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1
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]
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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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Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12
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
Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12
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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Mini-Reviews in Medicinal Chemistry, 2014, Vol. 14, No. 12
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
Sangshetti et al.
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
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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
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Accepted: September 25, 2014