Final

THIENOPYRIMIDINE DERRIVATIVES

ABSTRACT

A series of substituted benzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3-

d]pyrimidin-4-ylhydrazone (VIIa-b) were prepared by the displacement reaction

between various aldehyde and 4-hydrazino-5,6,7,8-tetrahydro[1]benzothieno[2,3-

d]pyrimidine (VII), which was obtained by refluxing 4-chloro-5,6,7,8-

tetrahydro[1]benzothieno[2,3-d]pyrimidine (VI) with hydrazine hydrate. Compound

VI was obtained by refluxing 5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-

4(3H)-one (IV) with phosphorus oxychloride. Compound IV was obtained by

cyclization of ethyl 2-amino-4, 5, 6, 7-tetrahydro-1-benzothiophene-3-carboxylate

(III) with formamide. Compound III was obtained by refluxing cyclo hexanone (I),

sulphur and ethylcyanoacetate (II) in ethanol (Gewald thiophene synthesis). The

synthesized compounds have been characterized by IR, 1H NMR and Mass spectral

data. All the synthesized compounds were screened for antimicrobial activities.

Compounds VIIa and VIIb were found to have excellent antimicrobial activity

against Staphylococcus aureus and Staphylococcus mutants when compared with

standard used (amoxicillin-clavulanic acid).

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 1


ABBREVIATIONS

Abs. : absolute

AIDS : acquired immunodeficiency syndrome

Ar : aryl

ATCC : American type culture collection

ATPase : adenosine triphosphatase

Bn : benzyl

Bu : butyl

cAMP : adenosine - 3’5’-monophosphate

cGMP : guanosine - 3’5’-monophosphate

CMC : carboxy methyl cellulose

CNS : central nervous system

DMF : N,N-dimethyl formamide

DMSO : dimethyl sulphoxide

ED : effective dose

EGFR : endothelial growth factor

Et : ethyl

Etc. : Et cetera

FT/IR : Fourier transform/infrared

g : gram(s)

GCMS : gas chromatography mass spectrum



GnRH : gonadotropin releasing hormone

h : hour(s)

HIV : human immunodeficiency virus

IC50 : inhibitor concentration

IR : infrared

ket : ketanserine

kg : kilogram(s)

lb : pound(s)

LD : lethal dose

M : molar (concentration)

m.p : melting point

Me : methyl

MHz : mega hertz

ml : milliliter

mm : millimeter

mol : mole(s)

nM : nano mole

NMR : nuclear magnetic resonance

Ph : phenyl

ppm : parts per million

Pr : propyl

psig : pounds per square inch gauze

rit : ritanserine



s : seconds

SEM : standard error mean

Thi : thiophene

TLC : thin layer chromatography

TMS : tetramethylsilane

VEGFR : vascular endothelial growth factor

Vs : versus

µg : microgram

µM : micro mole

0C : centigrade degrees

1H NMR : proton nuclear magnetic resonance

5-HT : 5-hydroxy tryptamine



LIST OF FIGUURES

FIGURE NO NAME OF FIGURE PAGE

NO

1 IR spectrum of 4-hydrazino-5,6,7,8-

tetrahydro[1]benzothieno[2,3-d]pyrimidine (VI) 46

2

IR Spectrum of 3,4,5-trimethoxybenzaldehyde

5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-

hydrazone (VIIa)

48

31H NMR spectrum 3,4,5-trimethoxybenzaldehyde

5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-

ylhydrazone(VIIa)

49

4. IR spectrum of 2-hydroxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno [2,3-d] pyrimidin-4-

ylhydrazone (VIIb)

51

5. 1H NMR spectrum of 2-hydroxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno [2,3-d]pyrimidin-

4-ylhydrazone(VIIb)

52



LIST OF TABLES

TABLE

NONAME OF TABLE

PAGE

NO

1

Physical data of substituted benzaldehyde 5,6,7,8-

tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-

hydrazone (VIIa-b) 43

2

Spectral data of substituted benzaldehyde 5,6,7,8-

tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-

hydrazone (VIIa-b)44

3.

Antimicrobial activity of substituted benzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-

4-ylhydrazone (VIIa-e)55



1. INTRODUCTION

Medicinal Chemistry is concerned with the invention, discovery, design,

identification and preparation of biologically active compounds, the study of their

metabolism, the interpretation of their mode of action at the molecular level and the

construction of structure activity relationships.

The thorough research in the field of medicinal chemistry has led to the

discovery and synthesis of excellent therapeutic agents. Now the man has achieved a

remarkable success in combating many of the deadly diseases, which threatened the

existence of human race. He is also successful in eradicating certain types of diseases

completely. But still his research and development work is continuing to control and

eradicate terrible diseases like cancer and AIDS.

The chemistry of heterocyclic compounds has taken a major share in the

remarkable progress of medicinal chemistry. The role of heterocyclic compounds has

become increasingly important not only in the medicinal field but also in the field of

agriculture industry to a larger extent. The main goal of medicinal chemists is to plan

the synthesis of new and biologically active drugs.

This thesis deals with the investigation carried out by the writer in this

laboratory on the “Synthesis, characterization and biological activities of substituted

benzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-ylhydrazone”

Before discussing the experimental procedures adopted and the results obtained, a

brief introduction to therapeutic agents based on this ring and related moieties and in

particular a literature survey on the investigations carried by earlier workers on the

synthesis and evaluation of the heterocyclic compounds based on the above ring

moieties would be presented in this chapter.

A large number of organic therapeutic agents have been developed during the

last 35 years and these are now available to us in dosage forms suitable for the

treatment of the diseases and often used to maintain our health. These organic

compounds range from simple homocyclic compounds like aspirin to complex

heterocycles like tubocurarine, metacurine etc.

Most important biochemical compounds and drugs of natural origin contain

heterocyclic ring structures. The presence of heterocyclic structures in diverse type

of compounds is indicative of the profound effects. Examples included to research



leading to a wide variety of modern drugs such as chlordiazepoxide (tranquillizer),

methazolamide (carbonic anhydrase inhibitor), guanethidine (antihypertensive),

stanozolol (anabolic), cyclophosphamide and thiotepa (antineoplastic),

hydrochlorothiazide (diuretic and antihypertensive), imipramine (antidepressant),

lucanthone (antischistosomal), and many others.

It has been estimated that more than half of all therapeutic agents consist of

heterocyclic compounds. The heterocyclic ring system in many cases comprises the

very core of the active moiety or pharmacophore. For example, the antibiotic activity

of cephalosporin antibiotics is clearly attributable to the presence of the fused

azetidone ring, while the anxiolytic activity of the benzodiazepines can be traced of

the aryl fused diazepine present in these drugs. Examples discussed in this chapter and

those that follow have been chosen because either their heterocyclic component is

believed to form part of a pharmacophore or alternatively, they illustrate aspects of

the chemistry of particular heterocyclic rings. Many drugs do exists in which the

heterocyclic component is a surrogate for open chain amine, as illustrated by those

drugs bearing piperidine or pyrolidine rings in lieu of open chain tertiary amines.



1.1 THIENOPYRIMIDINE

Fusion of thiophene to a pyrimidine nucleus gives rise to three positional

isomers : thieno[2,3-d]pyrimidine (1), thieno[3,2-d]pyrimidine (2) and thieno[3,4-

d]pyrimidine (3).

N

N

S

N

NS N

NS

(1) [2,3-d] (2) [3,2-d] (3) [3,4-d]

One general strategy for the synthesis of thieno[2,3-d]pyrimidines (1) consists

of the condensation of a suitable 2-amino-3-thiophene carboxylate, 2-amino-3-

thiophene carboxamide (or) 2-acylamino-3-thiophene carboxylate with reagent that

provide the remaining fragment required for cyclization to the condensed system,

example formamide, imidates, nitrites, urea, aromatic amines, ammonium salts of

organic acids, N,N’-dimethylphosphorodiamidates and 2-chloropyrimidines. Thus

using a modified Niementowski reaction and heating 2-amino-3-

methoxycarbonylthiophene (4) in formamide for two hours at 2000C yields (5).

Refluxing (5) with phosphorus oxychloride in the presence of pyridine gives 4-

cholorothieno[2,3-d] pyrimidine (6). The chlorine atom in (6) is easily replaced by

nucleophilic agents like sodium methoxide in methanol, sodium phenoxide in phenol,

ammonia, hydrazine, etc.

S NH2

COOMe

80%

i

N

NH

S

O

ii

N

N

S

Cl

iii, iv

N

N

S

(4) (5) (6) (7)

i, formamide, 200 0C, 2 h; ii, phosphorus oxychloride; iii, hydrazine hydrate; iv,

ethanol, sodium ethoxide, reflux.

Another general methods for the synthesis of condensed pyrimidines is

reaction of o-amino carbonyl compounds (7) (ketones, esters, amides, nitrites) with



nitriles (8) under acidic conditions. Presumably an amidine intermediate (9) is

involved which undergoes intramolecular cyclization by nucleophilic attack on the

carboxyl function to yield the pyrimidine (10).

(8) (9) (10)

X

Y

= COPh, COOEt, CONH 2, CN; Z= Ph, OH, NH 2

2-Mercaptothieno[2,3-d]pyrimidine-4(3H)-ones (12) were synthesized by

cyclization of 2-aminothiophene-3-carboxylates or carboxamides (11) either by direct

reaction with thiourea or by reaction with isothiocyanate via the corresponding N,N’-

disubstituted thioureas as intermediates.

SCH3

CH3

NH2

COOEtThiourea

170 - 175 0C N

NH

S

CH3

CH3

O

SH

(11) (12)

4-Hydrazinothieno[2,3-d]pyrimidines (13) have been used as starting material

for the synthesis of tricyclic triazolo- and tetrazolothienopyrimidines (14).

N

N

S

NHNH2

HNO2

N

N

S

NN

N

Several ribofuranosyl nucleosides of the thieno[2,3-d]pyrimidine (15) ring

system have been prepared by condensation of the silylated base with 1-o-acetyl-


NH

N

S

NH2

O

i, ii, iii

N

N

S

NH2

O

OHOH2C

OH OH

i, hexamethyldisilazane, ammonium sulfate, reflux; ii,1-o-acetyl-2,3,5-tri-o-benzoyl-D-ribofuranose, tin(IV)chloride, 1,2-dichloroethane; iii, methanol, ammonia.

(15)


2,3,5-tri-o-benzoyl-β-D-ribofuranose in 1,2-dichloroethane in the presence of

tin(IV)chloride. These nucleosides are analogs of cytidine. Uridine analogs have been

prepared from thieno[2,3-d]pyrimidine-2,4-diones.

3-Aminothiophene-2-carboxylates (16) are suitable starting materials for the

synthesis of thieno[3,2-d]pyrimidines (17).

S COOMe

NH2

i

80% S COOMe

NH CHO

ii

90%

N

NHS

O

iii 65%

N

NS

Cl

iv

80%

N

NS

i, formic acid, sodiumacetate, 95%, 1h; ii, ammonium formate, formamide, 140 0C, 7h; iii, POCl3 ; iv, Pd/C, MgO, H2.


(16)

(17)

S

MeOOC

ClH3N+

i59%

S

MeOOC

NHOHC

ii46%

iii, 71%

N

NHS

O

S

NHOHC

O

NH2

i, sodium acetate, formic acid, 100 0C, 1h; ii, ammonium formate, formamide, 140-145 0C, 6h; iii, methanolic ammonia, room

Temperature; IV, sodium methoxide, 40h, room temperature.

(18) (19)

(20)

(21)


Electrophilic substitution reactions of thieno[2,3-d]pyrimidine occur at position 7.

Thieno[3,4-d]pyrimidine derivatives were prepared for the first time by Baker

and coworkers. Where as the application of Niementowski reaction to (18) yielded

only traces of (19), treatment of the N-formyl derivative (21), with ammoniumformate

and formamide at 1450C for 6h gave a 46% yield of thieno[3,4-d]pyrmidin-4-one

(20). The action of ammonia in methanol on (19) with subsequent base catalyzed ring

closure of the bisamide (21) is a preferred way for the preparation of (20)1.

1.2 Literature Review

Several investigations have been carried out by earlier workers on the

synthesis, characterization and pharmacological activities of heterocyclic compounds

containing the thienopyrimidine moiety. A literature survey was, therefore carried out

on such investigations. The survey is limited to 2006-1989.


N

NS

E+

E= NO2, Cl, Br

N

NS

E


Yujia Dai and coworker2(2006) have synthesized some thienopyrimidine

derivatives (22) and screened for their multitargeted Receptor Tyrosine Kinase

Inhibitors activity screening. Compound 28 and 76 give a very good activity

N

N

S

NH2

NH2

(CH2)n Ar or H

Me or (CH 2)n-1 Ar

(22)

Haruhisa and coworker3(2006) have synthesized some thienopyrimidine

derivatives (23) and screened for their antimalarial activity screening.

Thienopyrimidine analogue 15 exhibited a potent antimalarial activity and a high

therapeutic selectivity both in vitro and in vivo, suggesting that 15 is a good

antimalarial candidate.

N

NS CONHR 3

OR2

R1

R4

(23)

Tarikere and coworker4(2006) have synthesized some thienopyrimidine

derivatives (24) and screened for their anticancer activity screening. One of

compound showed good anticancer activity.

N

N

S

NHR

R3

R2

R1

(24)

Dickerson and coworkers5 (2005) have synthesized some thienopyrimidine

derivatives (25) and (26) and screened for their Erb kinase inhibitor activity for



treating cancer. One derivative showed inhibitor activity vs. EGFR-2 and ErbB-4

protein tyrosine kinases with a pIC50≥ 5.5.

N

N

NR3R2

A1

A2

R1

one of A 1 and A 2 is S and the other is CH

(25)

N

N

NH

S

O

Cl

F

NH

N

O

Seema Kanwar and Sharma6 (2005) have synthesized some 2-[1- (4-

methoxyphenyl)-4-oxo-azetidin-2-yl]-5,6,7,8-tetrahydro[4,5]thieno[2,3-d]pyrimi

dine-4(3H)-one derivatives (27). The compound showed antibacterial activity.

S

NH

N

O

N R

O

(27)


(26)


Wang and coworkers7 (2004) have synthesized hetroaryl fused pyrimidinyl

compounds including thieno [3,2-d]pyrimidine derivatives (28) and screened for KSP-

inhibiting activity and anticancer activity.

S

N

N

O

BrN

O

CH3

N

O

NH2

CH3

CH3

(28)

Dhanoa and coworkers8 (2004) synthesized piperidinyl

amino(benzo)thienopyrimidines (29) and screened for their use as 5-HT2 receptor

ligands. Compound showed 5-HT2 receptor antagonist activity.

N

NS

NH

N

R2

R1

(CH2)n-R

Maria Modica and coworkers9 (2004) have synthesized piperazinyl-substituted

thieno[2,3-d]pyrimidine-4(3H)one derivatives (30) as 5-HT3 receptor ligands. One of

its derivatives exhibited the highest affinity for the 5-HT3 receptor and behaves as

noncompetitive antagonist.


(29)


S N

N

N

N

R4

R1

R2

SCH3

(30)

Cho and coworkers10 (2004) have synthesized some new thienopyrimidines

(31) as gonadotropin-releasing hormone antagonists. One compound of this invention

in-vivo showed IC50 value of 0.0001µM in an assay for human GnRH receptor

antagonism.

N

NS

N

(CH2)n-R4

R3

NH

NH

OR1O

O

O

R2

F F

Zavarzin and coworkers11 (2004) have synthesized some thieno[2,3-

d]pyrimidine derivatives (32) from monothiooxamides.

N

NS CONHR 3

OR2

R1

R4

(32)


(31)


Michaelides and coworkers12 (2004) have synthesized 1-[4-(4-amino-6-

methylthieno [2,3-d]pyrimidin-5-yl)phenyl]-3-phenylurea (33) as kinase inhibitor.

N

N

NH2

S

CH3

NH

O

NH Ph

(33)

Fraley and coworkers13 (2003) have synthesized thienopyrimidine derivative

(34) as mitotic kinesin inhibitors for the treatment of cancer. This derivative inhibited

human polyhistidine tagged KSP motor domain with an IC50 value of ≤ 50µM.

N

N

S

O

N

CH3

NO

Br

CH3

CH3

(34)

Dyachenko14 (2003) has synthesized 1,2-dihydro-5,6-

tri(tetra)methylenespiro(cyclopentane(cyclohexane))-2-thieno-[2,3-d]pyrimidin -

4(3H)-thiones (35).



S

NH

NH

SEt

(35)

Dumas and coworkers15 (2002) have synthesized some thienopyrimidines (36)

as inhibitors of prolylpeptidase, inducers of apoptosis and cancer treatment agents. All

the derivatives were found to inhibit polypeptidase at or below of 10µM.

N

N

S

X

N[CH2]n-R2R1

(36)

Adams and coworkers16 (2003) have synthesized thienopyrimidines (37) as

TIE-2 and/or VEGFR-2 kinase inhibitor useful against hyperproliferative diseases.

N

N

X

D

AR1

R2

(37)

Tumkevicius and coworkers17 (2003) have synthesized 4,6-disubstituted

thieno[2,3-d]pyrimidines (38) from 4,6-dichloro-2-methylthiopyrimidine-5-

carbaldehyde.



N

N

S

R1

NR2

MeS

(38)

Munchoff and coworkers18 (2002) have synthesized some thienopyrimidines

(39) and (40) as anticancer agents. Some compounds are effective at 0.2-0.5g/day for

a 70 kg human.

N

N

S

NR2R1

R3N

NS

NR2R1

R3

(39) (40)

Uoto and coworkers19 (2002) have synthesized some thieno [2,3-d]pyrimidine

derivatives (41) and (42) as cyclin-dependent kinase 4 (cdk4) inhibitors having

antitumor activity owing to cell cycle regulation.

N

N

S

NR4

R2

A

R1

R3

N

NS

NR4

R2

A

R1

R3

(41) (42)



Manish Shah and coworkers20 (2002) have synthesized some N-substituted-

2-(6-phenylthieno[3,2-d]pyrimidin-4-yl)hydrazinecarbothioamide derivatives (43) and

evaluated for their antimicrobial activity. Compounds give very good antimicrobial

activity.

N

N

S

NHNH

S NH

R

(43)

Umeda and coworkers21 (2002) have synthesized thienopyrimidine

derivatives (44) as cGMP-specific phosphodiesterase inhibitors. Several compounds

of this invention showed potent inhibitory activity against PDE5 vs. IC50 of 14nM

shown by sildenafil.

N

N R3

NH

S

R5

R4

R1

R2

(44)

Pamukcu and coworkers22 (2000) have synthesized some thienopyrimidine

derivatives (45) for inhibiting neoplastic cell growth.



N

N

S

NHR

R3

R2

R1

(45)

Walter23 (1999) has synthesized novel 3-substituted-2-butyl-6-

chlorothieno[2,3-d]pyrimidin-4(3H)-one derivatives (46) as fungicides. Some

compounds showed strong efficacy against P. leucotricha on apple shoots at 0.06%

a.i.

N

NS

Cl

O

Bu

Pr-n

(46)

Hosni and coworkers24 (1999) have synthesized newer thieno[2,3-d]pyrimidines

and their quaternized derivatives (47), (48), (49) and (50) with molluscidal activity.

Some of the synthesized products showed significant activity against the intermediate

host of schistosomiasis.



NH

NS

O

R

S

N

NS

O

NHR'

S

NCHOEt

N

NS

NHR2

Me

S

N

NS

NR2

Me

S

Me

Jun Katada and coworkers25 (1999) have synthesized a new series of

thienopyrimidine derivatives (51) and examined their cytotoxic effects on several cell

lines. One of the derivatives, NSL-1406, was shown to exert potent cytotoxic effects

on leukemia cell line.

N

NS

NH

Cl

(51)

Maria and coworkers26 (1998) have synthesized 3-benzyl-2-butylthieno[3,2-

d]pyrimidin-4(3H)-one (52) N-substituted-2-butylthieno[3,2-d] pyrimidin-4-amine

(53) as selective type 4 phosphodiesterase inhibitors. Of these 2-butyl-4-


(47) (48)

(49) (50)


cyclohexylaminothieno [3,2-d]pyrimidine has an interesting profile and good activity

in cAMP potentiation.

N

N

S

CH3

O

N

N

S

CH3

NHR

(52) (53)

Jonas and coworkers27 (1998) have synthesized thienopyrimidines (51) as

phosphodiesterase V inhibitors.

(54)

Matthias Rehwald and Karl Gewald28 (1998) have synthesized thieno[2,3-d]

pyrimidines (55) from 2-alkoxy-5-cyano-4-thioxopyrimidine intermediates.

N

NH

S

Ph

O

COPh

NH2

(55)



Chen and coworkers29 (1997) have synthesized thienopyrimidines (56) as

corticotrophin-releasing factor antagonists.

N

NS

R2

R1

R3

R

(56)

Desai and coworkers30 (1997) have synthesized 3-N-substituted –thioureido-2-

methyl-6-phenylthieno[3,2-d]pyrimidin-4(3H)-ones (57) and evaluated for their

antimicrobial activity against B. megaterium, S. citrus, E. coli and S. typhosa.

N

N

S

Ph

CH3

O

NH

NHRS

(57)

Minsheng Zhang and Richard31 (1997) have synthesized 2-aminothieno [2,3-

d]pyrimidine derivatives (58) via a Gewald precursor.

N

N

SNH2

ROBn

OBn

(58)



Maria Modica and coworkers32 (1997) have synthesized

[[arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives (59) as high-

affinity, selective 5-HT1A receptor ligands.

N

NS

R1

R2

O

S

R3

(CH2)n

N

X

R4

(59)

Kadthala Shekar Manjunath and coworkers33 (1997) have synthesized 2-

chloromethyl3-N-substituted-arylthieno[2,3-d]pyrimidin-4-ones (60) and evaluated

for CNS depressant activity. Some compounds have shown marked sedative action.

N

NS

O

N

O

R1

R2

R3

(60)

Furuya and coworkers34 (1996) have synthesized thienopyrimidine derivatives

(61) as prophylactic or therapeutic agents for the treatment of hormone dependent

diseases. These derivatives are effective as fertility controlling agents in both sexes.



N

NS

O(CH2)r

R4

O

R2

R1

R3

(61)

Andanappa and coworkers35 (1996) have synthesized 2-aminomethyl-3-aryl-

5,6,7,8-tetrahydro(b)/5,6-dimethylthieno[2,3-d]pyrimidin-4-ones (62) and evaluated

for their antihyperlipaemic activity. Most of the compounds are found to be active.

Some are comparable to that of standard (gemfibrozil).

N

NS

O

R1

CH2X

R2

R

(62)

Edward and coworkers36 (1996) have synthesized several thieno[2,3-

d]pyrimidine analogues (63) and (64) of the potent antitumor agent N-{4-[2-(2-amino-

4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5yl)ethyl]-benzoyl}L-glutamic acid (LY

231514).

N

N

S

R1

R2

NH

COOH

O

COOH

N

N

S

R5

R4

COOMe


(63)

(64)


Christine Fossey and coworkers37 (1995) have synthesized 5’-Halo-2’3’-lyxo-epoxy

and 2’,3’-unsaturated thieno[3,2-d]pyrimidine nucleosides (65) and evaluated for

antiviral activity. None of the compounds in this series exhibited significant antiviral

activity against HIV at the doses tested.

N

NHS

O

OO

OHOH

R

(65)

Desai and coworkers38 (1995) have synthesized 2-methyl-3-N-

arylsulfonamido-6-phenylthieno[3,2-d]pyrimidine-4(3H)-ones (66) and evaluated for

their antimicrobial activity.

N

N

S

CH3

O

NHSO2R

Ph

(66)

Robert and coworkers39 (1995) have synthesized substituted 2,4-

diaminothienopyrimidines (67) and (68) as reversible inhibitors of the gastric (H+/K+)-

ATPase. Some compounds proved to be effective inhibitors of stimulated acid

secretion in both the rat and dog when dosed intravenously.



(67) (68)

Fabrice Jourdan and coworkers40 (1994) have synthesized thieno[3,2-d]

pyirmidine-2,4-diones cyclic and acyclic nucleosides (69) as potential antiHIV agents.

N

NHS

O

O

R

O

Shishoo and coworkers41 (1994) have synthesized some 2-substituted-6-phenyl

and 7-phenyl-thieno[3,2-d]pyrimidin-4(3H)-ones (70) and (71).

NH

N

S

CH2CO2C2H5

O

Ph NH

N

S

O

Ph

R

(70) (71)


(69)


Andre Rosowsky and coworkers42 (1993) have synthesized 2,4-

diaminothieno[2,3-d]pyrimidine analogues (72) of trimetrexate and piritrexim as

potential inhibitors of P. carinii and T. gondii dihydrofolate reductase.

N

N

S

NH2

NH2

(CH2)n Ar or H

Me or (CH 2)n-1 Ar

(72)

Shirish and coworkers43 (1993) have synthesized some new thieno[3,4-d]

pyrimidines and C-nucleosides (73). Preliminary biological studies indicate that

adenosine analogue is a potent growth inhibitor of several mammalian tumor cell

lines.

N

N

S

R1

OR2

OH OH

(73)

Shishoo and Jain44 (1993) have synthesized 4-amino-2-substituted-

aminothieno[2,3-d]pyrimidines (74) and evaluated for their antifolate and antimalarial

activities.

N

NS

NH2

R2

R1

NR3R4

(74)



Ogawva and coworkers45 (1993) have synthesized substituted 2,4 –dioxo-

thienopyrimidin-1-acetic acids (75) and evaluated for their aldose reductase inhibitor

activity. Most of the compounds were showed potent aldose reductase inhibitory

activity with IC50s in the 10-8 M range.

N

N

X

Y

Z

O

O

COOH

R1

R2

R3

Pathak and coworkers46 (1992) have synthesized some [1,2,4]triazolo[4,3-a]

thieno[3,2-e]pyrimidine-5(4H)-ones (76) and evaluated for CNS depressant and

analgesic activities. Two compounds exhibited significant CNS depressant and

analgesic activities.

N

NS

OR1

R2

N

NR

(76)

Ronald and coworkers47 (1992) have synthesized N-substituted thieno[3,4-d]

pyrimidine-2,4-diones (77).

NH

N

S

O

O

CH2CH2R

(77)


(75)


Pathak and coworkers48 (1991) have synthesized N-(N’,N’’-

disubstituted)amino-3-phenyl-thieno[2,3-d]pyrimidin-4(3H)-ones (78) and tested for

their analgesic and CNS depressant activities.

N

NS

O

NR3R4

R2

R1

(78)

Grant Buchanan and coworkers49 (1991) have synthesized some

hydroxyalkylated pyrrolo- and thieno[3,2-d]pyrimidines (79) and evaluated for their

antiviral activity.

N

N

S

NH2

R

(79)

Press and coworkers50 (1991) have synthesized series of thieno [3,2-d]-,

[3,4-d]- and [2,3-d]pyrimidinedione derivatives (80) as selective 5-HT2 antagonists.


(80)

N

N

O

O

CH3 R

R1

Thi


N-H2C

O

F

N-H2C

F

F

R=ket=

R=rit=

Kosaku Hirota and coworkers51 (1990) have synthesized 6-substituted

thieno[2,3-d]pyrimidin-2,4(1H,3H)-diones (81).

N

N

S

O

O

R

CH3

CH3

(81)

Shishoo and coworkers52 (1990) have synthesized 2-substituted thieno[2,3-d]

pyrimidin-4(3H)-ones (82) and evaluated for their antihyperlipaemic activity. One of

the derivative was found comparable to that of clofibrate and riboflavin tetrabutyrate.

NH

NS

CH3

CH3O

CH2X

(82)



Shishoo and coworkers53 (1989) have synthesized some 2-substituted

quinazolin-4-ones and thienopyrimidines (83) and (84) of biological interest.

NH

NS

R2

R1O

RS

N

NH

R1

R

O

(83) (84)

Mitsuo Sugiyama and coworkers54 (1989) have synthesized angular annelated

oxazolo[2,3-b]thienopyrimidin-5-one derivatives (85), (86) and (87) and evaluated for

gastric antisecretory activity in pylorus-ligated rats.

NH

N

S

O

O

NH

N

S

O

O

NH

NS

O

O

(85) (86) (87)

Mitsuo Sugiyama and coworkers55 (1989) have synthesized 2,3-dihydro-5H-

oxazolo[3,2-a]thieno[3,2-d],[3,4-d] and [2,3-d]pyrimidine derivatives (88) and were

evaluated for gastric antisecretory activity.

N

N O

T

(88)



2. SCOPE AND OBJECTIVES

It has been estimated that more than half of therapeutic agents available today

are made up of heterocyclic compounds. The heterocyclic ring system in many case

are the very core of the active moiety or pharmacore, for example the antibiotic

activity of cephalosporin antibiotics is clearly attributable to the presence of the fused

azetidone ring. While the anxiolytic activity of the benzodiazepines can be traced to

the aryl fused diazepine present in these drugs.

Chemical modifications of drug molecules of a series having optimal activity

is widely used and continue to be an important factor in new drug discovery studies.

In order to obtain new, effective and safe drugs has led today’s researchers to improve

the existing drugs by increasing their potency, duration of action and by decreasing

the toxic side effects. Structure activity studies show that variations in ring system or

minor group extent distinct pharmacological effect upon the drug molecules.

Thienopyrimidine derivatives have been reported to have a variety of

activies. For example thienopyrimidines displayed anticancer4,5,15,18,19,,22,25,36,43,

antiviral37,40,49, antimicrobial2,6,20,30,38,42, antihyperlipaemic35,52, 5-HT1A,5-HT2,5-HT3

receptor antagonist8,9,32,50, gastric antisecretory39,54,55, CNS depressant33,48,

phosphodiesterase inhibitor21,26,27, molluscidal24, antifungal23, antimalarial44,

analgesic48, fertility controlling34, gonadotropin-releasing hormone antagonist10 and

aldose-reductase inhibitor46 activities. In other words the thienopyrimidine moiety is

an important structural feature of many biologically active compounds.

It was proposed, therefore, to synthesize some new thienopyrimidine

containing compounds. These structural moieties were characterized in terms of their

IR, NMR and mass spectral analysis to elucidate their structure. It is likely that their

new derivatives with some modification in their chemical structure may result in some

profound change in the pharmacological response. It may increase, decrease or alter

the nature of the response.



The reaction, reagents and conditions are given in the following scheme;



3. EXPERIMENTAL

Organic chemists are frequently facing the problem of characterizing and

ultimately elucidating the structure of organic compounds. The worker in the field of

natural products has the prospects of isolating such compounds from the sources in a

pure state and then determining their structure. On the other hand, the synthetic

organic chemist encounters new or unexpected compounds in the course of

investigations into the applicability of new reagents or techniques or as byproducts of

established reactions.

All reactions were carried out under prescribed laboratory conditions. All the

reactions requiring anhydrous conditions were conducted in well dried apparatus.

The solvents and reagents used in the synthetic work were of laboratory

reagent grade and were purified by distillation and crystallization techniques wherever

necessary and their melting points were checked with the available literature.

Melting points of newly synthesized compounds were determined by open

capillary method and were uncorrected. The final products were purified by

recrystalization and micro TLC checked purity.

The IR spectra of the compounds were recorded on JASCO FT/IR-5300

spectrometer using KBr pellet. 1H NMR spectra were recorded in a BRUKER DPX-

400MHz spectrometer using TMS as internal standard.



3.1 SYNTHESIS

Synthesis of ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate

(III)

A mixture of cyclohexanone (I) (1.03ml, 0.01mol), sulphur (0.32g, 0.01mol),

ethyl cyanoacetate (II) (1.07ml, 0.01mol), morpholine (0.87ml, 0.01mol) and absolute

alcohol (10ml) were refluxed for 6-7h and kept overnight. The crude product

separated was filtered, washed with chilled ethanol and dried. Yield 1.8g, 80%.

Synthesis of 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (IV)

A mixture of ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-

carboxylate (III) (2.25g, 0.01mol) and formamide (15ml) were refluxed at 160-1800C

for 6h and then allowed to cool at room temperature. The solid separated was filtered,

washed with water, dried and recrystalized from DMF-water (2:1) to get white

crystals. Yield 1.6g, 78%.

Synthesis of 4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine (V)

5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (IV) (2.06g,

0.01mol) was dissolved in 10ml phosphorus oxychloride containing 1.5 ml,

triethylamine and the mixture was refluxed for 90 minutes in an oil bath at 1400C. The

excess of phosphorus oxychloride was removed under reduced pressure and the

suspension was poured into cold water and neutralized with 10% sodium hydroxide

solution. The residue was collected, washed with water, dried and recrystalized from

DMF-water (2:1). Yield 1.7g, 75%.

Synthesis of 4-hydrazino-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine (VI)

4-Chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine (V) (2.24g, 0.01

mol), hydrazine hydrate (0.01 mol) was dissolved in butanol then add and refluxed for

2 h. The solution was added to the water contain HCl. The residue was collected,

washed with butanol, dried and recrystalized from ethanol. Yield 1.5 g. 67 %.



Synthesis of 4-(dimethylamino)benzaldehyde 5,6,7,8-tetrahydro[1]

benzothieno[2,3-d]pyrimidin-4-hydrazone (VIIa)

4-Hydrazino-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine (VI)

(2.20g, 0.01 mol) and N,N dimethylamino benzaldehyde (1.49 g, 0.01 mol) were

refluxed in ethanol (50 ml) for 5 h the solid obtain was filtered out and recrystalized

from ethanol to get brick red colour precipitate. Yield 1.6 g. 73%.

Synthesis of 2,4-dichlorobenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno [2,3-d]

pyrimidin-4-hydrazone (VII b)

4-Hydrazino-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine(VI)

(2.20g, 0.01 mol) and 2,4 dichloro benzaldehyde (1.75 g, 0.01 mol) were refluxed in

ethanol (50 ml) for 5 h the solid obtain was filter out and recrystalized from glacial

acetic acid to get green colour precipitate. Yield 1.5 g, 69%.



3.2 Antimicrobial activity

The antimicrobial activity of synthesized compounds was evaluated by the

zone of inhibition method56. This method is based on the diffusion of an antibiotic

from a filter paper disc through the solidified culture media of a petridish used for the

study. Growth of inoculated microorganism is inhibited entirely in a circular area

“zone” around the filter paper disc containing a solution of the antibiotic and the test

compounds.

The organisms were maintained on nutrient agar slants. One loopful of each

strain of microorganism was transferred into a suitable agar slant by using a sterile

Pasteur loop. These slants were incubated for 24h at 370C for bacteria and 250C for

fungi and were observed for the growth of the organism with naked eye for their

turbid nature. The presence of turbidity indicated the growth and stability of the

culture for further work.

Materials

Microorganisms used:

Bacterial strains:

Staphylococcus aureus (gram positive)

Staphylococcus mutants (gram positive),

Pseudomonas aeruginosa (gram negative),

Salmonella typhi (gram negative),

Fungal strains:

Candida albicans and

Rhizopus stolonifer

Drugs (control):

Cefixime (antibacterial)

Ketoconazole (antifungal)



Preparation of stock culture

From the cultures, which were maintained on nutrient agar slants, one loop full

of the respective organisms were taken and aseptically transferred to 100ml of a

sterile nutrient broth in a flask, which was shaken thoroughly and incubated at 370C

for bacteria and 250C for fungi.

Preparation of culture medium:

Composition of Mueller Hinton agar medium

Beef infusion 300ml

Casein hydrolysate 16g

Starch 1.5g

Agar 15g

Distilled water 1000ml

pH 7.2 ± 0.2

The medium was prepared by dissolving the specified quantity of the

dehydrated medium in purified water and was dispersed in 20ml volumes in to test

tubes. The test tubes were closed with cotton plugs and were sterilized by

autoclaving at 121°C (15 lb psig) for 15 minutes. The contents of tubes were

poured aseptically in to sterile petri plates (90mm diameter) and allowed to

solidify.

Preparation of drug solution

The drug solutions were prepared by dissolving in dimethyl sulphoxide

(DMSO). The solutions of the test drugs were prepared at the concentration of

1000mg/ml in DMSO. The solutions of standard drugs cefixime and ketoconazole

were prepared at the concentration of 1000 mg/ml in DMSO.



Method

Previously liquefied Muller Hinton Agar media was inoculated with the

requisite quantity of the suspension of the microorganism, the suspension was added

to the medium at a temperature between 40 – 50 0C and the inoculated medium was

poured immediately into dried Petri dish to occupy a depth of 3 - 4 mm. The Petri

dishes were allowed to be sterilized at 160 – 170oC for 24 h, before use.

The paper disc (No – 2 Whatmann) was cut down into a small disc (6 mm in

diameter) and sterilized in the hot air oven, and then impregnated with the test

solutions and standard solution. The dried discs were placed on the surface of the

medium.

After all the drugs are added Petri dishes were left standing for 1 to 4h at room

temperature, as a period of pre-incubation diffusion to minimize the effects of

variation in time between the application of different solutions. All the Petri dishes

were incubated for 24 h at the required temperatures, i.e. 370C for bacteria and 250C

for fungi. After incubation the diameters of the circular inhibition zones were

measured.



4. RESULTS AND DISCUSSION

4.1 Synthesis and characterization of the compounds

Table 1

Physical data of substituted benzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3-

d]pyrimidin-4-hydrazone (VIIa-b)

COMPOUND

R R1 R2 R3 RECRYSTALIZATION SOLVENT

%YIELD

M.P (0C) MOLECULAR FORMULA

MOLECULAR WEIGHT

RF VALUE

VIIa - OCH3 OCH3 OCH3 CHCL3 78 200-202 C20H22O3N4S 398.47 0.4

VIIbOH -

- - GAA 78 245-247 C17H16ON4S 324.90 0.6

Table 2



Spectral data of substituted benzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-hydrazone (VIIa-b)

COMPOUND

R R1 R2 R3 IR (KBR) 1H NMR (400MHZ, CDCL3, Δ)

N-H str

O-H str C-H

aliphatic

C=N str

C-N str

2-pyrimidinyl-H

Ar-H

N-H -(CH2)

2-

-(CH2)

2-

N=CH

-OCH3

-N( CH3

)2

-OH

VIIa - OCH3 OCH3 OCH3

3367 cm-1

- 2935 cm-1

1622 cm-1

1338 cm-1

8.3 7.40 10.4 2.87 1.94 7.6

3.9

- -

VIIb OH

- - -

-

3526 cm-1

2933 cm-1

1626 cm-1

1227 cm-1

8.4 7.2 12 2.85 1.94 8.6

-- 7.

6

Synthesis of 4-hydrazino-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine

(VI)



The Synthesis of 4-hydrazino-5,6,7,8-tetrahydro[1]benzothieno[2,3-

d]pyrimidine (VI) can be given by the following scheme;

The compound (VI) with melting point of 160-162 0C was analyzed for

C10H12N4S. The IR spectrum of the compound by KBr method is given in figure 1. It

exhibits intense bands at 2935 cm-1 (aliphatic C-H str), 3308 cm-1 (NH stretching),

1633 cm-1 (NH bending), 1227 cm-1 (C-N stretching), and 578 cm-1 (C-S stretching).

The data confirms the structure of the compound.



FIGURE: 1

IR spectrum of 4-hydrazino-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]

pyrimidine(VI)



Synthesis of 3,4,5-trimethoxybenzaldehyde5,6,7,8-tetrahydro[1]benzothieno[2,3-

d]pyrimidin-4-hydrazone (VIIa)

The synthesis of 3,4,5-trimethoxybenzaldehyde 5,6,7,8-

tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-ylhydrazone (VIIa) can be given by the

following scheme;

The compound (VIIa) with melting point of 2000C was analyzed for

C20H22N4O3S.The IR spectrum of the compound by KBr method is given in figure 7. It

exhibits intense bands at 3367 cm-1(N-H str) 2935 cm-1 (aliphatic C-H str), 1622 cm-1

(C=N) and 1338 cm-1 (C-N). The 1H NMR spectrum in CDCl3 is given in figure 8. It

shows peaks at : 10.4 (S,1H,N-H), 8.4 (s, 1H, 2-pyrimidinyl-H), 7.6 (s,N=CH,1H),

7.30 (s, 2H, Ar-H ), 3.9 (s, 9H, -OCH3), 2.87 (m,4H,(CH2 )2 ), 1.94 (m,4H,(CH2 )2

)The data confirms the structure of the compound.



Figure 2

IR Spectrum of 3,4,5-trimethoxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-hydrazone (VII)



Figure:3

1H NMR spectrum 3,4,5-trimethoxybenzaldehyde 5,6,7,8-

tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-hydrazone(VIIa)



Synthesis of 2-hydroxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno [2,3-

d]pyrimidin-4-hydrazone (VIIb)

The synthesis of 2-hydroxybenzaldehyde 5,6,7,8-tetrahydro[1]

benzothieno[2,3-d]pyrimidin-4-hydrazone( VIIb) can be given by the following

scheme;

The compound (VIIb) with melting point of 245-2470C was analyzed for

C17H16OS.The IR Spectrum of the compound by KBr method is given in figure 9. It

exhibits intense bands at 3526 cm-1(O-H str) 2933 cm-1(aliphatic C-H str), 1626 cm-1

(C=N) and 1227 cm-1 (C-N)). The 1H NMR spectrum in CDCl3 is given in figure 10. It

shows peaks at : 12 (s, N-H, 1H), 8.6 (N=CH,1H, s), 8.4 (s,1H, 2-pyrimidinyl-H),

7.6 (s,OH,1H), 7.2 (s,4H,Ar-H), 2.85 (m,4H,(CH2)2) ,1.94(m,4H,(CH2 )2 ).The data

confirms the structure of the compound.



Figure 4

IR spectrum of 2-hydroxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno [2,3-d] pyrimidin-4-hydrazone (VIIb)



Figure : 5

1H NMR spectrum of 2-hydroxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno [2,3-d]pyrimidin-4-hydrazone(VIIb)

4.2 Antimicrobial activity



In vitro tests are used as screening procedure for new agents and for testing the

susceptibility of individual isolates from infections to determine which of the

available drugs might be useful therapeutically. Due to the development of

sulphonamides and pencillins, in vitro measurement of susceptibility of microbes to

chemotherapeutic agents has been use.

A drug is considered to have bacteriostatic or fungistatic activity when it

inhibits the activity of bacteria or fungi respectively and bactericidal or fungicidal

activity and its kill bacteria and fungi. Important factors for antimicrobial activity for

size of the inoculum, metabolic state of microbe, pH, temperature, duration of

interaction, concentration of inhibitor and presence of interference substances.

The development of resistance among various pathogenic microbes towards

the antibiotics has increased the impetus for investigating new antimicrobial agent.

When a compound was found to have positive therapeutic index, a new series of

related compounds are synthesized in the hope that one of them would be more

effective than the existing one. A drug, which kills or inhibits the growth of microbes,

is known as antimicrobial agent.

Antibacterial activity was carried out on four bacterial strains, namely

Staphylococcus aureus (gram positive), Staphylococcus mutants (gram positive),

Pseudomonas aeruginosa Salmonella typhi (gram negative), Pseudomonas

aeruginosa (gram negative) and antifungal activity was carried out on two fungal



strains, namely Candida albicans and Rhizopus stolonifer. The results are shown in

and table.

Compound VIIa has no significant activity against antibacterial organisms

used for the screening but good activity against Candida albicans.

Compound VIIb have good activity against Staphylococcus aureus,

Pseudomonas aeruginosa. The zone of inhibition produced by this compound is

comparatively good than that of standard used for Staphylococcus aureus,

Staphylococcus mutants and Candida albicans.



Table 3

Antimicrobial activity of substituted benzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-ylhydrazone (VIIa-e)

NA: no activity at this amount of test compound or standard

Zone of inhibition of *Amoxicillin-clavulanic acid = 22mm (S. aureus), 18 mm (P. aeruginosa) (for gram positive bacteria)

Zone of inhibition of **Cefixime = 12 mm (S. typhi), 10 mm (S. mutants) (for gram negative bacteria)

Zone of inhibition of *** Ketoconazole = 12 mm (C. albicans), 10 mm (R. stolonifer) (anti fungal)

5. CONCLUSION


MICROORGANISM COMPOUND VIIC (1MG/ML)

COMPOUND VIID (1MG/ML)

CONTROL(1MG/ML)

Staphylococcus aureus

36 36 100*

Pseudomonas aeruginosa

44 33 100*

Salmonella typhi

67 33 100**

Staphylococcus mutants

NA 30 100**

Candida albicans 67 50 100***

Rhizopus stolonifer 40 60 100***


This thesis deals with the Synthesis, Characterization and Antimicrobial

activities of Some Derivatives of substituted benzaldehyde5,6,7,8

tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-ylhydrazone.

The first chapter of the thesis deals with a brief introduction to the therapeutic

agents based on the above rings and related moieties and in particular a literature

survey on the investigation carried out by earlier workers on the synthesis and

evaluating heterocyclic compounds based on the above said ring moieties.

The second chapter explains the scope and object of the present investigation

in detail. In particular, it explains how thienopyrimidines are an important structural

feature for biologically active compounds and the scheme of compounds proposed to

be synthesized and investigated in the present work for their Biological and

antimicrobial activities.

The third chapter of the thesis explains in detail the experimental procedures

that are adopted in the present investigation.

The fourth chapter of the thesis deals with the results obtained in the present

study along with detailed discussion on the results supported by reaction schemes,

tables, figures, etc.,

The following are some of the important findings in the present study:

1) Thienopyrimidine derivatives were synthesized in good yields (60-78%).

2) Compound VIIa exhibited good antibacterial activitie.

3) Compound VIIa and VIIb exhibited good antibacterial activity against

Staphylococcus aureus, Paseudomonas aeruginosa, Salmonella typhi and the

zone of inhibition produced by this compound was comparable to that of the

standard used.

4) The synthesized compounds apart from the antimicrobial activities in the

present thesis are believed to exert various other activities such as anticancer,

gastric antisecretory, anti-HIV, antimalarial and fertility controlling activities.

As there is an increase in the incidence of AIDS and cancer, these compounds

may be evaluated for their anti-HIV and anticancer activities in future.

6. FUTURE PLAN



The synthesized compounds apart from the anticonvulsant, analgesic and

antimicrobial activities in the present thesis are believed to have

• Anticancer,

• Gastricantisecretory,

• Anti-HIV and

• Selective 5-HT receptor ligand activities

• Antihyperlipidemic

• Antiviral activity

As there is an increase in the incidence of AIDS and cancer, these compounds

may be evaluated for their anti-HIV and anticancer activities in future.

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