Studies on the synthesis of antiulcer agents. V. Synthesis and antiulcer activity of dihydrobenzofuranone derivatives

In the preceding paper, we reported that 1-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]piperidine(1a) and 4-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]morpholine(1b) have potent antiulcer activities. In this paper, propionic acid derivatives (2,3) and oxyacetic acid derivatives (4, 5, 10) were prepared by converting the acryloyl moiety into propionyl and oxyacetyl groups, and tested for antiulcer activities. As a result, [3-oxospiro[benzofuran-2(3H),1'-cyclopropan]5-yloxy]-a cetamide(4j) exhibited significant antiulcer activities.     

Studies on the synthesis of antiulcer agents. IV. Synthesis and antiulcer activity of dihydrobenzofuranone derivatives

The derivatives of 3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5-yl]acrylic acid were synthesized and tested for antiulcer activities. As a result, 1-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]piperidine(3t) and 4-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]morpholine(3u) exhibited potent antiulcer activities.     

Novel pyrazole derivatives as potential promising anti-inflammatory antimicrobial agents

Four series of 1H-pyrazole derivatives have been synthesized. The first series was synthesized starting by condensing the hydrazine derivatives 1a-d with 4-(1-ethoxycarbonyl-2-oxopropyl)azobenzoic acid 2a in ethanol or glacial acetic acid to generate the corresponding pyrazoline derivatives 3a-d. Likewise, heating 1a-d with 4-(1-acetyl-2-oxopropyl)azobenzoic acid 2b gave rise to the pyrazole derivatives 4a-d. Similarly, reaction of 1a-d with ethyl 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylazo)-3-oxobutanoate 2c or 3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl azo)pentane-2,4-dione 2d in ethanol or glacial acetic acid led to the corresponding pyrazoline derivatives 5a-d or pyrazole derivatives 6a-d. The newly synthesized compounds were evaluated for their anti-inflammatory-antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compound 6c, proved to be the most active anti-inflammatory-antimicrobial agent in the present study with a good safety margin and no ulcerogenic effect.     

Non-steroidal antiinflammatory agents. Synthesis of novel 2-pyrazolyl-4(3H)-quinazolinones

Four novel series of pyrazolyl-4(3H)-quinazolinones have been prepared through the reaction of 3-aryl-2-hydrazino-4(3H)-quinazolinones with antipyrylazo-derivatives of ethyl acetoacetate, acetylacetone or diethyl malonate. These series of compounds are 3-aryl-2-[1-ethoxycarbonyl-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H - pyrazol-4-yl)hydrazono-2-propylidene]hydrazino-4(3H)-quinazo linones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]-4(3H)-quinaz olinones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)azo -3,5- dimethyl-1H-pyrazol-1-yl]-4(3H)-quinazolinones and 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3,5-dioxo-pyrazolidin-2-yl]-4(3H)-quinazolinones. The antiinflammatory activity of some representatives of the prepared compounds was studied.     

Synthesis and pharmacological evaluation of newer thiazolo [3,2-a] pyrimidines for anti-inflammatory and antinociceptive activity

A new series of thiazolo [3,2-a] pyrimidine derivatives was designed and synthesized using 4-fluoroaniline and ethylacetoacetate as starting material. Anti-inflammatory activity was assessed by the rat paw edema method and antinociceptive activity was evaluated by thermal stimulus technique. The compounds 5-(4-chlorophenyl)-2-(4-fluorobenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid (4-fluorophenyl)amide (3l) and 2-(4-chlorobenzylidene)-5-(4-fluorophenyl)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid (4-fluorophenyl)amide (3q) were found to possess significant anti-inflammatory and antinociceptive activities. These compounds also showed lower ulcerogenic activity and higher ALD₅₀ values. Compounds with an aryl ring substituted with a smaller electron withdrawing group at the fourth position displayed better activity than the other derivatives.     

Synthesis and properties of 2H-2-(4-substituted -1-piperazinylalkyl)-4,6-dimethyl-3-oxo-2,3-dihydroisothiazolo [5,4-b] pyridines

The preparation of a number of derivatives of 2H-4,6-dimethyl-3-oxo-2,3-dihydroisothiazolo [5,4-b] pyridine (1) containing 4-methyl(phenyl, heteroaryl)-1-piperazinylalkyl moiety by two routes has been described. Preliminary results of pharmacological screening of compounds synthesized showed antipsychotic activity of 2H-2-13-(4-phenyl-1-piperazinyl)propyl-3-oxo-2,3-dihydroisothiazolo [5.4-b] pyridine (4f).     

4-Heterocyclyloxy-2H-1-benzopyran potassium channel activators

The reaction of 2,4-dihydroxypyridine (2) with 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1) yielded the 4-[(1,2-dihydro-2-oxo-4-pyridyl)oxy] compound 3a, accompanied by small amounts of the isomeric 4-(1,2-dihydro-4-hydroxy-2-oxo-1-pyridyl) compound 4. This could also be prepared by hydrogenation of the benzyloxy derivative 5. Reaction of 3,6-pyridazinediol (10) with 1 (R = CN) gave the 4-[(1,6-dihydro-6-oxo-3-pyridazinyl)oxy] compound 11a, which in turn rearranged on heating with NaH in DMSO into the 4-(1,6-dihydro-3-hydroxy-6-oxo-1-pyridazinyl) compound 12. A series of 6-substituted analogues (R = CO2Me, CSNH2, NO2, Br) of 3a and 11a were synthesized. N-Alkylation led to compounds 14a-c (R = Me, Et, CHMe2). The 4-heterocyclyloxychromenes 9 and 16a were obtained by alkaline hydrolysis of their 3-camphorsulfonates. The racemic pyridazinyloxy compounds 11a and 14a could be resolved via their diastereomeric camphorsulfonates or camphanates. The differences between the 4-heterocyclyloxychromanols and the isomeric N-substituted compounds 4 and 12 were elucidated in the course of extensive NMR investigations. While in DMSO the former appeared to be conformationally flexible molecules the latter were rigid. All compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats, using doses of 1 mg/kg. High and long lasting activities were found for the pyridyloxy compounds 3a and 3d, the pyridazinyloxy compound 11a, and its N-alkylation products, as well as for the 3S,4R-enantiomers 20a and 22a. (-)-(3S,4R)-3,4-Dihydro-4-[(1,6-dihydro-1-methyl-6-oxo-3- pyridazinyl)oxy]-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (22a) was selected for further development.     

Synthesis and Antiinflammatory and Analgesic Activity of the Products of 3-Imino-(3H)-Furan-2-One Recyclization under the Action of Substituted Hydrazines

A series of 6-aryl-4-(1,5-dimetyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylimino)-1,4-dihydro-2H-pyridazin-3-ones and 4-[2-aryl-1-(2,4-dinitrophenylamino)-2-oxo-1,2-dihydropyrrol-3-ylidenamino]-1,5-dimetyl-2-phenyl-1,2-dihydropyrazol-3-ones were synthesized via recyclization of 1,5-dimethyl-4-(5-aryl-2-oxo-furan-3-ylidenamino)-2-phenyl-1,2-dihydropyrazol-3-ones under the action of substituted hydrazines. Most compounds exhibit weak antiinflammatory and analgesic activity.__________Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 1, pp. 13 – 16, January, 2005.     

Facile synthesis of fused pyrazolo[1,5-a]pyrimidinepyrazolo [1,5-a]triazines and N-sulphonamidopyrazoles as antiinflammatory

Interaction of hydrazine hydrate with methyl (2-E)-2-cyano-3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-3-(methylsulphanyl)-2-propenoate 2 which was obtained by the reaction of methyl-2-cyano-3,3-bis(methylsulphanyl) acrylate 1 with 4-amino-1-phenyl-2,3-dimethyl pyrazoline-5-one afforded methyl-5-amino-3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-1H-pyrazole-4-carboxylate 3a. The pyrazolin derivative 3a is a good precursor for the synthesis of pyrazolo[1,5-a]pyrimidines which is based on the interaction of 3a with alpha,beta-unsaturated nitrile derivatives. The biological effects of some of the newly synthesized compounds were also investigated as antiinflammatory, analgesic and antipyretic drugs. Compounds 2b, 4a, 3a, 3b, 2a and 4b were found to have significant antiinflammatory activity in descending order in comparison to control groups phenylbutazone. Compounds 3a, 2a, 4b, 4a, 2b and 3b have analgesic activity in decreasing order. Compound 3a was the most potent and had 82.6% potency of Novalgin. Compounds 2b, 2a, 3b, 4b, 3a and 4a were found to have significant antipyretic activity in descending order. Compounds 2a, 4b induced no ulcerogenic activity, while compounds 3b, 2b, 4a and 3a showed only slight ulcerogenic activity.     

Synthesis and antiulcer activity of novel 5-(2-ethenyl substituted)-3(2H)-furanones.

In order to investigate new antiulcer agents, spizofurone 1 (AG-629) was fragmented and reassembled to generate 5-phenyl-2,2-dimethyl-3(2H)-furanone (bullatenone, 2). Because of the antiulcer activity of 2,5-phenyl-substituted 2,2-dimethyl-3(2H)-furanones (3-6) were made and shown to have poor activity. Insertion of an ethenyl link between the furanone and phenyl rings gave 5-(2-phenylethenyl)-2,2-dimethyl-3(2H)- furanone (7). This compound had better activity than 2. Compounds 8-41 were synthesized to evaluate the SAR in 5-(2-ethenyl substituted)-3(2H)-furanones. Electron-withdrawing substituents on the aromatic ring (8, 10, 19, and 20) gave 2-3-fold higher activity. Further increases in the activity were found when the phenyl ring was replaced by heterocyclic nuclei. Compounds that contained a thiophene (29), pyridine (24-26), or quinoline ring (32) had the best activity. Replacement of the methyl group on the furanone ring with a phenyl (34) or p-fluorophenyl (40) substituent in the 2-pyridine series gave compounds with activity that ranked with the best obtained in this study. The best compounds from the above SAR studies were evaluated in the ethanol-necrosis model for duration of cytoprotection action. Compounds 19, 24, and 29, which had the best duration of action, were tested with AG-629 in the acidified aspirin and indomethacin-induced lesion models. Only compound 24 had equivalent activity with AG-629 in both models.     

Orally active aldose reductase inhibitors: indazoleacetic, oxopyridazineacetic, and oxopyridopyridazineacetic acid derivatives.

Benzothiazole side chains featured in zopolrestat (1a) and its congeners were incorporated into oxophthalazineacetic acid replacements, including indazole, pyridazinone, and pyridopyridazinone with a pendant acetic acid moiety. Potent aldose reductase inhibition activity among resulting compounds is as widespread as it is in the earlier zopolrestat series, thus lending further support to our hypothesis that there is a binding site on the aldose reductase enzyme with strong affinity for benzothiazoles. Representative new compounds 1-[(5,7-difluoro-2-benzothiazolyl)-methyl]-1H-indazoleacetic acid (62), [6-[[5-(trifluoromethyl)benzothiazol-2-yl]methyl]-8-oxo- 6H-pyrido[2,3-d]-pyridazin-5-yl]acetic acid (70), 3,4-dihydro-4-oxo-5,6-dimethyl-3-[(5,7-difluorobenzothiazol-2-yl) methyl]-1-pyridazineacetic acid (79), and 3,4-dihydro-4-oxo-5,6-cyclohexano-3-[[5-(trifluoromethyl) benzothiazol-2-yl]-methyl]-1-pyridazineacetic acid (82) are potent aldose reductase inhibitors with IC50s of 30, 2.1, 5, and 52.2 nM, respectively. The best of these compounds, 79 and 82, also inhibit accumulation of sorbitol in rat sciatic nerve in a model of diabetic complications, when administered orally at 10 mg/kg. The inhibition values are 76 and 61%, respectively. In addition to benzothiazole, we have examined its surrogates effective in potentiating aldose reductase inhibition activity, including benzoxazole and aryl[1,2,4]oxadiazole. Structure-activity relationships emerging from this program are also discussed.     

Synthesis and molluscicidal activity of new cinnoline and pyrano [2,3-c]pyrazole derivatives

2-(3-Hydroxy-5,5-dimethylcyclohexylidene)malononitrile 5 undergoes an azo coupling reaction with aryldiazonium salts to afford 3-amino-2-aryl-6,6-dimethyl-8-oxo-2,6,7,8-tetrahydrocinnoline-4-carbonitriles 7. Upon reflux in acetic acid, these compounds were acetylated to give the cinnoline derivatives 9. The pyrazolones 10a, b react with 3-furfurylidene- and 3-thienylidene-malononitrile derivatives 11a, b to afford the pyrano[2,3-c]pyrazole derivatives 13a-d. These newly synthesized compounds show generally a moderate molluscicidal activity to Biomphalaria alexandrina snails.     

Research on substances with antiviral activity. VIII. Benzindanoncarboxylic acids]

New derivatives (esters, amides, nitriles, amidines, thiosemicarbazones and guanylhydrazones) of 1H-benz[e]indene-2,3-dihydro-5-methyl-1-oxo-3-carboxylic acid and 1H-benz[e]indene-2,3-dihydro-7-methyl-3-oxo-1-carboxylic acid were prepared and tested for antiviral activities in vitro against vaccinia virus, HID stock and parainfluenza type 3 virus, HA-I/CR-8 stock. Four compounds (II g), (II i), (III b), (III g), showed weak activity in vitro against vaccinia virus.     

Synthesis and antiinflammatory activity of some-2-substituted alpha-methyl-5-benzimidazoleacetic acids.

The synthesis of alpha-methyl-5-benzimidazoleacetic acid (17), its 2-amino, 2-phenyl, 2-(4-chlorophenyl), and 2-(4-chlorophenyl)-1-methyl derivatives (18,4,3, and 5, respectively), and alpha-methyl-2-oxo-2,3-dihydro-5-benzimidazoleacetic acid (19) is described. None of the compounds were effective in reducing carrageenan-induced edema in rat paws.     

Permanently charged chiral 1,4-dihydropyridines: molecular probes of L-type calcium channels. Synthesis and pharmacological characterization of methyl(omega-trimethylalkylammonium) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate iodide, calcium channel antagonists

We report the synthesis of the single enantiomers of permanently charged dihydropyridine derivatives (DHPs with alkyl linker lengths of two and eight carbon atoms) and their activities on cardiac and neuronal L-type calcium channels. Permanently charged chiral 1,4-dihydropyridines and methyl (omega)-trimethylalkylammonium) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate iodides were synthesized in high optical purities from (R)-(-) and (S)-(+)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-+ ++pyridinecarboxylic acid, obtained by resolution of racemic 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-pyridi necarboxylic acid. Competition binding experiments with radioligand [3H]-(+)-PN200-110 and the block of whole cell barium currents through L-type calcium channels in GH4C1 cells show that the compounds with the eight-carbon alkyl linker optimally block the L-type Ca2+ channels, and that the S-enantiomer is more potent than the R-enantiomer.     

Pyridazinones. 2. Synthesis and antisecretory and antiulcer activities of thiourea and 2-cyanoguanidine derivatives

In an effort to develop new types of antiulcer agents, we synthesized a series of novel 2-[omega-(thioureido)alkyl]- and 2-[omega-(cyanoguanidino)alkyl]-3(2H)-pyridazinone derivatives. All target compounds were evaluated for gastric antisecretory activity in the pylorus-lygated rat by the method of Shay, and selected compounds were evaluated in the stress-induced ulcer test in rats. Structure-activity relationships were established. Two series of the compounds had significant activity in antisecretory and/or antiulcer tests. The molecular features essential for the activities are a thiourea group or a 2-cyanoguanidine group, a phenyl group in the C-6 position of the 3(2H)-pyridazinone ring, a four-carbon chain length between the 3(2H)-pyridazinone ring and the functional group, and a methyl group at the N-3 position of the functional group. Among them, the three thiourea derivatives (24, 26, and 38) and the six 2-cyanoguanidine derivatives (61, 62, 65, 75, 85, and 86) had the most potent antisecretory and/or antiulcer activities. These compounds are not histamine H2-receptor antagonists.     

Heteroarotinoids. Synthesis, characterization, and biological activity in terms of an assessment of these systems to inhibit the induction of ornithine decarboxylase activity and to induce terminal differentiation of HL-60 cells

The synthesis of certain heteroarotinoids has been achieved, namely the systems (2E,4E,6E)-3,7-dimethyl-7-(1,2,3,4-tetrahydro-4,4-dimethyl-6 -thiochromanyl)-2,4,6-heptatrienoic acid (1a), ethyl (2E,4E,6E)-3,7-dimethyl-7- (1,2,3,4-teterahydro-4,4-dimethyl-6-thiochromanyl)-2,4,6- heptatrienoate (1b), (2E,4E,6E)-3,7-dimethyl-7-(1,2,3,4-tetrahydro-4,4-dimethyl-6 -chromanyl)-2,4,6-heptatrienoic acid (1c), 2-phthalimidoethyl 3,7-dimethyl-7-(1,2,3,4-tetrahydro-4 4-dimethyl-6-thiochromanyl)-2,4,6-heptatrienoate (1d), methyl (E)-p-[2-(4,4- dimethyl-6-chromanyl)-1-propenyl]benzoate (2a), (E)-p-[2-(4,4-dimethyl-6-chromanyl)-1-propenyl]benzyl alcohol (2b), (E)-p-[2-(4,4-dimethyl-6-chromanyl)-1-propenyl]benzonitrile (2c), (E)-p-[2-(4,4-dimethyl-6-chromanyl)-1-propenyl]benzaldehyde (2d), methyl 4-[2-(2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-1-propenyl] benzoate (3a), and (E)-p-[2-(2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-1- propenyl]benzoic acid (3b). Characterization via elemental, IR, 1H NMR, and 13C NMR analyses was completed for these heterocycles. The biological activity of these heteroarotinoids was assayed by either the suppression of the 12-O-tetradecanoylphorbol 13-acetate (TPA) induced synthesis of ornithine decarboxylase (ODC) in mouse skin or the induction of differentiation of human (HL-60) promyelocytic cells. In the ODC assay, systems 1a-c exhibited strong activity (within 10% of or less than the control) whereas alcohols 2b and 3a showed good activity (within 50% of the control) as compared to either 13-cis-retinoic acid or trans-retinoic acid. Moderate activity was observed with 2a and 2b while 1d and 2c were essentially inactive. With the HL-60 assay, 1a and 1c were approximately 2- and 5-fold less active, respectively, than trans-retinoic acid. In contrast, 2a, 3a, and 3b induced differentiation of only a very small percentage of the cells. Acids 1a and 1c were the most active heteroarotinoids in the two biological assays. Consequently, the presence of the heteroatom does not eradicate the activity of the heteroarotinoids and thus they may have potential as chemotherapeutic agents.     

Synthesis and anti-HIV activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulfonamide and its derivatives.

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives were synthesized by reaction of isatin and its derivatives with sulphadimidine. Their chemical structures have been confirmed by IR, (1)H NMR data and elemental analysis. Investigation of anti-HIV activity of compounds were tested against replication of HIV-1 (IIIB) and HIV-2 (ROD) strains in acutely infected MT-4 cells and the activity compared with standard azidothymidine. Among the compounds tested, 4-[(1,2-dihydro-2 oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its N-acetyl derivative were the most active compounds.     

EFFECTS OF CHROMAN DERIVATIVES ON PLATELET AGGREGATION INDUCED BY SOME AGGREGATING AGENTS IN RABBITS

1. We synthesized 10 chroman derivatives (CD-1 to CD-10) derived from khellactone, including praeruptorin A and praeruptorin B and examined the effects of these compounds on rabbit platelet aggregation. 2. These compounds exhibited an inhibitory effect on platelet-activating factor (PAF)-induced platelet aggregation and their effects were more potent on PAF-induced platelet aggregation than on adenosine triphosphate (ADP)-, arachidonate (AA)- or collagen-induced platelet aggregation. In particular, (±)-cis-5-methoxy-6-methoxycarbonyl-2,2-dimethyl-3,4-ditiglyloxychro-man (CD-6), (±)-cis-5-methoxy-6-(2-methoxycarbonylethenyi)-2,2-dimethyl-3,4-ditiglyloxychroman (CD-8), (±)-cis-3,4-diacetoxy-5-methoxy-2,2-dimethyl-6-propylchroman (CD-9) and (±)-cis-5-methoxy-2,2-dimethyl-6-propyl-3,4-ditiglyloxy-chroman (CD-10) showed a moderate inhibition of PAF-induced platelet aggregation. 3. From these findings, it is suggested that compounds with potent PAF antagonist activities have the following features: (i) a tiglyloxy moiety is required at the 3 and 4 positions; and (ii) the methoxy moiety is also required at the 5 position of chroman skeleton in khellactone.     

Synthesis and activity of novel 5-substituted pyrrolo[2,3-d]pyrimidine analogues as pp60(c-Src) tyrosine kinase inhibitors

Therapy with receptor tyrosine kinase inhibitors provides an improved treatment option in a number of diseases such as cancer, myocardial infection, osteoporosis, stroke, and neurodegeneration. We have designed, synthesized, and evaluated a series of novel 2-amino-5-[(benzyl)imino]methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4-one 7a and 2-amino-5-[(substituted-benzyl)imino]methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4-one 7b-e derivatives as potential tyrosine kinase inhibitors. These compounds were synthesized by condensation reaction using 2-tritylamino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde 5 and appropriate benzylamines followed by detritylation. Compounds were evaluated for their inhibitory activity toward tyrosine phosphorylation for the pp60c-Src tyrosine kinase. Compounds 7a, 7d, and 7e demonstrated potent inhibitory activities against pp60c-Src tyrosine kinase with IC50 values of 13.9, 34.5, and 78.4 microM, respectively. Dihalogenated compounds 7d and 7e have 3 to 7-times lower IC50 values than that of the parent compound 7a.