Final

THIENOPYRIMIDINE DERRIVATIVES
ABSTRACT
A series of substituted benzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3d]pyrimidin-4-ylhydrazone (VIIa-b) were prepared by the displacement reaction between various aldehyde and 4-hydrazino-5,6,7,8-tetrahydro[1]benzothieno[2,3d]pyrimidine (VII), which was obtained by refluxing 4-chloro-5,6,7,8tetrahydro[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]pyrimidin4(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
THIENOPYRIMIDINE DERRIVATIVES ABBREVIATIONS
Abs. AIDS Ar ATCC ATPase Bn Bu cAMP cGMP CMC CNS DMF DMSO ED EGFR Et Etc. FT/IR g GCMS GnRH
: : : : : : : : : : : : : : : : : : : : :
absolute acquired immunodeficiency syndrome aryl American type culture collection adenosine triphosphatase benzyl butyl adenosine - 35-monophosphate guanosine - 35-monophosphate carboxy methyl cellulose central nervous system N,N-dimethyl formamide dimethyl sulphoxide effective dose endothelial growth factor ethyl Et cetera Fourier transform/infrared gram(s) gas chromatography mass spectrum gonadotropin releasing hormone
THIENOPYRIMIDINE DERRIVATIVES h HIV IC50 IR ket kg lb LD M m.p Me MHz ml mm mol nM NMR Ph ppm Pr psig rit s : : : : : : : : : : : : : : : : : : : : : : : hour(s) human immunodeficiency virus inhibitor concentration infrared ketanserine kilogram(s) pound(s) lethal dose molar (concentration) melting point methyl mega hertz milliliter millimeter mole(s) nano mole nuclear magnetic resonance phenyl parts per million propyl pounds per square inch gauze ritanserine seconds
THIENOPYRIMIDINE DERRIVATIVES SEM Thi TLC TMS VEGFR Vs g M

0
: : : : : : : : : : :
standard error mean thiophene thin layer chromatography tetramethylsilane vascular endothelial growth factor versus microgram micro mole centigrade degrees proton nuclear magnetic resonance 5-hydroxy tryptamine
C H NMR
5-HT
LIST OF FIGUURES
THIENOPYRIMIDINE DERRIVATIVES Figure no 1 Name of figure IR spectrum of 4-hydrazino-5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidine (VI) 46 Page no
2 IR Spectrum of 3,4,5-trimethoxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4hydrazone (VIIa) 48
3
1
H NMR spectrum 3,4,5-trimethoxybenzaldehyde ylhydrazone(VIIa)
49
5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-
4.
IR spectrum of 2-hydroxybenzaldehyde 5,6,7,8tetrahydro[1]benzothieno [2,3-d] pyrimidin-4ylhydrazone (VIIb)
51
5.
H NMR spectrum of 2-hydroxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno [2,3-d]pyrimidin4-ylhydrazone(VIIb)
52
LIST OF TABLES
Table no
Name of table Physical data of substituted benzaldehyde 5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-
Page no
hydrazone (VIIa-b)
43
Spectral data of substituted benzaldehyde 5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidin-42 hydrazone (VIIa-b) 44
3.
Antimicrobial activity of substituted benzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin4-ylhydrazone (VIIa-e)
55
THIENOPYRIMIDINE DERRIVATIVES 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 obtained, a Before discussing the experimental procedures adopted and the results
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), DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 7
THIENOPYRIMIDINE DERRIVATIVES 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
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 8
THIENOPYRIMIDINE DERRIVATIVES 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[3,4d]pyrimidine (3).
N N S N N S N N
(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-3thiophene 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-3methoxycarbonylthiophene (4) in formamide for two hours at 2000C yields (5). Refluxing (5) with phosphorus oxychloride in the presence of pyridine gives 4cholorothieno[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.
O COOMe i S NH2 80% HN N S ii N N S Cl iii, iv N N S
(4)
(5)
(6)
(7) iv,
i, formamide, 200 0C, 2 h; ii, phosphorus oxychloride; iii, hydrazine hydrate; 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 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 9
THIENOPYRIMIDINE DERRIVATIVES involved which undergoes intramolecular cyclization by nucleophilic attack on the carboxyl function to yield the pyrimidine (10).
Y H3C X H3C RCN Gaseous HCL Dioxane S H2 N N R R Y X N N S Z CH3
+
S NH2
(8)
X
(9)
(10)
= COPh, COOEt, CONH 2 , CN; Z= Ph, OH, NH2 Y
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,Ndisubstituted thioureas as intermediates.
O H3C COOEt Thiourea HN
0
CH3 CH3
H3C
NH2
7 -0
C 1
7 H5S
(11)
(12)
4-Hydrazinothieno[2,3-d]pyrimidines (13) have been used as starting material for the synthesis of tricyclic triazolo- and tetrazolothienopyrimidines (14).
HN N N S NH2 N HNO 2 N N S N N
10
THIENOPYRIMIDINE DERRIVATIVES 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-acetyl2,3,5-tri-o-benzoyl--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.
11
2 t C i O S H N
i , O n , i H ( 1 h , i I e i V o x m , ) a e c a m t i h c e h i l e t a i o t h n r y o i l l d , e 2 i , s a 3 i m 1 , l m , 5 a o 2 z n t a i d r n a i e . c , h o l a o b m r e m n o e z n t o i h y u a l m n e D s u ; r l i f b a o t f e u , r a r n e o f s l e u x , ;
(15)
12
THIENOPYRIMIDINE DERRIVATIVES 3-Aminothiophene-2-carboxylates (16) are suitable starting materials for the synthesis of thieno[3,2-d]pyrimidines (17).
NH2 i S COOMe 80% S
NH
CHO ii N HN O iii 65% S
COOMe
9 0%
(16)
N N S
N iv 80% N Cl S
(17)
i, formic acid, sodiumacetate, 95%, 1h; ii, ammonium formate, formamide,

0
140
C, 7h; iii, POCl3 ; iv, Pd/C, MgO, H2.
Electrophilic substitution reactions of thieno[2,3-d]pyrimidine occur at position 7.

E N N S E
+
N N S
E= NO 2, Cl, Br
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.
13
0 2 + 3 0 7 4 O H % 5 i N C M S
T(19) f (18) iC, 1h; ii, ammonium formate, (21) (20) , 1 6 i H 9 l e e o , i C H O m r 6 , O p m s C h e a o ; r m d a i i t d u i u e m i r , , e a ; 1 c m 4 e e I 0 t t V a h , 1 t a 4 e n s 5 , o o l d f i i o c u r m a i m m c m e o t a n h c i o i a x d , i , d r e 1 o , 0 o 0 m 4 0 h , r o o DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC m t
14
m p e r a t u r e
.
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. 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
NH2 N H2 N N S Me or (CH2 )n-1 Ar (CH2 )n Ar or H
(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
15
THIENOPYRIMIDINE DERRIVATIVES therapeutic selectivity both in vitro and in vivo, suggesting that 15 is a good antimalarial candidate.
R2 R1 S N O N R4
CONHR 3
(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.
NHR N R3 N S 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.
R2 R1 A1 A2
R3
N N
one of A1 and A2 is S and the other is CH
(25) DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 16
O H H N S N N
N N
Cl
(26)
Seema Kanwar and Sharma6 (2005) have synthesized some 2-[1- (4methoxyphenyl)-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.
O H N N S O
(27) Wang and coworkers7 (2004) have synthesized hetroaryl fused pyrimidinyl compounds including thieno [3,2-d]pyrimidine derivatives (28) and screened for KSPinhibiting activity and anticancer activity.
17
O N S Br N O N O N CH3 CH3 NH2
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 (CH2 )n-R R1 R2 S N HN N
(29)
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.
R4 N
R1 R2 S
N N N SCH 3
18
THIENOPYRIMIDINE DERRIVATIVES (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 0.0001M in an assay for human GnRH receptor antagonism.
(CH2 )n-R4 R3 R1 O O NH NH S F N N O N R2
O F
(31)
Zavarzin and coworkers11 (2004) have synthesized some thieno[2,3d]pyrimidine derivatives (32) from monothiooxamides.
R2 R1 S
O N N R4
CONHR 3
(32) Michaelides and coworkers12 (2004) have synthesized 1-[4-(4-amino-6methylthieno [2,3-d]pyrimidin-5-yl)phenyl]-3-phenylurea (33) as kinase inhibitor.
19
O NH NH NH2 N N S Ph
CH3
(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 50M.
O S N O N N CH3 N CH3
CH3
Br
(34) Dyachenko14 -4(3H)-thiones (35). (2003) has synthesized 1,2-dihydro-5,6-
tri(tetra)methylenespiro(cyclopentane(cyclohexane))-2-thieno-[2,3-d]pyrimidin
20
NH NH S 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 10M.
R1 S N N [CH2 ]n-R2
N X
(36) Adams and coworkers16 (2003) have synthesized thienopyrimidines (37) as TIE-2 and/or VEGFR-2 kinase inhibitor useful against hyperproliferative diseases.
R1 N R2 N X A D
(37)
Tumkevicius and coworkers17 thieno[2,3-d]pyrimidines carbaldehyde. (38) from
(2003) have synthesized 4,6-disubstituted 4,6-dichloro-2-methylthiopyrimidine-5-
21
NR2 N MeS N S
R1
(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.
R1 S R3
R2
R1
R2
N N
R3 S N
(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.
R4 S R2 N R1 N A R1 N R2 R3 S N R4 N A
N R3
(41)
(42) 22
THIENOPYRIMIDINE DERRIVATIVES 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 S HN S NH N
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.
R1 R4 R5 S N HN N R3 R2
(44)
Pamukcu and coworkers22 (2000) have synthesized some thienopyrimidine derivatives (45) for inhibiting neoplastic cell growth.
23
NHR N R3 N S 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.
O N S N Pr-n
Cl
Bu
(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.
24
O NH S N R
O N S N N CHOEt
NHR'
(47)
(48)
NHR2 N S N Me
NR2 N S N Me
Me
(49)
(50)
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.
Cl
HN N S N
(51) Maria and coworkers26 (1998) have synthesized 3-benzyl-2-butylthieno[3,2d]pyrimidin-4(3H)-one (52) N-substituted-2-butylthieno[3,2-d] pyrimidin-4-amine DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 25
THIENOPYRIMIDINE DERRIVATIVES (53) as selective type 4 phosphodiesterase inhibitors. Of these 2-butyl-4cyclohexylaminothieno [3,2-d]pyrimidine has an interesting profile and good activity in cAMP potentiation.
N S O N N CH3 S N NHR CH3
(52)
(53)
Jonas and coworkers27 (1998) have synthesized thienopyrimidines (51) as phosphodiesterase V inhibitors.
R3
R4 HN R2 (CH2 )n
N S N X
R1
(54) Matthias Rehwald and Karl Gewald28 (1998) have synthesized thieno[2,3-d] pyrimidines (55) from 2-alkoxy-5-cyano-4-thioxopyrimidine intermediates.
Ph HN O N
NH2 COPh S
26
THIENOPYRIMIDINE DERRIVATIVES (55)
Chen and coworkers29 (1997) have synthesized thienopyrimidines (56) as corticotrophin-releasing factor antagonists.
R1 N R2 N R S R3
(56)
Desai and coworkers30 (1997) have synthesized 3-N-substituted thioureido-2methyl-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 Ph S O N CH3
NH NHR
(57)
Minsheng Zhang and Richard31 (1997) have synthesized 2-aminothieno [2,3d]pyrimidine derivatives (58) via a Gewald precursor.
27
OBn R N H2 N N S
OBn
(58)
Maria
Modica
and
coworkers32
(1997)
have
synthesized
[[arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives (59) as highaffinity, selective 5-HT1A receptor ligands.
R1 R2 S
O N N R3
(CH2 )n N
X R4
(59) Kadthala Shekar Manjunath and coworkers33 (1997) have synthesized 2chloromethyl3-N-substituted-arylthieno[2,3-d]pyrimidin-4-ones (60) and evaluated for CNS depressant activity. Some compounds have shown marked sedative action.
28
R2 O R1 R3
N S N N
(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.
R3 R4 S N R1 (CH2 )r O N R2
(61) Andanappa and coworkers35 (1996) have synthesized 2-aminomethyl-3-aryl5,6,7,8-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).
R R2 R1 S N O N CH2 X
(62)
29
THIENOPYRIMIDINE DERRIVATIVES Edward and coworkers36 (1996) have synthesized several thieno[2,3d]pyrimidine analogues (63) and (64) of the potent antitumor agent N-{4-[2-(2-amino4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5yl)ethyl]-benzoyl}L-glutamic 231514).
R1 N R2 N S O COOH NH
acid
(LY
COOH
(63)
R5 N R4 N S
COOMe
(64)
Christine Fossey and coworkers37 (1995) have synthesized 5-Halo-23-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.
O HN R O N S
HO
OH
(65)
30
THIENOPYRIMIDINE DERRIVATIVES 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 Ph S O N CH3
NHSO 2 R
(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.
R2 R1 S N R3 R4 R3 R4 R2 R1
N S N
(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.
31
O HN O O N R S
(69)
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).
Ph N Ph S O NH CH2 CO 2 C2 H5 S O N NH R
(70)
(71)
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.
NH2 N H2 N N S Me or (CH2 )n-1 Ar (CH2 )n Ar or H
(72) Shirish and coworkers43 (1993) have synthesized some new thieno[3,4-d] pyrimidines and C-nucleosides (73). Preliminary biological studies indicate that DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 32
THIENOPYRIMIDINE DERRIVATIVES adenosine analogue is a potent growth inhibitor of several mammalian tumor cell lines.
R1 N N
R2
S O
HO
OH
(73) Shishoo activities.

R1 R2 S N NH2 N NR3R4
and
Jain44
(1993)
have
synthesized
4-amino-2-substituted-
aminothieno[2,3-d]pyrimidines (74) and evaluated for their antifolate and antimalarial
(74)
Ogawva and coworkers45 (1993) have synthesized substituted 2,4 dioxothienopyrimidin-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.
O R1 Y R2 Z N COOH X N O
R3
(75)
33
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.
O N S N N R N
R1 R2
(76) Ronald and coworkers47 (1992) have synthesized N-substituted thieno[3,4-d] pyrimidine-2,4-diones (77).
O NH N O
CH 2 CH 2 R
(77)
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.
O N S N NR3R4
R1 R2
34
THIENOPYRIMIDINE DERRIVATIVES (78)
Grant
Buchanan
and
coworkers49
(1991)
have
synthesized
some
hydroxyalkylated pyrrolo- and thieno[3,2-d]pyrimidines (79) and evaluated for their antiviral activity.
NH2 S N R N
(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.
O H3C Thi N R1 N R
(80)
35
-H2 C O N F F
R=ket=
R=rit=
-H2 C
Kosaku Hirota and coworkers51 (1990) have synthesized 6-substituted thieno[2,3-d]pyrimidin-2,4(1H,3H)-diones (81).
O H3C N N CH3 S
(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.
H3C H3C S N O NH CH2 X
(82)
36
THIENOPYRIMIDINE DERRIVATIVES Shishoo and coworkers53 (1989) have synthesized some 2-substituted quinazolin-4-ones and thienopyrimidines (83) and (84) of biological interest.
R R1 R2 S N O NH R S O R1 N NH
(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.
O S S N NH O N O NH O S N O NH O
(85)
(86)
(87)
Mitsuo Sugiyama and coworkers55 (1989) have synthesized 2,3-dihydro-5Hoxazolo[3,2-a]thieno[3,2-d],[3,4-d] and [2,3-d]pyrimidine derivatives (88) and were evaluated for gastric antisecretory activity.
T N
N O
(88)
37
THIENOPYRIMIDINE DERRIVATIVES 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 todays 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. receptor For example thienopyrimidines gastric displayed anticancer4,5,15,18,19,,22,25,36,43, CNS depressant33,48, antimalarial44, antiviral37,40,49, antimicrobial2,6,20,30,38,42, antihyperlipaemic35,52, 5-HT1A,5-HT2,5-HT3 antagonist8,9,32,50, antisecretory39,54,55, molluscidal24, phosphodiesterase inhibitor21,26,27, antifungal23,
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; DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 38
COOEt
Abs alcohol Morpholine Reflux 7 hReflux 7 h S (III)
CH2 CN
COOEt
NH2
HCONH2 1 60- 1 80 C 60- 1 80 C 1 Reflux 6 hReflux 6 h
Cl N S (V) N POCl3
O NH
Triethylamine S N Reflux 90 min 140 c Reflux 90 min 140 c (IV) R1 R2 R1
Butanol NH2 NH2
R3 R2 HN N R
HN
NH2
OHC R Ethanol R3
N S (VI) N
N S N
(VII a-b)
3. EXPERIMENTAL DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 39
THIENOPYRIMIDINE DERRIVATIVES 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 DPX400MHz spectrometer using TMS as internal standard.
3.1
SYNTHESIS
40
THIENOPYRIMIDINE DERRIVATIVES 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)
41
THIENOPYRIMIDINE DERRIVATIVES 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 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 42
THIENOPYRIMIDINE DERRIVATIVES 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
43
THIENOPYRIMIDINE DERRIVATIVES 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 Casein hydrolysate Starch Agar Distilled water pH 300ml 16g 1.5g 15g 1000ml 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 121C (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 1000 g/ml in DMSO. The solutions of standard drugs cefixime and ketoconazole were prepared at the concentration of 1000 g/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 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 44
THIENOPYRIMIDINE DERRIVATIVES 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
45
THIENOPYRIMIDINE DERRIVATIVES Table 1 Physical data of substituted benzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3d]pyrimidin-4-hydrazone (VIIa-b)
R1 R2
R3 HN N R
N S N
Compound
R1
R2
R3
Recrystaliza tion solvent
%yiel d
M.P (0C)
Molecular Formula
Molecular weight
Rf value
VIIa VIIb
OCH3
OCH3 -
OCH3 -
CHCL3 GAA
78 78
200-202 245-247
C20H22O3N4S C17H16ON4S
398.47 324.90
0.4 0.6
OH
Table 2 Spectral data of substituted benzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3d]pyrimidin-4-hydrazone (VIIa-b)
46
R1 R2
R3 HN N R
N S N
Com poun d
R1
R2
R3
IR (KBr)
H NMR (400MHz, CDCl3, )
N-H str
O-H str C-H alip hati c
C= N str
C-N str
2pyri mid inyl -H
ArH
N-H
(CH 2)2-
(CH 2)2-
N = C H
O C H3
N( C H3 )2
O H
VIIa
OCH3
OCH3
OCH3 336 7 cm-1 293 5 cm-1 162 2 cm-1 133 8 cm-1 8.3 7.40 10.4 2.87 1.94 7. 6 3. 9 -
VIIb
O H
352 6 cm-1 293 3 cm-1 162 6 cm-1 122 7 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)
47
THIENOPYRIMIDINE DERRIVATIVES The Synthesis of 4-hydrazino-5,6,7,8-tetrahydro[1]benzothieno[2,3d]pyrimidine (VI) can be given by the following scheme;
Cl Butanol N S N Hydrazine hydrate S (VI) (V)
HN
NH2
N N
The compound (VI) with melting point of 160-1620C 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.
48
FIGURE: 1 IR spectrum of 4-hydrazino-5,6,7,8-tetrahydro[1]benzothieno[2,3-d] pyrimidine(VI)
49
THIENOPYRIMIDINE DERRIVATIVES Synthesis of 3,4,5-trimethoxybenzaldehyde5,6,7,8-tetrahydro[1]benzothieno[2,3d]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;

OCH3 CHO OCH3
OCH3 HN NH2 H3CO N S (VI) N OCH3 Ethanol S N (VIIc) OCH3 HN N
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.
50
Figure 2 IR Spectrum of 3,4,5-trimethoxybenzaldehyde tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-hydrazone (VII) 5,6,7,8-
51
Figure:3
1
H NMR spectrum 3,4,5-trimethoxybenzaldehyde 5,6,7,8-
tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-hydrazone(VIIa)
52
THIENOPYRIMIDINE DERRIVATIVES Synthesis of 2-hydroxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno [2,3d]pyrimidin-4-hydrazone (VIIb) The scheme;

HO CHO HN NH2 OH HN N S (VI) N Ethanol S N (VIId) N
synthesis
of
2-hydroxybenzaldehyde
5,6,7,8-tetrahydro[1]
benzothieno[2,3-d]pyrimidin-4-hydrazone( VIIb)
can be given by the following
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.
53
Figure 4 IR spectrum of 2-hydroxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno [2,3-d] pyrimidin-4-hydrazone (VIIb)
54
Figure : 5
1
H NMR spectrum of 2-hydroxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno [2,3-d]pyrimidin-4-hydrazone(VIIb)
4.2 Antimicrobial activity

THIENOPYRIMIDINE DERRIVATIVES 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. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 56
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 5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-ylhydrazone (VIIa-e)
57
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) MICROORGANISM Compound VIIc (1mg/ml) 36 44 67 Compound VIId (1mg/ml) 36 33 33 Control (1mg/ml) 100* 100* 100**
Staphylococcus aureus Pseudomonas aeruginosa Salmonella typhi
Staphylococcus mutants Candida albicans Rhizopus stolonifer
NA 67 40
30 50 60
100** 100*** 100***
Zone of inhibition of *** Ketoconazole = 12 mm (C. albicans), 10 mm (R. stolonifer) (anti fungal)
5. CONCLUSION
THIENOPYRIMIDINE DERRIVATIVES 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
59
THIENOPYRIMIDINE DERRIVATIVES 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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THIENOPYRIMIDINE DERRIVATIVES 28. 29. 30. 31. 32. Matthias, Rehwald; Karl, Gewald, Heterocycles., 48, (1998). Chen, Chen; Webb, Thomas R.; McCarthy, James R.; Moran, Terence J., Patent. Chem. Abstr. 127, 234327 (1997). Desai, J. R.; Parikh, A. R.; Chauhan, N. A., J. Ind. Chem. Soc., 74, 160 (1997). Minsheng, Zhang; Richard, W. Harper, Bioorg. & Med. Chem. Lett. 7, 16291634 (1997). Maria, Modica; Maria, Santagati; Filippo, Russo; Luca, Parotti; Luca, De Gioia; Carlo, Selvaggini; Mario, Salmona; Tiziana, Mennini, J. Med. Chem. 40, 574-585 (1997). 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. Kadthala, S. M.; Shamanna, Mohan; Laxmi V. G. N.; Shishoo, C. J., Arzneim. Forsch., 47, 1005-1008 (1997). Furuya, Shuichi; Choh, Nobuo; Kato, Koichi; Hinuma, Shuji, Patent. Chem. Abstr. 125, 247795 (1996). Andanappa, K. G.; Shivakumar, G. K.; Ramakrishn, I. A.; Shashikant, R. P.; Chanbasappa, S. M.; Shishoo, C. J., Arzneim. Forsch., 46, (1996). Taylor, Edward C.; Patel, Hemantkumar H.; Sabitha, Gowravaram; Chaudhari, Rajendra, Heterocycles, 43(2), 349-65 (1996). Christine, F.; Daniel, Laduree; Max, Robba, J. Heterocyclic Chem., 32, 627 (1995). Desai, J. R.; Parikh, A. R.; Chauhan, N. A., J. Inst. Chem., 67(5), 136-137 (1995). Robert, J. I.; Thomas, H. B.; Peter, B.; David, J. K.; Colin, A. L.; Malcom, L. M.; Michael, E. P.; Colin, J. T., J. Med. Chem., 38, 2763-2773 (1995). Fabrice, J.; Daniel, L.; Max, Robba, J. Heterocyclic Chem., 31, 305 (1994). Shishoo, C. J.; Pathak, U. S.; Jain, K. S.; Devani, I. T.; Chhabria, Ind. J. Chem., 33B, 436-440 (1994). Andre, R.; Clara, E. M.; Joel, E. W.; James, H. F.; James, J. H.; John, J. Mc.; Sherry, F. Q., J. Med. Chem., 36, 3103-3112 (1993). Shirish, A. P.; Brian, A. O.; Robert, S. K., J. Heterocyclic Chem., 30, 509 (1993). Shishoo, C. J.; Jain, K. S., J. Heterocyclic Chem., 30, 435-440 (1993). Ogawva, K.; Yamawaki, I.; Matsusita, Y. I.; Nomura, N.; Kador, P.F.; Kinoshita, J. H., Eur. J. Med. Chem., 28, 769-781 (1993).
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THIENOPYRIMIDINE DERRIVATIVES 46. 47. 48. 49. 50. Pathak, U. S.; Gandhi, N. V.; Singh, S.; Warde, R. P.; Jain, K. S., Ind. J. Chem., 31B, 223-229 (1992). Ronald, K. R.; Caroline, E. N.; Rihard, A. R.; Dieter, H. K., Synth. Commu., 22(22), 3221-3227 (1992). Pathak, U. S.; Singh, S.; Padh, I. Ind. J. Chem., 30B, 618-619 (1991). Buchanan, J. G.; David, A. C.; Richard, H. W.; Michael, R. H., J. Chem. Soc. Perkin Trans. 1 (1991). Press, J. B.; Russell, R. K.; McNally, J. J.; Rampulla, R. A.; Falotico, R.; Scott, C.; Moore, J. B.; Offord, S. J.; Tobia, J., Eur. J. Med. Chem., 26, 807813 (1991). 51. 52. 53. 54. 55. 56. Kosaku, H.; Mitsuomi, S.; Shigeo, S., J. Heterocyclic Chem., 27, 717 (1990). Shishoo, C. J.; Devani, M. B.; Bhadti, V. S.; Rathod, I. S.; Goyal, R. K.; Gandhi, T. P.; Patel, R. B.; Naik, S. R., Arzneim. Forsch., 40, (1990). Shishoo, C. J.; Devani, M. B.; Ananthan, S.; Jain, K. S.; Bhadthi, V. S.; Mohan, S.; Patel, L.J., Ind. J. Chem., 28B, 1039-1047 (1989). Mitsuo, S.; Toshiaki, S.; Hiroshi, F., Heterocycles, 29, 985 (1989). Mitsuo, S.; Toshiaki, S.; Keiichi, T.; Hiroshi, F., Chem. Pharm. Bull. 37, 2717-2722 (1989). A.L.Barry, The Antimicrobial Suceptibility Test: Principal and Practice Lea & febiger, Philadelphia,180(1976)
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THIENOPYRIMIDINE DERRIVATIVES

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

THIENOPYRIMIDINE DERRIVATIVES ABBREVIATIONS

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

THIENOPYRIMIDINE DERRIVATIVES SEM Thi TLC TMS VEGFR Vs g M

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

THIENOPYRIMIDINE DERRIVATIVES Figure no 1 Name of figure IR spectrum of 4-hydrazino-5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidine (VI) 46 Page no

2 IR Spectrum of 3,4,5-trimethoxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4hydrazone (VIIa) 48

H NMR spectrum 3,4,5-trimethoxybenzaldehyde ylhydrazone(VIIa)

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

H NMR spectrum of 2-hydroxybenzaldehyde 5,6,7,8-tetrahydro[1]benzothieno [2,3-d]pyrimidin4-ylhydrazone(VIIb)

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Name of table Physical data of substituted benzaldehyde 5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-

Spectral data of substituted benzaldehyde 5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidin-42 hydrazone (VIIa-b) 44

Antimicrobial activity of substituted benzaldehyde 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin4-ylhydrazone (VIIa-e)

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

= COPh, COOEt, CONH 2 , CN; Z= Ph, OH, NH2 Y

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

NH2 i S COOMe 80% S

CHO ii N HN O iii 65% S

i, formic acid, sodiumacetate, 95%, 1h; ii, ammonium formate, formamide,

C, 7h; iii, POCl3 ; iv, Pd/C, MgO, H2.

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

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

one of A1 and A2 is S and the other is CH

(25) DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC 16

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

O N S Br N O N O N CH3 CH3 NH2

(28) Dhanoa and coworkers8 (2004) synthesized piperidinyl

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

(34) Dyachenko14 -4(3H)-thiones (35). (2003) has synthesized 1,2-dihydro-5,6-

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

Tumkevicius and coworkers17 thieno[2,3-d]pyrimidines carbaldehyde. (38) from

(2003) have synthesized 4,6-disubstituted 4,6-dichloro-2-methylthiopyrimidine-5-

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

THIENOPYRIMIDINE DERRIVATIVES (55)

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

[[arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives (59) as highaffinity, selective 5-HT1A receptor ligands.

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

THIENOPYRIMIDINE DERRIVATIVES 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.

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(73) Shishoo activities.

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

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

THIENOPYRIMIDINE DERRIVATIVES (78)

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

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY , NPC

Abs alcohol Morpholine Reflux 7 hReflux 7 h S (III)

HCONH2 1 60- 1 80 C 60- 1 80 C 1 Reflux 6 hReflux 6 h

100 100* 100***