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1.
2,4-Diamino-5,7-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-d]pyrirnidine, 2,4-diamino-9H-mdeno[1′,2′:4,5]thieno[2,3-d]pyrimidine, 2,4-diamino-5H-indeno[2′,1′:4,5]thieno[2,3-d]pyrimidine, 9,11-diamino-5,6-dihydronaphtho[1′,2′:4,5]thieno[2,3-d]pyrimidine, 7,9-diamino-5,6-dihydronaphtho[2′,1′:4,5]thieno[2,3-d]pyrimidine, 2,4-diamino-7-benzy]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine, and various 2,4-diamino-5,6,7,8-tetrahydro-[1]benzothieno[2,3-d]pyrimidines were synthesized by cyclization of the requisite fused 2-aminothio-phenene-3-carbonitriles utilizing chloroformamidine hydrochloride in diglyme. Several compounds exhibited strong inhibitory effects against Streptococcus faecalis (MGH-2), Staphylococcus aureus (UC-76), Streptococcus faecium (ATCC 8043), Lactobacillus casei (ATCC 7469), and Pediococcus cerevisiae (ATCC 8081) in vitro, and three compounds displayed antimalarial activity against Plasmodium berghei in mice and P. falciparum (Uganda I) in vitro.  相似文献   

2.
Five previously undescribed trimetrexate analogues with bulky 2′-bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2-[2-(2-bromo-3,4,5-trimethoxyphenyl)ethyl]-1,l-dicyanopropene with sulfur in the presence of N,N-diethylamine afforded 2-amino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methyl-thiophene-3-carbonitrile ( 15 ) and 2-amino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethyl]thiophene-3-car-bonitrile ( 16 ). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methylthieno[2,3-d]pyrimidine ( 8a ) and 2,4-diamino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethylthieno[2,3-d]pyrimidine ( 12 ) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4-diaminoquinazoline-6(or 5)-carbonitriles with 2-bromo-3,4,5-trimethoxyaniline, were 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)-5-chloro-quinazoline ( 9a ), 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 10 ), and 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 11 ). Enzyme inhibition assays revealed that space-filling 2′-bromo substitution in this limited series of dicyclic 2,4-diaminopyrimidines with a 3′,4′,5′-trimethoxyphenyl side chain and a CH2, CH2CH2, or CH2NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.  相似文献   

3.
New substituted 4,6-diamino-7-hydroxypyrido[4,3-d]pyrimidin-5(6H)-ones were synthe-sized by treatment of ethyl 4-amino-6-(ethoxycarbonylmethyl)-2-phenylpyrimidine-5-car-boxylic acid with hydrazine hydrate and phenylhydrazine. In the case of methylhydrazine, the reaction proceeded in an unusual way and afforded a product identified, relying on NMR data, as functionally substituted 8-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-7-ylidene)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine comprising two amineimide fragments. A diacetyl derivative of this compound was obtained.  相似文献   

4.
2 Various4-diamino-6-(benzyl and pyridyhnethyl)-5,6,7,8-tetrahydropyrido(4,3-d]pyrimidines (IX) have been synthesized for antimalarial and antibacterial evaluation. Alkylation of 4-amino-3-cyano-1,2,5,6-tetrahydropyridine (VI) with the requisite α-chlorotoluene or picolyl chloride in 2-butanone afforded the corresponding 4-amino-3-eyano-1-(benzyl and pyridvlmethyl)-1,2,5,6-tetraliydropyridines (VIII) (16–73%), which were cyclized to the pyrido[4,3-d]pyrimidines (IX) utilizing guanidine carbonate in dimethylformamide. Alternatively, VI was condensed with guanidine carbonate in ethyl cellosolve to give 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine (VII) (52%), which upon treatment with the appropriate α-ehlorotoluene in dimethyllormamide gave other 2,4-diamino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines (IX) (26–27%). Kight compounds were active orally against Plasmodium berghei in mice at doses ranging from 3.9 to 125 mg./kg./day for 6 days (0.6 to 19 times as potent as quinine hydrochloride), while three compounds displayed activity when administered in a single subcutaneous dose of 640 mg./kg. Four substances exhibited in vitro activity against Streptococcus faecalis (MGH-2), normal (UC-76) and drug-resistant (S18713) Staphylococcus aureus, and Streptococcus pyogenes ((1203), with MIC's ranging from > 0.25 to 10 μg./ml. Data on the inhibitory effects of various pyrido[4,3-d]pyrimidines against Streptococcus faecalis R (S. faecium var. durans, ATCC 8043), S. faecalis A (aminopterin, metholrexate-resistant), and Lactobacillus plantarum (ATCC 8014) is summarized.  相似文献   

5.
6.
Ready, convenient synthesis for 8-cyano-7-ethoxy-4-oxo-9-phenyl-2-substituted-1,2,3,-4-tetrahydropyrido-[3′,2′:,4,5]thieno[3,2-d]pyrimidines 5 , 8-cyano-7-ethoxy-4-oxo-9-phenyl-2-substituted-3,4-dihydropyrido[3′,2-: 4,5]thieno[3,2-d]pyrimidines 6 , 4-chloro-8-cyano-7-ethoxy-9-phenyl-2-substitutedpyrido[3′,2′:4,5]thieno[3,2-4 -pyrimidines 7 and 8-cyano-7-ethoxy-2-(2′-nitrophenyl)-9-phenyl-4-substitutedpyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidines 8-18 from 2-chloro-3,5-dicyano-6-ethoxy-4-phenylpyridine 1 via 3,5-dicyano-6-ethoxy-2-mercapto-4-phenylpyridine 2 and aminocarboxamide 4 are reported. In addition, the reaction of hydrazino derivative 12 with reagents such as formic acid and triethyl orthoformate yielded the fused tetraheterocyclic 8-cyano-9- ethoxy-5-(2′-nitrophenyl)- 7-phenylpyrido[3′,2′:4,5]thieno[2,3-e]-1, 2,4-triazolo[4,3-c]pyrimidine system 19 .  相似文献   

7.
A convenient one-step reaction with cyanoguanidine was used to convert alicyclic ketones to previously undescribed 2,4-diamino-5,6,7,8-tetrahydroquinazolines with a one-, two-, or three-carbon bridge in the carbocyclic ring. Although the yields of the desired products were modest, the principal advantage of this one-step process was that it provided easy access to a variety of novel bridged heterocyclic ring systems whose synthesis from sterically hindered ketones by other methods would have required multiple steps with an even lower overall yield. The products were tested as inhibitors of dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, and rat liver with a view to examining the effect of a space-filling bridge on binding. The most potent and selective compound in the group was 4,6-diamino-3,5-diazatricyclo[7.2.1.02,7]dodeca-2,4,6-triene ( 13 ), whose potency and selectivity approached those of trimethoprim, a drug commonly used to treat P. carinii and T. gondii infection. 3,5-Diamino-4,6-diazatricyclo[6.2.1.02,7]-undeca-2,4,6-triene ( 14 ), the analog of 13 with a one-carbon rather than a two-carbon bridge showed similar potency and selectivity against the T. gondii enzyme, but was a weak and nonselective inhibitor of P. carinii dihydrofolate reductase. The other compounds tested were likewise weak and nonselective.  相似文献   

8.
Some novel indeno[2,1-b]thiophenes, indeno[1′,2′:4,5]thieno[2,3-d][1,2,3]triazines, indeno[1′,2′:4,5]thieno[2,3-d]pyrimidines, indeno[1′,2′:4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidines, and indeno[1′,2′:4,5]thieno[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines 2–16 were prepared starting with 2-aminoindeno[2,1-b]thiophene-3-carboxylic acid amide ( 1 ). Furthermore, the antimicrobial evaluation of the prepared products showed that many of them revealed promising antimicrobial activity.  相似文献   

9.
An efficient synthesis of spiro compounds via two different pathways from the reactions of isatins, 3-phenylisoxazol-5(4H)-one (3-ethylisoxazol-5(4H)-one), and pyrazol-5-amine (6-aminopyrimidine-2,4(1H,3H)-dione) were reported. The catalyst Amberlyst-15 could be easy recycled and reused for many time without any appreciable loss in catalytic activity. The new type spiro compounds were gained through the ring-opening of isatins process. The structures of spiro[indoline-3,4′-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo[5,4-b]quino line-4,5′-pyrrolo[2,3-d]pyrimidine]-2′,4′,6′(1′H,3′H,7′H)-trione, and spiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-2,6′(5′H)-dione were successfully confirmed by 1H NMR, 13C NMR, HRMS, and X-ray crystal diffraction analysis.  相似文献   

10.
A series of diaminobenzo[f]- and diaminobenzo[h]pyrimido[4,5-b]quinolines 1–11 were designed as 5-deaza tetracyclic nonclassical, lipophilic antifolates. The compounds were designed as conformationally semi-rigid and rigid analogs of 2,4-diamino-6-phenyl- 12 and 2,4-diamino-7-phenylpyrido[2,3-d]pyrimidines 13 and 14 . The target compounds were synthesized by cyclocondensation of chlorovinyl aldehydes obtained from appropriately substituted 1- or 2-tetralone, with 2,4,6-friaminopyrimidine. Compounds 1–11 were evaluated as inhibitors of P. carinii and T. gondii dihydrofolate reductases. These pathogens cause fatal opportunistic infections in AIDS patients. In addition, the selectivity of these agents was evaluated using rat liver dihydrofolate reductase as the mammalian source. In general the benzo[f]pyrimido[4,5-b]quinolines 1–5 were more potent than the corresponding benzo[h]pyrimido[4,5-b]quinoline analogues 6–11 against P. carinii and rat liver dihydrofolate reductase and were equipotent against T. gondii dihydrofolate reductase. Compounds 6–11 were moderately selective towards T. gondii dihydrofolate reductase with IC50S in the 10−7 M range. In contrast analogues 1–5 lacked selectivity against P. carinii or T. gondii dihydrofolate reductase and were, in general, potent inhibitors of rat liver dihydrofolate reductase with IC50S in the 10−8 M range. Analogues 1 and 4 were evaluated against a series of tumor cell lines in vitro and were found to have moderate antitumor activity (IC50 10−6 M). The structure activity/selectivity relationships suggest that benzo[f]pyrimido analogues 1–5 with the phenyl ring substitution in the “upper” portion of the tetracyclic ring are better accommodated within the rat liver (mammalian) dihydrofolate reductase and P. carinii dihydrofolate reductase active sites compared to the benzo[h]pyrimido analogues 6–11 which have the phenyl ring substitution in the “lower” portion of the tetracyclic ring. In contrast T. gondii dihydrofolate reductase does not discriminate between the isomers and binds to both series of compounds with similar affinities.  相似文献   

11.
12.
4,8-Dimethyl-6,7,8,9-tetrahydropyrido[4′,3′:4,5]thieno[2,3-e][1,2,4]triazolo[3,4-a]-4H-pyrimidin-5-ones, 7-methyl-2,3,6,7,8,9-hexahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrrolo[1,2-a]-1H, 10H-pyrimidin-10-one, 8-methyl-1,2,3,4,7,8,9,10-octahydropyrido[4′,3′:4,5]thieno[2,3-d]-11H-pyrimidin-11-one, and 9-methyl-2,3,4,5,8,9,10,11-octahydro[4′,3′:4,5]thieno[2,3-d]azepino-[1,2-a]-1H, 12H-pyrimidin-12-one which consist four new heterocyclic ring systems were synthesized from 2-amino-3-carbethoxy-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine.  相似文献   

13.
The effect of conformational restriction of the C9‐N10 bridge on inhibitory potency and selectivity of trimetrexate against dihydrofolate reductase, was studied. Specifically three nonclassical tricyclic 1,3‐diamino‐8‐(3′,4′,5′‐trimethoxybenzyl)‐7,9‐dihydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidin‐6(5H,8H)‐one ( 4 ), 1,3‐diamino‐8‐(3′,4′,5′‐trimethoxybenzyl)‐9‐hydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidin‐6‐(8H)‐one ( 5 ) and 1,3‐diamino‐(8H)‐(3′,4′,5′‐trimethoxybenzyl)‐7,9‐dihydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidine ( 7 ) antifolates were synthesized. The tricyclic analogues 4 and 5 were obtained via the regiospecific cyclo‐condensation of the β‐keto ester 17 with 2,4,6‐triaminopyrimidine. The analogue 7 was obtained via reduction of the lactam 4 with borane in tetrahydrofuran. Compounds 4, 5 and 7 were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii and rat liver. All three compounds were more selective than trimetrexate against Pneumocystis carinii dihydrofolate reductase and significantly more selective than trimetrexate against Toxoplasma gondii dihydrofolate reductase compared with rat liver dihydrofolate reductase.  相似文献   

14.
《合成通讯》2013,43(11):1757-1764
ABSTRACT

N-glycosylation of 2,4-bis-O-(trimethylsilyl)-pyrimidine bases with 2-deoxy-2-fluoro-3,5-di-O-benzoyl-1-(Br, OBz)-α-d-arabinose derivatives are reported. 1-Bromo-arabinose provides high yield and a favorable anomeric ratio (β/α) of pyrimidine nucleoside in either MeCN or CH2Cl?CH2Cl. This method should be suitable for the synthesis of 2′-deoxy-2′-[18F]fluoro-1-β-d-arabinofuranosyluracil derivatives.  相似文献   

15.
Reaction of 1,2,3,4-tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine with 3-bromoprop-1-yne gave 1-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4a ), 3-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4b ), and 1,3-diprop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4c ). Subsequent boiling of 1,3-diprop-2′-ynylpyrido-[2,3-d]pyrimidine-2,4-dione ( 4c ) in formic acid afforded 1-methylimidazo[1,2-a]pyridyl-N-prop-2′-ynylamide ( 5 ) and 1-acetonyl-3-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 6 ).  相似文献   

16.
6,7-Dihydropyrido[3,4-d]pyrimidine-2,4(1H,3H)-diones were obtained in high yields from the reaction of 5-formyl-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione ( 1 ) and primary amines. For this pyridopyrimidine synthesis the following reaction pathway is proposed; the [1,5]-hydrogen shift of 1 gives a 5,6-dihydro-5,6-dimethylenepyrimidine-2,4(1H,3H)-dione intermediate. The cycloaddition reaction of the intermediate with aldimines from 1 and the primary amines affords 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4(1H,3H)-diones, which are dehydrated to the final products.  相似文献   

17.
An efficient synthesis of the unknown 2′-deoxy-D-threo-tubercidin ( 1b ) and 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) as well as of the related nucleosides 9a, b and 10b is described. Reaction of 4-chloro-7-(2-deoxy-β-D-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine ( 5 ) with (tert-butyl)diphenylsilyl chloride yielded 6 which gave the 3′-keto nucleoside 7 upon oxidation at C(3′). Stereoselective NaBH4 reduction (→ 8 ) followed by deprotection with Bu4NF(→ 9a )and nucleophilic displacement at C(6) afforded 1b as well as 7-deaza-2′-deoxy-D-threo-inosine ( 9b ). Mesylation of 4-chloro-7-{2-deoxy-5-O-[(tert-butyl)diphenylsilyl]-β-D-threo-pentofuranosyl}-7H-pyrrolo[2,3-d]-pyrimidine ( 8 ), treatment with Bu4NF (→ 12a ) and 4-halogene displacement gave 2′, 3′-didehydro-2′, 3′-dideoxy-tubercidin ( 3 ) as well as 2′, 3′-didehydro-2′, 3′-dideoxy-7-deazainosne ( 12c ). On the other hand, 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) resulted from 8 by treatment with diethylamino sulfurtrifluoride (→ 10a ), subsequent 5′-de-protection with Bu4NF (→ 10b ), and Cl/NH2 displacement. 1H-NOE difference spectroscopy in combination with force-field calculations on the sugar-modified tubercidin derivatives 1b , 2 , and 3 revealed a transition of the sugar puckering from the 3′T2′ conformation for 1b via a planar furanose ring for 3 to the usual 2′T3′ conformation for 2.  相似文献   

18.
Diethyl azodicarboxylate and 3,4,5,6‐tetrachloro‐1,2‐benzoquinone react with cyclopentano‐ and cycloheptano‐fused thienopyrimidines to form the oxidative dimer of the starting material via S—S bond formation. Reaction of two equivalents of 2,2′‐(cyclohexa‐2′,5′‐diene‐1,4‐diylidene)dimalononitrile with thienopyrimidines afforded 3‐(4′,4′‐dicyanomethylene‐cycloalka[a]‐2,5‐dienyl)‐4‐oxo‐6,7,8,9‐tetrahydro‐5H‐cyclo‐hepta[4,5]‐[1,3]thiazolo[3,2‐a]‐thieno[2,3‐d]pyrimidin‐2‐ylidene‐2‐dicarbonitriles. The thioenopyrimidines react with 2‐[1,3‐dioxo‐1H‐inden‐2(3H)‐ylidene]malononitrile to produce 1,3,5′‐trioxo‐1,3,3′,5′‐tetrahydrospiro‐(indene‐2,2′‐thiazolo[2,3‐b]‐cycloalkyl[b]‐thieno[2,3‐d]pyrimidine)‐3′‐carbonitriles. However, the reaction of thienopyrimidines with 2,3‐dicyano‐1,4‐naphthoquinone proceeded to afford the fused cycloalkyl‐thieno form of naphtho[1,3]thiazolo[3,2‐a]thieno[2,3‐d]pyrimidine‐6.7,12‐triones. Reaction of 2‐hydrazino‐5,6,7,8‐tetrahydrobenzo[b]thieno[2,3‐d]pyrimidine‐4(1H)‐one with dimethyl acetylenedicarboxylate and ethyl propiolate, respectively, afforded cyclohexano‐fused (Z)‐dimethyl 2[(E)‐4‐oxo‐3,4‐dihydrothieno[2,3‐d]pyrimidine‐2(1H)‐ylidene)hydrazono]succinate and thieno‐pyrimidinotriazine. Both oxidative dimers of thienopyrimidines showed high inhibition of Hep‐G2 cell growth compared with the growth of untreated control cells. Moreover, the cycloheptano‐fused thiazinothienopyrimidine indicates a promising specific antitumor agent against Hep‐G2 cells because its IC50 is < 20 μM.  相似文献   

19.

Ethyl 4,5-dioxo-2-phenyl-4,5-dihydro-1H-pynole-3-carboxylates reacted with indan-1,3-dione and 3-amino-1-phenylbut-2-en-1-one or 3-aminobut-2-enenitrile to give 3-benzoyl-2-methyl-2′,5-dioxo-5′-prienyl-1,1′,2′,5-tetrahydrospiro[indeno[1,2-b]pyridine-4,3′-pyrroles] and 2-methyl-2′,5-dioxo-5′-phenyl-1,1′,2′,5-tetrahydrospiro[indeno[1,2-b]pyridine-4,3′-pyrrole]-3-carbonitriles, respectively.

  相似文献   

20.

A method was developed for the synthesis of pyrano[4,3-b]thieno[3,2-e]pyridine derivatives based on the reaction of 3-amino-7-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]thieno[3,2-e]pyridine-2-carboxylic acid ethyl ester with chloroacetic acid chloride, triethyl orthoformate, hydrazine hydrate, and also phenyl chloroformate. The synthesis of various new representatives of pyrano[2″,3″:5′,6′]pyrido[3′,2′:4,5]thieno[3,2-dl-pyrimidine series was carried out.

  相似文献   

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