Indian Journal of Chemistry Vol. 40B , March 2001 , pp. 21 3-221

Synthesis and anti-cancer activity of pyridine and thiazolopyrimidine derivatives using 1-ethylpiperidone as a synthon

a* a Abou El-Fotooh G Hammam , Mohie A Sharar' & Naglaa A Abd El-Hafez

aNational Research Centre, Applied Organic Chemistry Lab, Dokki , Cairo, Egypt

bChemistry Department, Faculty of Science, Cai ro Uni versity, Egypt

Received 16 lw1e / 999; accepted (revised) 20 September 2000

3,5-Bisarylmethylene-1 -ethylpiperidone 2 on reacti on with thiourea yield the thi oxopyrimidine deri vati ves 3, whi ch on condensati on with bromoacetic ac id, 2-bromopropanoic acid or 3-bromopropanoic acid afford thi azolopyrimidine 4, 2-methyl-thi azolopyrimidines 5 and thiazinopyrimidine deri va ti ves 6, respecti vely. Compounds 7 and 8 are also obtained via condensation of compounds 3 with 3-chloropentan-2,4-dione , bromoaceti c ac id and aromatic aldehydes, respectivel y. However, compounds 8 are prepared directly by condensation of compounds 4 with aromati c aldehydes.

Compounds 2 on condensation with malononitrile in ethanol/piperidine or aceti c acid/ammonium acetate mi xture give py ridopyran 9 and pyridopyrid ine 10, respecti vely. Also compound 10 could be prepared directly from compound 9. Compounds 2 when condensed with phenylhydrazine, ethyl cyanoacetate or guani dine hydrochloride yields pyridopyrazole 11, pyridopyridone 12 and pyridoaminopyrimidine deri vati ves 13, respecti vely.

In our previous work , we have fo und that the fu sed pyrimidine ring sys tem containing substituted seven­membered ring 1

·2 or substituted six-membered ring3

·5

have proved to be active anti-cancer and herbi cidal agents6

·7

. The bio logical acti vity of the pyrimidine heterocyclic compounds may be attributed to the presence of a subunit such as

In the present work , we use N-ethylpiperidone as a sy nthon fo r the synthes is of some newly heterocyc lic compounds (2 ---? 13), a combination of ring sys tem which mi ght be expected to possess hi gh biological activity.

Results and Discussion The ass ignment of the structures of all the new

sy nthesized compounds were based on elemental analys is and spectral data (IR, mass, 1HNMR).

The 1-ethyl-4-piperidone 1 was reacted with aromatic aldehydes in ethanol and KOH to yield 3,5-bi sarylmethylene-1 -ethyl-4-piperidones 2a-g. The IR spectra of compounds 2a-g showed peak at 1672 cm·1

(C=O). The 1HNMR spectrum (CDCI3) of compound 2d exhibited signals at 7.7 (2H, s, benzy lic protons) , 7.6-7.2 (8 H, m, Ar-H), 3 .7 (4H, s, 2CH2 of pyrido

nucleus), 2.6 (2H, q , CH2) and 1.1 (3 H, t, CH3) and its mass spectrum showed peaks of M+ at m/z 459 (5 1%), [M ++2] at 461 (base peak, 100%), [M+ +2/ M+, 195%], 430 (M+-C2H5) and 262 (430-PhBr).

Compounds 2 were reacted with thiourea in alcohol and KOH to yield 4-aryl-8-arylmethylene-6-ethyl-1 ,2 ,3,4, 7 ,8-hexahydro-SH-pyrido [ 4 ,3-d]pyri midine-2-thiones 3a-f (Scheme 1). The IR spectra of compounds 3a-f showed peaks at 3448 (NH) and 1190 cm- 1 (C=S) . The 1HNMR spectrum (CDCb ) of compound 3d showed s ignals at 7 .5-7 . 1 (9H, m, Ar­H +benzylic proton), 5.00 (I H, s, pyrimidine proton) , 3 .5-3 (4H , 2b, 2CH2 of pyrido nucleus), 2.4 (2H, b, CH2) and 0.9 (3H, t, CH3) and its mass spectrum showed peaks of M+ at m/z 517 , 60%, [M+ +I] at 518 (base peak, I 00%) and 348 (M+ -C HPhBr) .

Thioxopyrimidine 3a-f on treatment wi th bromoacetic acid, 2-bromopropanoic ac id or 3-bromopropanoic acid in a mi xture of aceti c ac id, acetic anhydride and fu sed sodium acetate gave 5-ary 1-9-ary lmethy lene-7 -ethy 1-SH-2,3,6, 7 ,8,9-hexah ydro­pyrido [4,3-d]thi azolo [3,2-a]pyrimidin-3-ones 4a -d . The formation of the cycli zed product as 4 is tentatively favoured over the isomeri c structure 4' due to the pyrimidine proton of the thi azo lo deri vatives ( 4---? 7) whi ch is deshielded by about 0.6 ppm relative to the thioxopyrimidine proton of compound 3, also in analogy with previous derivati ves9

·10

; 5-aryl-9-aryl­methylene-7-ethyl-2-methyl-5H-2,3,6,7,8,9-hexahydro-

214

0

6 ArCHO

EtOH/KOH

I CHf:H3

1

X

X

INDIAN 1 CHEM., SEC B, MARCH 2001

0 oC1:JCHQ X I X

0 CH

CH2CH3

2

X

BrCH2COOH

AcOH!Ac20

04'

X

CH

4

3

4

CH3BrCHCOOH ·

AcOH!Ac20 /

Br(CH2)2COOH

AcOH!Ac20

X

6

BtCH2COOH/ArCHO

AcOH/Ac20 .

ArCHO

Scheme I

8

(H2Nnc~s

EtOH/KOH

~ X~CH

7

X

3

CICH(COCH3)2 Pyridine!KOH

HAMMAM eta/.: SYNTHESIS OF PYRIDINE & THIAZOLOPYRIMIDINE DERIY AT! YES 215

pyrido[4,3-d]thiazolo[3,2-a]pyrimidin-3-ones Sa-c and 6-aryl-1 0-arylmethylene-8-ethyl-2,3,7,8,9, I O-hexahydro-6H-pyrido[ 4,3-d]pyrimido[2, l-b ]-1 ,3-thiazin-4-ones 6a-c, respectively (Scheme 1) ..

The IR spectra of compounds 4a-d showed peak at 1734 cm· 1 (C=O). The 1HNMR spectrum (CDC13) of 4a showed signals at 7.4-7 (9H, m, ArH +benzylic proton), 5.5 (I H, s, pyrimidine proton), 3.7 (2H, d, thiazole ring), 3.6, 3.4, 3.1, 2.7 (4H, 4d, 2CH2 of pyrido nucleus), 2.4 (2H, q, CH2) and 0.9 (3H, t, CH3)

and its mass spectrum showed peaks of M+ at rn/z 437 (43 %) [M+-1] at 436 (base peak , 100%) and 362 (M+­PhF).

The IR spectra of compounds Sa-c showed peak at 1729 cm- 1 (C=O). The 1HNMR spectrum (DMSO) of compound Sb showed signals at 7.6-7.2 (9H, m, ArH +benzylic proton), 5.6 (I H, s, pyrimidine proton), 4.4 (I H, q, methine proton of thiazole ring), 3.6-3.3 (4H, m, 2CH2 of pyrido nucleus) , 2.4 (2H, q, CH2), 1.6, 1.4 (3H, 2dd, CH3 of thiazole ring) and 0.9 (3H, t, CH3)

and its mass spectrum showed peaks of M+ at rn/z 571, [M+ +2] at 573 (base peak, 100%), 493 (M+ -C2H5) and 403 (M+ -CHPhBr).

The IR spectra of compounds 6a-c showed peak at 1715 cm· 1 (C=O). The 1HNMR spectrum (CDCI 3) of compound 6c showed signals at 7.6 (I H, s, benzylic proton), 6.6, 6.4 (4H, 2s, ArH), 6.0 (I H, s, pyrimidine proton), 3.8 (18H, s, 6 OCH3), 3.7-3.5 (4H, m, 2CH2

of thiazine ring), 3.1-2.7 (4H, m, 2CH2 of pyrido nucleus), 2.5 (2H, q, CH2) and 1.0 (3H, t, CH3) and its mass spectrum showed peaks of M+ at rn/z 595 (base peak, 100%) and 428 [M+-Ph(OCH3)3).

Also, compounds 3 on reaction with 3-chloropentane-2,4-dione in pyridine at room temperature in the presence of KOH gave 2-acetyl-5-aryl-9-arylmethylene-7 -ethy 1-3-me thy 1-6,7 ,8, 9-tetrahydro-5 H -pyrido[ 4,3-d]­thiazolo[3 ,2-a]pyrimidines 7a,b . The IR spectra of compounds 7a,b showed peak at 1659 cm· 1 (C=O). The 1HNMR spectrum (CDCI3) of compound 7a showed signals at 7.4-6 .9 (9H, m, ArH +benzylic aproton), 5.00 (I H, s, pyrimidine proton), 3.7-2.7 (4H, 4d, 2CH2 of pyrido nucleus), 2.4 (2H, q, CH2), 2.3 (6H, s, 2CH3) and 0.9 (3H, t, CH3) and its mass spectrum showed peaks of M+ at rn/z 477, [M+-1] at 476 (base peak, 100%) and 382 (M+-PhF).

The thiazolopyrimidines 4a-d were allowed to react with aromatic aldehyde in the presence of glacial acetic acid, acetic anhydride and fused sodium acetate to yield 5-aryl-2,9-diarylmethylene-7-ethyl-2,3,6, 7 ,8,9-hexahydro-SH -pyrido[ 4,3-d] thiazolo[3,2-a ]­pyrimidin-3-ones 8a-e which could be prepared from

compounds 3a-f in one pot reaction in good yield by adding the appropriate aromatic aldehyde to a mixture of 3, bromoacetic acid, fused sodium acetate and glacial acetic acid/acetic anhydride. The IR spectra of compounds 8a-e showed peak at 1707 cm·1 (C=O) (this shift to lower frequency is due to conjugation with exocyclic double bond) . The 1HNMR spectru m (CDCI3) of compound Sa showed signals at 7.6-6 .9 (13H, m, ArH + benzylic protons), 5.6 (IH, s, pyrimidine proton), 3.9-3.7 (6H, 2s, 2 x OCH3), 3.5-2.8 (4H, m, 2CH2 of pyrido nucleus), 2.4 (2H, q, CH2) and 0 .9 (3H, t, CH3) and its mass spectrum showed peaks of M+ at rn/z 585, 555 (M+ -C2H5) and 460 (555 -PhF).

Compounds 2 were reacted with malononitrile 11 in a mixture of ethanol/piperidine at room temperature to yield 2-amino-4-aryl-8-arylmethylene-6-ethyl-5 ,6,7,8-tetrahydropyrano[3,2-c]pyridine-3-carbonitrile 9a-f. The formation of 9 from 2 is outlined in Chart 1.

The formation of 9 through the reaction of 2 with malononitrile in the presence of piperidine as a basic catalyst could probably take place via Michael reaction of the active methylene compound at the ~­unsaturated carbon affording the open-chain adduct intermediate. The latter is simultaneously cyclized to the corresponding pyran 9 under the effect of basic environmental reaction conditions (Scheme II) .

The IR spectra of compounds 9a-f showed peaks at 3470, 3332 (NH2) and 2197 cm· 1 (CN). The 1HNMR spectrum (CDCb) of compound 9b showed signals at 7.3-6.8 (9H, m, ArH + benzylic proton), 4.5 (2H, s, NH2, 0 20 exchangeable), 4.0 (I H, s, proton of pyran ring), 3.6-2.7 (4H, 4d, 2CH2 of pyrido nucleus), 2.4 (2H, q, CH2) and 0.95 (3H, t, CH3), and its mass spectrum showed peaks of M+ at rn/z 405 (52%),

Chart 1

216 INDIAN J CHEM., SEC 8, MARCH 2001

OH ammonium acetate

AcOH CN

X

10 9

CHz(CN)2 CH2(CN)2 ammonium EtOH!pip acetate 0 AcOH

Oc"C("Q X 1 X

HN=C(NH2)2.H

EtmVNaOH

Cl

13

NC-CH2COOEt ammonium acetate

""':::

El

2

12

PhNHNH2

EtOHIEt3N

0

CN

X X

11

Scheme II

[M+-1] 404 (base peak, 100%), 36 1 [M+-C2H5], 310 [M+ -Ph F) and 214 (31 0-PhF) .

Further, compounds 2 were reacted with malono­nitrile and ammonium acetate in glacial acetic acid under reflux to yield 4-aryl-8-arylmethy lene-6-ethyl-2-hydrox y-5 ,6, 7 ,8-tetrahydropyrido[ 4,3-b ]pyridine-3-carbonitrile lOa-d . The 1R spectra of compounds lOa­d showed peaks at 3433 (OH) and 2224 cm·1 (CN). The 1HNMR spectrum (DMSO) of compound lOc showed signals at 7.7-7.45 (9H, m, ArH +benzylic proton), 7.4 (I H, s, OH), 3.6-3.1 (4H, 2m, 2CH2 of pyrido nucleus), 2.4 (2H, q, CH2) and 0 .8 (3H, t, CH3)

and its mass spectrum showed peaks of M+ at m/z 436 (54%), [M++2] at 438 (27 %), 408 (M+-C2H5) and 310 (M+-CHPhCI, base peak, 100%).

Compounds 2 on condensation with phenyl hydrazinc in boiling ethanol and triethylamine as a

catalyst gave 3-aryl-7 -arylmethylene-5-ethyl-2-pheny 1-2,3 ,3a,4,6, 7 -hexahydropyrido[ 4,3-c ]pyrazoles lla-e. The 1R spectra of compounds lla-e showed peak at 1597 cm· 1 (C=N). The 1HNMR spectrum (CDCI3) of compound lla showed signals at 7.5 (I H, s, benzylic proton), 7.4-6 .8 (ISH, m, ArH), 4.6, 4 . 1 (2H , 2d, CH2-a of pyrido nucleus), 3.3 (4H, m, CHz- b,

He, Hd). 2.6 (2H, q, CHz) and 1.0 (3H, t, CH3), and its

mass spectrum showed peaks of M+ at rnlz 393 (base peak 100% ), 364 (M+ -C2H5) and 316 (M+ -Ph) .

Compounds 2 were condensed with ethyl cyanoacetate in the presence of ammonium acetate under heating at 180°C to yield 4-aryl-8-arylmethylene-6-ethyl-2-oxo-1 ,2,5,6,7,8-hexahydropyrido[4,3-b ]pyridinc-3-carbonitrile 12a-c. The IR spectra of compounds 12a-c showed peaks at 3426 (NH), 22 17 (CN) and 1656 cm- 1 (C=O). The 1HNMR spectrum (DMSO) of

HAMMAM eta/.: SYNTHESIS OF PYRIDINE & THIAZOLOPYRIMIDINE DERIVATIVES 217

compound 12b showed signals at 12.8 (I H, b, NH), 7.6 (IH, s, benzylic proton), 7.5-7.3 (8H, m, ArH), 3.1-2.8 (4H, m, 2CH2 of pyrido nucleus), 2.4 (2H, q, CH2) and 0.8 (3H, t, CH3), and its mass spectrum showed peaks of M+ at m/z 436 (base peak, 100% ), [M++2] at 438, 310 (M+-CHPhCI) and 380 (M+­HNCH2C2Hs).

Compounds 2 when condensed with guanidine hydrochloride in the presence of alcohol and NaOH 2-amino-4-aryl-8-arylmethylene-6-ethyl-5,6,7,8-tetrahy­dropyrido[ 4,3-b ]pyrimidines 13a-d. The IR spectra of compounds 13a-d showed peaks at 3486, 3388 cm· 1

(NH2). The 1HNMR spectrum (CDCI3) of compound 13b showed signals at o 8.1 (I H, s, benzylic proton), 7.6-7.2 (8H, m, ArH), 5.45 (2H, s, NH2, exchangeable with 0 20), 3.7, 3.5 (4H, 2s, 2 CH2 of pyrido nuclus),

2.5 (2H, q, CH2) and 1.0 (3H, t, CH3), and its mass spectrum showed peaks of M+ at m/z 411 (75%), [M++2] at 413 , [M+-2] at 409 (base peak, 100%), 381 (M+-CzH5) and 285 (M+-PhCI).

Experimental Section Melting points were taken on Electrotherma lA

9000 SERIES Digital Melting Point apparatus and are uncorrected . IR spectra were recorded on Carlizeise spectrometer model "UR10" using KBr, 1HNMR spectra on a Varian Gemini 200 MHz using TMS as an internal standard, and mass spectra on a Finnigan SSQ 7000 mass spectrometer. All the reactions were monitored on TLC.

3,5-Bisarylmethylene-1-ethyl-4-piperidone 2a-g. To a mixture of 1 (0.01 mole) and aromatic aldehydes (0.02 mole) in ethanol (100 mL) was added KOH (I g) in H20 (5 mL). The mixture was stirred at room temperature for 1/2 hr, the solid formed was collected, washed with water and crystallized from the proper solvent (Table I).

Preparation of thioxopyrimidine 3a-f. To a boiling mixture of compound 2 (0.01 mole) in ethanol (100 mL) containing lg KOH in H20 (0.5 mL) was added thiourea (0.0 I mole), and the reaction mixture was refluxed for 3hr, allowed to cool and the solid formed was filtered off and crystallized from the proper solvent (Table 1).

General procedure for the preparation of compounds 4a-d, Sa-c and 6a-c. A mixture of compound 3 (0.10 mole), bromoacetic acid (0.01 mole) , 2-brompropanoic acid (0.01 mole) or 3-brompropanoic acid (0.01 mole) and fused sodium acetate (6 g) in glacial acetic acid (30 mL) and acetic anhydride (10 mL) was rcfluxcd for 3 hr, then

allowed to cool and poured gradually with stirring onto cold water. The solid formed was filtered off and crystallized from the proper solvent (Table 1).

Synthesis of compounds 7a,b. A mixture of compound 3 (0.01 mole) and 3-chloropentane-2,4-dione (0.01 mole) was dissolved in pyridine (20 mL), then KOH (0.01 mole) in ethanol (30 ml) was added. The whole mixture was stirred at room temperature for 5 hr, then poured onto cold water. The solid formed was collected and crystallized from the proper solvent (Table I).

Synthesis of compounds Sa-e. (a) A mixture of compound 3 (0.01 mole), bromoacetic acid (0.01 mole), fused sodium acetate (6 g) in glacial acetic acid (30 mL), acetic anhydride (I 0 mL) and aromatic aldehyde (0.01 mole) was refluxed for 3hr. The reaction mixture was cooled and poured onto cold water, the solid formed was collected and crystallized from the proper solvent (Table I).

(b) A mixture of compound 4 ( 1.0 g), equimolecular amount of appropriate aromatic aldehyde and glacial acetic acid (30 mL) and acetic anhydride ( 10 mL) was refluxed for 1 hr, cooled and poured onto cold water. The solid formed was collected and crystallized from the proper solvent (Table 1). Note: method (a) gives better yield than method (b).

Synthesis of compounds 9a-f .A mixture of compound 2 (0.01 mole) and malononitrile (0.01 mole) was dissolved in a mixture of ethanol (100 mL) and piperidine (20 mL) and the whole mixture was stirred at room temperature for 1/2 hr. The solid formed was collected, washed with water and crystallized from the proper solvent (Table 1).

Synthesis of compounds lOa-d. A mixture of compound 2 (0.01 mole), malononitrile (0.01 mole) and ammonium acetate (0.08 mole) in glacial acetic acid (30 mL) was refluxed for 6 hr, then allowed to cool and poured onto cold water. The solid formed was collected and crystallized from the proper solvent. Also, compound 10 could be prepared by the reaction of compound 9 with ammonium acetate in glacial acetic acid under reflux for 3 hr (Table I) .

Synthesis of compounds lla-e. To a mixture of compound 2 (0.01 mole) and phenylhydrazine (0.01 mole) in ethanol (50 mL), a few drops of triethylamine were added. The mixture was then refluxed for 4 hr, and cooled. The solid formed was collected and crystallized from the proper solvent (Table I).

Synthesis of compounds 12a-c. A mixture of

218 INDIAN J CHEM., SEC B, MARCH 200 I

Table I - Physical data of compounds 2a-g, 3a-f, 4a-d, Sa-c, 6a-c, 7a.b, 8a-e, 9a-f, lOa-d, lla-e, 12a-c and 13a-d

Compd X m.p.°C Yield Mol. formu la (solvent) (%) (Mol. wt)

2a H 122 87 C21H2,NO (E) (303.39)

2b 4-F 130 95 C21H19F2NO (E) (339.37)

2c 4-CI 180 92 C2,H,9Cl2NO (E) (372.27)

2d 4-Br 184 90 C2,H,9Br2NO (E) (461.35)

2e 3,4-(0CHJ)2 197 85 C2.5H29NO.s (E) (423.48)

2f 2,5-(0CHJh 148 87 C2sH29NOs (E) (423.48)

2g 3,4,5-(0CH3h 137 78 C21H33N07 (E) (483.53)

3a H 224 75 C22H23N3S (D) (36 1.43)

3b 4-F 175 85 CnH21F2N3S (M+D) (397.42)

3c 4-CI 210 80 C22H2,CI2N3S (D) (430.32)

3d 4-Br 232 87 CnH21 Br2N3S (D) (5 19.40)

3e 2,5-(0CHJ)2 165 70 C26HJ,N3S04 (E) (48 1.60)

3f 3,4,5-(0CHJh 162 85 C2sH35N3S06 (D) (541.65)

4a 4-F 175 88 C24 H2, F2N3SO (M) (437.5)

4b 4-CI 284 90 C24H2,Cl2N3SO (M+D) (470.40)

4c 4-Br 292 95 C24H2,Br2N3SO (M+D) (559.40)

4d 3,4,5-(0CHJh 156 80 C3oH3sN3S07 (M+D) (581.67)

Sa 4-CI 226 85 C2sH23CI2N3SO (E) (484.42)

Sb 4-Br 198 80 C2sH23Br2N3SO (E) (573.42)

Sc 3,4,5-(0CHJh 158 75 C3,H37N3S01 (E) (595.70)

6a 4-F 195 75 C2sH23F2N3SO (E) (451.53)

6b 4-Br 186 62 C2sH23Br2N3SO (E) (573.42)

6c 3,4,5-(0CH3)3 184 79 C3,H37N3S07 (E) (595.70)

7a 4-F 130 55 C27H25F2N3SO (D) (477.56)

7b 4-Br 263 45 C21HzsBr2N3SO (D) (599.36)

Sa 4-F I 3,4-(0CHJ)z 156 75 C33H29F2N3S03 (M) (585 .65)

8b 4-B r /4-CI 196 80 C3,H24Br2CIN3SO (E) (681.84)

8c 4-CI /4-CI 179 78 C3,Hz4CI3N3S03 (M) (589.94)

HAMMAM et al.: SYNTHESIS OF PYRIDINE & THIAZOLOPYRIMIDINE DERIVATIVES 219

Table I-Physical data of compounds 2a-g, 3a-f, 4a-d, Sa-c, 6a-c, 7a,b, 8a-e, 9a-f, lOa-d, lla-e, 12a-c and 13a-d (Contd)

Compd

8d

8e

9a

9b

9c

9d

9e

9f

lOa

lOb

lOc

lOd

lla

llb

llc

lld

lle

12a

12b

12c

13a

13b

13c

13d

X

2,5-(0CH3h/4-Br

H I 3,4,5-(0CHJh

X'= H 4-F

4-CI

4-Br

H

4-F

4-CI

4-Br

H

4-CI

4-Br

4-F

4-CI

4-Br

4-F

4-CI

4-Br

m.p.°C (solvent)

149 (M) 160 (M) 198 (H) 205 (E) 230 (E) 128 (E) 150 (E) 187 (E) 278

(M+D) 287 (D) 299 (D) 306 (D) 184 (E) 168 (E) 183 (E) 220 (E) 165 (E) 245

(M+D) 285

(M+D) 302

(M+D) 169 (E) 205 (E) 212 (E) 138 (E)

E =Ethanol; D =Dioxane; M =Methanol

Yield (%)

68

65

85

95

92

87

75

63

52

64

68

72

83

75

79

64

58

55

64

53

62

58

60

55

Mol. formula (Mol. wt)

C3sH29BrN3SOs (683.56) C34H33N3S04 (579.69) C24H23N30 (369.45) C24H2,F2N30 (405.44) C24H2,CI2N30 (438.34) C24H21Br2N30 (527.24) C2sH33N30s (491.57) C3oH39N307 (553.63) C24H2,N30 (367.44) C24H19F2N30 (403.42) C24H19CI2N30 (436.32) C24H19Br2N30 (525.22) C21H21N3 (393.52) C21H2sCI2N3 (462.4) C21H25Br2N3 (551 .30) C3,H3sN304 (513.62) C33H39N306 (573.67) C24H19F2N30 (403.42) C24H,9CI2N30 (436.32) C24H19Br2N30 (525.22) C22H2oF2N4 (478.42) C22H20CI2N4 (411.32) C22H2oBr2N4 (500.22) C26H30N404 (462.54)

All compounds gave satisfactory C, H, N, Sand halogen analysis.

compound 2 (0.01 mole), ethyl cyanoacetate (0.01 mole) and ammonium acetate (0.08 mole) was heated in an oil-bath at 180°C for 8 hr, and cooled. The reaction mixture was triturated with ethanol to give

yellow crystals, which were crystallized from the proper solvent (Table 1).

Synthesis of compounds 13a-d. To a solution of compound 2 (0.01 mole) in ethanol (50 mL) and

220 INDIAN J CHEM., SEC B, MARCH 200 1

NaOH (0.8 g) in H20 ( 1 mL) was added guanidine hydrochloride (0.01 mole). The mixture was retluxed for 5 hr., allowed to cool and poured onto cold water. The solid formed was filtered off and crystallized from the proper solvent (Table 1).

Biological Evaluation (Table II) Some of the synthesized compounds were selected

and screened for thier anti-cancer activity. Each compound was tested at five different concentration against 60 cell lines of nine types of human cancers, namely Leukemia, Lung, Colon, CNS, Melanoma, Ovarian, Renal, Prostate and Breast cancers.

Results are expressed as logJO Giso. which is the

drug concentration (M) causing a 50% reduction in the net protein increase in control cells during the

Table II-Anti-cancer activities of compound 3c, 3f, Sc, 9c, IOc and lib

Types of cancer

Leukemia

Lung

Colon

CNS

Melanoma

Ovarian

Renal

Prostate Breast

Leukemia

Lung

Colon

CNS

Melanoma

Ovarian

Renal

Prostate

Cell line

3c

MOLTA-4 CCRF-CEM HOP-92 A549/ATCC HCT-15 HCC-2998 SNB-75 U251 UACC-62 SK-MEI-28 IGROV I OVCAR-3 A498 786-0 PC-3 HS 578T

3f

CCRF-CEM RPMI-8226 A 549/ ATCC EK VX Colo 205 HCT-15 SF-268 SNB-19 LOXIMVI M 14 IGROV I OVCAR-8 786-0 CAK-1 PC-3 DU-145

-5 -4.8 -4.9 -4.6 -4.4 -4.2 -4.5 -4.4 -4.5 - 4.6 -4.5 -4.2 -4.6 -4.4 -4.4 -4.3

- 4.5 -4.8 -4.6 -4.9 - 4.8

4.6 -5 -4.5 -4.4 -4.8 -4.7 -4.8 -4.6 -4.8 -4.6 -4.5

Table II- Anti-cancer activities of compound 3c, 3f, Sc, 9c, IOc and llb

Types of cancer

Breast

Leukemia Lung

Colon CNS Melanoma

Ovarian Renal Prostate Breast

Leukemia

Lung

Colon CNS

Melanoma

Ovarian

Renal

Prostate

Breast

Leukemia CNS

Leukemia

Lung Colon

CNS Melanoma

Ovarian

Renal Prostate Breast

+

Cell line

HS 578T MCF7

8c

CCRF-CEM NCI -H522 HOP-62 HCT-116 SF-268 SK-MEL-2 UACC-62 OVCAR-3 786-0 PC-3 HS 578T

9c

CCRF-CEM K262 A549/ATCC NCI-H460 HCT-116 SNB-75 SF-268 SK-MEL-5 MALME-3M IGROV I OVCAR-4 786-0 CAK-1 PC-3 DU-145 MDA-MB-23 1 MCF7

JOe

SR SNB-75

llc

CCRF-CEM MOLT-4 HOP-62 HT-29 HCC-2998 U251 SK-MEL-28 SK-MEL-2 OVCAR-3 IGROVI CAK-1 PC-3 MDA-MB-435 MOA-N

log 10 GI50

+ -4.9 -4.7

-4.8 -5.2 -4.8 -4.4 -4.6 -4.6 -4.5 -4.8 -5 - 4 -4.6

-4.8 -5 -4.8 -4.9 -4.8 -4.9 -4.7 -4.9 -4.8 -4.7 -4.6 -4.9 -5 -4.8 -4.5 -4.9 -4.5

- 4.8 -4.2

-5.1 -5.4 -5.8 -5.7 -5.8 -5.7 -5 .6 -5.8 -5.8 -6 -6 -6 -5.4 -5.5

Reference compound: 5-tluorodeoxy uridine ~1 0 GI50 =- 4.7).

HAMMAM et al. : SYNTHESIS OF PYRIDINE & THIAZOLOPYRIMIDINE DERIVATIVES 22 1

drug incubation . These compounds showed activity 12

nearly at low concentration (Table II) .

Conclusion In our preveous work 1 we reported that fused

pyrimidine derivatives were proved to be active anti­cancer agents . In the present work we can suggest that the anti-cancer activity is due to the presence of nitrogen heterocyclic compounds and the difference in activity between them is due to the various substituents in the phenyl group of the molecule.

Acknowledgement Authors thank Dr V L Narayanan and Edward

Sausville, National Institute of Health, Meryland, USA, for anti-cancer screening.

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Chem Eng Data, 24, 1979, 377.

2 Hammam A G, Abd El-hafez N A, Midura W H & Mikolajczyk M, Z Naturforfch , 55b, 2000, 417.

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4 Hammam A G, Zaki M E A & EI-Assasy M E, Egypt J Pharm Sci, 38, 1997,29 1.

5 Hammam A G, Zaid I F & Hawas U W, Synthesis and

reactions of son1e heterocyclic compunds r!f anticancer activity, M. Sc. Thesis, 1996.

6 Ali M I, Hammam A G & Mohamed S F, J Phosphorus all(/

Sulfur, 39, 1988, 24. 7 Hammam A G, Hussa in S M & Kotob I R, J Phosphorus,

Sulfur and Silicon, 47, 1990, 47. 8 Rovnyak G, Shu V & Schwartz J, J Heterocyclic Chem , 18,

1981, 327.

9 Ali M I & Hammam A G, J prakt Chem , 3 18, 1976, 1038. 10 .Ali M I, El-Kaschef M A F & Hammam A G, J Chem Eng

Data, 20, 1975. 128. II Dell C P, Howe T J & Prowse W G, J Heterocyclic Chem , 31.

1994, 749. 12 Bhatt J J, Shah B R, Shah H P, Trivedi P B, Undavia N K &

Desai N C, Indian J Chem, 338, 1994, 189.