Synthesis and quantitative structure-activity relationships of antiallergic 2-hydroxy-N-1H-tetrazol-5-ylbenzamides and N-(2-hydroxyphenyl)-1H-tetrazole-5-carboxamides

The synthesis and antiallergic activity of a series of 2-hydroxy-N-1H-tetrazol-5-ylbenzamides and isomeric N-(2-hydroxyphenyl)-1H-tetrazole-5-carboxamides is described. A relationship between structure and intravenous antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) test has been established using a Hansch/Free-Wilson model and used to direct studies toward potent derivatives. The contribution of physicochemical properties to activity is discussed. One member of this series, N-(3-acetyl-5-fluoro-2-hydroxyphenyl)-1H-tetrazole-5-carboxamide (3f), which was selected for further evaluation, has an ID50 value of 0.16 mg/kg po and is 130 times more potent than disodium cromoglycate (DSCG) on intravenous administration.     

Antiallergic agents. 2. N-(1H-tetrazol-5-yl)-6-phenyl-2-pyridinecarboxamides

A new series of N-(1H-tetrazol-5-yl)-6-phenyl-2-pyridinecarboxamides was prepared to determine the effects of substituents on the benzene and pyridine rings on antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) assay after oral administration. One member of this series, N-(1H-tetrazol-5-yl)-4-methyl-6-[4-(methylamino)-phenyl]-2- pyridinecarboxamide (231), has an ED50 value of 0.8 mg/kg po and is 85 times more potent than disodium cromoglycate (DSCG) on intravenous administration. Further evaluation of 231 as a clinically useful antiallergic agent is in progress.     

The antianaphylactic effect of derivatives of 4-oxoquinazoline, 4-oxoquinazol-3-yl-benzoic acid and 4-oxoquinazol-3-yl-acetic acid in the rat

Derivatives substituted at position 2 of 4-oxochinazolin as well as derivates of oxochinazolin-3-yl-benzoic acid and 4-oxochinazolin-3-yl-acetic acid had been tested for their antianaphylactic activities in the passive (PCA) and/or active cutaneous anaphylaxis (ACA) in rats. At i.p. administration (ACA) or intracutaneous (i.c.) administration (PCA) most of the derivates displayed a moderate antianaphylactic activity which et best could be compared to the theophylline activity. Only the free acids of the 4-oxochinazolin-3-yl-acetic acid derivatives were active at i.c. administration. All compounds tested remained inactive at p.o. administration.     

Troponoids. 3. Synthesis and antiallergy activity of N-troponyloxamic acid esters.

A number of oxamic acid derivatives of tropones and tropolones were synthesized and their antianaphylactic activity was determined in passive paw anaphylaxis (PPA). Several of these esters possessed oral activity. A comparison of the effect on the biological activity of the esters and the corresponding acid and its salt is reported. The experiments suggesting a relationship between the activity and the bioavailability of the ester 19 are also described. A study of the fate of ester 19 in serum on oral or intravenous administration to rats and dogs is reported. In vitro results of the effect of the compounds 19, 45, and 45a on the activity of the guinea pig lung and beef heart phosphodiesterase are presented. The various factors that may contribute to the antiallergy activity of compounds of this series are discussed.     

Antiallergic and cytoprotective activity of new N-phenylbenzamido acid derivatives.

A series of new N-phenylbenzamido acid derivatives was synthesized and evaluated for their ability to inhibit the IgE-mediated passive cutaneous anaphylaxis in the rat (PCA), as well as for their capacity to inhibit gastric mucosal damage induced by the oral administration of absolute alcohol in the rat. Some of these new derivatives exhibit potent antiallergic and cytoprotective activity, 20-80 times higher than that of the reference, disodium cromoglycate (DSCG). Structure-activity relationships are discussed. The antiallergic activity of one of the more potent compounds of this series, i.e. 4-(1H-tetrazol-5-yl)-N-[4-(1H-tetrazol-5-yl)phenyl]benzamide (compound 44, CR 2039) was further evaluated in vivo. This compound antagonizes the bronchoconstriction induced by aerosolized ovalbumin in both anesthetized and conscious IgE sensitized guinea pigs with ID50 of 3.7 mg/animal (tracheal insufflation) and 20 mg/kg (im). Further cytoprotective effects were evaluated in gastric ulcer models induced by the acute oral administration of hypertonic sodium chloride solution or by acetic acid and by the subchronic administration of glucose in fasted animals. In the models used experimentally CR 2039 is effective, whereas DSCG seems to be devoid of any protective activity. Such a potent antiallergic and mucosal protectant could provide a new potential agent in the therapy of atopic allergic diseases.     

Synthesis of 2-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) benzo heterocycles. A novel series of orally active antiallergic agents

A series of new 2-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) benzo heterocycles has been prepared. These compounds were tested as inhibitors of antigen-induced release of histamine (AIR) in vitro from rat peritoneal mast cells (RMC) and as inhibitors of IgE-mediated rat passive cutaneous anaphylaxis in the rat (PCA). Most of this new class of antiallergic agents showed good activity in the RMC assay. The most potent compound, 3-chloro-2-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl)benzo[b]thiophe ne (6t), with an I50 value of 0.2 microM, is 15 times more potent than disodium cromoglycate (DSCG) in the RMC assay. Many compounds were orally active in the PCA test, and several of these compounds showed higher potency when given in this way to that shown by DSCG when given intraperitoneally.     

1,2,4-Triazolo[4,3-a]quinoxaline-1,4-diones as antiallergic agents

A series of new 1,4-dihydro-1,2,4-triazolo[4,3-]quinoxaline-1,4-diones has been prepared. These compounds were tested as inhibitors of antigen-induced release of histamine (AIR) in vitro from rat peritoneal mast cells (RMC) and as inhibitors of IgE-mediated rat passive cutaneous anaphylaxis (PCA). Most of this new class of antiallergic agents showed good activity in the RMC and PCA tests. The most potent compound, 2-acetyl-7-chloro-5-n-propyl-1,2,4-triazolo[4,3-a]quinoxaline-1,4-dione (1x), with an I50 value of 0.1 microM, is 30 times more potent than disodium cromoglycate (DSCG) in the RMC assay.     

Synthesis and antiallergic activities of 1,3-oxazolo[4,5-h]quinolines

A series of new 1,3-oxazolo[4,5-h]quinolines has been prepared. These compounds were tested as inhibitors of antigen-induced release of histamine (AIR) in vitro from rat peritoneal mast cells (RMC) and as inhibitors of IgE-mediated passive cutaneous anaphylaxis in the rat (PCA). After several modifications of the original lead, the most potent compound of the series was determined to be 5-chloro-1,3-oxazolo[4,5-h]quinoline-2-carboxylic acid methyl ester (4a). It has an IC50 of 0.3 microM in the RMC assay and an ED50 (intraperitoneal) of 0.1 mg/kg in the PCA test, which is 10 times and 60 times more potent than disodium cromoglycate (DSCG), respectively. Of greater importance, it is orally active (ED50 = 0.5 mg/kg) as an inhibitor of the PCA test.     

Structure--activity relationships in a series of novel 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylic acid antiallergy agents

A series of more than 50 new 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylic acid derivatives and related compounds with substituent variations at the 2, 3, and 5--9 positions was prepared and evaluated for antiallergy activity using the rat PCA assay. These compounds were obtained by the condensation of the appropriately substituted 2-aminoquinoline-3-carboxamides with dialkyl oxalates, followed by further chemical transformations. More than two-thirds of the compounds prepared exhibited intravenous activity ranging from 1 to 400 times disodium cromoglycate (DSCG). Structure--activity data suggest that the presence of a carboxylic acid moiety at the 2 position affords optimal potency and that esters are preferred for good oral absorption. Best oral activity, with ED50 values ranging from 0.3 to 3.0 mg/kg, was displayed by ethyl esters with methoxy and/or ethoxy groups at the 7 and 8 positions.     

5-Isoquinolinesulfonamide derivatives. 2. Synthesis and vasodilatory activity of N-(2-aminoethyl)-5-isoquinolinesulfonamide derivatives

A new series of aromatic sulfonamides, the N-(2-aminoethyl)-5-isoquinolinesulfonamide derivatives, 3, was synthesized from 5-isoquinolinesulfonic acid and shown to possess vasodilatory action. Vasodilatory activity was evaluated in vivo in terms of increases in arterial blood flow in dogs after local injection in the femoral and/or vertebral arteries. When the alkylene group between the two nonaromatic nitrogen atoms was ethylene, the most potent activity was obtained. Alkylations of either of the two nonaromatic nitrogens yielded more active compounds, although bulky or excessively long alkyl groups reduced the potency. Among these derivatives, 27 and 47 were equipotent to diltiazem, which is used clinically as a cardiovascular drug. These two compounds also had antihypertensive and vasodilatory activities when administered intravenously, although the activities were less than that of diltiazem when given by this route.     

Pyrido[3',2':4,5]thieno[3,2-d]-N-triazines: a new series of orally active antiallergic agents

A new series of orally active mediator release inhibitors, pyrido[3',2':4,5]thieno[3,2-d]-N-triazines, was synthesized and evaluated for antiallergic activity. Several products showed high activity as inhibitors or wheal information in the rat passive cutaneous anaphylaxis screen and as inhibitors of histamine release from passively sensitized rat mast cells. Many compounds were orally active in the PCA test. The most potent compound, 7-phenylpyrido-[3',2':4,5]thieno[3,2-d]-1,2,3-triazin-4(3H)- one (10) with an I50 value of 0.05 microM, was 60 times more potent than disodium cromoglycate (DSCG) in the RMC assay.     

强效镇痛剂研究——Ⅱ.3-甲基芬太尼类衍生物的合成及镇痛活性

本文报道了N-[1-(β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7209)和N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7302)等一系列3-甲基芬太尼类衍生物的合成及镇痛活性。绝大部分该类衍生物均具有典型的吗啡样镇痛活性,是一类结构较简单、易于合成、镇痛作用极强的麻醉镇痛剂。化合物7302的ED₅₀为0.0022mg/kg(ip,小鼠,热板法),比芬太尼强28倍,竟达吗啡的6318倍,为我们至今合成该类衍生物中作用最强者。     

Studies on antianaphylactic agents. 7. Synthesis of antiallergic 5-oxo-5H-[1]benzopyrano[2,3-b]pyridines

5-Oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acids 23 and their tetrazole analogues 24 were synthesized from 4-oxo-4H-1-benzopyran-3-carbonitriles 3 or 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehydes 4. When administered intravenously, they exhibited antiallergic activity in a reaginic PCA test in rats. In the carboxylic acid series, the activity was influenced by the substituents at the 2-position and increased substantially in the following order: Me, OMe less than NH2 less than OH, H less than NHOMe. On the other hand, in the tetrazole series, 2-unsubstituted derivatives showed the highest activity. Regardless of the kinds of substituents at positions 2 and 3, compounds bearing an alkyl group, especially an isopropyl group at the 7-position, were superior in activity to the corresponding unsubstituted compounds. Among these alkyl derivatives, 3-carboxylic acid derivatives, i.e., 23c (7-ethyl), 23g (2-amino-7-isopropyl), 23r [2-(methoxyamino)-7-isopropyl], and a 3-tetrazole derivative 24c (7-isopropyl), were 41-184 times as potent as disodium cromoglycate. They also exhibited remarkable activity when administered orally; clinical studies on 23g (AA-673) are in progress.     

1-(2-pyridinyl)piperazine derivatives with antianaphylactic, antibronchospastic, and mast cell stabilizing activities

New 1-(2-pyridinyl)piperazine derivatives were synthesized and tested as inhibitors of the reaginic passive cutaneous anaphylaxis in the rat (PCA), of the histamine-induced bronchospasm in the guinea pig, and of the rat mesenteric mast cell degranulation induced by compound 48/80. On the basis of test results, a series of N-(substituted phenyl)-omega-[4-(2-pyridinyl)-1-piperazinyl]alkanamides was prepared. The nature of substituents at the anilide ring strongly influenced mast cell stabilizing activity, whereas it was less determining in the case of the other two tests. No clear correlation between the most common physicochemical parameters (pi, sigma, Vw volume) of substituents and activity could be detected. With regard to the position of substituents at the anilide ring, the rank order of potency, in the PCA and bronchoconstriction tests, was para greater than meta greater than ortho. Introduction of substituents in the 1-(2-pyridinyl)piperazinyl moiety of the N-(substituted phenyl)propanamide derivatives hardly affected activity, or the effect was deleterious. Some of the new compounds exhibited a simultaneous remarkable activity in all the three assays employed.     

Synthesis and antiallergic activity of some acidic derivatives of 4H-pyrimido[2,1-b]benzazol-4-ones

Reactions of 2-aminobenzothiazole, 2-aminobenzoxazole, and 2-amino-1-methylbenzimidazole with dimethyl aminofumarate (DMAF) or diethyl ethoxymethylenemalonate (DEEM) led to 2- or 3-carboxy-4H-pyrimido[2,1-b]-benzazol-4-ones, respectively. Subsequent derivatization of these carboxylic acids gave the corresponding tetrazolylcarboxamides and tetrazoles. These acidic compounds were tested in the rat passive cutaneous anaphylaxis (PCA) assay as potential antiallergic agents. Many of the compounds displayed activity comparable to that shown by disodium cromoglycate (DSCG) when tested by the intraperitoneal route, and some, unlike DSCG, also showed activity when tested orally.     

Quinazoline antifolates inhibiting thymidylate synthase: variation of the N10 substituent

The synthesis of 12 new 5,8-dideazafolates with isopropyl, cyclopropylmethyl, 2-fluoroethyl, carbamoylmethyl, phenacyl, 3-fluorobenzyl, 5-uracilylmethyl, carboxymethyl, 2-carboxyethyl, 3-cyanopropyl, 3-hydroxypropyl, and cyanomethyl substituents at N10 is described. In general, the synthetic route involved monoalkylation of diethyl N-(4-amino-benzoyl)-L-glutamate, coupling of the resulting secondary amine with 2-amino-6-(bromomethyl)-4-hydroxyquinazoline hydrobromide in N,N-dimethylacetamide with calcium carbonate as the base, and deprotection using mild alkali. The cyanomethyl derivatives was found to be unexpectedly base labile and was therefore prepared by mild acid deprotection of a di-tert-butyl ester. The compounds were tested as inhibitors of purified L1210 thymidylate synthase (TS). Four members of the series were more potent that the N10-hydrogen compound, but none was superior to the previously described N10-propargyl-5,8-dideazafolic acid. Selected compounds were examined as inhibitors of purified L1210 dihydrofolate reductase (DHFR). As desired, N10 substitution in general reduced DHFR inhibitory activity; these results are discussed. As a measure of cytotoxicity, the compounds were examined for their inhibition of the growth of L1210 cells in culture. None of the new substituents conferred enhanced potency relative to N10-propargyl-5,8-dideazafolic acid (ID50 = 5 microM), which, as the best TS inhibitor and a relatively poor DHFR inhibitor, continues to lead this series.     

Synthesis of some thiazoline and thiazolidinone derivatives of 1,4-benzoquinone as potential antimicrobial agents

Three novel series of benzoquinone derivatives were synthesized, namely: N-(3-aryl-4-phenylthiazolin-2-ylidene)-N-(1,4-benzoquinone carbonyl) hydrazines; N-(3-aryl-5-carbethoxy-4-methylthiazolin-2-ylidene)-N-(1,4- benzoquinone carbonyl)hydrazine and N-(3-arylthiazolin-4-one-2-ylidene)-N-(1,4- benzoquinone carbonyl) hydrazines. These series were prepared by oxidation of the new hydroquinone precursors. The antimicrobial activity of representative compounds of benzoquinone, as well as of hydroquinone derivatives was studied.     

Studies on anti-allergic agent. I. 1,2,3-trisubstituted-2-propen-1-one derivatives, 3,4-disubstituted-4-oxo-2-butenoic acids and the related compounds]

A new series of 1,2,3-trisubstituted-2-propen-1-one derivatives (9a-v, 10a-j, 13a-c, 14a-j) and 3,4-disubstituted-4-oxo-2-butenoic acids (6a-i, 7a-n) with azole compounds were synthesized. Inhibitory activities against rat passive cutaneous anaphylaxis (PCA) reaction and histamine release from rat mast cells were tested. The ester derivatives (7a-n, 14a-j) exhibited a more potent inhibitory activity against histamine release compared with alkylamine (9a-v), beta-hydroxyethoxy (10a-j) and carboxylic acid (6a-i, 13a-c) derivatives, but somewhat weaker in their anti-PCA activity. Structure-activity relationships were discussed.     

Studies on 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives and their analgesic activities. 1.

The preparation and analgesic activities of a series of the entitled compounds (5-22) and the optical isomers of the 1-cyclohexyl derivative 5 are described. Reactions of N,N-bis(2-chloroethyl)-1,2-diphenylethylamine (3) with ammonia and primary amines gave N-(1,2-diphenylethyl)piperazine (4) and N1-substituted derivatives (5-20, 22), respectively. The alkylation of 4 afforded 12-21. Compounds 5-18 and 22 were also obtained by the reactions of 1,2-diphenylethylamine (23) and N-substituted 2,2'-dichlorodiethylamine. Racemate 5 was resolved with (+)- or (-)-2'-nitrotartranilic acid into its optical isomers [(+)-5 and (-)-5], and the absolute configuration of (+)-5 was determined to be S configuration by the synthesis and optical rotatory dispersion measurements. The most active members in this series of compounds were 5-7, which were approximately as potent as (-)-morphine. In the case of 5, the more potent enantiomer (S)-(+)-5 has the opposite configuration to that of (-)-N,N-dimethyl-1,2-diphenylethylamine (Spa) or (-)-morphine with respect to the (C-9) asymmetric center and belongs to a new series of compounds having potent analgesic activity.     

New antihistaminic N-heterocyclic 4-piperidinamines. 1. Synthesis and antihistaminic activity of N-(4-piperidinyl)-1H-benzimidazol-2-amines

The synthesis of a series N-(4-piperidinyl)-1H-benzimidazol-2-amines and the preliminary evaluation of their in vitro and in vivo antihistaminic activity are described. Cyclodesulfurization of (2-aminophenyl)thioureas with mercury(II) oxide resulted in 2-aminobenzimidazole intermediates, which were monoalkylated on the endo-nitrogen atom. After deprotection of the piperidine nitrogen atom with 48% aqueous hydrobromic acid solution, the title compounds were obtained by three different methods, viz. alkylation, reductive amination, or oxirane ring-opening reactions. The in vivo antihistaminic activity was evaluated by the compound 48/80 induced lethality test in rats and histamine-induced lethality test in guinea pigs after oral and/or subcutaneous administration. The duration of action, for a selected number of compounds, was studied in the guinea pig. The phenylethyl derivatives showed the most potent antihistamine properties after oral administration in both animal species.