Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: synthesis and pharmacological properties of 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-ben zoazepine-1-carbonyl]benzanilide and 4'-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1- carbonyl]benzanilide derivatives

Arginine vasopressin (AVP) has a dual action, i.e. vasoconstriction and water reabsorption via V1A and V2 receptors, and may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of AVP antagonists for both V1A and V2 receptors based on the hypothesis that the blockade of both V1A and V2 receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl ]benzanilide (exo-olefin isomer) and 4'-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1-carbonyl]benzanilide (endo-olefin isomer) were synthesized and examined to have AVP antagonist activity for both V1A and V2 receptors. As a result, it was found that the (E)-exo-olefin isomers showed more potent binding affinity compared with endo-olefin isomers. Among these (E)-exo-olefin isomers, (E)-N-methyl-{1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahyd ro-1H-1 -benzoazepin-5-ylidene}acetamide (14) exhibited the most potent binding affinity and (E)-N-methyl-(1-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-2,3,4,5- tetrahydro-1H-1-benzoazepin-5-ylidene)acetamide (20) exhibited a high AVP antagonist activity for both V1A and V2 receptors after intravenous administration. Details of the synthesis and pharmacological properties of this series are presented.     

Synthesis of aminomethyl derivatives of 3-methyl-4,7-dihydro-3H-imidazo[4,5-d][1,2,3]triazin-4-one

New aminomethyl derivatives of 3-methyl-4,7-dihydro-3H-imidazo[4,5-d][l,2,3]triazin-4-one were synthesized by Mannich reaction. These Mannich bases is also possible to prepare by reaction of 7(5)-hydroxymethyl-3-methyl-4,7(5)dihydro-3H-imidazo[4,5-d][l,2,3]triazin-4-one with amines. The compounds obtained exist in solutions as mixtures of N⁵ and N⁷ isomers, and the fraction of the latter grows with the polarity of the solvent.     

Synthesis of pyrazolo[4,5-d]- and pyrazolo[4,5-c][1]benzazepine derivatives. IV

Following our reports on synthetic tricyclic analogues of antitumor anthramycin the synthesis of some isomers pyrazolo[4,5-d]- and pyrazolo[4,5-c][1]benzazepine derivatives is reported.     

Synthesis of substituted 4H-thiazolo[4,5-b][1]benzothiopyran-4-ones as possible schistosomicidal agents

Summary Interaction of ethyl 2-acetamido-5-bromothiazole-4-carboxylate (2) with 2-methyl-5-chlorothiophenol (3) afforded the thioether4, which was hydrolysed to the corresponding carboxylic acid5. Attempted cyclization of5 to6 yielded the decarboxylated product7. On the other hand, interaction of 2-acetamido-5-bromothiazole (9) with thiosalicylic acid (10) yielded the thioether11, which was cyclized to compound12. Acid hydrolysis of12 yielded the amino derivative13, which was reacted with certain selected alkyl halides using sodium hydride to afford compounds14–18.

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Synthese von substituierten 4H-Thiazolo[4,5-b][1]benzothiopyran-4-onen als mögliche schistosomicide Wirkstoffe

Zusammenfassung Die Reaktion von Ethyl 2-Acetamido-5-bromthiazol-4-carboxylat (2) mit 2-Methyl-5-chlorthiophenol (3) ergab den Thioether4, der zur entsprechenden Carbonsäure5 hydrolysiert wurde. Die versuchte Cyclisierung von5 zu6 ergab das Decarboxylierungsprodukt7. Andererseits ergab die Reaktion von 2-Acetamido-5-bromthiazol (9) mit Thiosalizylsäure (10) den Thioether11, der zu Verbindung12 cyclisiert werden konnte. Saure Hydrolyse von12 ergab das Aminoderivat13, das mit geeigneten Alkylhalogeniden unter Verwendung von Natriumhydrid zu den Verbindungen14–18 führte.

     

Polycondensed nitrogen heterocycles. IX. 5,6-dihydro-7H-pyrrolo[1,2-d][1,4]benzodiazepin-6-one

The reaction of amino derivative I with bromoacetyl bromide led to the formation of a complex mixture from which, in addition to the title compound, which was formed in low yield, compounds III, IV and VI were separated. Pyrrolo[1,2-d][1,4]benzodiazepine V was obtained in 85% yield when the bromoamide III was treated with an equimolar amount of potassium t-butoxide.     

Synthesis of new imidazo[4,5-d][1,3]diazepine derivatives from 5-amino-4-(cyanoformimidoyl)imidazoles

N¹-[(Z) -2- Amino-1,2-dicyanovinyl]formamidines 1a-d react readily with tosyl isocyanate to form novel 8-amino-3-substituted-5-oxo-7-tosylaminoimidazo[4,5-d][1,3]diazepines 6a-d rather than the 6-cyano-2-oxopurine derivatives 5a-d expected. Compound 5a has been synthesized from 1a by reaction with ethyl chloroformate and base-catalyzed cyclization of the resultant 5-ethoxycarbonylamino-4-(cyanoformimidoyl)imidazole. Treatment of the 5-amino-4-cyanoimidazoles 7a and b with tosyl isocyanate under similar conditions gives the 4-cyano-5-(3′-tosylureido)imidazoles 8a and b , which on treatment with ethanolic ammonia cyclizes to the corresponding isoguanines 10a and b .     

2-(2-Furyl)-5,6-dihydro-1(3)H-acenaphtho[4,5-d]imidazole. Synthesis and electrophilic substitution reactions

2-(2-Furyl)-5,6-dihydro-1(3)H-acenaphtho[4,5-d]imidazole was synthesized by the Weidenhagen reaction of acenaphthene-4,5-diamine with furfural. Alkylation of the title compound with methyl iodide in KOH-DMSO gave isomeric 1- and 3-methyl derivative, the latter being the major product. 2-(2-Furyl)-3-methyl-5,6-dihydro-3H-acenaphtho[4,5-d]imidazole was subjected to electrophilic substitution reactions (bromination, nitration, formylation, acylation, and sulfonation. Depending on the conditions, electrophilic attack was directed at the furan ring or acenaphthene fragment or both these.     

Synthesis of pyrimido [4,5-c] pyridazine (4-deazafervenulin), pyrazolo[3,4-d] pyrimidine and 6-(pyrazino-1-yl)pyrimidine derivatives

The synthesis of several pyrimido[4,5-c]pyridazine (4-deazafervenulin) ( 1 ), pyrazolo[3,4-d]-pyrimidine ( 2 ) and 6-(pyrazino-1-yl)pyrimidine ( 9 ) analogs has been accomplished from 6-hydrazinouracil ( 3 ). This compound could not be used as starting material for the preparation of indolo[3,2-c]pyridazino[3,4-d]pyrimidine derivatives ( 8 ) because it yielded the corresponding hydrazones ( 7 ).     

[1,3]Dioxolo[5,6][1]benzothieno[2,3-c]-quinolin-6(5H)-ones

Summary The reaction of 3,4-methylenedioxycinnamic acid (1) with thionyl chloride resulted in the formation of 7-chlorothieno[2,3-f]-1,3-benzodioxole-6-carbonyl chloride (2) and cinnamoyl chloride (3). Subsequent reaction of the former withp-substituted anilines led to the formation of 7-chloro-N-(p-substituted phenyl)-thieno[2,3-f]-1,3-benzodioxole-6-carboxamides (4a–c) which on photocyclization afforded 2-substituted [1,3]dioxolo[5,6][1]benzothieno[2,3-c]quinolin-6(5H)-ones (5a–c) in fairly good yields and high purity. The structures have been confirmed by IR,¹H NMR, and analytical methods.Accepted for presentation at the Hong Kong International Symposium on Heterocyclic Chemistry (August 13–16, 1995)     

Polycyclic N-heterocyclic compounds. XLI. Synthesis of 4-substituted 6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepines, 1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzazepines and their related compounds as a series of potential blood platelet aggregation inhibitors

As a series of polyheterocyclic compounds for exploitation as anti-platelet agents, tricyclic heterocyclic compounds, 4-substituted 6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepines 3–6, 9, 12–14 , and 16–26 , having nitrogen, oxygen, or sulfur containing functional groups at the 4-position, were prepared. In addition, tetra-cyclic heterocyclic compounds, 3-methyl-1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzaze-pinium chloride ( 7 ), 1,2,5,6-tetrahydro-4H-imidazo[1′,2′:1,6]pyrimido[5,4-d][1]benzazepines 10a-e , 2,3,6,7-tetrahydro-1H 5H-pyrimido[1′,2′:1,6]pyrimido[5,4-d][1]benzazepine ( 11 ), and 1,2,5,6-tetrahydro-4H-thiazolo-[3′,2′:1,6]pyrimido[5,4-d][1]benzazepinium chloride ( 15 ) via ring closure of 4-(hydroxyalkylamino)- 6, 9a-e , and 3c , and 4-(2-hydroxyethylthio)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine ( 14 ) with phosphoryl chloride or thionyl chloride, respectively, were also prepared. Their inhibitory activities against collagen-induced aggregation of rabbit blood platelets in vitro were investigated. Among them, compound 5 having a morpholino group at the 4-position on the tricyclic nucleus, which enhanced the activity more than 14-fold as compared with aspirin, was found to have the most satisfactory in inhibitory activity.     

Synthesis and antitumor activities of a new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives

A new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives have been designed and synthesized.The antitumor activities of the target compounds have been evaluated in vitro against two human cancer cell lines including A549 (human alveolar adenocarcinoma cell) and H460 (human lung cancer) by MTT assay.Most of the target compounds exhibited significant antitumor activities against A549 and H460 cancer cell lines.The most potent compound 4-(benzo[d][1,3]dioxol5-yl)-8,9-difluoro-2-(4-methylpiperazin-1-yl)-4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine (CH05) (IC50=0.44 M,3.07 M) was 2.0 and 8.4 times more active than gefitinib (IC50=0.89 M,16.81 M) against A549 and H460 cell lines,respectively.     

Polycyclic N-heterocyclic compounds. 55. A novel reaction of N-(5,6-dihydro[1]benzothiepino[5,4-d]pyrimidin-4-yl)amidine or its amide oxime derivatives with hydroxylamine

The reactions of N-(5,6-dihydro[1]benzothiepino[5,4-d]pyrimidin-4-yl)amidines or its amide oxime derivatives with hydroxylamine hydrochloride under basic condition gave abnormal cyclization products via a ring cleavage of pyrimidine component accompanied with a ring closure of [1,2,4]oxadiazole.     

Highly potent and orally active non-peptide arginine vasopressin antagonists for both V1A and V2 receptors: synthesis and pharmacological properties of 4'-[(4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-y l)carbonyl]-2-phenylbenzanilide derivatives

A series of compounds structurally related to 4'-[(4,4-difluoro-5-methylidene-2,3,4,5-tetrahydro-1H-1-benzoaz epin-1-yl) carbonyl]-2-phenylbenzanilide were synthesized and evaluated for arginine vasopressin (AVP) antagonistic activity. Compounds with a (Z)-olefin geometry at the 5-position of benzoazepine possessed potent affinity for both the V1A and V2 receptors. Further study has shown that one of these derivatives, (Z)-4'-(?4,4-difluoro-5-[(4-dimethylaminopiperidino)carbonylmet hylene]-2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yI?carbonyl)2- phenylbenzanilide monohydrochloride (29, YM-35471), exhibits exceptionally potent affinity for both of V1A and V2 receptors, even when administered orally. The synthesis and pharmacological properties of this compound are detailed in this paper.