):

Zdeněk Polívka ◽

Jiří Holubek ◽

Miloš Buděšínský ◽

Oluše Matoušová ◽

Emil Svátek ◽

...

Keyword(s):

Methyl Iodide ◽

Methyl Derivative ◽

Sulfonium Salt ◽

Sulfonium Salts ◽

Central Effects ◽

Tertiary Alcohols ◽

Antihistamine Activity ◽

Grignard Reactions ◽

By Products

Thioxanthone, 10,11-dihydrodibenzo[a,d]cyclohepten-5-one, dibenzo[b,e]thiepin-11(6H)-one, its 2-methyl derivative, and thieno[2,3-c]-2-benzothiepin-4(9H)-one were reacted with 4-tetrahydrothiopyranylmagnesium bromide and the obtained tertiary alcohols IVabc, VIc, and XIX were dehydrated to the olefinic sulfides IXabc, Xc, and XXI. Addition of methyl iodide afforded the title compounds XIabc, XIIc, and XXII. The Grignard reactions were accompanied by the 1,6-addition giving the ketones XVI-XVIII as by-products. The reductive properties of tetrahydrothiopyranylmagnesium bromide were most striking in the case of reaction with 2-chlorothioxanthone; the isolation of thioxanthene and thioxanthone showed that nuclear dehalogenation took also place. Reactions of 11-chloro-6,11-dihydrodibenzo[b,e]thiepin and benzhydryl chloride with tetrahydrothiopyran-4-ol gave the sulfides XXV and XXVIII; whereas the latter reacted with methyl iodide under the formation of sulfonium salt XXIX, the former was cleaved and gave 4-hydroxyl-1-methyltetrahydrothiopyranium iodide (XXVI). The sulfonium salts are free of the central effects but their antihistamine activity is rather low.

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Mechanistic Studies of the Antiallergic Activity of Phyllanthus amarus Schum. & Thonn. and Its Compounds

Molecules ◽

10.3390/molecules26030695 ◽

2021 ◽

Vol 26 (3) ◽

pp. 695

Author(s):

Nur Zahirah Abd Rani ◽

Kok Wai Lam ◽

Juriyati Jalil ◽

Hazni Falina Mohamad ◽

Mohd Shukri Mat Ali ◽

...

Keyword(s):

High Performance ◽

Binding Assay ◽

Radioligand Binding ◽

Positive Control ◽

Phyllanthus Amarus ◽

H1 Receptor ◽

Antiallergic Activity ◽

Ketotifen Fumarate ◽

Antihistamine Activity ◽

Basophilic Leukemia

Phyllanthus amarus Schum. & Thonn. (Phyllanthaceae) is a medicinal plant that is commonly used to treat diseases such as asthma, diabetes, and anemia. This study aimed to examine the antiallergic activity of P. amarus extract and its compounds. The antiallergic activity was determined by measuring the concentration of allergy markers release from rat basophilic leukemia (RBL-2H3) cells with ketotifen fumarate as the positive control. As a result, P. amarus did not stabilize mast cell degranulation but exhibited antihistamine activity. The antihistamine activity was evaluated by conducting a competition radioligand binding assay on the histamine 1 receptor (H1R). Four compounds were identified from the high performance liquid chromatography (HPLC) analysis which were phyllanthin (1), hypophyllanthin (2), niranthin (3), and corilagin (4). To gain insights into the binding interactions of the most active compound hypophyllanthin (2), molecular docking was conducted and found that hypophyllanthin (2) exhibited favorable binding in the H1R binding site. In conclusion, P. amarus and hypophyllanthin (2) could potentially exhibit antiallergic activity by preventing the activation of the H1 receptor.

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