Synthesis and Biological Activity of Substituted-4,5,6,7

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Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines: A Review Jaiprakash N. Sangshetti1*, Abhay S. Zambare2, Firoz A. Kalam Khan1, Indrajeet Gonjari3 and Zahid Zaheer1 1

Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Rauza Baugh, Aurangabad-431001 (MS) India; MGM’s Jawaharlal Nehru Engineering College, Aurangabad-431002 (MS) India; 3Government College of Pharmacy, Vidyanagar, Karad-415 124 (MS) India 2

Abstract: 4,5,6,7-Tetrahydrothieno pyridine is an important class of heterocyclic nucleus. Various 4,5,6,7-tetrahydrothieno pyridine derivatives have been synthesized and evaluated for various biological activities in different models with desired findings. Some analogs have shown potent biological activities and may be considered as lead molecule for the development of future drugs. Number of drug molecules are available in the market and many molecules are in clinical development containing 4,5,6,7-tetrahydrothieno pyridine nucleus as an important core. This review is an attempt to organize the chemical and biological aspects of 4,5,6,7-tetrahydrothieno pyridine analogs reported in last 20 year to till date. Review mainly focuses on the important role of the core in synthesis of drug or drug intermediates giving emphasis on synthetic schemes and biological activities of the different 4,5,6,7-tetrahydrothieno pyridine analogs.

Keywords: 4,5,6,7-Tetrahydrothieno pyridine, biological activities, lead molecules, clinical development. INTRODUCTION

S

4,5,6,7-Tetrahydrothieno pyridine (THTP) and their derivatives are an important heterocyclic compounds that are widely distributed in nature. The sulfur and nitrogen containing heterocycles have emerged as an important class of molecules in past decade due to their biodiversities from the industrial perspective and thus rise is seen in development of sulfur and nitrogen containing heterocycles. THTP is one such sulfur and nitrogen containing heterocycle having varied biological activities like anti-inflammatory, vasodilator and blood platelet aggregation inhibitory action. Depending on the position of the nitrogen atom, four different THTP systems namely, 4,5,6,7-tetrahydrothieno[2,3-d]pyridine or 4,5,6,7tetrahydro-thieno[3,2-c]pyridine (1), 4,5,6,7-tetrahydrothieno [2,3-c]pyridine (2), 4,5,6,7-tetrahydrothieno[3,2-b]pyridine (3), and 4,5,6,7-tetrahydrothieno[2,3-b]pyridine (4) are possible. The structure of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1) consists of piperidine (also called tetrahydropyridine) which is an amine heterocycle consists of a six-membered ring with five methylene bridges (-CH2-) and one amine bridge (-NH-) fused to a five membered heterocyclic ring thiophene (also commonly called thiofuran). Although the THTP (1) is now readily available on a large scale from various commercial sources, it was originally synthesized in a variety of ways. The most straightforward route was from thiophene-2-carbaldehyde (5)

HN

4,5,6,7-tetrahydrothieno[2,3-d]pyridine or 4, 5, 6, 7-tetrahydro-thieno [3, 2-c] pyridine

4,5,6,7-tetrahydrothieno[2,3-c]pyridine 2

1 S

H N

S

N H

4,5,6,7-tetrahydrothieno[3,2-b]pyridine 3

4,5,6,7-tetrahydrothieno[2,3-b]pyridine 4

which was subjected to a Henry reaction with nitro-methane. Reduction of the nitro olefin function to the corresponding alkylamine followed by reaction with formaldehyde gave the corresponding imine (6) [1]. Treatment of the latter with hydrochloric acid initiates a Pictet–Spengler reaction to furnish the desired heterocycle in high overall yield (90 %) (Scheme 1). A potential selective 5-HT reuptake inhibitor, 4-(4bromophenyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (10) has been synthesized by reacting oxazolidine (7) and thiophen-2-ylmagnesium bromide (8) to form 2-(benzylmethylamino)-1-aryl ethanols (9) which then treated with polyphosphoric acid yields 4-aryltetrahydroisoquinoline (Scheme 2) [2].

*Address correspondence to this author at the Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Rauza Baugh, Aurangabad-431001 (MS) India; Tel: +91 240 2381129; E-mail: [email protected]

1389-5575/14 $58.00+.00

S

HN

© 2014 Bentham Science Publishers

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Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12 O

S

Sangshetti et al. S

MeNO 2 NaBH 4 HCHO

S

aq. HCl NH

H

N

6

5

1

Scheme (1). Pictet-Spengler reaction for preparation of THTP 1. Ar

Ar

N OH

O

7 S

Toluene Conc. HCl

PPA N S

Ar

N S

9

10

Br Mg

8

Scheme (2). O

O

O SH

OH C N

O Et

N

POCl 3

OE t

13

OEt

KOH HBr

H2O

N H.H Br

S

Cl

O

11

12

14

Scheme (3).

The THTP (1) can also be accessed by assembling the thiophene ring (Scheme 3). In this scenario N-protected 4-piperidone (11) is subjected to Vilsmeier reaction conditions to produce the reactive chloroaldehyde species (12) which, upon treatment with ethyl mercaptoacetate (13), cyclizes to the heterocyclic structure although in only low isolated yield. Simple base hydrolysis of the ester followed by decarboxylation generates the desired product (14) [3]. BIOLOGICAL ACTIVITY Clinically, THTP (1-4) derivatives have shown potent biological efficacy with minimal side effects. So by considering its clinical output and safety margin, the THTP nucleus has become the prime choice of the researchers for future study. Currently, THTP represents a widely used lead structure with multitude of interesting applications in the numerous pharmacological fields. Thus, various biological activities (Fig. 1) have been reported and explored till date. Fusion of other nuclei like benzene, indole, oxadiazole, triazole rings to the THTP nucleus enhances the pharmacological activities than its parent nucleus. In search of novel therapeutic agents, various versatile moieties were appended in the THTP nucleus via the interaction between functionalized THTP with various nucleophilic and electrophilic reagents. This review is a systematic attempt to compile the chemical and pharmacological aspects of various synthesized THTP analogs along with their reported synthetic route over the last 20 years till date.

Antimicrobial activity We have reported the use of nano (ZnO-TiO2) catalyzed synthesis of new 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine derivatives 16. The derivatives were synthesized by refluxing 2-(6,7dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazide 15 with substituted aldehydes using nano (ZnO-TiO2) as catalyst in ethanol (Scheme 4). Furthermore, the synthesized derivatives have been screened for their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis and antifungal activity against Candida albicans, and Aspergillus niger. Among the synthesized derivatives, 2,6-dichlorophenyl and 4-fluorophenyl analogs showed promising antibacterial (MIC range= 25-100 µg/mL) as well as antifungal (MIC range= 20-120 µg/mL) activities when compared with standards ampicillin (MIC range= 100-250 µg/mL) and miconazole (MIC range= 12.5-25 µg/mL), respectively [4]. Kalaria et al. [5] have described the synthesis of several tetrahydrothieno [2,3-c]pyridin-2-yl) urea derivatives (23). The reaction was performed by reacting one active methylene containing moiety (17) with a sulfonyl function (18) to afford the sulfonyl compound (19) which on treatment with sulfur powder gave 2-aminothiophene ring (20) system and followed by derivatization of amino into urea by mixed anhydride method (Scheme 5). Most of the synthesized tetrahydrothieno [2,3-c]pyridin-2-yl)urea derivatives at 500µg/ml concentration have shown significant antibacterial activity against Bacillus substilis,

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

3

al

Antituberculosis

4,5,6,7-Tetrahydrothienopyridine

ele

t An

t

t

idem ic

lat

an e ss r p id e

n tih yper lip

tic a be tidi An

An t ip

A

Antiinf lam matory

re

leis hm an i

ic hm ryt ar

M

An ti

s eou lan l e isc

ti An

A 1ce ade pt no or s ag ine on ist

Antimicrobial

Anticancer

Fig. (1). Various biological activities reported for 4,5,6,7-tetrahydrothieno Pyridines. R

Ethylboromo acetate NH

S

2

NH2NH2.H2O S

O

O

RCHO N

Nano(ZnO-TiO2)

NHNH2 EtOH, reflux

15

N S

N N

16

Scheme (4).

Escherichia coli, Klebsiella pneumonia, and Streptococcus aureus and antifungal activity against Aspergillus niger, and Candida albicans. Several new substituted tetrahydrothieno [2,3-c]pyridin2-yl) Schiff’s base derivatives (27) have been synthesized and evaluated for antimicrobial activity. The reaction of sulfonyl compound (24), and 2-cyanoacetamide (25) in presence of morpholine and sulphur powder afforded 2amino thiophene ring (26) system and followed by derivatization into Schiff’s base using different aromatic aldehydes (Scheme 6). The compound with R= 2-methoxy5-methylphenol showed potent antimicrobial activity against Gram positive bacteria (Staphylococcus aureus, and Bacillus subtilis), Gram negative bacteria (Escherichia coli, and Salmonella peratyphi B) and fungi strains (Candida albicans and Aspergillus niger) at concentration of 250 µg/mL [6]. A facile condensation of 1-(4-aminophenyl)-2-(6,7dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethanone (28) with aromatic aldehydes to afford the corresponding 1-(4-(substituted arylidene amino) phenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin5(4H)-yl)ethanone (29) in good yields have been reported

[7]. Cyclocondensation of compound (29) with thioglycolic acid yielded 3-(4-(2-(6,7-dihydrothieno [3,2-c] pyridin5(4H)-yl) acetyl) phenyl)-2-substituted aryl thiazolidin-4-one (30) (Scheme 7). All the synthesized derivatives have been evaluated for their antifungal and antibacterial activities on various strains of fungi and bacteria. Compound with 4-CH3 phenyl (Zone of inhibition: 64-77 mm) against fungi and compound with 4-OCH3-phenyl (Zone of inhibition: 49-76 mm) against bacteria have shown good inhibitory activity. Patel et al. have described the synthesis of biologically active asymmetrical 3,5-disubstituted-1,2,4-oxadiazoles (35) (Scheme 8) and evaluated for antimicrobial activity. The thienopyridine hydrochloride (31) reacted with cyano acetylchloride compound (32) to get adduct (33). The adduct (33) was reacted with hydroxylamine to get hydroxamic acid derivative (34) followed by derivatization to obtain 1,2,4oxadiazole derivatives (35). With regards to the structureactivity relationship of the oxadiazoles derivatives, the compound with 4-nitrophenyl (-Ar) group exhibited enhanced antibacterial (MIC range= 2-8 µg/mL) and antifungal (MIC range= 2-8 µg/mL) activities [8].

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Sangshetti et al.

Cl O

S

O

O O

TFA, TEA

+

S

N H

N

O

O

19 17

18

Ethyl 2-isocyano S8 acetate O

O

O

H2N

NH O

Cl

O

O

O S O

S

21

N N O O

S

S

O

O

H2 A R-N , TE SO DM

22

20 O O

NH

O N

S

S

NH O

O

R

23

Scheme (5). O O O S

N

O + NC

Morpholine, Sulphur NH2 EtOH, 70-80

O

24

O

3-4 h

S

NH2

N

0C

O S

25

NH2

26

Reflux and R-CHO AcOH Stirring 1h O O S

NH2

N

O S

N

27 R

Scheme (6).

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

NH2

N

N

Ar

N

Ar-CHO

Ar

O S

O

SHCH2COOH

29

Anh. ZnCl2/DMF

S

28

S N

O N O S

30

Scheme (7). O

NH.HCl

O

Cl

+ S

N

MeCN, TEA

NC

CN NH

HN S

H

31

H

32

33 CHCl3 NH2OH. HCl

Reflux TEA O H O

NH

H

N NH N

Ar-CHO S

N

N

Toluene

C

HO

S

NH2

N

O

34

35

Ar

Scheme (7). H N NH.HCl

Eythylbromoacetate

N

N

NH2NH2.H2O O

S

S

R

36 CHO

31

R

R

ZnCl2 DMF

SHCH2COOH

R H N

4-Chlorobenzaldehyde NaOAc

H N N

N S

Phenylhydrazine Glacial AcOH NaOAc

O S N N

Cl

38

Scheme (9).

N

N S O

S O

37

5

6

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Sangshetti et al.

A series of novel compounds, N-(3-(4-chloro phenyl)2,5-diphenyl-3,3a-dihydro-2H-pyrazolo[3,4-d]thiazol-6(5H)yl)-2-(6,7-dihydrothieno-[3,2-]pyridine-5(4H)-yl)acetamide (38) (Scheme 9) was synthesized and evaluated for antimicrobial activity. The N-(5-(4-chlorobenzylidene)-4oxo-2-phenylthiazolidin-3-yl)-2-(6,7-dihydrothieno[3,2-c] pyridine-5(4H)-yl)acetamide (36) was cyclized by cyclocondensation reaction using thioglycolic acid. The thiazolidinone derivatives (37) were reacted with 4chlorobenzaldehyde followed by phenylhydrazine to afford target compounds (38) [9]. In the synthesis of this novel series, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (31) has been used as a starting material. Among the synthesized derivatives, the compound with 4-hyroxy-3methoxyphenyl (-Ar) group (MIC= 0.85 µg/mL) showed the most potent antibacterial activity against B. subtilis when

compared with standard tetracycline (MIC= 23.50 µg/mL). The compound with 3,4-diethoxyphenyl (-Ar) group (Zone of inhibition= 92 % at concentration of 1000 ppm) was found to possess good antifungal activity against C. glabrata than reference standard miconazole (Zone of inhibition= 90 % at concentration of 1000 ppm). Salahuddin et al. [10] demonstrated the cyclization and chlorination of 2-amino-5-benzyl-4, 5, 6, 7-tetrahydrothieno [3,2-c] pyridine-3-carboxamide (39) to yield compounds (40) which on reaction with different amines yielded final compounds (41-46) (Scheme 10). All synthesized derivatives were evaluated for antibacterial activity and all compounds showed good to moderate activity (Zone of inhibition: 6-30 mm) at concentration of 100 µg against two Gram-positive bacteria (B. subtilis and B. pumilis) and two Gram-negative Cl

F3COC F3COC

HN R

N H2N

Cl N N S

41 H2N NH2 HN

H2N

CONH2

R

N N

N

N

NH2 S

S

42

39

N HN

CHO

N N

H N

H2N

POCl3

HN

HN

R

R

N

N N

N N S

Cl

43

R

N

Pyridine N N

NH

N H N

S

40

HN N

NH2

Where R= H, 4-Cl

N

R

N N S

44 N NH2 HN N

N

R

N N S

45

HO

OH H2N

HN N N N S

46

Scheme (10).

R

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

7

O Cl

R1

O

R1

S

O

Triethyamine

+

S

N

O

Tetrahyhydrofuran O

N H.HCl

O

47

49

48

S8 Ethylcyanoacetate

O R1

O

O R1 NH

N

S

O

DMF S

Formamidine acetate

O N

S

51

O

N

O S

50

NH2 R2

POCl3 Triethylamine

Cl R1

O HN R1

N

N

S

2-Methoxyethanol O

O S

N

N

Triethylamine S

N

52

O S

N

53

Scheme (11).

bacteria (S. aureus and E. coli) when compared with standard ampicillin (Zone of inhibition: 20-30 mm). Mittal et al. [11] reported several new substituted tricyclic compounds i.e. 7-(phenylsulfonyl)-N-(phenyl)5,6,7,8-tetrahydropyrido[4’,3’:4,5]-thieno[2,3-d]pyrimidin4-amine (53) from 7-(phenylsulfonyl)-4-(chloro)-5,6,7,8tetrahydropyrido[4’,3’:4,5]-thieno[2,3-d] pyrimidine (52) using piperidin-4-one hydrochloride (48) and benzenesulfonyl chloride (47) as the starting material (Scheme 11). All the synthesized compounds are evaluated for their antibacterial activity against Bacillus substilis, Escherichia coli, Klebsiella pneumoniae, and Streptococcus aureus and antifungal activity against Aspergillus niger, Aspergillus flavus, Fusarium oxisporium, and Trichoderma viride, respectively. Most of the synthesized compounds exhibited mild to moderate anti-microbial activity against the tested microorganisms when compared with standard drugs (ciprofloxacin and fluconazole for anti-bacterial and antifungal, respectively). The compound with 4-Br at phenyl ring has shown significant antibacterial activity. A novel series of 3-amino-7-(phenylmethyl)-2phenylamino-5,6,7,8-tetrahydropyrido [4',3':4,5] thieno[2,3 d]pyrimidine (56) (Scheme 12) was synthesized and tested for their in vitro antibacterial and antifungal activity against variety of microorganisms [12]. Among the synthesized derivatives, the compounds like, 3-amino-7-benzyl-4-(2chloro-4-nitrophenyl)-5,6,7,8-tetrahydropyrido [4',3':4,5] thieno [2,3-d ] pyrimidine (Zone of inhibition: 20-23 mm) and 3-amino-7-benzyl-4-(2-bromo-4-nitrophenyl)-5,6,7,8tetrahydropyrido [4',3':4,5] thieno [2,3-d] pyrimidine (Zone of inhibition: with electron withdrawing group i.e. NO 2 group attached to a phenyl ring at ortho and para positions have shown good activity against all tested bacteria (Staphylococcus aureus, Bacillus subtillis, Escherichia coli, and Pseudomonas aeruginosa) and fungi (Candida albicans, and Aspergillus niger) at concentration of 10 µg/disc when

compared with standards ciprofloxacin (Zone of inhibition: 25-28 mm) and pyrimithanil (Zone of inhibition: 25-26 mm), respectively. Patel et al. synthesized a series of novel metal-based bactericidal complexes of the type Cu(II)(Ln)2(H2O)2]•xH2O (61). Metal complexes (61) were screened for in vitro antibacterial activity against Bacillus subtillis, Pseudomonas aeruginosa, Escherichia coli and Serratia marcescens bacterial strains and compared against standard ciprofloxacin. The compound with R= 5-OCH3 showed good antibacterial activity (Zone of inhibition: 29-34 mm) at concentration of 10 mg/mL when compared with standard ciprofloxacin (Zone of inhibition: 35-52 mm). The enhanced antimicrobial activity was explained by overtone’s concept and Tweedy’s chelation theory. According to Overtone’s concept of cell permeability, the lipid membrane that surrounds the cell favors the passage of only lipid-soluble materials, which indicates that liposolubility is an important factor controlling the antimicrobial activity. On chelation, the polarity of the metal ion will be reduced to a greater extent owing to the overlap of the ligand orbital and partial sharing of the positive charge of the metal ion with donor groups. Further, it increases the delocalization of π-electrons over the whole chelate ring and enhances the lipophilicity of the complexes. This increased lipophilicity enhances the penetration of the metal chelate into lipid membranes and blocks the metal binding sites in the enzymes of microorganisms. These metal chelates also disturb the respiration process of the cell and thus block the synthesis of proteins, which restricts further growth of the organisms. Furthermore, the mode of action of the compounds may involve the formation of a hydrogen bond through the azomethine/carbonyl/amine group with the active center of cell constituents resulting in interference with the normal cell process [13].

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Sangshetti et al. NH2

O COOEt N

NHPh

PhNCS, EtOH NH2 N

N

NH2NH2.H2O

S

C6H5H2C

N

54

S

C 6H 5H 2C

R

55 POCl3

NH2

NH

Cl NH2

N N

NHPh

Dry pyridine N

N

C6H5H2C

R-NH2

NHPh N

N C6H5H2C

S

S

57

56

Scheme (12). H N O Cl

O O

S NH.HCl

S

O O

N

+

MeCN

S

N H

31

O

TEA

59

S

58

OH

H+/ H2O R N O

S N

CHO

R Cu S

H2O O O

O

O

S

N

EtOH

S

O R

HO

Cu(NO3)2.3H2O

H2O

N

N

O

S

60

N

S

R

O

61

Scheme (13). NO2

F NH .HCl

S

N

MeCN +

Reflux

F

31

62 F

63

F

S

NO2

Raney-Ni, NH2NH2.H2O

Benzyl chloroformate

O

O

n-BuLi S

O N

N

(R)-glycidyl butyrate

S

O N

N

NHR'

65

R F

64

Scheme (14).

A number of THTP substituted oxazolidinones were synthesized (Scheme 14) and further screened against a panel of Gram-positive pathogens including methicillinresistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis [14]. The highest activity was observed when thiourea was used in side chain. Among the

synthesized compounds (65), N-{3-[4-(6,7-Dihydro-4H-thieno [3,2-c]pyridin-5-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylethyl}thiourea (MIC range= 0.5-4 µg/L) showed equally potent antibacterial activity comparableto linezolid (MIC range= 0.25 -4 0.5-4 µg/L) and eperezolid (MIC range= 0.54 µg/L).

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines

Our group [15] has reported the first novel amalgamation of 1,2,3-triazoles, piperidines, and thieno pyridine rings (Scheme 15) and evaluated antifungal activity of all the synthesized derivatives (69). All the synthesized derivatives showed moderate to good antifungal activity against all the tested fungal strains, except Cryptococcus neoformans. Two compounds with R= methane sulfonyl (MIC range= 25-50 µg/mL) and R= p-chlorobenzoyl (MIC range= 40-45 µg/mL) showed significant antifungal activities when compared with standard miconazole (MIC range= 12.5-25 µg/mL).

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

demethylase. ADMET properties of synthesized compounds were also analyzed and showed good drug like properties. Antileishmanial Activity We have reported a series of N’-substitutedbenzylidene2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazide derivatives (72) (Scheme 17) and evaluated for antileishmanial activity against Leishmania donovani promastigotes [17]. Two compounds with Ar= 2Chlorophenyl (IC50= 295.80 µM) and Ar= 4-N,NDimethylaminophenyl (IC50= 273.75 µM) showed significant antileishmanial activity when compared with standard sodium stilbogluconate (IC50= 537.92 µM). Antimicrobial study revealed that compound with Ar= 4-Chlorophenyl (MIC range= 25-125 µg/mL), had potent as well as broad spectrum antibacterial activity when compared with ampicillin (MIC range= 100-250 µg/mL) and compound with Ar= 2,4-Dimethoxyphenyl (MIC range= 25-50 µg/mL), showed promising antifungal activity when compared with miconazole (MIC range= 12.5-25 µg/mL). Also, none of the synthesized compounds showed cytotoxicity up to tested

Recently, we have reported a novel series 5-((5substituted-1-H-1, 2, 4-triazol-3-yl) methyl)-4, 5, 6, 7tetrahydrothieno [3, 2-c] pyridine (71) as antifungal agents [16]. The target compounds were synthesized from thienopyridine hydrazide (70), substituted aromatic nitriles using 4-dimethylaminopyridine (DMAP) as a catalyst under microwave irradiation (Scheme 16). Compound (Ar= 4-Fbenzyl) (MIC= 15 µg/mL) was more potent against Candida albicans when compared with miconazole (MIC= 25 µg/mL. Docking study showed good binding mode in the active site of fungal enzyme P450 cytochrome lanosterol 14αOSO2CH3 N

N

S

N

N N

N N HN

MeCN

+ S

N

TEA

1

N

Boc

66 Boc

67

DCM TEA N

S

N

N

S

N

N N

N

RX, DCM

N

TEA, CuI

N N H

R

69

68

Scheme (15). H N N O

S

70

Scheme (16).

NH2

9

N

Ar- CN, EtOH DMAP, MW (700 W)

N

Ar N

S

71

NH

10 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

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Anti-inflammatory Activity

concentration (300 µg/mL). Further, docking study against pteridine reductase 1 enzyme of Leishmania donovani showed good binding interactions. ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.

Maffrand et al. [19] disclosed the process for the preparation of thieno [2,3-c]- and [3,2-c]pyridines (89, and 93) as anti-inflammatory agents by reacting corresponding THTPs (86, and 90) with sulfonyl chloride to give corresponding alcohols (87, and 91) and oxidation of these alcohols gave corresponding ketones (88, and 92) which in presence of basic agent yields targeted compounds (89, and 93) (Scheme 19). The anti-inflammatory activity of synthesized compounds was evaluated according to two methods: (i) Method of localized carrageenin-induced edema; and (ii) Method of the ovalbumin-induced systemic edema. The percent anti-inflammatory activity of synthesized compounds were 40-45 % (1 h), 45-49 % (2 h), 48-52 % (3 h), and 49-52 % (4 h) in case of carrageenin-

Antiarrhythmic Activity Various heterocyclic thieno[2,3-c]pyrimidine and thieno [2,3-c]pyridine derivatives fused with thiophene moiety (74, 76, 78, 79, 80, 81, 83, and 85) with antiarrhythmic activities had been reported [18]. The authors claimed that the antiarrhythmic activities of the compounds (% increase in LD100= 66-91 %) were more potent than procaineamide (% increase in LD100= 65 %) and lidocaine (% increase in LD100= 65 %) as positive antiarrhythmic controls.

Ar NH

NH2

NH

N

Ar-CHO, EtOH AcOH, Reflux

O

N

N O

S

S

70

72

Scheme (17). Cl

COOEt O

Cl N N

S

R

NH N

R

Thiurea

NH

Cl

PhNCS

O O

74

COOEt

82

O

Cl

PhNCS

COOEt

S

PPA

N R Where R= Et, n-Pr

S

N O

R

O

N

S

COOEt

N H 76

S

ClCOCH3

84

AcOH

NHCOCH3 S

R

AcOH

73

O

COOEtS

CH2=CHCH2NCS O

81

COOEt O

N H

O

NH2

N H

S

75

R

N 80

NH N

TEA

MeCN

N

S

Cl O

R

S

R

AcOH

79

NH N

Cl

N H

S

O Cl

S

COOHO

Cl 83

O

NH

O

O

TEA

N

77 Dry HCl

S

R

O EtOOC

CH2

NH

O N N R

S

S O

Scheme (18).

R

N

85

O

N N

N R S 78

N

S

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

11

OH

OH

ClSO2R3

R1

R1 N

NH

S

S

SO2R3 R2

R2

86

87 oxidation

OH

O

Metal alkali

R1 N

R1 N

S

S

89

R2

SO2R3 R2

R2

88

R2 SO2R3 NH

ClSO2R3

N

R1

R1 S

S

91

OH

OH

90 oxidation R2

R2 SO2R3 N

Metal alkali

R1 S

N R1 S

OH

93 R1/R2/R3= branched or straight chain aliphatic alkyl radical

O

92

Scheme (19).

induced edema and 44-53 % (2 h), and 50-61 % (3 h) in case of ovalbumin-induced systemic edema. Fujita et al. [20] reported the synthesis of 4,5,6,7tetrahydrothieno[2,3-c]pyridine derivatives (96) (Scheme 20) and evaluated for their ability to inhibit LPS-stimulated production of TNF-α (Tumor Necrosis Factor-α). Among synthesized derivatives, compound with R1= COOEt, R2= Et2N, and R3= H had shown excellent in vitro (IC50= 6.2 µM) and in vivo (% Inhibition at 50 mg/Kg= 92.3 %) activities. Thieno-pyridine derivatives, (98 and 100) with antiinflammatory (in rat) and analgesic (in mice) have been reported [21] wherein the derivatives are prepared by cyclizing a N-[2,2-(OX)2]ethyl-α,α’-[(3-thienyl)alkyl]methylamine (97) or a N-[2,2-(OX)2]ethyl- α,'-[(2-thienyl)-alkyl]methylamine (99) treating with hydrochloric acid, and the desired compounds being obtained as the hydrochloride salt. Various pharmacological activities were performed at a dosage of 100 mg/kg. The percentages of anti-inflammatory activity of synthesized compounds were 38-43 % (1 h), 47-55 % (2 h), and 53-60 % (5 h) in case of carrageenin-induced edema and

45-56 (2 h), and 56-65 (3h) in case of ovalbumin-induced systemic edema. The acetic acid induced analgesic activities were 68-76 % (30 min), 62-69 % (1 h), 58-63 % (2 h), and 50-58 % (3 h). It was reported that the derivatives protected the animals against blood platelet aggregation to an extent of more than 90%. Amselem et al. synthesized 5-0-cyanobenzyl-4,5,6,7tetrahydrothieno[3,2-c]pyridine maleate derivatives (103) by reacting substituted compound (101) with halogenated derivative (102) (Scheme 22). The derivatives were therapeutically valuable in view to have anti-inflammatory and blood-platelet aggregation activities. The percentages of anti-inflammatory activity of synthesized compounds were 36-45 % (1 h), 47-53 % (2h), and 55-59 % (5 h) in case of carrageenin-induced edema and 48-54 % (2 h), and 53-64 % (3 h) in case of ovalbumin-induced systemic edema at the dose of 100 mg/kg. The synthesized derivatives showed a substantial activity and protect the test animals against blood-platelet aggregation in a ratio of the order of 95%.

12 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

Sangshetti et al.

O

R1

R1

R2COX, pyridine

NCCH2R1

NH2

TEA, DMF N

N

R3X, NaH DMF

N

S

H3CO

S

H3CO

R3 N R2 O

OCH3

96

95

94

R1/R2/R3= COOEt or COOH

Scheme (20). R

CH(OX)2 R CH

NH NH.HCl

HCl H2O

+ 2XOH S

S 97

OH 98

OH

R

HCl H2O

CH S

HN

+ 2XOH NH.HCl

S CH(OX)2

99

R 100

R= Alkyl groups

Scheme (21). R3

R2

S

( )n

+ X

NH

R1

R2

S R

Na2CO3 DMF

N

R1

R

( )n

102 101

103

R3

R1/R2/R3 = H, Cl, F, OH, NO2, NH2, lower alkyl group X= Halogen atoms n= an integer from 1-15

Scheme (22). S

S

Condensation +

Z-(CHR1)n-R

N

R2

104

N

R2

(CHR1)n

106

105

R, Z

Z= Halogen atoms R= Ph, halogen, OH, NO2, lower alkyl R1= H, halogen, OH, lower alkyl R2= H, halogen n= An integer from 1-2

S

N

R2

(CHR1)n

107 R

Scheme (23).

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines

Castaigne [23] in his patent disclosed derivatives (107) with potential anti-inflammatory, vasodilator and blood platelet aggregation inhibition activity. The derivatives were synthesized by condensing substituted THTP (104) with halogenated derivative (105) to give an intermediate, i.e. pyridinium salt (106) which further was converted to final compounds (Scheme 23). Among the synthesized derivatives, compound 5-parachlorobenzyl-4,5,6,7-tetrahydro thieno[3,2-c]pyridine hydrochloride showed the percentages of anti-inflammatory activity (localized carrageenin-induced edema) which were 45 % after one hour, 51 % after two hours, 52 % after three hours and 55 % after five hours at the dose of 100 mg/kg. For ovalbumin-induced systemic edema method of anti-inflammatory activity, the same compound showed percentages of anti-inflammatory activity which were 62 % after two hours and 70 % after three hours. The compound had protected the test animals against blood plate aggregation in a ratio greater than 95 %. The peripheral and cerebral vasodilatator action demonstrated a marked increase of the cerebral rate of flow associated with a decrease of the peripheral vascular resistance. A synthetic method for thienopyridine derivatives (110) was reported by Maffrand and co-workers (Scheme 24). The derivatives were reported to possess anti-inflammatory antiarrhythmic and an inhibiting action on blood platelet aggregation [24]. The compound, 6-(2-hydroxy-2p.methoxyphenylethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine had shown percentages of anti-inflammatory activity which were 44 % after 1 hour, 52 % after two hours, and 60 % after five hours in case of localized carrageenin-induced edem method and 42 % after two hours, and 61 % after three hours in case ovalbumin-induced systemic edema method at dose of 100 mg/kg in rats after oral administration. The compound had protected the test animals against blood plate aggregation in a ratio greater than 91 %. The compound had also shown protection in dogs against the arrhythmic effects induced by injection of high dosages of adrenalin.

+ Hal-X

CH3CN

NH

S R

108

N

S

X R

109

110 R= H, CH3, Cl, F, NO2 etc. X= Alkyl or phenyl

Scheme (24).

Antihyperlipidemic Activity Several derivatives of THTP were synthesized (113-115) (Scheme 25) and evaluated for their abilities to inhibit lipopolysaccharide (LPS)-stimulated production of TNH-α in rat whole blood [25]. In a study, it was found that 3-(2chlorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3c]pyridine analogs showed excellent activity in oral dosing. It has been proposed that esters may play an important role in the in vivo activity. In case of ester class, compound with R1= OCH3,

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

13

and R2= CH(CH3)2 had shown good in vitro (IC50= 2.6 µM) inhibitory activity. Antidepressant Activity Schneider et al. [26] reported a series of substituted 4aryltetrahydrothieno [2,3-c] pyridine (119) by acid-catalyzed cyclization of 1-aryl-2-[(2-thienylmethyl) amino] ethanol derivatives (118) (Scheme 26). The reported derivatives were scanned for their antidepressant activity by demonstrating their ability to inhibit the uptake of norepinephrine (NE) and serotonin (5-HT) and to prevent tetrabenazine-induced ptosis (TBZ) in mice. Moreover, they concluded that substitution at 2nd position of the fused thiophene ring and a p-substituted phenyl ring was the most favorable for high potency and selectivity of these compounds. The compound with R1= CH2OH, R2= 4-CH3, R3= H, and R4= CH3 showed good inhibition of neurotransmitters i.e. NE (IC50= 0.05 µM) and 5-HT (IC50= 1.2 µM). Anticancer Activity Zheng et al. [27] reported simple one pot ring expansion methodology useful in the synthesis of thieno[2,3-d]azepine derivatives (122) by converting chloromethyl tetrahydrothienopyridine (120) to N-benzyl or N-allyl thienoazapines (121) in presence of benzyl bromide or allyl bromide and potassium carbonate using acetonitrile as solvent. Further, N-benzyl or N-allyl thienoazapines (121) was reduced in presence of sodium cyanoborohydride in acetic acid to give thieno[2,3d]azepine (122) in good yields (Scheme 27). The synthesized derivatives were screened for anticancer activity. Romagnoli et al. [28] synthesized 2-amino-3-(3’,4’,5’trimethoxybenzoyl)-6-substituted-4,5,6,7-tetrahydrothieno [2,3-c]pyridine derivatives (126) and screened for their antimitotic activity. In this particular reaction, 2-amino-3(3,4,5,-trimethoxybenzoyl)-4,5,6,7-tetrahydrothieno[b] pyridine molecular skeleton (124) was utilized for the synthesis of a series of inhibitors of tubulin polymerization (Scheme 28). Among the series, 2-amino-3-(3,4,5-trimethoxybenzoyl)-6methoxycarbonyl-4,5,6,7-tetrahydrothieno[b]pyridine showed good anticancer activity having IC50 values ranging from 2590 nM against four cancer cell lines by interacting strongly with tubulin by binding to the colchicines site. Antiplatelet Activity Bouisset et al. [29] patented a process for preparation of THTP derivative (109) wherein an ester of α-bromo(2chloro)phenylacetic acid (127) was reacted with THTP (1) in presence of a base in a polar solvent to give a final compound (Scheme 24). The compound (128) said to have platelet aggregation inhibiting activity. Ticlopidine (130) is an antiplatelet drug in the thienopyridine family. It is an adenosine diphosphate (ADP) receptor inhibitor and used in patients in whom aspirin is not tolerated, or in whom dual antiplatelet therapy is desirable. The usual dose is 250 mg twice daily by the oral route. Ticlopidine (130), 5-(o-chlorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine has been synthesized in many different ways [30-36]. The one method reported for synthesis of ticlopidine was N-alkylation of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine with 1-chloro-2-(chloromethyl)benzene (Scheme 30).

14 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

Sangshetti et al.

Cl

Cl O

O

O

NCCH2COAr

NaNO2

S, Et3N/DMF N

75% H2SO4

NH2 N

R1

R1

111

N

S

R1

S

113

112

R2COX Pyridine

R3X NaH, DMF

Cl

Cl

O

O

R3

COR2 N

NH N

N

S

R1

S

R1

R3

115

114

R1= H, or Ac R2/R3= Lower alkyl groups

Scheme (25). HO R3 HO

R2

CHO +

116

118

NaBH4

H2N

S

R1

S

R1

117

R2

N

NH2R3

AlCl3 or CH3SO3H

R4MgBr R3 R1/R2= H, Cl, F, OH, NO2, NH2 etc. R3/R4= Alkyl or aryl

N R4 S

R2 R1

119

Scheme (26). Cl

H3CO2C

R

NH

R N

NaBH3CN AcOH, rt

S

R= Bn or allyl 120

Scheme (27).

RBr, K2CO3 CH3CN, reflux S

HS

H3CO2C

N

COOCH3

121

122

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12 OCH3 H3COC

O H3COC

S8, TEA

O

Urea

CH3COCl

N

NHCOCH3

R1 HN

S

97

n ocy , Is A TE

OCH3 H3COC

123

ate

Toluene Saponification OCH3 H3COC

H3COC O

H3COC O NHCOCH3

H N

N

R2

S

NH2

125

HN

X

S

124

NaOH

OCH3 H3COC

H3COC O

NH2

H N

N

S

R2

R2= Alkyl or phenyl X= S, N, O

126

X

Scheme (28). COOCH3

NH

Ester of !-bromo (2-chloro) phenylacetic acid

+ S

1

N

Pyridine S

Cl

127

128

Scheme (29). CH2Cl Cl

Cl

S

+ HN

N

1

Scheme (30).

S

Pyridine

129

130

15

16 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

Sangshetti et al.

The another way of making ticlopidine (130) was by alkylating thiophene (132) with ethylene oxide (133), forming 2-(2′-hydroxy)ethylthiophene (134) which on reaction with p-toluenesulfonic acid chloride (135) gave the corresponding tosylate (136). Substitution of the tosyl group using 2-chlorobenzylamine (137) gave an amine (138), which under reaction conditions for chloromethylation cyclized to the desired ticlopidine (Scheme 31).

Ticlopidine (130) suppresses aggregation of thrombocytes and possesses antiaggregant activity. It is believed that its action is connected to its effect on thrombocyte membranes and the reduction in quantity of released adenosine diphosphate and serotonin, which facilitate aggregation of thrombocytes. In wide-ranging clinical trials, ticlopidine presented a number of advantages compared to aspirin. Synonyms of this drug are ticlid, anagregal, and ticlosan. Suzuki et al. [37] have used ticlopidine in treating cancer and prevents cancer metastasis against AH-130 tumor cells.

Katsuyoshi Yamakawa has patented two synthetic intermediates (144, and 145) useful for production of ticlopidine hydrochloride (146) in an economical manner on industrial scale (Scheme 32).

Ambrogio et al. [38] reported a one step synthetic method for preparation of THTP derivatives (149) by reacting compound (147) with cyclic dioxy or a cyclic dithio

OH S

O

135

O

+

O O

S

132

S SO2Cl

S

133

136

H3C

134

NH2

Cl

137 Cl

S

S N H

CH2O/HCl N

138

Cl

130

Scheme (31). O

NH

CN

CN

NH(CH2CH2CH2CN)2

NaH

Acid halides HCl

139 N

N H

140

R1

R2SO2X

141

HSCH2COOR3 H+

Cl Cl

H2N

COOR1 N

143

R1OOC

S

CH2X

NH2

Ethanol S

144 HNO2 NaPH2O2

N H

142

Cl

Cl

S

H2O N

HCl N

HCl

R1OOC

146

S

145

Scheme (32).

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines

S

NH R2

Cyclic dioxy or cyclic dithio

+ R1

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

R1

60-1000C atm. pressure HCl

N

S

147

148

17

R2

149 R1 and R2= Lower alkyl, lower alkylene phenyl and substituted alkylene phenyl

Scheme (33).

O

HCl.HN

Na2CO3

F O + S

N

MeCN

O

O

Br

S

F

150

152 MeCN Ac2O 00C, 4 hrs DMAP, NMM

151

O

O

O

N

Isopropanolic hydrochloride

O

N O

O

.HCl

S

F 154

S

F 153

Scheme (34).

(148) in presence of a catalyst (HCl) (Scheme 33). This method avoids the use of formaldehyde and gives relatively pure product. This is new method of preparing thieno[3,2c]pyridine derivatives such as ticlopidine hydrochloride (130). Prasugrel (154) is a platelet inhibitor developed by Daiichi Sankyo Co. and produced by Ube and currently marketed in the United States in cooperation with Eli Lilly and Company for acute coronary syndromes planned for percutaneous coronary intervention (PCI). It is an adenosine diphosphate receptor antagonist and approved for use in Europe in February 2009, and is currently available in the UK. On July 10, 2009, the US Food and Drug Administration approved the use of prasugrel for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with PCI. Prasugrel hydrochloride (5-[(1R,S)-2-cyclopropyl-1-(2fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c] pyridin-2-yl acetate hydrochloride) (154), have been synthesized [39] by reacting 5,6,7,7a-tetrahydrothieno[3,2c]pyridin-2(4H)-one hydrochloride (150) with 2-bromo-1cyclopropyl-2-(2-fluorophenyl)ethanone (151) in presence of a base to form an intermediate (152) which in presence of acetic anhydride, a base (N-methylmorpholine) and catalytic amount of 4-dimethylaminopyridine forms 5-(2-cyclopropyl1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-

c]pyridin-2-yl acetate (153) which upon treatment with isopropanolic hydrochloride gave the target compound (154) with an overall yield of 58% (Scheme 34). Hana et al. [40] disclosed a new method for manufacturing of prasugrel (154) by using 3-cyclopropyl-1(2-fluorophenyl)-3-oxopropyl methanesulfonate (159) for alkylation of 2-oxo-thienotetrahydro-pyridine (160) to yield compound (161). The advantage of this method includes possibility to use cheaper starting material such as o-fluorobenzaldehyde (155) and to avoid problematic halogenation leading to α-haloketones. The acetylation of compound (161) led to the formation of final product, prasugrel (154) (Scheme 35). Kitabatake et al. [41] had synthesized N-formyl-4,5,6,7tetrahydrothieno[3,2-c]pyridines (167) via trifluoroacetic acid catalyzed cyclization of formyliminium ion (165), which was produced by imination of 2-(cyclopenta-1,3-dien1-yl)ethanamine (164) and a carbonyl compound (163) using titanium (IV) tetraisopropoxide followed by formylation with acetic-formic anhydride in a one-pot procedure (Scheme 36). This modified Pictet-Spengler reaction provided a convenient method for preparing 4,5,6,7tetahydrothieno[3,2-c]pyridines (167) possessing various substituents at C-4 position.

18 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

Sangshetti et al. O

O

OH

OSiMe3 H

MgX

Me3SiCN

F

157 N

F F

155

158

156

MeSO2Cl

O O OSO2Me HN O

N O

F

160

S

S

F

161

159

Acetylation reagent

O

N O S

F

O

154

Scheme (35).

S

S O NH2

S

Ti(O-iPr)4

HCOOH Ac2O

+ R1

R2

N

N

162

163

R1

R1

165 164

CHO

R2

R2

TFA

S

S

HCl NH

NaOH

N CHO

R1

R2

167 R1= H, CH3, and Ph R2= CH3, C2H5, n-C3H7, n-C4H9, and Ph

R1

R2

166

Scheme (36).

Master et al. [42] synthesized a series of derivatives of 4,5,6,7-tetrahydrothieno [3, 2-c]pyridine (168). They synthesized various amide derivatives of 4,5,6,7tetrahydrothieno [3, 2-c]pyridine with variety of substituted phenyl and aliphatic moiety (Scheme 37) and evaluated for inhibition of activation of human complement activity and

intrinsic hemolytic activity on erythrocytes of these amide derivatives. The compound with R= 3-acetylthio-2benzylpropionyl was found to be the most active complement inhibition activity (sensitized sheep RBCs inhibition) (IC50= 78 µM).

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines

Cheng et al. [43] synthesized a series of 4,5,6,7tetrahydrothieno [3,2-c]-pyridine (174) and evaluated for in vivo antiplatelet aggregation activities. In this particular reaction, 4,5,6,7-tetrahydrothieno [3,2-c]-pyridine was prepared by Lodewijk method and utilized as an intermediate in synthesis of target compounds (Scheme 38). The synthesized compounds were evaluated for their antiplatelet aggregation activities and showed moderate to good activity for inhibition of platelet P2Y12 (20-55.8 %). The maximum aggregation (%) was found to be between 23.7 to 42.9 %.

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

Same group [44] based on the previous approach has further designed and synthesized some more derivatives by removing the halogen atom from the benzene ring (Scheme 39). These derivatives (177) have been evaluated for their anti-platelet aggregation activities. The synthesized compounds showed the anti-platelet aggregation activities in range of 14.8-48.3 % (Maximum aggregation %) and inhibition ratio in range of 11.9-73.0 %. They have further studied these compounds for 3D-QSAR using CoMFA and CoMSIA models and result revealed that compounds with O

O N H .H Cl X

N

R

TEA MeCN

S

R

S

31 168 O

O

NH .H C l X

N

R

CHCl3 DCC/ DMAP

S

R

S

31

168 X= Cl R= Benzyl or cinnamyl

Scheme (37). C OOH

Br

C OO H

Red phosphorus, Br2

Br

C OOC H 3

CH3OH, Conc. H2SO4

100-120 0C, 8 hrs

Ref lux, 4 hrs

169

171

170

NH

S O

R2OH K2CO3

1 O

N H N H2

80% N2H4.H2 O, EtOH

N

OC H 3

N

Reflu x S

S

173

Cl

Cl

172 CHO R

CH3OH H N

O

R N

N

S

Cl

174 R= H, Cl, F, NO2, NH2, et.

Scheme (38).

19

R1

20 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

Sangshetti et al.

small volume R2 (less bulky and less hydrophobic group) showed good activity, and F (less bulky, less hydrophobic and richer electronic density group) on benzene ring was preferable.

Challa et al. [46] had described one pot synthesis and characterization of new 5-[2-(1H-tetrazol-5-yl)-biphenyl-4ylmethyl]-4,5,6,7-tetrahydro-thieno[3,2-c]pyridines (185) using amides (183) (Scheme 41). All the tetrazole derivatives (185) were evaluated for showing moderate to significant platelet aggregation inhibitor activity. Antiplatelet activity for all the new compounds was performed in vitro following Born’s turbidimetric methods using clopidogrel as standard drug. The compound with R= 4-Chlorophenyl showed most potent antiplatelet activity with percentage inhibition of platelet aggregation 55 % when compared with standard clopidogrel (% inhibition of platelet aggregation: 39 %).

Chuangwei et al. [45] patented the method for preparing prasugrel (154). They synthesized the prasugrel by converting o-fluorobenzyl cyclopropyl ketone (178) into αcyclopropylcarbonyl-2-flurobenzyl halide (179) using dibromohydantoinhydantoin (DBDNH) as halogenating agent in acetic acid as solvent. The 2-oxo-4,5,6,7tetrahydrothieno[3,2-c]pyridine p-toluenesulfonate (180) was reacted with α-cyclopropylcarbonyl-2-flurobenzyl halide (179) to get intermediate (161) which on acylation gave final compound i.e. prasugrel (154) as a gum (Scheme 40).

One of the most successful platelet aggregation inhibitors currently on the market is clopidogrel (189) which is a chiral tetrahydrothieno [3,2-c]pyridine derivative (Scheme 42).

COOCH3

CONHNH2

N

N

80% N2H4.H2O C2H5OH

S

S

176

R1

175

R1

CHO

CH3OH R2

N O

NH R2

N

S R1

177

R1/R2= H, Cl, F, CH3, NO2, NH2 etc.

Scheme (39). Br

DBDNH/AcOH O

O

F

F

178

179 NH.TSOH

TBAB, NABr O DMF S

180

F

F

TEA DMF

O

O N AcO

N O S

S

161 154

Scheme (40).

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines HO

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12 Cl

O

O N

N

PCl5 DCM

S

DCM

R-NH2 R

HN

S

182

181

R

21

HN

O

Cl

N N S

PCl5 S

Toluene

184

183

NaN3 DMF H2O N

R

N

N

R= H, phenyl, 2-chloro phenyl, 3-chloro phenyl, 4-chloro phenyl, 2,3-dichloro phenyl, 3,4-dichlorophenyl, 2-fluro phenyl, 4-fluro phenyl, 2,5-difluro phenyl, 2,3,4-trifluro phenyl.

N N

S

185

Scheme (41). CN

Br

NaHCO3 MeOH reflux

HN

CN

+

N

S

Cl

187

1

186

S

Cl

TEBA MeOH NaOH

COOMe

COOMe N

S

Cl

L-CSA H2O Toluene

N

S

Cl

189

188

Scheme (42).

This tricyclic motif was prepared by a nucleophilic substitution of α-bromo-2-chlorophenyl acetonitrile (186) with THTP (1). Subsequent hydrolysis of the secondary nitrile (187) under phase transfer conditions gave the free acid which was converted to the methyl ester (188). In order to obtain the desired S-enantiomer of clopidogrel, a classical resolution with 0.5 equivalent of L-camphorsulfonic acid (LCSA) in toluene was used. The desired enantiomer (189) was collected as a crystalline salt in greater than 98% yields [47]. A compound, methyl-(+)-(S)-α-(2-chlorophenyl)-6,7dihydrothieno[3,2-c]pyridine-5(4H)-acetate bisulfate (clopidogrel bisulphate) (190) was patented by Mukarram and co-workers as inhibitor of platelet aggregation with purity of 99.96% [48]. In this invention, inventor reported that ethyl acetate was the solvent of choice for getting (+)(S)-Clopidogrel bisulfate in good yield and highly pure form.

COOCH3

N

.H2SO4 S

Cl

190

Madivada et al. [49] suggested an improvement in the synthesis of clopidogrel (190) starting with the reaction of ochloro benzaldehyde (191) with 4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridine (31) by employing Strecker synthesis (Scheme 43). Desired isomer of clopidogrel (190) was separated from the racemic clopidogrel (193) by using L-(-)camphor sulfonic acid (CSA) as a resolving reagent. Bisulphate salt of clopidogrel (190) was prepared by employing sulfuric acid. Another approach reported includes

22 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

Sangshetti et al. CN Cl

NH.HCl

+ S

1.0 eq. NaCN 60-65 0C, 2 hrs H2O 100%

N

S

CHO

31

Cl

191

187 t-BuOH 3.0 eq. KOH 80-850C

COOCH3

CONH2

H2SO4

.H2SO4 S

MeOH Acetone

Cl

S

Cl

(±) 193

192

0.9 eq. CSA Acetone H2SO4 COOCH3

N

.H2SO4 S

Cl

190

Scheme (43). OTs

S

3.0 Vol. Toluene 1.65 eq. TEA

+ HO

197

194 COOMe

SO2Cl

195

1.5 Vol. Toluene 3.0 eq. K2HPO4

H2N Cl

198 COOCH3

COOMe

N

.H2SO4 S

Cl

HN

22 eq. HCHO DCM, Acetone 0.92 eq, H2SO4

190

.HCl S

Cl

199

Scheme (44).

tosylation of compound (194) with compound (195) in the presence of triethylamine and toluene (Scheme 44). In this method, they have opted non-hydrolytic, inexpensive and highly recoverable solvents like toluene instead of methyl acetate, ethyl acetate and acetonitrile to avoid solvent impurities. The production of the blockbuster clopidogrel (190) is a convincing example for the synthetic potential of follow-up reactions of optically active cyanohydrins [50]. In the first

step, (R)-2-chlorobenzaldehyde cyanohydrins (201) was prepared by almond meal catalyzed by the addition of HCN to 2-chlorobenzaldehyde (200). The cyanohydrin (201) was then transformed into the corresponding α-hydroxy carboxylic ester (202), which was reacted with tetrahydrothieno [3,2-c]pyridine (1) after activation with phenyl sulfonylchloride (203) to give clopidrogel (190) (Scheme 45).

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines Cl

O

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

Cl

OH

H

Cl

OH

H

Almond meal extract + HCN 200

H

MeOH HCl

CN

DIPE/H2O

23

COOMe

201

202 pyridine RSO2Cl

Cl

Cl

HN

S MeOOC

OSO2R

S

1

H COOMe

CH2Cl2/K2CO3

H

190 (S)-configuration

203 (R)-configuration

Scheme (45). Cl ZnBr NH

+ S

204

1 O MeO

MeCN

MeCN CH2O 205

H O

206

Cl Cl

S

MeO N N O

130

S

190

Scheme (46).

An aryl zinc reagent, 2-chlorophenyl zinc bromide (204) has been used as a nucleophile in the Mannich-related multicomponent synthesis of clopidogel (190) and ticlopidine (130) [51]. In this particular reaction, 2-chlorophenyl zinc bromide (204) reacts with an alkyl glyoxylate (206) and THTP (1) to give clopidogel (190). Also, a three component reaction of compound (204), formaldehyde (205) and THTP (1) gives ticlopidine (130) which demonstrates strategy for synthesis of the benzylamine backbone (Scheme 46). The compounds were obtained in good yields through this practical and straightforward procedure. Kiwon Jung and co-worker [52] described the first solidphase synthesis of the enantiomerically pure (+)-(S)clopidogrel from the commercially available Wang resin with overall 52% yield with optical purity of 98.0 % (Scheme 47). In this method, Br-containing resin (208) was first prepared from compound (207) using the standard OH-

to-Br conversion conditions involving Ph3P and Br2. The resin (208) was further reacted with (R)-2-chloromandelic acid (209) and CsCO3 to give [4-({[(2R)-2-(2-chlorophenyl)2-hydroxy- acetyl]oxy}methyl)phenoxy]methyl resin (210). The OH group in the resin (210) was then converted to the PhSO2 group (211) for further fictionalization by reacting compound (210) with benzenesulfonyl chloride and Et3N. A nucleophilic displacement of the PhSO2 group in the resin (211) was carried out with 4,5,6,7-tetrahydrothieno[3,2c]pyridine hydrochloride (31) to afford the compound (212). The desired product (213) was obtained by cleaving the resin (212) using CF3COOH (TFA) 5% in CH2Cl2, and the enantiomerically pure (2S)-(2-chlorophenyl)(6,7-dihydrothieno [3,2-c]pyridin-5(4H)-yl)acetic acid (213) was obtained in 62% overall yield. The acid (213) was further methylated under the typical acetylation conditions using SOCl2 to furnish the target compound, (+)-(S)-clopidogrel (190), in

24 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

Sangshetti et al.

O

O

PPh3, CH2Cl2 Br2 OH

Br

208

207

Cl

OH

Cs2CO3 DMF

COOH

209 O Cl

OH O

210

PhSO2Cl DMAP CH2Cl2 Et3N

O

O Cl

OSO2Ph O

211 TEA

O

NH.HCl

CH2Cl2 S

S O

31

H N O Cl

212 O

CF3COOH (TFA) 50% in CH2Cl2 O

Cl

S MeOOC

SOCl2 MeOH

OH

N

H

190 (S)-configuration

S

213

Cl

Scheme (47).

84% yield. The HPLC analysis revealed the optical purity of 98.0 % for this compound.

in an inert solvents (acetonitrile, aromatic hydrocarbons, and ethers) (Scheme 49).

A novel compound 2-silyloxy-4,5,6,7-tetrahydrothieno [3,2-c]pyridine (215), which serves as an intermediate in preparation of numerous medicinal compounds having antiplatelet and elastase inhibitory activity have been prepared by reacting 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one (160) with halogenated silane (214) [53]. The 2-silyloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (215) has been further used in formation of bioactive compounds like 5-alkyl-2-silyloxy-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine (217) and 2-acyloxy-5-alkyl-4,5,6,7-tetrahydrothieno[3,2c]pyridine (218) (Scheme 48).

Aubert and group [55] prepared compound (223) by reacting 4,5,6,7-tetrahydrothieno[3,2-c]prridine (1) with an α-chlorophenyl acetate (222) in the presence of an alkali metal carbonate such as potassium carbonate in an inert solvent such as DMF, THF or 1,2-dimethoxy ethane at temperature between 60 0C, and boiling point of solvent (Scheme 50). The derivatives have been evaluated for bloodplatelet aggregation inhibitory and antithrombotic activities.

Busacca et al. [54] synthesized the compound (221) having antiplatelet aggregation activity by reacting 4,5,6,7tetrahydrothieno[3,2-c]pyridine (1) with theobromine or theophylline haloderivative (220) in presence of acid binding agents, preferably tertiary bases (triethylamine or pyridine)

Koike and subordinates [56] disclosed tetrahydrothienopyridine derivatives (225) analogs which have the ability to inhibit blood platelet aggregation and can be used for treatment and prophylaxis of thrombosis and embolisms (Scheme 51). The bleeding time observed for synthesized compounds was between 2.13 to 2.75 h at dose of 3 mg/kg in mice. The compounds have also shown potent inhibition of blood platelet aggregation (57.1-100 %) at the doses of 1, 3, and 3 mg/kg in rats.

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines R1

NH O

+ R2

Si

X

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12 R2

Tertiary amine

R3

R1 Si NH

S

O

R3

160

S

214

R5

215 R4

R1/R2/R3= Alkyl group having 2 to 10 carbon atoms R4= H, alkoxy/ alkyl group with 2 to 10 carbon atoms R5= Halogen, alkoxy/ alkyl group with 1to 4 R2 R1 carbon atoms X= Halogen atom R3 Si R6= Alkyl group with 1 to 6 carbon atoms

Tertiary amine 216

X

R4 R5 N

O S R2

217

R1

R4 R5

R3

Si NH

Base Acylating agent

O S

215 R2 R3

N R6COO S

218

R4

R1

R4 R5

R5

Si N

Hydrolysis

O

N O

S

S

219

217

Acid hydrolysis R4 R5 N R6COO S

218

Scheme (48). A (CH2)m

NH

+ X(CH2)m-C-(CH2)n-A S O

1

220

(CH2)n C

N

TEA CH3CN

O S

221 m= 0 or 1; n= 0, 1, 2, 3 or 4; A = 3,7-dimethylxanthine-1-yl or l,3-dimethylxan thine-7-yl residue

Scheme (49).

O

OR

NH

+

Inert solvent

1

OR

N

Cl

S

S

222 X

Scheme (50).

O

Alkali metal carbonate

223

X

X= Halogen atom

25

26 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

Sangshetti et al. R2

R2 R1

NH

R1

+

N

X

S S

1

225

224

R3

R3

R1/R2/R3= H, OH, NO2 X= Halogen atom

Scheme (51). S NH2

S

S R1CHO, EtOH TEA

TFA NH N

226

R1 227 Method 1

NH2

S

R1 228 S

R1CHO, EtOH TEA or R1CHO, Benzene TFA

NH

226

228

Method 2

NH2

S

R1COCl, TEA DCM or R1COOH, HOBt EDAC, DMF

R1

O

R1

S

N H

229

POCl3/P2O5

226 S

S NH

NaBH4 MeOH

N

R1 228

R1 230 Method 3

S

S NH

R2COCl, Et3N DMF or R2CO2H, HOBt EDAC, DMF

R1 228

N

R1 229

R2

O R1/R2= Substituted phenyl

Scheme (52).

Antidiabetic Activity Madsen et al. [57] synthesized substituted THTP (228) via imine route (Method 1) and amide routes (Method 2, and Method 3). The synthesized derivatives (229) were first class potent non-carbohydrate glucose-6-phosphatase catalytic enzyme inhibitors. The structure-activity relationship (SAR) of these compounds indicates that: (i) a tetrahydrothieno[3,2c]pyridine core ring system and the isomeric [2,3-c] system were equipotent and much better than the corresponding benzo analog, 1,2,3,4-tetrahydro-isoquinoline; (ii) the

4-substituent of the tetrahydrothieno [3,2-c]pyridine ring has to be a phenyl group, optionally substituted with a lipophilic 4-substituent, such as triflouromethoxy or chloro; (iii) the 5-substituent of the tetrahydrothieno[3,2-c]pyridine ring has to be a substituted benzoyl; anisoyl and (E)-3-furan-3-ylacryloyl were the best of the investigated groups and; (iv) substitution in the benzoyl ortho position seemed to be forbidden, whereas substitution in the meta position was tolerated only if a methoxy para substituent was present. Optically resolved (S) configuration compound (R1= 4-CF3Ph and R2= 4-OCH3Ph)

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines R3

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12 R3

R4

+

R2

THF or DMF Reducing agent

27

R4

R2

N

NH

S

S

230

231 R 1

R1

R5-L R3

R4

R2 N S

Reducing agent: Sodium borohydride, lithium aluminium hydride, lithium triethylborohydride and aluminium hydride L= Good leaving group (halogen, sulphate, sulfonate or acyl) R1/R2/R3/R4/R5= H, Cl, F, OH, NO2, NH2 etc.

R5 R1

232

Scheme (53).

showed potent inhibition of glucose-6-phosphatase with IC50 value of 0.16 µM. Madsen et al. [58] synthesized THTP derivatives (232) (Scheme 53) which were normoglycemic agents (i.e., compounds that are able to normalize blood glucose levels from hyper-/hypoglycemic conditions) that interact with the glucose-6-phosphatase catalytic enzyme activity, and hence make them useful in the treatment and prevention of various diseases of the endocrinologic system, especially ailments related to carbohydrate metabolism and especially the glucose metabolism, e.g. hyperglycemia, diabetes mellitus, and especially non-insulin dependent diabetes mellitus (NIDDM) including long-term complications, such as retinopathy, neuropathy, nephropathy, and micro- and macroangiopathy, and hypoglycemia resulting from, e.g., glycogen storage disease. Moreover, compounds are useful in the prophylactic treatment of hyperlipidemia, hypertension, liver and bile diseases, and atherosclerosis associated with diabetes. The compounds are especially useful in the treatment of diseases associated with an increased or reduced activity of the glucose-6-phosphatase complex, (G-6-Pase catalytic enzyme). The compounds were preferably characterized by having a glucose-6-phosphatase inhibitory activity corresponding to an IC50 value of less than 100 µM, more preferably less than 10 µM, even more preferably less than 1 µM, still more preferably less than 100 nM. Anti-tuberculosis Activity Samala and his group [59] described the design of twenty six, 2, 6-disubstituted 4,5,6,7-tetrahydrothieno[2,3c]pyridine-3-carboxamide derivatives (229, 230, and 231) by molecular hybridization and synthesized from piperidin-4one (48) by five step synthesis (Scheme 54). Compounds were evaluated for Mycobacterium tuberculosis (MTB) for pantothenate synthetase (PS) inhibition study (in vitro activities against MTB PS), and cytotoxicity against RAW 2647 cell line. Among the synthesized compounds, 6-(4nitrophenylsulfonyl)-2-(5-nitrothiophene-2-carboxamido)4,5,6,7-tetrahydro thieno [2,3 c]pyridine-3-carboxamide was

found to be the most active compound with IC50 of 5.87 ± 0.12 µM against MTB PS, MIC value of 9.28 µM and it was non-cytotoxic at 50 µM. Nallangi et al. [60] synthesized twenty derivatives of 2,6disubstituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3carboxamide (236) (Scheme 55). Compounds were evaluated in vitro against Mycobacterium tuberculosis (MTB), and cytotoxicity against RAW 264.7 cell line. All the synthesized compounds have shown moderate to good activity against Mycobacterium tuberculosis. Among the synthesized compounds, the compound with R= cyclopentyl and R1 = CH3 was found to be the most active compound against MTB with MIC of 5.06 µM and was more potent than ethambutol (MIC= 7.64 µM), ciprofloxacin (MIC= 9.41 µM) and standard lead compound SID 92097880 (MIC= 9.15 µM). This compound also showed MTB MIC of 5.06 µM in the presence of an efflux pump inhibitor verapamil, and showed no cytotoxicity at 50 µM. A1-adenosine Receptors Agonists Baraldi et al. [61] synthesized new series of 2-amino-3benzoylthiophenes (240) and (241) from base-catalyzed condensation of carbonyl compounds (237) and nitriles (238) (Scheme 56). These derivatives were allosteric enhancers of A1-adenosine receptors. The compounds had shown good to excellent antagonist activity and were also allosteric enhancers. The compound (47 % inhibition) with R= 4-Cl found to be more potent than PD 81,723 (7 % inhibition) and caused significant reductions of cAMP content of CHO: huA1 cells at a concentration of 0.1 µM. A microwave-assisted synthesis of thieno [2,3-c]pyridine derivatives (246) as a new series of allosteric enhancers at the adenosine A1 receptor have been reported (Scheme 57) [62]. The compound with R=2-CF3C6H5 had inhibited forskolin-stimulated cAMP accumulation in a concentrationdependent manner from 1 to 10 µM with a maximum inhibition of 37 %. Comparable with reference compound PD 81,723 (48 %).

28 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12 O

Sangshetti et al. O

O

NH2

O NC

(Boc)2O, Et3N CH2Cl

NH2

25

N H.HCl

48

NH2

Morpholine, S BocN EtOH

N Boc

S

225

224

DIPEA DCM

O R1

NH2

NH2

TFA DCM

NH

NH HN

BocN

S

S

R1

R1

227

228

O

O

R2SO2Cl TEA

R2NCO, TEA DMF R1

R2NCS, TEA DMF

R1

R1

O

O

O

Cl

226

O

O

HN

HN

HN O

O

H2N O

H2N

H2N

S

S

N

N

N R2 N H

O

S

O

229

S

R2

R2 S

O

230

231

N H

R1 = 5-Nitrothiophen-2-yl R2 = 5-Nitrofuran-2-yl

Scheme (54).

Miscellaneous Activities A novel synthetic route involving a microwave-assisted cyclization reaction using silica gel as solid support catalyst in the synthesis of imidazo- pyrimidopyrido-[4’,3’:4,5]thieno [2,3-d]pyrimidines (251) has been reported [63]. The reaction was carried out by reacting ethyl 2-amino-3-cyano4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (247) with triethyl orthoformate in the presence of a catalytic amount of acetic anhydride to give 2-ethoxymethyleneamino-3cyano-4,5,6,7-tetra-hydrothieno[2,3-c]pyridine-6-carboxylic acid ethylester (248). Compound (248) reacted with various amines in presence dioxane at room temperature to afford the 3-substituted-4-imino-3,4,5,6,7,8-hexahydropyrido [4’,3’:4,5] thieno[2,3-d]pyrimidine-7-carboxylic acid ethyl ester (250). Further, microwave irradiation of (250) gave the target compound (251) as potential broncho-dilator (Scheme 58). A series of polyheterocyclic based on 4,5,6,7tetrahydothieno[2,3-c]pyridine has been reported [64]. In this reaction, a starting compound ethyl 2-amino-6-methyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (252) has been utilized to form 4,8-dimethyl-6,7,8,9tetrahydropyrido[4’,3’:4,5]thieno[2,3-e][1,2,4]triazolo[3,4-

a]-4H-pyrimidin-5-ones (256). Aminoester (252) reacted with catalytic amount of phosphorus oxychloride to give tetracyclic compounds (258) (Scheme 59). These tetracyclic compounds are well known for their biological activity. CONCLUSION 4,5,6,7-tetrahydrothieno pyridines are ubiquitous heterocycles which display versatile biological activities. 4,5,6,7-tetrahydrothieno pyridine analogs display potent antibacterial, anti-inflammatory and antiplatelet activities. Fusion of 4,5,6,7-tetrahydrothieno pyridine with various heterocyclic moieties has been reported to show improved chemical and pharmacological activities. The heterocyclic system containing oxadiazole, thiazolidinone, pyrimidine, oxazolidine and 1,2,3-triazole in fused form with 4,5,6,7tetrahydrothieno pyridine exhibit significant broad-spectrum antimicrobial activities. Recently, 4,5,6,7-tetrahydrothieno pyridine acetohydrazides have been reported for antileishmanial activity against Leishmania donovani promastigotes. Pyridine and pyrimidine coupled heterocycles have shown potent antiarrhythmic activity potent procaineamide and lidocaine. 4,5,6,7-tetrahydrothieno pyridine and its analogs have shown promising anti-inflammatory activity.

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12 O NH2 H2N

O

O S

(Boc)2O, TEA DCM

S8, Morpholine EtOH

N H.HCl

N

N

48 O

O

O

O

233

232

RCOOH EDCI, HOBt TEA, DCM R

O

R

HN

O

H2N

HN

O

O H2N

S

TFA DCM

S

CF3COOH N

235

N H.CF3COOH O

Acetylchloride, Et3N CH2Cl2

O

234 R

O HN O H2N S

R= Acetyl R1= CH3

N R1

236

Scheme (55). O

O

Br

CN

KCN, EtOH H2O

O

R3

R2COCH2R3, S8 Morpholine EtOH

R1

237

R2 S R1

H2N

238

R4

239

O S8, morpholine

N

EtOH

97 R4

S

HN

S N NH2

NH2

O

HBr/CH3COOH

O

R1= H, Cl, F, NO2 etc R2/R3/R4= Alkyl group R1

241

Scheme (56).

R1

240

29

30 Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

Sangshetti et al. R O R O

O

N-Boc-4-piperidone, S8 Morpholine, EtOH CN

R

NH2 N

NHAc HN S

244

S

Boc

242

AcCl, Pyridine DCM TFA DCM

MnO2 Toluene

243

R R

O O

NaOH EtOH NH2

NHAc N S

N S

245

246

R= Substituted phenyls

Scheme (57). CN

CN

NH2 N

CH(OEt)3 Ac2O

S

EtO2C

N N S

EtO2C

247

EtO

248 RNH2

R

HN

HO

N

HN (CH2)n N

N N EtO2C

N

S

EtO2C

249

N

250

S

MW N

(CH2)n-1 N

N N EtO2C

n= 2 or 3 R= NH2, PhCONH, Ph, CH2CH2OH, CH2CH2CH2OH, C(CH3)2CH2OH

S

251

Scheme (58).

2-Chlorobenzoyl at 3rd position and ester group at 2nd position of 4,5,6,7-tetrahydrothieno[2,3c]pyridine analogs showed excellent antihyperlipidemic activity by oral dosing. Further, 4,5,6,7-tetrahydrothieno[2,3c]pyridine analogs having substitution at 2nd position of the fused thiophene ring with a p-substituted phenyl ring have found to be favorable for high potency and selective antidepressant activity. The antiplatelet activity of 4,5,6,7-tetrahydrothieno pyridine analogs have been well reported and established. There are many bioactive molecules like ticlopidine, prasugrel, and clopidogrel currently in clinical use as antiplatelet agent. Other activity

like antidiabetic, antituberculer have also been reported for 4,5,6,7-tetrahydrothieno pyridine derivatives. This current review showed that 4,5,6,7-tetrahydrothieno pyridine and its analogs have broad range of biological activities. However, each segment of activity need to be further explored and extensive research is required to find novel analogs suitable for clinical applications. The more comprehensive and organized study of structure activity relationship of these synthetic derivatives will shed more light on its chemical arrangement and its correlation with its pharmacological activity.

Synthesis and Biological Activity of Substituted-4,5,6,7-tetrahydrothieno Pyridines

Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12

S

N

31

S N NH2

SH

N

CH3NCS

N COOC2H5

253

252

O

Ethanolic KOH CH3I

S N NHNH2

N

S

N

N

NH2NH2.H2O

N

SCH3

255

O

N O

254

RC(OC2H5)3 R N S N N

N

R= H, CH3, C2H5

N

256

O S

S

N

NH2

N

O

N

POCl3 +

(CH2)n HN

252

N

COOC2H5

(CH2)n

257

O

258

Scheme (59).

CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest.

[5]

ACKNOWLEDGEMENTS The authors are thankful to the Mrs. Fatma Rafiq Zakaria Chairman Maulana Azad Educational Trust and Principal, Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad 431 001 (M.S.), for providing the facilities.

[6]

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4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine as antimicrobial agents. Bioorg. Med. Chem. Lett., 2013, 23(7), 2250–2253. Kalaria, R.; Mittal, M.; Rajyaguru, C.; Upadhyay. Synthesis, characterization and antimicrobial activity of substituted tetrahydrothieno [2,3-c]pyridin-2-yl)urea derivatives. J. Chem. Pharm. Res., 2012, 4(3), 1566-1572. Kalaria, R.; Odedara, R. J.; Dave, R. S.; Rajyaguru, C.; Upadhyay, J. J. Synthesis, characterization and antimicrobial activity of substituted tetrahydrothieno [2,3-c]pyridin-2-yl) schiff base derivatives. J. Appl. Tech. Environ. Sanitation, 2012, 2(2), 109-114. Kedia, J.; Nimavant, K. S.; Vyas, K. B. Synthesizes and antimicrobial evaluation of novel heterocyclic compounds. J. Chem. Pharm. Res., 2012, 4(4), 1864-1867. Patel, Y. S.; Patel, P. N.; Patel, H, S. Biological evaluation and spectral studies of asymmetrical 3,5-disubstituted-1,2,4oxadiazoles. Int. Res. J. Pure Appl. Chem., 2014, 4(3), 315-326. Modi, V. P.; Patel, P. N.; Patel, H. S. Synthesis, spectral investigation and biological evaluation of novel noncytotoxic tetrahydrothieno[3, 2-c]pyridine hydrazide derivatives. Der Pharm. Lettre, 2011, 3(4), 120-133. Salahuddin, Md.; Singh, S.; Shantakumar,S. M. Synthesis and antimicrobial activity of some novel benzo thieno pyrimidines. Rasayan J. Chem., 2009, 2(1), 167-173. Mittal, M.; Sarode, S. M.; Vidyasagar, G. Synthesis, characterization and antimicrobial activity of substituted tricyclic compounds: 5,6,7,8-tetrahydro pyrido[4',3':4,5]thieno[2,3d]pyrimidines. Int. J. Pharm. Bioscis., 2011, 2(2), 188-196.

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Received: June 02, 2014

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Revised: September 16, 2014

33

Accepted: September 25, 2014

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