Polycyclic N‐Heterocyclic Compounds. Part 82: Synthesis and Evaluation of Anti‐Platelet Aggregation Activity of 2,4‐Disubstituted 5,6‐Dihydro[1]benzothiepino[5,4‐d]pyrimidine and Related Compounds

We have synthesized a large number of tricyclic 2‐substituted 4‐alkylamino‐5,6‐dihydro[1]benzothiepino[5,4‐d]pyrimidines as part of our research to develop new effective anti‐platelet drugs. A variety of alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising anti‐platelet candidates with potencies superior to aspirin.     

Polycyclic N‐Heterocyclic Compounds. Part 86: Synthesis and Evaluation of Antiplatelet Aggregation Activity of 2,4‐Disubstituted 9‐Chloro‐5,6‐dihydropyrimido[5,4‐d]benzazepine and Related Compounds

Libraries of tricyclic 2‐substituted 4‐alkylamino‐9‐chloro‐5,6‐dihydropyrimido[5,4‐d]benzazepines and tetracyclic 12‐substituted 8‐chloro‐1,2,5,6‐tetrahydro‐4H‐imidazo[1′,2′:1,6]pyrimido[5,4‐d]benzazepines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.     

Polycyclic N‐Heterocyclic Compounds. Part 80: Synthesis and Evaluation of Effects on In Vitro Pentosidine Formation of 5,6‐Dihydro[1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidine and Related Compounds

Reaction of 3‐(3‐cyanopropylthio)[1]benzothiophene‐2‐carbonitrile with tert‐BuONa gave 5‐amino‐1,2‐dihydro[1]benzothieno[3,2‐d]thieno[2,3‐b]pyridine and 5‐amino‐2,3‐dihydro[1]benzothieno[3,2‐b]thiepin‐4‐carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles, [1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidines. All of our new tetracyclic products were evaluated for in vitro inhibitory activity on the formation of pentosidine, which is one of representative advanced glycation end products.     

Polycyclic N‐Heterocyclic Compounds. Part 79: Synthesis of 2,4‐Disubstituted 6,7‐Dihydro‐5H‐benzo[6,7]cyclohepta[1,2‐d]pyrimidines as Potential Antiplatelet Aggregators

Libraries of tricyclic 2‐substituted 4‐alkylamino‐6,7‐dihydro‐5H‐benzo[6,7]cyclohepta[1,2‐d]pyrimidines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.     

Polycyclic N‐Heterocyclic Compounds. Part 75: Synthesis of 2,4‐Disubstituted 5,6‐dihydro[1]benzoxepino[5,4‐d]pyrimidines and 12‐Substituted 1,2,4,5‐Tetrahydro[1]benzoxepino[4,5‐e]imidazo[1,2‐c]pyrimidines as Potential Antiplatelet Aggregators

Libraries of tricyclic 2‐substituted 4‐alkylamino‐5,6‐dihydro[1]benzoxepino[5,4‐d]pyrimidines and tetracyclic 12‐substituted 1,2,4,5‐tetrahydro[1]benzoxepino[4,5‐e]imidazo[1,2‐c]pyrimidines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.     

Polycyclic N‐Heterocyclic Compounds. 56 Reaction of N‐(5,6‐Dihydro[1]benzoxepino[5,4‐d]pyrimidin‐4‐yl)amidine or Its Amide Oxime Derivatives with Hydroxylamine Hyrdochloride

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

Polycyclic N‐Heterocyclic Compounds. Part 81: Synthesis and Evaluation of Pentacyclic 1,2,4,5‐Tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]imidazo[1,2‐c]pyrimidine and Related Compounds as Potential Antiplatelet Aggregators

Dehydrative ring closure reactions were carried out on fused 4‐(2‐hydroxyethylamino) (or 2‐hydroxyethoxy or 2‐hydroxyethylthio)pyrimidines ( 2a , 2b , 2c ) to give fused 2,3‐dihydroimidazo[1,2‐c] (or 2,3‐dihydrooxazolo[3,2‐c] or 2,3‐dihydrothiazolo[3,2‐c])pyrimidines. This reaction produced the pentacyclic 1,2,4,5‐tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]imidazo[1,2‐c]pyrimidine ( 3a ) and 1,2,4,5‐tetrahydro[1]benzothieno[2′,3′:6,7]thiepino[4,5‐e]thiazolo[3,2‐c]pyrimidinium chloride ( 3c ) from the 2‐hydroxyethylamino‐derivative and 2‐hydroxyethylthio‐derivative, respectively. In contrast, 2‐hydroxyethoxy‐derivative ( 2b ) gave the rearrangement product, 3‐(2‐chloroethyl)‐5,6‐dihydro[1]benzothieno[3′,2′:2,3]thiepino[4,5‐d]pyrimidin‐4(3H)‐one ( 4 ). Effects of the synthesized compounds on collagen‐induced platelet aggregation were also evaluated.     

Polycyclic N‐Heterocyclic Compounds,Part 71: Synthesis and Bronchodilator Evaluation of 5‐Substituted 1,2‐Dihydrofuro[3,2‐f][1,7]naphthyridines and Related Compounds

Several 5‐substituted 1,2‐dihydrofuro[3,2‐f][1,7]naphthyridines were synthesized as part of our research to develop new effective bronchodilators. Amines, sulfanyls, and alcohols were used as substituents at the fifth position. Tetracyclic compounds were also obtained. Evaluation of the effects of the newly synthesized compounds on carbamoylcholine chloride‐induced contractions of trachea revealed one promising bronchodilator candidate with potency comparable to that of 3‐isobutyl‐1‐methylxanthine.     

Synthesis of Oxazolo[5,4‐d][1,2,4]triazolo[4,3‐a]pyrimidines as a New Class of Heterocyclic Compounds

Several new derivatives of oxazolo[5,4‐d]pyrimidine ( 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h ) have been synthesized through the reaction of 2,4‐dichloro‐6‐methyl‐5‐nitropyrimidine ( 2 ) with aryl carboxylic acids in refluxing POCl₃. Further treatment of compounds ( 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h ) with hydrazine hydrate gave the hydrazine derivatives ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h ) that were subsequently cyclized into a novel heterocyclic system, oxazolo[5,4‐d][1,2,4]triazolo[4,3‐a]pyrimidine ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l , 5m , 5n , 5o , 5p ) and ( 7a , 7b , 7c , 7d ) on treatment with triethylorthoesters or carbondisulfide and alkylhalides, respectively.     

Polycyclic N‐Heterocyclic Compounds,Part 69: Synthesis of 5‐amino‐1,2‐dihydro[1]benzofuro[3,2‐d]furo[2,3‐b]pyridines and their transformations to related compounds

Reaction of 3‐(3‐cyanopropoxy)[1]benzofuran‐2‐carbonitriles with potassium tert‐butoxide gave 5‐amino‐1,2‐dihydro[1]benzofuro[3,2‐d]furo[2,3‐b]pyridines and 5‐amino‐2,3‐dihydro[1]benzofuro[3,2‐b]oxepin‐4‐carbonitriles as new ring systems. Reactions of the 5‐chloro derivative, obtained from 5‐amino‐1,2‐dihydro[1]benzofuro[3,2‐d]furo[2,3‐b]pyridine, produced a dihydrofuran ring‐opened compound and 5‐substituted compounds. J. Heterocyclic Chem.,(2011).     

Polycyclic N‐Heterocyclic Compounds. Part 78: Synthesis of N‐[2‐([1,2,4]Oxadiazol‐5‐yl)cyclohepten‐1‐yl]formamide Oximes and Their Evaluation as Inhibitors of Platelet Aggregation

N‐[2‐([1,2,4]Oxadiazol‐5‐yl)cyclohepten‐1‐yl]formamide oximes were synthesized by fusion of (6,7,8,9‐tetrahydro‐5H‐cyclohepta[1,2‐d]pyrimidin‐4‐yl)amidines with hydroxylamine hydrochloride through a subsequent rearrangement reaction. Effects of the products as well as the structurally related N‐[4‐([1,2,4]oxadiazol‐5‐yl)‐2,3‐dihydro[1]benzoxepin‐5‐yl]formamide oximes and N‐[4‐([1,2,4]oxadiazol‐5‐yl)‐2,3‐dihydro[1]benzothiepin‐5‐yl]formamide oximes on platelet aggregation were evaluated.     

Polycyclic N‐Heterocyclic Compounds,Part 72: Reaction of N‐([1]Benzofuro (or Benzothieno)[3,2‐d]pyrimidin‐4‐yl)formamidine and N‐(Pyrido[2,3‐d]pyrimidin‐4‐yl)formamidine Derivatives with Hydroxylamine Hydrochloride

The reactions of N‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)formamidines with hydroxylamine hydrochloride gave rearranged cyclization products via ring cleavage of the pyrimidine component accompanied by a ring closure of the 1,2,4‐oxadiazole to give N‐[2‐([1,2,4]oxadiazol‐5‐yl)[1]benzofuran‐3‐yl)formamide oximes. N‐([1]Benzothieno[3,2‐d]pyrimidin‐4‐yl)formamidines and N‐(pyrido[2,3‐d]pyrimidin‐4‐yl)formamidines with hydroxylamine hydrochloride gave similar results.     

Polycyclic N‐Heterocyclic Compounds 73: Synthesis and Evaluation of 5‐Substituted 1,2‐Dihydrofuro[2,3‐c]isoquinolines as Inducers of Lipoprotein Lipase mRNA Expression

Several 5‐substituted 1,2‐dihydro[2,3‐c]isoquinoline derivatives were synthesized as part of our research to develop new diabetes drugs. Amines and sulfanyls were used as substituents at the 5th‐position. Evaluation of the effects of the newly synthesized compounds on lipoprotein lipase mRNA expression in 3T3‐L1 preadipocytes revealed one promising candidate with potency comparable to that of troglitazone.     

Polycyclic N‐Heterocyclic Compounds. Part 84: Reaction of N‐(pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4‐yl)amidines or N‐(pyrido[2′,3′:4,5]furo[3,2‐d]pyrimidin‐4‐yl)amidines with Hydroxylamine Hydrochloride

The reactions of nine N‐(pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4‐yl)amidines ( 3 ) with hydroxylamine hydrochloride produced new cyclization products. These were formed via ring cleavage of the pyrimidine component followed by a 1,2,4‐oxadiazole‐forming ring closure to give N‐[2‐([1,2,4]oxadiazol‐5‐yl)thieno[2,3‐b]pyridin‐3‐yl]formamide oximes ( 11 ). Reaction of six N‐(pyrido[2′,3′:4,5]furo[3,2‐d]pyrimidin‐4‐yl)amidines ( 12 ) with hydroxylamine hydrochloride gave similar results. Effects of the newly synthesized compounds on pentosidine formation were also evaluated.     

Synthesis and In Vitro Antitumor Activity of New Isoxazolo[5,4‐d]Pyrimidine Systems

The reaction of 5‐amino‐3‐methylisoxazole ( 1 ) with aldimines 2 , 3 , 4 , 5 , 6 , 7 gave basic side chain 5‐amino‐3‐methylisoxazole derivatives 8 , 9 , 10 , 11 , 12 , 13 . Annulations of derivatives 8 , 9 , 10 , 11 , 12 , 13 with anisaldehyde afforded the target isoxazolo[5,4‐d]pyrimidines 14 , 15 , 16 , 17 . Treatment of 1 with isatin ketimine anil 18 resulted in the formation of derivative 19 , which further cyclized with anisaldehyde afforded the spirotetracyclic system 20 . Mannich reaction of 1 with primary amine such as methylamine and benzylamine gave the corresponding isoxazolo[5,4‐d]pyrimidine derivatives 21 and 22 , respectively. The newly synthesized compounds were tested for their antitumor activity.     

An expedient synthesis of novel,fused pyrimido[4,5‐d]pyrimidine and pyrimido [5,4‐e] [1,2,4]triazolo[4,3‐c]pyrimidine analogues from 4‐amino‐2,6‐dichloro‐pyrimidine

A number of potent pyrimido[4,5‐d]pyrimidine have efficiently been synthesized by the condensation of 4‐amino‐2,6‐dichloropyrimidine with various substituted benzaldehyde followed by cyclization with ammonium thiocyanate. Also, these newly synthesized derivatives were utilized for the construction of novel pyrimido[5,4‐e][1,2,4]triazolo[4,3‐c]pyrimidine analogues via oxidative cyclization involving 1,5‐hydrogen abstraction. Structure of all the newly constructed derivatives was corroborated by the elemental and spectral data. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:245–253, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20177     

An Efficient Four‐component Synthesis of Spiro[indoline‐pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]triones

A four‐component reaction in the presence of Alum [KAl(SO₄)₂·12H₂O] as an inexpensive and reusable catalyst using the ionic liquid as an effective green reaction media is reported.