108
Current Organic Chemistry, 2011, 15, 108-127
Synthetic Thiazolidinediones: Potential Antidiabetic Compounds Aurelio Ortiz* and Estibaliz Sansinenea Facultad de Ciencias Químicas de la Benemérita Universidad Autónoma de Puebla, Puebla Pue., 72570, México Abstract: Type 2 diabetes mellitus is a growing health problem across the world. Thiazolidinediones, a new class of oral antidiabetic agents, appear to be ideally suited for the treatment of this disease. The examination of the clinical efficacy of different thiazolidinediones has been extensive. This review summarizes the current state of the cut concerning the clinical use of different thiazolidinediones, starting from the first synthetic thiazolidinediones to the recently developed glitazones. A main focus of this review is the description of the chemistry of these compounds including their synthesis.
Keywords: Thiazolidinediones, antidiabetic compounds, glitazones. 1. INTRODUCTION Type 2 diabetes mellitus is a growing health problem across the world. In 2025, the number of people with diabetes is expected to rise up to 300 million [1]. This chronic disease is characterized by hyperglycemia and numerous other metabolic abnormalities. Among these, there are three major pathophysiologic abnormalities associated with type 2 diabetes: impaired insulin secretion, excessive hepatic glucose output, and insulin resistance in skeletal muscle, liver and adipose tissue [2-4]. Thiazolidinediones, a new class of oral antidiabetic agents, appear to be ideally suited for the treatment of this cluster of metabolic abnormalities [5]. Thiazolidinediones lower blood glucose and insulin levels in various animal models, and in humans they can preserve or even improve -cell function. Although the exact interaction mechanism of thiazolidinediones still remains to be elucidated, the improvement in insulin sensitivity can at least in part be attributed to a reduction in the levels of circulating free fatty acids. These agents seem to exert their effects, at least to a great extent, by activation of the PPAR receptor. Their clinical potency correlates closely with their ability to bind to the PPAR receptor [4, 6]. The number of different thiazolidinediones examined for their clinical efficacy has been extensive [7, 8]. This review summarizes the current state of the cut concerning the clinical use of different thiazolidinediones and focuses on different aspects of the chemistry of these compounds, including their synthesis. 2. COMMERCIAL THIAZOLIDINEDIONES
All thiazolidinediones have a thiazolidine-2,4-dione structure, but they differ in their side chains, which alter their pharmacologic and side-effect profiles. Among thiazolidinediones there are some that have been clinically examined and these are representative as potential antidiabetic drugs (Fig. 1). a. Troglitazone Troglitazone (1) (Rezulin, Parke-Davis, Morris Plains, New Jersey), the first commercially distributed thiazolidinedione agent for type 2 diabetes mellitus, and has a number of attractive attributes.
*Address correspondence to this author at the Facultad de Ciencias Químicas de la Benemérita Universidad Autónoma de Puebla, México; Tel: 01-52-222-2295500 ext 7518; Fax: 01-52-222-2295584; E-mail:
[email protected]
1385-2728/11 $58.00+.00
n tio
u b i r
t is
D r o F t o
N
It reduces insulin resistance and increases insulin-stimulated glucose disposal, resulting in improved glycemic control and decreased insulin requirements in treated patients [9-12]. In addition, it is orally dosed once a day, and readily absorbed from the gastrointestinal tract. Furthermore, it does not induce hypoglycemia and does not appear to interfere with other drugs. Because of these attributes, troglitazone has received widespread use since its introduction in March 1997. In January 1997, Rezulin (troglitazone 1) was approved as drug for the treatment of type 2 diabetes by the Food and Drug Administration (FDA) of the United State Government. The troglitazone story is full of many controversial opinions that have led to many critical articles [13, 14]. Between one and two million patients were treated with this agent from 1997 through the end of February 2000, when troglitazone was completely withdrawn from the market. In the UK, the Medicine Control Agency withdrew the drug only six weeks after it had been introduced, which was based on numerous reports of liver failure associated with the use of troglitazone [15,16]. Reversible elevations of the levels of alanine aminotransferase (ALT) greater than three times normal were documented in less than 2% of treated patients. The exact nature of the hepatotoxicity remained controversial, however, initial reports described the hepatotoxicity of troglitazone as a rare event that occurred without explanation and was not dosedependent. Because of this problematic, initially, the manufacturer had introduced a series of labeling changes for troglitazone [12], and recommended close monitoring of liver enzyme levels and clinical signs of liver dysfunction, until the drug finally was withdrawn once and for all in 2000. Troglitazone ((±)-5-[4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]- benzyl]-2,4-thiazolidinedione) (1) [17] has been synthesized by different routes. Yoshioka [18] synthesized troglitazone (1) by the following sequence: reduction of (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2carboxylic acid (6, Trolox), protection with the methoxymethyl (MOM) group and arylation with p-chloronitrobenzene, provided the nitro derivative compound (7). Remotion of the MOM group and reprotection with acetic anhydride followed by hydrogenation gave the amino derivative (8), which by Meerwein arylation was transformed to the corresponding phenylchloropropionate (9). Compound (9) gave the corresponding troglitazone (1) by reaction with thiourea and subsequent complete hydrolysis, as shown in Scheme 1.
© 2011 Bentham Science Publishers Ltd.
Synthetic Thiazolidinediones: Potential Antidiabetic Compounds
Current Organic Chemistry, 2011, Vol. 15, No. 1 109
O
O Me Me
Me
O
O
Me
NH
S
O O
HO
O
Ciglitazone 2
Troglitazone 1
Me
NH
S
O
O Et
NH
S
O
N O
Englitazone 3
N
O
Me
Me
O
MOMO
D r o F t o Me 6
NH2
Me
O
Me
Me
Me
O
vi
AcO
Me 8
Me
Me
O
Me
O
7
Me
O
Me
AcO
N
Me
t is
ii, iii
HO
O
Me
i
u b i r NO2
Me COOH
Me
n tio
NH
S
O
Rosiglitazone 5 Fig. (1). Structures of representative thiazolidinediones with potential antidiabetic activities.
Me
O
Pioglitazone 4 O
Me N
NH
S
O
Me
O
iv v
CH2CHC(O)OC2H5 Cl
O
vii
9 O
S
NH O
HO
Troglitazone 1 Scheme 1. Reagents and conditions for the preparation of troglitazone. i) LiAlH4, ii) NaH, DMF, 1h at rt., MOMCl, benzene, 1h at rt, iii) NaH, DMSO, benzene, 20 min at 60 oC, p-ClC6H4NO2 , 1h at 60 oC, iv) AcOH, H2SO4 , 10 min at 60 oC, pyridine, Ac2O, 1h at 30 oC, v) MeOH, benzene, 3 h under a hydrogen pressure, Pd-C, vi) acetone, H2O, HCl, NaNO2, ethyl acrylate, Cu2O, 30 min at 40 oC, vii) thiourea, sulfolane, 80 min at 115 to 120 oC, AcOH, HCl, H 2 O, 12 h at 85 to 90 oC. Me
A further general method to generate thiazolidinediones consist of a Knoevenagel condensation between the aldehyde and the 2,4thiazolidinedione in refluxing toluene, containing a catalytic amount of piperidinium acetate or benzoate, followed by reduction using the Mg-MeOH electron transfer technique reported by Watt et al. [19]. For this purpose 6-benzyloxy-2,5,7,8-tetramethylchroman-2carbinol (10) was prepared by a known method [20] and converted to mesylate (11) in excellent yield (90%). The mesylate (11) was treated with 4-hydroxybenzaldehyde in the presence of t-BuOK in DMF to furnish aldehyde (12), which was then condensed with 2,4thiazolidinedione in the presence of piperidinium benzoate to give the unsaturated thiazolidinedione analogue (13). This can be re-
duced by CH3OH-Mg [19] to yield the saturated thiazolidinedione (14). Removal of the benzyl group afforded troglitazone (1), as shown in Scheme 2 [21]. Yoshioka [18] synthesized further derivatives of troglitazone (1) (15-30), (Table 1), and measured their biological activities, giving the best results for troglitazone (1). Compounds (15) and (16) were prepared by reaction of (9) with thiourea followed by partial hydrolysis. Compound (16) was also obtained by acetylation of (1). Compounds (17-19), (21), and (27-30) were prepared from the corresponding chroman carboxylic acids [22] in a similar manner to that used for the preparation of (1). Compounds (20), (22), and (26) were prepared by reaction of the corresponding phenylchloropropionates, which are analogues of (9), with thiourea. Compounds (23-
110 Current Organic Chemistry, 2011, Vol. 15, No. 1
CHO
Me
Me Me
Ortiz and Sansinenea
O
Me
O
Me L
iii
O
ii BnO
BnO
Me
Me 10 L= OH 11 L= OSO2CH3
12
i O O
Me Me
Me Me
Me
O
Me
S
O
NH O
iv
RO
O
14 R = Bn 1R=H
Me
13
BnO
Me
NH
S
O
O
v
Me Scheme 2. Reagents and conditions for the preparation of troglitazone. i) MeSO2Cl, Et3N, CH2Cl2, 2h, 25 oC, ii) 4-hydroxybenzaldehyde, t-BuOK, DMF, 15 h, 25 oC, iii) 2,4-thiazolidinedione, piperidine, benzoic acid, toluene, 120 oC, 2-4 h, iv) Mg/MeOH, 45 oC, 8 h, v) CH3COOH-HCl (3:1), 70-80 oC, 24-48 h. Table 1.
n tio
Thiazolidinedione Derivatives of Troglitazone Synthesized by Yoshioka
u b i r O
R5 R4
R1 O
t is
(CH2)n O
R3O
D r o F t o R2
N
Compound
R1
R2
R3
R4
R5
Me
Me
Me
Me
S
NH
Z
n
Z
Yield (%)
1
O
39
1
NH
26
1
Me
Me
H
15
Me
Me
H
16
Me
Me
Ac
Me
Me
1
O
78
17
Me
Me
H
Me
Me
2
O
77
18
Me
H
H
t-Bu
H
1
O
82
19
Me
H
H
t-Bu
H
2
O
94
20
Me
H
Ac
t-Bu
H
2
NH
56
21
Me
H
H
Me
H
1
O
87
22
Me
H
Ac
Me
H
1
NH
19
23
Me
Me
PhCO
Me
Me
1
O
62
24
Me
Me
3-PyCO
Me
Me
1
O
75
25
Me
Me
PrCO
Me
Me
1
O
56
26
Me
Me
Ac
MeO
MeO
2
NH
48
27
Me
Me
H
MeO
MeO
2
O
18
28
H
Me
H
Me
Me
1
O
57
29
Et
Me
H
Me
Me
1
O
54
30
i-Bu
Me
H
Me
Me
1
O
41
25) were prepared by acylation of (1) using the corresponding acylating agent. Lohray et al. [21] modified troglitazone (1) through insertion of an N-Me group between the chroman moiety and the phenoxyethyl moiety, resulting in compound A which has improved euglycemic and hypolipidemic activity. The N-Me group in structure A can be incorporated also in a cyclic structure (compound B) (Fig. 2).
b. Ciglitazone Ciglitazone (2), the first agent in the thiazolidinedione drug class, is a clofibrate analogue which has been developed by Sohda et al. [23]. In 1982 it was screened as a potential lipid-lowering agent and found to have unexplained glucose-lowering effects, ameliorating insulin resistance and normalizing effects of plasma
Synthetic Thiazolidinediones: Potential Antidiabetic Compounds
Current Organic Chemistry, 2011, Vol. 15, No. 1 111
Me Me
O
Me
O
O N S
HO
A
O Me Me
O
Me
Me O
HO
Me
O
Me
Troglitazone 1
Me
O
Me
NH
S
O
NH
N
HO Me
O
B
Fig. (2). Modifications of the troglitazone structure via insertion of an N-Me group.
glucose and insulin without causing hypoglycemia even at very high doses [24], but due to the unsatisfactory efficacy, safety profile and liver toxicity it was abandoned [25]. Sohda et al. [23] synthesized many thiazolidinedione derivatives but only 5-[4-(1-methylcyclohexylmethoxy)-benzyl]thiazolidine-2,4-dione (ciglitazone 2, ADD-3878) exhibited the most favorable properties in terms of activity and toxicity. They used three different methods to prepare ciglitazone 2, of which the first gave the best yield. In this method, reaction of 1-methylcyclohexylmethanol (31) with 4-chloronitrobenzene (32) by means of NaH in hot DMSO gave 4-(1-methylcyclohexylmethoxyl)nitrobenzene (33), which was reduced with H2 over Pd/C in methanol to yield 4(1-methylcyclohexylmethoxyl)aniline (34). Diazotation of (34) with NaNO2 and HCl in water afforded a solution of the corresponding
diazonium chloride (35), which was condensed with methyl acrylate (36) by means of Cu2O affording methyl 2-chloro-3-[4-(1methylcyclohexylmethoxyl)phenyl]propionate (37). Cyclization of (37) with thiourea (38) by means of sodium acetate in hot 2methoxyethanol gave 2-imino-5-[4-(1-methylcyclohexylmethoxy) benzyl]thiazolidin-4-one (39), which was finally hydrolyzed with HCl in a refluxing mixture of 2-methoxyethanol – water to give ciglitazone 2 in 88% yield, as shown in Scheme 3.
Me
Me
Cl
OH
32
In the second method, methyl 2-chloro-3-[4-(1-methylcyclohexylmethoxyl)-phenyl]propionate (37) [26,27] was reacted with KSCN to give 3-methyl 3-[4-(1-methylcyclohexylmethoxyl) phenyl]-2-thiocianatopropionate (40) which was hydrolyzed with HCl to form ciglitazone (2) in 70% yield, as shown in Scheme 4. NO2
NH2
Me
O
ii
33
i
31
N
O
u b i r
t is
D r o F t o NO2
n tio
34 Cl
N2+
Me
H2C
O
Cl-
COOMe
O
36
S
S
Me
COOMe
O
O
38
NH2
v O
NH Me
Me
NH
H2N
37
iv
35
iii
vi
NH
S
O
O
Ciglitazone 2
39
Scheme 3. Reagents and conditions for the preparation of ciglitazone. i) NaH, DMSO, 70 oC, 30 min, ii) H2 , Pd/C, MeOH, rt, iii) NaNO2 , HCl, H2O, iv) methyl acrylate, Cu2O, 35 oC, v) thiourea, NaOAc, 2-methoxyethanol, 100 oC, vi) HCl, 2-methoxyethanol/H2O. SCN Cl Me
Me
COOMe
COOMe O
O
i
ii
40
37 O Me
S
NH
O O Ciglitazone 2 Scheme 4. Reagents and conditions for the preparation of ciglitazone. i) KSCN, DMSO, 100 oC, 2h, ii) HCl, EtOH, reflux, 50 h.
112 Current Organic Chemistry, 2011, Vol. 15, No. 1
Ortiz and Sansinenea
mediated coupling of thiol with 5-bromo-2,4-thiazolidinedione (54) to give (56), which was then oxidized to the sulfone (55). Treatment of (55) with the alkoxide of (1-methylcyclohexyl)methanol gave the final ciglitazone derivative (57), as shown in Scheme 6.
In the third method, 4-(1-methylcyclohexylmethoxyl)nitrobenzene (33) was reduced with H2 over Pd/C in methanol and then reacted with NaNO2 and HBr in water to afford 2-bromo-3-[4-(1methylcyclohexylmethoxyl)phenyl]propionitrile (41), which was reacted with thiourea to give (42). Hydrolysis with HCl gave ciglitazone (2) in 80% yield, as shown in Scheme 5. Using the first method Sohda et al. synthesized some ciglitazone derivatives, as shown in Fig. (3), that exhibited different activities and toxicities, though ciglitazone (2) and compounds (43) and (44) had the most favorable profiles [23]. Zask et al. [28] described a ciglitazone sulfonyl derivative (57). Treatment of 2,4-thiazolidinedione (52) with n-BuLi gave (53) and a selective C-5 sulfonylation of (53) with sulfonyl chloride provided (55). An alternative two-step sequence utilized a base-
c. Englitazone With the purpose to obtain more potent and structurally distinct analogs of ciglitazone (3) a series of dihydrobenzopyran thiazolidine-2,4-diones (58-61) were synthesized by Clark et al. as shown in Table 2 [29]. These compounds represent conformationally restricted analogues of ciglitazone. Among these analogues Clark et al. [29] selected englitazone (3) for clinical studies (Fig. 4). Br
NO2 Me
Me O
n tio
CN
O
i
ii
41
33
u b i r O
NH Me
S
O
Me
NH
t is
NH
S
O
O Ciglitazone 2 Scheme 5. Reagents and conditions for the preparation of ciglitazone. i) H2, Pd/C, MeOH, rt, NaNO2 , HBr, H 2O, ii) thiourea, sulfolane, 110 oC, 2h, iii) HCl, reflux 8h. O O NH
42
iii
D r o F t o Me
O
N
NH
S
O
O
Ciglitazone 2
NH
S
O
43
O
O
O
N
NH
S
O
O
45
O
44
NH
S
O
NH
S
O
O
O
46
NH
S
O
O
47
O NH
S
O
O
48
N
O
S
O 49
O O
O
N
S
O
Me Fig. (3). Ciglitazone derivatives reported by Sohda.
50
NH
S
O O
NH
N
51
NH O
Synthetic Thiazolidinediones: Potential Antidiabetic Compounds
Current Organic Chemistry, 2011, Vol. 15, No. 1 113
O
O Li BuLi
O
Li
N
F
SO2Cl
F
SO2
NH S
S
55
O
53
O i
NH O
S O
52
O F
Br
SH
NH
Br2
F
S
NH
S
S O
54
56
O
O F
SO2
O NH
ii
O
S 55
SO2
NH S
O
n tio
57
O Scheme 6. Reagents and conditions for the preparation of ciglitazone sulfonyl derivatives. i) H 2O2, acetic acid, ii) NaH, (1-methylcyclohexyl)-methanol, DMF, 55 oC, 3 h. Table 2.
Dihydrobenzopyran Thiazolidine-2,4-Diones Derivatives Reported by Clark
O X
t is
NH S O
D r o F t o O
Compound
X
Yield (%)
3
2(R)-CH2Ph
68
58
2-Ph
56
59
2-CH2Ph
57
60
3,3-(CH2)5
50
61
2,2-(CH2)4
83
N
O
NH
S
O Englitazone 3
u b i r
Because of this, further types of these thiazolidinediones were prepared. Fusion of aryl aldehydes (62) with 2,4-thiazolidinedione afforded the olefinic thiazolidinediones (63) in excellent yields (44100%). Olefins (63) were subjected to catalytic hydrogenation in acetic acid using 10% palladium/carbon to achieve thiazolidinediones such as englitazone (3) in yields ranging from 30 to 90%, as shown in Scheme 7. The initial aryl aldehydes (62) were prepared from the corresponding dihydrobenzopyran precursors [30] by standard formylation procedures using phosphorus oxychloride/Nmethylformanilide [31], ,-dichloromethyl ether/titanium tetrachloride [32] or hexamethylenetetramine/ trifluoroacetic acid [33]. A new series of thiazolidine-2,4-diones was obtained by replacing the ether function of englitazone with various functional groups, i.e., a ketone, alcohol, sulfur, amino, carbonyl groups or olefin moiety [34]. While the sulfur and nitrogen analogues were somewhat inferior in potency, the alicyclic ketone (65) as well as the analogous ketone (66) possessed practically equivalent activity (Fig. 5). For its preparation, 2-bromo-3-(4-acetylphenyl)propanoic acid (63) was reacted with thiourea in sulfolane to give 5(4acetylbenzyl)thiazolidine-2,4-dione. Subsequently this intermediate was treated with benzaldehyde in ethanol and sodium methoxide to give (E)-5-[4-(3-phenyl-2-propenoyl)benzyl]thiazolidine-2,4-dione (64), which was treated with triethylsilane in trifluoroacetic acid to achieve 5-[4-(3-phenylpropionyl)benzyl]thiazolidin-2,4-dione (65), as shown in Scheme 8.
O
Fig. (4).
O
O
CHO i
X
X
S
O
O
63
62
NH
ii X
S
O
O
NH
O X = 2(R)-CH2Ph 3 Englitazone Scheme 7. Reagents and conditions for the preparation of englitazone. i) 2,4-thiazolidinediones, NaOAc, 140-190 oC, 30 min, ii) H 2, Pd-C. O O
S O
Fig. (5).
65
NH O
S O
66
NH O
114 Current Organic Chemistry, 2011, Vol. 15, No. 1
Ortiz and Sansinenea
O
O
COOH iii
i Me
Br O
NH
S
ii
63
O
S O
64
O
NH O
65
Scheme 8. Reagents and conditions. i) thiourea, sulfolane, 110 oC, 2N HCl, ii) benzaldehyde, NaOMe, ethanol, iii) triethylsilane, trifluoroacetic acid, 0 o C. OEt CH3 CHO CH3 O O EtOOC OEt i + Ph Cl Ph N N 68 69 O 67 O
O CH3 O NH
ii iii
Ph
S
N O
n tio
O
70
Scheme 9. Reagents and conditions for the preparation of darglitazone. i) NaH, THF, NaOH, 1N HCl, ii) 2,4-thiazolidinedione, piperidine, ethanol, reflux, iii) H2, Pd-C.
Replacement of the phenyl group by a 4-substituted oxazole leads to a remarkable jump in the pharmacological activity, as exemplified by (70) (CP-86,325), a compound called darglitazone. For the preparation of this drug, sodium hydride was added to a solution of (67), which was then combined in THF with ethyl-2-[4(diethoxymethyl)benzoyl]acetate (68) to give 4-[3-(5-methyl-2phenyl-4-oxazolyl)propionyl]benzaldehyde (69). This was treated with thiazolidine-2,4-dione and piperidine in ethanol to give 5-[[4[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]methylene]thiazolidine-2,4-dione, which was hydrogenated in THF in the presence of palladium on carbon to give darglitazone (70), as shown in Scheme 9 [34]. With the intention to change the substituents of thiazolidinedione of ciglitazone and its analogues, Hulin et al. [35] synthesized a series of benzofuran thiazolidinediones (71-76), as shown in Table 3.
t is
D r o F t o
N
Table 3.
Benzofuran Thiazolidinedione Derivatives Reported by Hulin et al.
O
R
O
CH3
N
O
NH
S
O Compound
R
71
Ph
72
4-ClPh
73
3-FPh
74
2-MePh
75
3-MePh
76
cyclohexyl
d. Pioglitazone Pioglitazone (4) (Actos®) was approved by the US Food and Drug Administration (FDA) in July 1999 and reached the US market in 1999 as first-line agent to be used alone or in combination with other drugs. Pioglitazone hydrochloride (ACTOS) is an oral
u b i r
antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS improves glycemic control while reducing circulating insulin levels [36]. Pioglitazone (4) [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione, belongs to a different chemical class and has a different pharmacological activity than sulfonylureas, metformin, or -glucosidase inhibitors. The molecule contains one asymmetric carbon, and is used in racemic form. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacological activity between the two enantiomers. Among several potent compounds of a series of 5-[4(pyridylalkoxy)benzyl]-2,4-thiazolidinediones, which were synthesized by Sohda et al. in 1990 [37], pioglitazone (4) (AD-4833, U72107) was selected as candidate for pharmacological studies and its hypoglycemic and hypolipidemic activity was reported [38, 39, 40]. For the preparation of pioglitazone (4), (5-ethyl-2-pyridinyl) ethanol (77) was converted to vinylarene (78), which was coupled with 4-aminophenol to give aniline (79). An alternative route to (79) consisted in the synthesis of nitrobenzene (80), which was reduced with H2 over Pd/C in methanol yielding (79). Meerwein arylation of (79) by radical coupling of the diazonium bromide of (79) with methyl acrylate in the presence of cuprous oxide provided -bromopropionate (81). Subsequent cyclization of the intermediate (81) with thiourea gave (82), which after acid hydrolysis afforded the desired pioglitazone (4), as shown in Scheme 10 [37]. Using the same method, later Sohda et al. [41], synthesized some thia-analogues (83-88) of pioglitazone (4), as shown in Table 4. Furthermore, they developed an alternative method for the synthesis of pioglitazone (4) involving catalytic hydrogenation of the 5-benzylidene-2,4-thiazolidinedione prepared by Knoevenagel condensation of the corresponding aldehyde (90) with 2,4-thiazolinedione [41]. Aldehyde (90) was obtained by a base-mediate coupling of 5-ethyl-2-pyridinylethanol (77) and 4-fluorobenzonitrile to achieve 4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzonitrile (89) followed by a treatment with Raney Ni. An alternative and more efficient one-pot route to (90) consisted in the tosylation of (77) and subse-
Synthetic Thiazolidinediones: Potential Antidiabetic Compounds
Et iii N
Current Organic Chemistry, 2011, Vol. 15, No. 1 115
Et
NO2
OH
N
77
O 80
i
iv Et
Et
NH2 v
ii
CO2Me
vi
O
N
N 78
Et
N
79
Br
O 81
O O vii
Et
Et
viii N
S
O
NH
N
O Pioglitazone 4
NH
82
NH
S
O
n tio
Scheme 10. Reagents and conditions for the preparation of pioglitazone. i) KOH, ii) 4-aminophenol, iii) NaH, 4-fluoronitrobenzene, iv) H2/Pd-C, v) NaNO2, aq.HBr, vi) methyl acrylate, Cu2O, vii) thiourea, NaOAc, viii) aq. HCl.
quent coupling with 4-hydroxybenzaldehyde in the presence of benzyltributylammonium chloride as a phase transfer catalyst. Knoevenagel condensation of the corresponding aldehyde (90) with 2,4-thiazolinedione gave 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzylidene]-2,4-thiazolidinedione (91). Catalytic hydrogenation of (91) furnished pioglitazone (4) in 65% yield, as shown in Scheme 11. Table 4.
5-[4-(2-Arylethylthio)benzyl]-2,4- Thiazolidinediones Derivatives Prepared by Sohda et al. O
Using the same method various 5-benzylidene-2,4-thiazolidinediones (44, 50, 91-94) were synthesized, as shown in Table 5 [41]. Table 5.
t is
D r o F t o R
N
NH
S
S
O
N
u b i r
5-Benzylidene-2,4-Thiazolidinediones Derivatives Reported by Momose et al.
R
N
O
Compound 44 50
O
S
NH
O
R
Yield (%)
H
73
2-Me
65
Compound
R
Yield (%)
91
5-Et
64
83
5-Et
75
92
5-Me
79
84
H
83
93
6-Me
78
85
3-Me
63
94
4,6-(Me)2
45
86
5-Me
79
87
6-Me
95
88
4,6-(Me)2
84
Et
Et
In the course of further chemical modifications of the antidiabetic pioglitazone (4), Sohda et al. prepared a series of 5-[4-(4azolylalkoxy)benzyl]-2,4-thiazolidinediones (95-108) and 5-[4-(2CN
i N 77
OH
N
O 89 ii
iii
Et
O CHO
Et
v
iv N
90
O
N vi
S
O 91
NH O
O
Et
N
O Pioglitazone 4
S
NH O
Scheme 11. Reagents and conditions for the preparation of pioglitazone. i) NaH, 4-fluorobenzonitrile, ii) Raney Ni, aq.HCO2H, iii) TsCl, PhCH 2NBu3Cl, aq.NaOH, iv) 4-hydroxybenzaldehyde, PhCH2NBu3Cl, aq.NaOH, v) 2,4-thiazolidinedione, piperidine, vi) H2, Pd-black, DMF, 50 oC 5h.
116 Current Organic Chemistry, 2011, Vol. 15, No. 1
Ortiz and Sansinenea
Further metabolites (114-116) of pioglitazone (4) were synthesized by Sohda et al. [43], as shown in Fig. (6).
azolylalkoxy)benzyl]-2,4-thiazolidinediones (109-113) [42] using the general procedure described above [37] (Scheme 10), as shown in Tables 6 and 7. Table 6.
5-[4-(4-Azolylalkoxy)Benzyl]-2,4-Thiazolidinediones Derivatives Reported by Sohda et al. O X
R1
R2 NH S
N
O O
R1
R2
X
Yield (%)a
95
H
Me
S
20
96
Me
H
S
21
Compound
a
97
Et
H
S
40
98
i-Pr
H
S
34
99
cyclohexyl
H
S
100
Ph
H
S
101
Me
H
O
102
Pr
H
103
Me
Me
104
Me
Et
105
cyclohexyl
H
106
Ph
107
Ph
Me
108
Ph
Et
D r o F t o
Table 7.
41
22
u b i r O
O
t is
Overall yield
n tio 26
H
O
O
O
11
46
31
13
29
O
52
O
21
5-[4-(2-Azolylalkoxy)Benzyl]-2,4-Thiazolidinediones Derivatives Reported by Sohda et al. O
R1
N a
N
R2
NH S
O
X
O
Compound
R1
R2
X
Yield (%)a
109
i-Bu
Me
O
27
110
cyclohexyl
Me
O
24
111
Ph
Me
O
34
112
Ph
Et
O
30
113
Me
Ph
O
21
Overall yield
OH
O H3C N O
O Pioglitazone 4
S
NH
O
H3C N
O
O
S
O
114
O
O HOOC
H3C N
O 115
Fig. (6). Metabolites of pioglitazone reported by Sohda et al.
S
NH N O
NH
O 116
S
NH O
Synthetic Thiazolidinediones: Potential Antidiabetic Compounds
Current Organic Chemistry, 2011, Vol. 15, No. 1 117
Knoevenagel condensation conditions defined by Sohda [37, 43] to give (121). Finally, they introduced a modified conjugate reduction protocol to give (114) in 98% yield, as shown in Scheme 13. For the synthesis of (115), compound (117) was treated with ethylene glycol to give (122). Reaction of (122) with formaldehyde yielded (123). The remaining steps were the same as given in Scheme 13, to achieve (115) in 98% yield, as shown in Scheme 14. The synthesis of compound (116) was performed in a similar manner. Compounds (125) and (126) were synthesized as described in Scheme 15. Pioglitazone (4) was oxidized to give (124), which was treated with trifluoroacetic anhydride (TFAA) in methylene dichloride, where upon aqueous NaHCO3 was added to give (125). Oxidation of (125) gave (126), as shown in Scheme 15 [44]. The former Upjohn Company, which had experience in the synthesis of pioglitazone analogues, developed an efficient six-step
5-Acetyl-2-methylpyridine (117) was treated with NaBH4 and followed by NaH and chloromethyl methyl ether addition to give the 2-pyridylethanol derivative (118), which was then condensed with p-fluoronitrobenzene. Subsequent catalytic hydrogenation of the nitro moiety followed by Meerwein arylation gave the 2-bromo3-phenylpropionate (119). Reaction of (119) with thiourea and acid hydrolysis gave (114). Oxidation of (114) was carried out using dimethyl sulfoxide (DMSO)-pyridine.SO3 complex to give the corresponding acetyl derivative (115), as shown in Scheme 12 [43]. Compound (116) was obtained by a similar method to that described for (114). Tanis et al. [44] developed improved syntheses of (114-116) and synthesized compounds (125) and (126). For the synthesis of (114), first compound (118) was prepared in similar manner as shown in Scheme 12. Coupling between (118) and 4-hydroxybenzaldehyde gave (120), which was subjected to the O
OCH2OCH3 i
H3C
H3C N
u b i r N
118
117 OH
vi
COOCH3
H3C
v OH
ii, iii
N
t is
O
H3C
NH
D r o F t o S
O
N
n tio
OCH2OCH3 iv
O
114
H3C
vii
O 119
O
N
Br
O
NH
S
O
O
115
Scheme 12. Reagents and conditions. i) NaBH4, ii) NaH, CH3OCH2Cl, iii) aq. HCHO, iv) NaH, p-fluoronitrobenzene, DMF, v) H2 , Pd-C, NaNO 2, aq.HBr, methyl acrylate, Cu2O, vi) thiourea, NaOAc, aq. HCl, vii) Pyr. SO3 /DMSO. OCH2OCH3 OCH2OCH3
i
H3C
N
ii
v OH
N 118
OCH2OCH3
iii
NH
S
N
O
N 120 OH
O
H3C
CHO
H3C
H3C
NH S
iv
O
O
N
O
O
121
O
114
Scheme 13. Reagents and conditions. i) DEAD, Ph3P, 4-HOPhCHO; ii) 2,4-thiazolidinedione, piperidine, EtOH, ; iii) NaBH4, CoCl2, dimethylglyoxime; iv) 2N aqueous HCl, .
O
O
H3C
O
i
ii
H3C
N
N 117
N 123
122 O
iii,iv
O
O
H3C
OH
O
H3C
v, vi N
O 115
S
NH O
Scheme 14. Reagents and conditions. i) ethylene glycol, pTsOH (1.25 equiv), toluene, , ii) aqueous CH2O, 150 °C, iii) DEAD, Ph3 P, 4-HOPhCHO, iv) 2,4thiazolidinedione, piperidine, EtOH, , v) NaBH4, CoCl2, dimethylglyoxime, vi) 2N aqueous HCl, .
118 Current Organic Chemistry, 2011, Vol. 15, No. 1
Ortiz and Sansinenea
O
O H3C
i NH
NH
S
O Pioglitazone 4
N
H3C
O
N
O
O
124
S O
O ii, iii
H3C
O
NH S
O
N OH
H3C
iv
S N
O
125
O 126
O Scheme 15. Reagents and conditions. i) MCPBA, CH 2Cl2, ii) TFAA, CH 2Cl2, , iii) aqueous NaHCO3, THF, iv) DMSO, P2O 5, Et3N, CH 2Cl2.
synthesis for the preparation of the pioglitazone analogue 5-[4-[2(5-ethylpyridin-2-yl)-2-oxoethoxy]-benzyl]-1,3-thiazolidine-2,4-dione (126) (PNU-91325) [45]. Dehydration of (127) with KOH afforded olefin (128). Epoxidation of (128) followed by subsequent ring opening of intermediate (129) with 4-hydroxybenzaldehyde provided (130). Knoevenagel condensation with 2,4-thiazolidinedione afforded olefin (131), which was reduced with NaBH4 to provide the diastereomeric mixture of alcohol (125). Oxidation of the carbinol to the ketone afforded the target pioglitazone analogue (126), as shown in Scheme 16 [45]. The final steps of the commonly used synthetic strategy for the preparation of glitazones, are exemplified in the Scheme 17. Knoevenagel condensation of the benzaldehyde (90) with 2,4H3C
i
N
N 128
127
OH
CHO
H3C
N
iv
OH
n tio
u b i r
H3C
ii
iii
N 129
O
O
H3C
O
N
N
S
O OH
130
NH
v
O
131
O
H3C
S
O
N
OH
NH
vi
O H3C N
O
125
O
thiazolidinedione yielded the benzylidenethiazolidinedione (91), which on reduction afforded pioglitazone (4). Reduction of the double bond in (91) has opened more possibilities to obtain new compounds and consequently has been studied extensively. Therefore an optimization of the reduction procedure was studied adjusting some variables such as time, amount of catalyst, temperature and quantity of NaBH4 [46]. With the intention to develop new antidiabetic agents, recently a synthesis of polymeric thiazolidinedione carrying pioglitazone was carried out [47]. First the monomer (133), thiazolidindionylethyl methacrylate, was prepared starting from pioglitazone (4), by introduction of a hydroxyethyl group at the nitrogen of pioglitazone. The resulting alcohol (132) was coupled with methacrylic
t is
D r o F t o H3C
NH
O O
126
S
NH O
Scheme 16. Reagents and conditions. i) KOH, ii) NBS, HOAc, t-BuOH, 0 oC, 2N NaOH, iii) 4-HOPhCHO, 1N NaOH, MTBE/toluene, iv) 2,4thiazolidinedione, pyrrolidine, MeOH, , v) NaBH 4, CoCl2 , dimethylglyoxime, THF/H2O/NaOH, vi) DMSO, P2 O5, Et3N, CH2Cl2. O Et CHO Et i NH S N O N O 90 91 O O Et ii N
O Pioglitazone 4
S
NH O
Scheme 17. Reagents and conditions for the preparation of pioglitazone. i) 2,4-thiazolidinedione, pyrrolidine, MeOH, , ii) NaBH 4, CoCl2, dimethylglyoxime, THF/H 2O/NaOH.
Synthetic Thiazolidinediones: Potential Antidiabetic Compounds
Current Organic Chemistry, 2011, Vol. 15, No. 1 119
was coupled with 4-fluorobenzaldehyde to give (138). Benzaldehyde (138) was coupled with 2,4-thiazolidinedione to achieve (139). Finally (139) was treated with magnesium in methanol to afford rosiglitazone (5) in 62% yield, as shown in Scheme 20 [50, 51]. Using the same method, later Lohray et al. [52], synthesized some indole and azaindole analogues (140-143) of rosiglitazone (5), as shown in Table 8. Compound (142), known as DRF-2189, was selected for further evaluation as a potential candidate for clinical studies. Similarly, several pyridyl- and quinolinyl containing 2,4thiazolidinediones having interesting cyclic amines as a linkers were prepared (144-147), as shown in Table 9 [53]. Oguchi et al. [54] designed and synthesized a series of imidazoylpyridine thiazolidinediones (148-153) starting from the corresponding pyridines, as shown in Table 10. These compounds represent conformationally restricted analogues of rosiglitazone (5). The synthetic method for each compound is described in Oguchi’s article [54]. Glitazones contain a stereogenic center at the C-5 position of the thiazolidinedione ring that is prone to racemization at physiological pH. Consequently, in animal models the individual enantiomers and racemates of glitazones show equivalent activity as antidiabetic agents, as shown by Sohda for the optical isomers of ciglitazone (2) [55]. Analytical methods for the separation of the enantiomers of rosiglitazone (5) have been described, using an asymmetric biosynthesis of (R)-(+)-rosiglitazone (5) [56]. The two enantiomers of rosiglitazone have been separated by chiral HPLC, showing that the S-enantiomer was more active in biological studies than the R-enantiomer [57]. This finding has been supported
acid in the presence of DCC and DMAP to yield the thiazolidindionylethyl methacrylate (133), as shown in Scheme 18. The pioglitazone monomer (133) was polymerized in the presence of benzoyl peroxide (BPO) to yield the conjugate pioglitazone polymer (134). Polymerization of (133) with methacrylic acid gave copolymer (135), as shown in Scheme 19 [47]. e. Rosiglitazone Rosiglitazone (Avandia®) was approved by the US Food and Drug Administration (FDA) in May 1999. Rosiglitazone maleate (AVANDIA) is an oral antidiabetic agent, which acts primarily by increasing the insulin sensitivity. AVANDIA improves glycemic control while reducing circulating insulin levels. Rosiglitazone maleate is not chemically or functionally related to sulfonylureas, biguanides, or -glucosidase inhibitors [48, 49]. Rosiglitazone (5) (±)-5-[[4-[2-(methyl-2-pyridinylamino) ethoxy]phenyl]methyl]-2,4-thiazolidinedione, has a single chiral center and is used as racemate, since due to rapid interconversion, the enantiomers are functionally indistinguishable. Several potent compounds of a series of [(ureidoethoxy) benzyl]-2,4-thiazolidinediones and [[(heterocyclicamino)alkoxylbenzyl]-2,4-thiazolidinedione and 5-[4-(pyridylalkoxy)benzyl]-2,4thiazolidinediones, were synthesized by Cantello et al. in 1994 [50]. Posterior modifications based upon a metabolite of ciglitazone led to the discovery of rosiglitazone (5) (BRL-49653), which was selected as candidate for clinical studies, and its hypoglycemic and hypolipidemic activity was reported [50,51]. For the preparation of rosiglitazone (5), 2-chloropyridine (136) was converted to 2-(methyl-2-pyridinylamino)ethanol (137), which
H3C
S
N
N
O Pioglitazone 4
u b i r
t is
D r o F t o O
H3C
NH
i
n tio
N
O
S 132
O
O
H3C
O
ii
O
O
N
OH
N
O S
N
O O Scheme 18. Reagents and conditions. i) iodoethanol, NaH, DMF, 0 oC to rt, 24 h, ii) methacrylic acid, DCC, DMAP, MC/THF, rt, 3h. 133
C O H3C N
N
O
S 133
N
134
n
O O
N O
i
O H3C
S
O
CH2
O O
O
ii
C O
H3C N
O
S
N
CH2 O
O
135 O Scheme 19. Reagents and conditions. i) benzoyl peroxide (12%), THF, 70 o C, 48h, ii) methacrylic acid, benzoyl peroxide, THF, 70 oC, 48 h.
C m
H2 C n
120 Current Organic Chemistry, 2011, Vol. 15, No. 1
Ortiz and Sansinenea
i
ii
Cl
N
N
136
OH
N
137
N
O
N Me
Me
138
CHO O
O Me
Me iii
N
N
S
O
NH
N
iv
N
O
O
Rosiglitazone 5
O
139
NH
S
Scheme 20. Reagents and conditions for the preparation of rosiglitazone. i) CH3NHCH 2OH, 150 oC, ii) NaH, DMF, 4-fluorobenzaldehyde, 80-120 oC, iii) 2,4thiazolidinedione, piperidine, acetic acid, toluene, reflux, iv) Mg, methanol. Table 9.
through a single-crystal X-ray diffraction analysis of the complex formed between the receptor and the S-enantiomer of rosiglitazone [58]. However, attempts to use the eutomer for therapeutic purposes turned futile when it was observed that the pure enantiomer underwent rapid racemization under physiological conditions, giving no net advantage of the tedious separation or synthesis of enantiomerically pure compounds [55, 56]. Table 8.
Pyridyl and Quinolinyl Analogues of 2,4-Thiazolidinediones Reported by Lohray et al.
Ar
u b i r O
t is Compound
O NH
D r o F t o S
O
O
Compound
R
140
N
N
Indole and Azaindole Analogues of 2,4-Thiazolidinediones Reported by Lohray et al.
R
N
Yield (%)
N
141
N
142
N
70
n tio O
144
145
N
Ar
N
S
NH
O
Yield (%)
65
N
N
O
88
N
N
63
146 N
83
92
Me
N
95
147 N
3. NOVEL THIAZOLIDINEDIONES 143
N
N
80
The differential rates of racemization between thiazolidinediones have been attributed to the differential rates of keto-enol tautomerism in these compounds [28, 59]. However, Hulin et al. [35] proposed that reversible S-oxide formation in vivo may be causing this racemization. To verify whether enolization or sulfoxide formation in glitazones is of importance in the mechanism for rapid racemization, Bharatam et al. realized ab initio molecular orbital and density functional studies. They concluded that the mechanism involving the formation of S-oxide derivative is thermodynamically and kinetically more favorable in the rapid racemization of thiazolidinediones [60].
As it has been described in the previous section, the pioneering discovery of ciglitazone (2) by Sohda et al. in 1982 [23] (Takeda, Inc.) opened a new route for the generation of novel antihyperglycemic agents that reverse the insulin resistance in type 2 diabetes mellitus patients. Some of these compounds have been introduced in clinical studies, i.e. troglitazone (1) (Sankyo and Parke-Davis) [18], englitazone (3) (Pfizer) [29], pioglitazone (4) (Takeda Chemical Industries, Inc./Upjohn) [37] and rosiglitazone (5) (SmithKline Beecham) [51]. Many further thiazolidinediones have been synthesized more recently that could be promising compounds for clinical studies. Momose et al. [59] described the syntheses of 5-substituted 2,4thiazolidinediones (154-160), which are shown in Table 11. The synthetic method for each compound is described in Momose’s article [59].
Synthetic Thiazolidinediones: Potential Antidiabetic Compounds
Table 10.
Current Organic Chemistry, 2011, Vol. 15, No. 1 121
Imidazoylpyridine Derivatives of Rosiglitazone Reported by Oguchi et al.
R3
R2
O
O
R4 N N
N
N
NH
S
nO
N
O
S
O
NH O
152
R1 R1
R2
R3
R4
n
Synthesis Method a
Yield (%)
148a
Me
Cl
H
H
1
A
53
148b
Me
H
H
H
1
A
25
148c
Me
H
H
H
3
A
63
148d
Et
H
H
H
1
A
46
148e
4-Ph-C6H4CH2
H
H
H
1
A
74
148f
Me
H
Cl
H
1
A
77
Me
H
Br
H
1
A
Me
H
H
Me
1
A
148i
Me
Me
H
Me
1
A
149a
Me
OMe
H
H
1
B
149b
Me
OEt
H
H
1
B
149c
Me
OiPr
H
1
B
149d
Me
OBn
H
1
B
90
1
B
1
B
72
1
B
15
2
C
3
H
1
C
6
43
68
u b i r
t is H
H
H
77
91
80
95
149e
Me
SPh
H
149f
Me
Ph
H
149g
Me
OH
H
150a
Me
H
H
150b
Ph
H
H
150c
4-Cl-C6H4CH 2
H
H
H
1
C
16
150d
Me
H
CF3
H
1
C
8
151
H
H
H
H
1
D
62
E
45
F
37
H
H
H
152 153
Me
H
H
H
0
97
The synthetic method is described in reference [54].
Table 11.
-(Azolylalkoxy-Phenyl)Alkyl Substituted 2,4-Thiazolidinediones Reported by Momose et al. O (CH2)m O
N Ph
a
n tio
148g 148h
D r o F t o
N a
Compound
O
Me
R
S
NH
(CH2)n O
Compound
R
m
n
Synthesis Method a
Yield (%)
154
H
2
2
C
56
155
H
2
3
A
13
156
H
1
2
D
58
157
H
1
3
D
65
158
H
1
4
D
26
159
H
1
5
D
49
160
OMe
1
3
A
15
The synthetic method is described in reference [59].
122 Current Organic Chemistry, 2011, Vol. 15, No. 1
Ortiz and Sansinenea
neutral oxovanadium(IV)-thiazolidinedione complexes (170a-c) were prepared by refluxing vanadyl sulfate and two equivalents of the appropriate ligand precursor (169a-c) in mildly acidic aqueous medium (pH 5), as shown in Scheme 24. The ligand preparation was realized as described in reference [63]. As described above, the synthesis of the thiazolidinedione ring has been performed starting from the corresponding -halo ester or -halo nitrile followed by reaction with thiourea or potassium thiocyanate and acid hydrolysis. Another method to form the thiazolidinedione ring was described by Ortiz et al., combining oxazolidinethione (171) and bromoacetyl bromide through an intramolecular nucleophilic substitution reaction, as shown in Scheme 25 [64]. Due to the importance of -lipoic acid (1,2-dithiolane-3pentenoic acid) as anti-inflammatory agent, the design and synthesis of hybrid lipoic-thiazolidinedione derivatives has been reported. Condensing amine (175) with lipoic acid (176) via the mixed anhydride gave amide (177). Selective reduction of the S-S bond in the dithiolane ring was readily achieved using sodium borohydride in THF:H2O (10:1), furnishing dithiane (178), as shown in Scheme 26 [65].
Nomura et al. [61] prepared a series of 3-[(2,4-dioxothiazolin5-yl)methyl]benzamide derivatives and selected 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide (KRP-297) (163) as potential drug. Knoevenagel condensation of aldehyde (161) and thiazolidine2,4-dione gave (162) followed by amide bond formation. Subsequent reduction provided (KRP-297) (Kyorin/Merck) (163), as shown in Scheme 21 [61]. An alternative method for the preparation of 5-[(2,4dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide (KRP-297) (163), consist of a Meerwein arylation of aniline (164) in the presence of cuprous oxide to give (165), followed by cyclization with thiourea and subsequent amide bond formation, as shown in Scheme 22 [61]. Recently, Wang et al. reported an improved related synthesis of KRP-297 (163), as shown in Scheme 23 [62]. Vanadium has insulin-like properties and stimulated the development of vanadium compounds as alternatives to the conventional diabetes therapy. A series of vanadium complexes using ligands containing a thiazolidinedione moiety were produced [63]. The
CHO
MeO
t is iii
S
ii
MeO
O
NH
HO
i
n tio
u b i r
O
O
O
O
MeO 162
D r o F t o 161
iv
F3C
N H
MeO
163
O
NH
S
O
KRP-297
Scheme 21. Reagents and conditions for the preparation of the KRP-297. i) thiazolidine-2,4-dione, AcONH4, AcOH, benzene, ii) HC1-AcOH, iii) amine, diethyl phosphorocyanidate, Et3N, DMF, iv) H 2, Pd-C, AcOEt-EtOH.
O
O
NH2
MeO
N
O
MeO
i
OMe
iii
F3C
165
164
NH
N H
ii
Br
MeO
MeO
O
O
S
MeO
O
163
Scheme 22. Reagents and conditions for the preparation of the KRP-297. i) (1) NaNO2, HBr, MeOH-acetone, (2) methyl acrylate, Cu2O, ii) (1) thiourea, EtOH, (2) HCI, sulfolane, iii) 4-(trifluoromethyl)benzylamine, diethyl phosphorocyanidate, Et3N, DMF.
O
O
O
NO2
MeO
i
MeO
NH2
MeO Br
MeO
165
164
166 O
O
iii
OMe
ii
MeO
MeO
O
N
HO
iv S
MeO
NH2
NH
HO S MeO
167
v O
168 O
O
NH
N H F3C
O
O
S
MeO
O
163 Scheme 23. Reagents and conditions for the preparation of the KRP-297. i) (1) SnCl2 , HCl, H 2O, 30 h, rt; (2) NaOH, H2O, pH 7; (3) Na 2CO3 , H2O, pH 10, ii) (1) HBr, NaNO2, H2O, Me2CO, -2 oC to 0 oC; (2) methyl acrylate, Cu2O, 20 h, rt, iii) (1) thiourea, AcONa, EtOH, 15 h, reflux; (2) Na2CO3, H2O, Et2O, hexane, rt, pH 9, iv) HCl, H 2O, Sulfolane, 4 h, reflux, v) diethyl phosphorocyanidate, 4-(trifluoromethyl)benzylamine Et3N, DMF, 8h, rt.
Synthetic Thiazolidinediones: Potential Antidiabetic Compounds
Current Organic Chemistry, 2011, Vol. 15, No. 1 123
O O
OH
O
O
i V O R
R
O 170 (a-c)
169(a-c) O S
O S
NH
R= HN
O S
NH
O
NH
O
O
O
a
O c
b
Scheme 24. Reagents and conditions. i) VOSO 4, H2O.
S O
NH
i
O
O
O ii
N
O iii
N
O 174
O
O
173
172
171
n tio
S
S
S
OH
N
u b i r
Scheme 25. Reagents and conditions: i) NaH, 0 oC, BrCOCH 2Br, -78 oC CH 2Cl2 , ii) NaIO4 , OsO 4, THF/H2O, iii) L-selectride, THF -78 oC. O S S O O i NH O N S S S S n HCl.HN O NH O O 177 175 n OH O 176
t is
D r o F t o
n = 1 or 4
SH
O
SH
ii
n
N
N
O
O
S NH
178 O
Scheme 26. Reagents and conditions: i) i-PrOCOCl, Et3N, DCM, 3 h, ii) NaBH4, THF-H2O, 0 °C, 1 h. CHO H N C O O i H +
HO
S
179
HO
52
S
CH2Cl
O
CH2
181
O
O ii NH
O
F
S
O
CH2 F
NH HO
180
S
iii
CH2
NH
O
182 Netoglitazone, MCC-555
O
Scheme 27. Reagents and conditions for the preparation of netoglitazone. i) piperidine, MeOCH2CH 2OH, ii) H2, Pd hydroxide, AcOEt, iii) NaH, DMF.
Netoglitazone, 5-[[6-[(2-fluorophenyl)methoxy]-2-naphthalenyl]methyl]-2,4-thiazo-lidinedione, (MCC-555) (183) is currently being investigated in clinical trials by Johnson and Johnson Pharmaceutical Research and Development, L.L.C, outside of Japan, [66] due to its antidiabetic activity [67, 68, 69]. This compound contains a thiazolidinedione (TZD) moiety and its synthesis was realized by Ueno et al. [70] (Mitsubishi Chemical Industries LtdTokyo Pharmaceuticals in the UK and Japan) [71]. 6Hydroxynaphthalene-2-carbaldehyde (179) was condensed through a Knoevenagel condensation reaction with 2,4-thiazolidinedione (52) to obtain compound (180), which was hydrogenated to obtain
(181). A subsequent Williamson reaction gave the desired netoglitazone (182), as shown in Scheme 27. In 2006, Sun et al. [72] realized an improvement of the synthesis of netoglitazone (182), as shown in Scheme 28. Rivoglitazone, 5-[[4-[(6-methoxy-1-methyl-1H-benzimidazol2-yl)methoxy]phe-nyl]methyl]-2,4-thiazolidinedione, (187) is currently being developed by Daiichi Sankyo Co., Ltd. [73] as a new oral agent for the treatment of type 2 diabetes [74, 75, 76] [Patent: EP-00745600, US-05886014]. This compound contains a thiazolidinedione (TZD) moiety and its synthesis was realized first by Nakamura et al. [73e]. Of the TZDs in clinical use or development
124 Current Organic Chemistry, 2011, Vol. 15, No. 1
Ortiz and Sansinenea
CHO
S
H N
O
O
+
O
C H
i
ii NH
HO
S
HO
179
180
52
O
CH2Cl F
S
F
O
C H O
S
CH2
NH
O
O
183
O
CH2 iii
NH CH2
F
O
182
Scheme 28. Reagents and conditions: i) piperidine, AcOH, PhMe, 4.5 h, reflux, ii) NaOH, Bu4 N.Br,H2O, PhMe, rt to 100 o C, 2.5 h, 100 oC, iii). H2, Pd, MeOH, dioxane, rt to 105 oC 4h. O
S NH2
N
OBut
C
t
O
+
O
O
NH
Me O
i
BuO
N
Me NH
H N
O
O
OMe 184
O
MeO
O
HO
O
186
u b i r
185
S
O
N
t is O
ii
O
n tio
S
N H
. HCl
187 Rivoglitazone Me Scheme 29. Reagents and conditions for the preparation of rivoglitazone. i) propanephosphonic acid cyclic anhydride, Et3N, CH2 Cl2 , AcOEt, ii) HCl, MeOH. N
MeO
D r o F t o
for the treatment of type 2 diabetes, rivoglitazone appears to be one of the most promising candidates. For the preparation of rivoglitazone, N-(2-Amino-5methoxyphenyl)-N-methylcarbamic acid tert-butyl ester (184) was condensed with compound (185) to give (186), which was transformed into the final product rivoglitazone (187), as shown in Scheme 29. An improvement of the synthesis was realized by Nakamura et al. [73c] that consisted in the transformation of 4-[2,4dioxothiazolidin-5-yl)methyl]phenoxyacetic acid (185) into 2-[4[(2,4-dioxo-5-thiazolidinyl)methyl]phenoxy]acetyl chloride (188), as shown in Scheme 30. The following steps to achieve rivoglitazone (187) were the same as shown in Scheme 29. Lee et al. synthesized a series of erythrose, ribose and substituted pyrrolidine derivatives containing 2,4-thiazolidinediones [77]. They also reported pyridines and purines containing 2,4thiazolidinediones [78]. In order to enhance their glucose- and lipid-lowering activities, they focused their attention on the modifi-
N
O
O
S
S NH O
NH O
i
O
O O
HO
O Cl
185
188
Scheme 30. Reagents and conditions: i) SOCl2, C 5H5N, CH 2Cl2, rt., 35 h, reflux.
cation of the pyrimidine moiety. As a result, they developed a novel substituted pyrimidine derivative called lobeglitazone (194), (Chong Kun Dang Pharmaceutical Corp.) [79, 80]. Lobeglitazone, 5-[4-{2-(6-[4-methoxyphenoxy]-pyrimidin-4-yl) methylaminoetho-xy-}benzyl]thiazolidine-2,4-dione, (194), is a second generation glitazone, antidiabetic derivative whose mechanism of action consists of insulin sensitizer. At this moment the development stage phase I is completed and phase II is now explored in Korea. It has shown a good bioavailability with dualactivity, lowering both blood glucose and lipid. Further, it has a long plasma half-life (~10 hr in human) and excellent safety and convenient medication properties, (once-a-day administration is possible), [Patent: USP 6787551, WO 03/080605, KR 0450700]. The synthesis was performed with the commercially available 4,6-dichloropyrimidine (189), which was reacted with pmethoxyphenol and NaH in DMF to afford the monosubstituted pyrimidine (190). N-arylation of 2-methylaminoethanol with (190) gave the pyrimidinyl aminoalcohol (191). The aldehyde (192) was prepared by O-arylation of the aminoalcohol (191) with 4fluorobenzaldehyde in the presence of NaH in DMF. Knoevenagel condensation of (192) with 2,4-thiazolidinedione in the presence of piperidine in EtOH afforded alkene (193). The olefin moiety of the benzylidene-2,4-thiazolidinedione (193) was reduced with Pd(OH)2 over carbon under hydrogen atmosphere to give the benzyl-2,4thiazolidinedione, lobeglitazone (194), in 75% purified yield, as shown in Scheme 31 [79]. Since the hydrogenation required a prolonged reaction time (about 60-72 h) together with potential safety problems, the authors developed a regioselective reduction of the benzylidene (193) to afford lobeglitazone (194), using the Hantzsch ester and SiO2 as catalyst [80].
Synthetic Thiazolidinediones: Potential Antidiabetic Compounds
Current Organic Chemistry, 2011, Vol. 15, No. 1 125
OCH3
OCH3 Cl
O
O i
N
ii
N 189
Cl
N 190
iii
N
N
N
Cl
OH
N 191
CH3 OCH3
OCH3 O
O
iv
v N
N N
O
N CH3
N
O
O
N
S 193 O
OCH3
u b i r
O N N
N
t is
O
S
CH3
D r o F t o 194
n tio
NH
CH3 CHO
192
Lobeglitazone
O
NH
O Scheme 31. Reagents and conditions for the preparation of lobeglitazone i) p-methoxyphenol, NaH, DMF, rt, 10 h, ii) 2-methylaminoethanol, EtOH, reflux, 24 h, iii) 4-fluorobenzaldehyde, NaH, DMF, rt, 5 h, iv) 2,4-thiazolidinedione, piperidine, EtOH, reflux, 24 h, v) Pd(OH)2, H2, DMF, rt, 36 h.
4. CONCLUDING REMARKS
Type 2 diabetes develops resistance and -cell dysfunction in the presence of insulin. Insulin resistance is associated with various risks for cardiovascular disease. Thiazolidinediones constitute an attractive treatment option, because they reverse insulin resistance and have the potential to improve many of the associated abnormalities in patients with type 2 diabetes. Besides ciglitazone, which was the first in the thiazolidinedione drug class, and pioglitazone and rosiglitazone, which are the two currently commercial available thiazolidinediones, many more derivatives were synthesized such as troglitazone, englitazone and darglitazone that, however, did not have success due to their toxicity. Many aspects of the interaction mechanism of thiazolidinediones remain obscure and need further exploration. Because of this, several new thiazolidinediones are explored in clinical studies for the treatment of type 2 diabetes. These include KRP297, netoglitazone (MCC-555), rivoglitazone and lobeglitazone. In this review we have focused on thiazolidinedione compounds that have been synthesized, in their chemistry and in their synthesis and how the need for the continued development of new antidiabetic agents, that are either more effective than currently available therapies, has lead to the synthesis of new analogues. Our knowledge of finding new structures and their mode of action should aid in future research to design new antidiabetic agents.
N
(from Morelos State University, UAEM) for critical reading of the manuscript. REFERENCES
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Accepted: 08 December, 2009
