synthesis of pteridines derivatives from different heterocyclic
TRANSCRIPT
www.derpharmachemica.comt Available online a
Scholars Research Library
Der Pharma Chemica, 2014, 6(3):194-219 (http://derpharmachemica.com/archive.html)
ISSN 0975-413X CODEN (USA): PCHHAX
194 www.scholarsresearchlibrary.com
Synthesis of pteridines derivatives from different heterocyclic compounds
Sayed A. Ahmed*, Ahmed H. Elghandour and Hussein S. Elgendy
Department of Chemistry, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt _____________________________________________________________________________________________ ABSTRACT A great attention has been paid to synthesize new compounds with new sites of action. In this context, the synthesis of pterdinies derivatives has been extensively studied because of their biological importance. They are known to regulate many biological processes and their deficiency induces many disease processes. In this mini review we aim to summarize the structure and methods of pterdinies derivatives synthesis from pyrimidines, pyrazines and other different heterocyclic compounds. Keywords: Pteridines, Pyrimidines, Pyrazines, Heterocyclic compounds. _____________________________________________________________________________________________
INTRODUCTION In medicinal chemistry, the chemist attempts to design and synthesize a medicine or a pharmaceutical agent, which will benefit humanity. The chemistry of heterocyclic compounds is the most important in the discovery of new drugs. Study of these compounds is of great interest both in theoretical as well as practical aspects [1] . Pteridines, pyrazino[2,3-d]pyrimidine compounds, are a group of heterocyclic compounds composed of fused pyrimidine and pyrazine rings [2]. Pteridines research has long been recognized as important for many biological processes, such as amino acid metabolism, nucleic acid synthesis, neurotransmitter synthesis, cancer, cardiovascular function, and growth and development of essentially all living organisms. Defects in synthesis, metabolism and/or nutritional availability of these compounds have been implicated as major causes of common disease processes [3], e.g. cancer, inflammatory disorders, cardiovascular disorders, neurological diseases, autoimmune processes, and birth defects [4]. In more detailed, pteridines are one of the most important heterocycles exhibiting remarkable biological activities because these compounds are constituents of the cells of the living matters [5]. For example, pteridine, is a precursor in the synthesis of dihydrofolic acid in many microorganisms. Where, pteridine and 4-Aminobenzoic acid are converted by the enzyme dihydropteroate synthetase into dihydrofolic acid in the presence of glutamate [6]. At structural level, pteridines have two major classes, ‘conjugated’ pteridines, which are characterized by relatively complex side chains, e.g. the vitamins folic acid, and ‘unconjugated’ pteridines, e.g. biopterin or neopterin bearing less complex side chains at the 6-position of the pterin [7]. Moreover, there are three main classes of naturally occurring pteridines namely, lumazines, isoalloxazine and pterins. Lumazines and isoalloxazines have oxo-substituents at the 2- and 4- positions with the difference being a phenyl ring annealed in the 6- and 7- position on the isoalloxazine. The most common class of naturally occurring pteridines are the pterins which have an amino group at the 2-position and an oxogroup at the 4-position [8]. Studies on developing new methods for new pteridines derivatives synthesis are getting increase therefore; here we aim to elucidate all available structures and methods related to pteridines.
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
195 www.scholarsresearchlibrary.com
2 Structure and compounds of pteridines. Pteridine ring 1 system is a pigment and consist of pyrazine ring and pyrimidine ring. This compound was found in the wings of insects and the eyes and skin of fish, amphibbia and reptiles. Pteridine also contains 4-hydroxy groups and two amino groups. - Xanthopterin 2 is butterfly wing pigments and it found in human urine, pancreas, kidneys, liver and wasp wings - Also isoxanthopterin 3, leucopterin 4 and erythropterin 5 are known as butterfly wing pigments. - Biopterin 6 is a widely occurring natural pterin, isolated from human urine, fruit fly, royal jelly of bees and Mediterranean flour moth. Folic acid 7, is one the most important compounds comprising pteridine nucleus in its molecules.
N
N N
N
1
NH
N N
NH
OO
NH2
NH
N NH
N
O
O
NH2
NH
N NH
NH
O
O
O
NH2
NH
N N
NH
OO
NH2
OH
OH OH
Xanthopterin Isoxanthopterin
Leucopterin Erythropterin
23
45
NH
N N
NO
NH2
H
OH OH
HCH3
Biopterin
6
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
196 www.scholarsresearchlibrary.com
3 Synthesis of pteridines:- 3. 1. From pyridines. Pteridines derivatives 10 can be prepared from Pyrimidines via Isay reaction [9-15] by condensation of 4,5-diamino pyrimidine-2,6-dione 8 with dicarbonyl compounds 9 (Scheme 1).
Scheme 1 Also 2,4-di amino-5-nitroso pyrimidine-6-one 11 condensed with aldhydes and ketones to produce pteridines derivatives 12 (Scheme 2) [16,17].
Scheme 2 4,6-di amino-5-nitroso-2-phenyl pyrimidine 14 with an active methylene 13 give different compounds of pteridines according to condition of reaction (Scheme 3) [18-21].
N
N N
NOH
NH2 CH2NH CONHCH
CH2
COOH
COOH
Folic acid
7
NH
N
O
NH2O
NH2 R1
R
O
O
NH
NH
N
N
O
NH2 R
R1
+
8 910
NH
N
O
NH2NH2
NONH
N N
NO
NH2 C6H5
C6H5COCH2CH3
11 12
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
197 www.scholarsresearchlibrary.com
Scheme 3
Xu et al. was reported that Diels-Alder reaction leads to the formation of a pterin derivatives 21 (Scheme 4) [22].
Scheme 4 Reaction [23] of nitrosopyrimidine 22 with dimethylphenacylsulfonium bromides 23 produced 7-aryl-2-dimethylamino-3,4,5,6-tetrahydropteridine-4,6-diones 24 which reduced by sodium dithionite to yield 7,8-dihydro derivatives 25 (Scheme 5).
N
N NH2NH2
OBzNO
R
O
Cl
N
N NH
NH2
OBzNO
O
RN
N N
N
NH2
OBz
O
ROH
N
N NH
N
NH2
OBz
O
R
O
+
1718 19 20
21
KOAc
NH2NH2
N
N
NH2
NH2
ON
Ph
O
Ph
N
N
N
N
NH2
Ph
Ph
N
N
N
N
NH2
NH2 Ph
Ph
+
13 14
15
16
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
198 www.scholarsresearchlibrary.com
Scheme 5
The use of methylenenitrile 27 in the condensation with 5-nitroso-2,4,6- triamino pyrimidine 26 provided triamterene 28 (Scheme 6) [24,25].
Scheme 6 1,3-Dimethyl-2,4,7-trioxo-1,2,3,47,8 hexahydropteridine-6-carboxylic acid 31 was prepared by reaction of 6-amino-5-nitroso uracils 29 with Meldrum’s acid 30 (Scheme 7) [26].
Scheme 7 Abdel-Latif et al [27] found that (6-Amino-5-nitroso-1-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-ylidene) malononitrile 32 reacts with ethylacetoacetate 33a and diethyl malonate 33b, in the presence of sodium ethoxide to
NH
N NH2N
ONO
X
SO
NH
NN
O
N
NH
O
X
Na2S2O4
NH
NN
O
NH
NH
O
X
+
Br-
+
22 2324
25
N
N
NH2
NH2NH2
NO
N
Ph
N
N
NH2
NH2 N
N
NH2
Ph+
26 27
28
N
N
O
OR
1
R2
NH2
NO
O
O
O
O
N
N
O
OR
1
R2
NH
N
O
COOH
R1
R2
CH3
R1
R2
R1
C2H5 R2
+ Piperidine
Heat
= =
= = H
= , = H
29 30 31
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
199 www.scholarsresearchlibrary.com
afford (6-Acetyl-7-oxo-1-phenyl-2-thioxo-1,2,3,4,7,8-hexahydropteridin-4-ylidene) malononitrile 34a and Ethyl 4-dicyanomethylidene-7-oxo-1-phenyl-2-thioxo-1,2,3,4,7,8-hexahydropteridine-6-carboxylate 34b respectively (Scheme 8).
Scheme 8
Methylglyoxal 36 with 2-phenylpyrimidine-4,5,6-triamine 35 yields 7-methyl derivative 37, however, in the presence of hydrazine the 6-methyl derivative 38 is isolated as the only product indicating the regiospecificity of the reaction (Scheme 9) [28-30].
Scheme (9):- The regioselective, one-step synthesis of 2,6-disubstituted-4-aminopteridines 41 from 2-substituted-4,5,6-triaminopyrimidine 39, dihydrohalides and ketoaldoximes 40 (Scheme 10) [31].
NH
N NH2SPh
NO
CNNC
Y
O O
OEt
NH
NSPh
CNNC
NH
N
O
Y
O
+EtONa / EtOH
Y = Me (a) , EtO (b).
32 33 34 a,b
N
N
NH2
NH2
NH2Ph H
CH3O
O
KOAc
NH2NH2
N
N N
NNH2
Ph CH3
N
N N
NNH2
Ph
CH3
+
35 36
37
38
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
200 www.scholarsresearchlibrary.com
Scheme 10
6-arylpteridin-7-one 44 can be prepared in good yield by the reaction of 4,5-diamino pyrimidine 42 with the N-acetylindolone 43 (Scheme 11) [32].
Scheme 11
5,6-Diaminopyrimidines 45 reacted with dimethyl acetylenedicarboxylate (DMAD) 46 to afford the corresponding pteridines 48 on reflux in methanol in one step through formation an intermediate 47 (Scheme 12) [33].
Scheme 12
Ethyl 7-aminopteridine-6-carboxylates 51 can be synthesized by treatment of 1, 3-dialkyl-5,6-diaminouracils 49 by unsaturated carbonyl compounds such as diethyl (E)-2,3-dicyanobutenedioate 50 (Scheme 13) [34].
N
N
NH2
NH2
NH2
R1 N
O
R2
OHN
N N
NNH2
R2
R1
H, SCH3, NH2, C6H5R1
R2
X = Cl, Br
CH3, CH2CH3, CH2X, C6H5, p-CH3-C6H4
+ +2HX MeOH
31-97%
=
=
3940
41
N
N
NH2
NH2 NAc
O
ON
N NH
N
ONHAc
+EtOH, reflux
77%
4243 44
N
N
OR
MeX NH2
NH2
CO2Me
CO2Me
N
N
OR
MeX NH2
NCO2Me
CO2CH3
N
N NH
NO
R
MeX O
CH2CO2Me
+MeOH, rt
5 min
R = H , Me
X = O , S
45 4647 48
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
201 www.scholarsresearchlibrary.com
Scheme 13
The reaction of 4,5-diamino-1,3-dimethyluracil 52 with benzylglyoxal 53 gave a mixture of pteridines, which were separated by column chromatography. However, when 2,4,5,6-tetraaminopyrimidine 55 reacted with benzylglyoxal 53 at pH 9–10, only the 7-benzyl pteridine 56 was obtained, which on hydrolysis afforded thecorresponding 4-oxopteridine 57. On the other hand, if the reaction was carried out at a pH below 8, a mixture of 6- and 7- benzylpteridines formed. In yet another method for introducing differentiated reactivity at carbon, the 6-benzylpteridine 61 was obtained selectively by the reaction of 2, 4, 5-triaminopyrimidin-5(1H)-one 58 with 2-bromo-3-phenylpropanal 59 (Scheme 14) [35].
Scheme 14 Condensation of 2,5,6 tri aminopyrimidine-4-(3H)-one 58 with the phenyl hydrazon derivative of a sugar 62 leads to the 6 substituted 2-aminopteridin-4(3H)-one 63 (Scheme 15) [36].
N
NX
OR
1NH2
NH2
R 2
O
O
CN
CN
OEtEtO N
NX
OR
1
R 2NH2
O
OEt+EtOH
reflux
49 50 51
N
N
O
O
NH2
NH2
O
O
HN
N
O
O N
N R1
R2
R1
CH2Ph R2
R1
H R2
CH2Ph
N
N
NH2
NH2
NH2NH2
O
O
H N
N
NH2
NH2 N
NNH
NNH2 N
NO
NH
N
ONH2
NH2NH2
H
O
BrNH
N
O
NH2 N
NH
NH
N
O
NH2 N
N
+
= , = H (28%)
= , = (59%)
+ PH 9-10
60%
0.1 M NaOH
80%
+
52 53 54
55 53
56
57
5859
60 61
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
202 www.scholarsresearchlibrary.com
Scheme 15 5, 6-diaminouracils derivatives 64 can be reacted with Ethoxy-imino-acetic acid ethyl ester 65 and 2-Nitrilo-acetamidic acid methyl ester 67 to yield 6-amino,7-hydroxy-tetrahydropteridine-2,4-dione 66 derivatives and 6,7-diaminolumazines 68 respectively ( Scheme 16) [37,38].
Scheme 16 2,4,5-Triaminopyrimidine-5(1H)-one 58 reacted with aliphatic fluorinated precursors to give different fluro pterins. In the case of bromotrifluoroacetone as the aliphatic precursor, the pyrimidooxazine was also isolated. 2-Amino-6-chloro-5-nitropyrimidin-4(3H)one 75 reacted with amino alcohol to give the 6-substituted pyrimidine 77 which on activation of the OH group with mesyl chloride and reduction of the nitro group with H2/Pd gave the 6-trifluoromethylpterin 79 (Scheme 17) [39-41].
NH
N
ONH2
NH2NH2
OH
OHR
NNH
Ph
OH
NH
N
O
NH2 N
N R
OH
OH
+
58 6263
N
N
O
O
NH2
NH2
R2
R1
NH
OEtEtO2C
NH
OMeNC
N
N
O
O N
N NH2
OHR
2
R1
N
N
O
OR
2
R1
N
N NH2
NH2
100%
5-63%
64
65
66
67
68
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
203 www.scholarsresearchlibrary.com
Scheme 17 Condensing of 6-chloro-5-nitro-pyrimidine 75 with amino carbonyl compounds 80, in a reaction known as the Polonovski–Boon cyclization [42,43] to form dihydropterin which can be oxidized to afford fully oxidized pterin. This regiospecific reaction has been used in synthesizing functionalized tetrahydrobiopterin 83 (Scheme 18) [44,45].
NH
N
ONH2
NH2NH2
ClF2CCOR NH
N
O
NH2 NH
N R
FF
ClF2CO2Et
NH
N
O
NH2 NH
NH
FF
O
BrCH2COCF3
NH
N
O
NH2 N
N CF3
NH
NNH2 NH2
NHO
CF3
NH
N
O
ClNH2
NO2CF3OH
NHCH2Ph
NH
N
O
NH2
NO2
NOH
CF3PhCH2
MsCl NH
N
O
NH2
NO2
NOMs
CF3PhCH2
H2/Pd
NH
N
O
NH2 N
N CF3
CF3COCOCF3
NH
N
O
NH2 N
N CF3
CF3 ClCF2COCF3
F
NH
N
O
NH2 NH
N CF3
F
+
+
i-
ii- DDQ
58
69
70
71
7273
74
7576 77
78
79
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
204 www.scholarsresearchlibrary.com
Scheme 18 Treatment of 2,4,5-triamino-6-butoxypyrimidine 84 by 2-formyloxiranes 85 to afforded 6-(1-hydroxyalkyl)-substituted pteridines (Biopterin) 87 (Scheme 19) [46,47].
Scheme 19 Condensation of 5,6-diamino-2-methoxypyrimidin-4(3H)-ones 88 with protected pentose phenyl hydrazones 89 of both D- and L-series such as D-ribose, D- and L-xylose, D- and L-arabinose which yielded pyrano[3,2-g]pteridines 91 (Scheme 20) [48-53].
NH
N
O
ClNH2
NO2 O
NH2
NH
N
O
NH
NH2
NO2
O
NH
N
O
NH
NH2
NH2
O
NH
N NH
NO
NH2
+
7580
8182
83
N
N
OBu
NH2NH2
NH2 H
O
O
OR
I2/HCO2H N
N
OBu
NH2 N
NOH
ORN
N
OBu
NH2 N
NOH
OH
AcO
O
HH
+MeOH
aqous KOH
R =
84 85 86 87
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
205 www.scholarsresearchlibrary.com
Scheme 20 6-Amino-2-(benzylsulfanyl)pyrimidin-4(3H)-one 92 was treated to give 5,6-Diamino-2-(benzylsulfanyl) pyrimidin-4(3H)-one 93 to react with biacetyl to yield 2-(Benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone 94 (Scheme 21)
[54].
Scheme 21 Reaction of 2,4,5-tri amino-6-hydroxy pyrimidine 95 with glyoxal, Bi acetyl, oxalic acid and benzil afforded to 2-amino-4-hydroxy pteridine, 2-amino-4-hydroxy-6,7-di methyl pteridine, 2-amino-4,6,7-tri hydroxy pteridine and 2-amino-6,7-di phenyl peteridine respectively 96 a-d (Scheme 22) [47,55].
Scheme 22 Reaction of α-bromo-β,β-diethoxypropanal 97 with 2,4,5-triamino-6-hydroxy pyrimidin 95 which by oxidation of the resulting 5,6-dihydropterin 98 and hydrolysis of the acetal (Scheme 23) [56].
N
N NH2O
RO
NH2
CH=NNHPh
CHOHCHOHCHOHCHOHCH2OH
MeOH/H2O/HClN
NO
RO
NH
N
O
OHOH
H
H
N
NO
RO
N
NOH
OH
OH+
2-mercapto ethanol
reflux
O
88
89
90 91
NH
N
O
NH2PhCH2S
HNO2
Na2S2O4
NH
N
O
NH2PhCH2S
NH2
R1
R1
O
O
NH
N
O
PhCH2S N
N R1
R1
R1
R1 CH2Ph
EtOH, reflux
a = Me 85%
b = 15%
92 9394
N
N
OHNH2
NH2NH2
R
R
O
O
N
N N
NOH
NH2
R
R
+11
a, R = R = H
b, R = R = CH3
c, R = R = OH
d, R = R = Ph
1
1
1
1
95 96
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
206 www.scholarsresearchlibrary.com
Scheme 23 Waller et al found that condensation of 2,4,5-triamino-6-hydoxypyrimidine 95 and 2,3 - Dibromopropionaldehyde 100 and p-aminobenzoylglutamic acid 101 were afforded Ptereidines derivatives 102 (Scheme 24) [57].
Scheme 24 Condensation of 5-arylazo-4-chloropyrimidines 104 with α-aminoketones or esters, followed by reduction (usually with Zn/HOAc) and thermal cyclization. The phenylazo moiety serves both as a precursor of the 5-amino group. This also prepared from 5-nitro-4-chloropyrimidines 108 (Scheme 25) [58].
Scheme 25
N
N
OHNH2
NH2NH2
Br CH(OEt)2
CHON
N
OH
NH2 N
NH
CH(OEt)2
N
N
OH
NH2 N
NH
CHO+
1-[O]
2- H
95 9798 99
N
N
OHNH2
NH2NH2
Br CH2Br
CHOCORNH2
N
N N
N
NH2
OHCH2Q R
+ +
R= OH, OEt, GluEt
95100 101 102
N
N
OH
NH2 Cl
PhN2ClN
N
OH
NH2 Cl
N=NPhNH2CH2COR
N
N
OH
NH2 NHCH2COR
N=NPh N
N N
N ROH
NH2
N
N N
N OHOH
NH2
N
N
X
NH2 Cl
NO2
N
N
X
NH2
NO2
NHCH2COR
N
N N
N RX
NH2
Zn, HOAc, [O] heatR= Me
Zn, HOAc, [O] heatR= OEt
103 104 105 106
107
108 109 110
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
207 www.scholarsresearchlibrary.com
Condensation between 4,5-diamino-2,6-dimercaptopyrimidine 111 and p-dimethoxybenzil 112 to afforded 6,7-Bis-(p-methoxyphenyl)-2,4-(1H,3H)-pteridinedithione 113 which by S-Methylation tetrabutylammonium fluoride (TBAF), as base, and an excess of methyl iodide, as alkylating agent, afforded dimethyl derivatives 114 (Scheme 26) [59].
Scheme 26 De Jonghe et al [60] found that, 5,6-diamino-pyrimidine derivatives were prepared by action of sodium ethoxide or sodium isopropoxide on 2,6-diamino-4-chloro-pyrimidine 115, to introduce an alkoxy substituent. Nitrosation of the pyrimidine ring, followed by reduction of the nitroso group (using sodium dithionite in water), the product was reacted with glyoxal, affording 2-amino-4-alkoxy-pteridine [61] Oxidation of product in trifluoroacetic acid with 30% H2O2 afforded the N-(8)-oxide derivative. The chlorine was introduced using acetyl chloride and trifluoroacetic acid, yielding 2-amino-4-alkoxy-6-chloro-pteridine 122 (Scheme 27) [62].
Scheme 27
Reagents and conditions: (a) R4H, Na, 160 _C, 6 h, 72%; (b) NaNO2, CH3COOH, H2O, 80 _C, 68%; (c) Na2S2O4, H2O, 60 _C, 61%; (d) glyoxal, ethanol or isopropanol, reflux, 4 h, 62%; (e) TFA, H2O2, 4 _C, 2 d, 32%; (f) AcCl, TFA, _40–0 _C, 72%; (g) ArB(OH)2, Na2CO3, Pd(PPh3)4, dioxane, reflux, 4 h, 20–70%. Introduction of a nitroso group at position 5 of 2,6-diamino-4-hydroxy-pyrimidine 126 and its subsequent reduction yielded the 5,6-diamino-pyrimidine derivative 128. The 6-(3,4-dimethoxyphenyl)-pteridine 129 was constructed by condensation reaction between pyrimidine and a-ketoaldoxime (which was prepared from the corresponding acetophenone derivative by oxidation with SeO2, followed by displacement reaction (Scheme 28) [60].
NH
NH
S
S
NH2
NH2
O
O
OMe
OMe
NH
NH
S
S
N
N
OMe
OMe
N
N
SMe
SMe
N
N
OMe
OMe
(Bu)4NF, THF
MeI+
111 112113 114
N
N
Cl
NH2NH2
N
N
R 4
NH2NH2
RN
N N
NR 4
NH2
N
N N
NR 4
NH2
O
N
N N
NR 4
NH2
Cl
N
N N
NR 4
NH2
R 6
NH2
-
+
ad e f
g
116: R = H
117: R = NO
118: R =
R = ethoxy or isopropoxy4
b
c
115 116 119120
121
122
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
208 www.scholarsresearchlibrary.com
Scheme 28 Reagents and conditions: (a) NaNO2, CH3COOH, H2O, 97%; (b) Na2S2O4, H2O, rt, 83%; (c) SeO2, dioxane, H2O, 50 _C; (d) acetonoxime, CH3OH, H2O, 50 _C, 2 h, 71% (over 2 steps); (e) 15, CH3OH, reflux, 3 h, 85. 3.2. From Pyrazines. 4-hydroxy pteridine [63] 131 can be prepared by the condensation of 3-amino pyrazine-4-carboxamide 130 with formic acid (Scheme 29).
Scheme 29 Cyclisation of 3-aminopyrazine-2-carboxamide 132 or its thio-analogue with triethyl orthoformate in acetic anhydride gave pteridin-4-one or-4-thione 133, respectively (Scheme 30) [64].
N
N
NH2
CONH2
N
N
N
N
OH
HCOOH
130 131
N
N
OHR
NH2NH2
NH
N N
N
OMe
OMe
O
NH2
OMeO
MeONOH
OMeO
MeOO
OMeO
MeO
e
d
c
126 : R = H
127 : R = NO
128 : R = NH2
a
b
126
123124
125
129
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
209 www.scholarsresearchlibrary.com
Scheme 30 Gabriel et al [65] found that pyrazine-2,3-dicarboxamide 134 by Hofmann reaction into lumazine (pteridine-2,4-dione) 136 (Scheme 31).
Scheme 31 2-amino-3-cyanopyrazine-5-carbaldehyde 137 was converted to dimethylacetal 138 which was cyclized to 2,4-diamino-5-formyl pteridinemethylacetal 139 with guanidine gave the dimethylacetal of 6-formylpterin 140, which was converted to 6-Formylpterin 141 with formic or trifluoroacetic acid (Scheme 32) [66].
Scheme 32 4-Unsubstituted pteridines 144 have been prepared by a modification of this route using pyrazinecarbaldehydes 142 as starting materials (Scheme 33) [67].
N
N
NH2
CNH2
X
N
N
N
NH
O
CH(OEt)3
Ac2O
X = O , S
132 133
N
N CONH2
CONH2N
N
NH
NH
O
ON
N CONH2
NCO
KOBr
134 135 136
N
N
NH2
NC CHO
N
N
NH2
NC CH(OMe)2
N
N N
NNH2
NH2
CH(OMe)2
N
N N
NOH
NH2
CH(OMe)2
N
N N
NOH
NH2
CHO
137 138139
140
141
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
210 www.scholarsresearchlibrary.com
Scheme 33 Methyl-3-(triphenylphosphoranylideneamino)pyrazine-2-carboxylate 145 used to obtain different pteridines by reaction with isocyanates followed by adding alcohols or amines (Scheme 34) [68,69].
Scheme 34
Methyl 3-chloropyrazine-2-carboxylate 150 and guanidine 149 were reacted to yield 2-aminopteridin-4-one 151. The product is best purified via the sodium salt; Methylation of pterin gives the unexpected N-methylated product 152 (Scheme 35) [70,71].
Scheme 35 Guanidine 149 was reacted again with Pyrazine derivatives 153 to afford new 4-imino pteridine derivatives154 (Scheme 36) [72].
N
N
NH2
CHO
N
N
N
N
RN
N
NHCOR
CHO NH3
142143 144
NH2
NH2NHN
N
Cl
MeO2CNH
N N
NO
NH2
N
N N
NO
NH2
Me
+
149 150 151152
N
N
N=PPh3
CO2Me
N
N
NCNR
CO2Me
R NH2
N
N
N
NR
O
NHR
N
N
N
NR
O
OR
RNCO
benzene , RT R OH
1
1
1
1145 146
147
148
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
211 www.scholarsresearchlibrary.com
Scheme 36 Substituted amidines have been found to react in good yield to give 6,7-unsubstituted pteridines from the corresponding pyrazine. Similarly, methyl-2-aminopyrazine-3-carboxylate 159 condensed, with the bis(dithioimidate) 158 giving access to an unusual N-3-substituted 2-methylthiopteridine-4-one 160. Also 1,3-dimethyllumazine system 163 can be prepared from methyl isocyanate 161 and a 5-aminomethyl-6-cyanopyrazine 162.The 5-chloromethylpyrazine 164 was reacted firstly with substituted aromatic amines and then with guanidine to form the compounds for evaluation (Scheme 37) [73].
Scheme 37
NH2
NH2NHN
N
MeNH Me
NCN
AcPh
N
N
Me
NAcPh
N
N
NH
MeNH2
+
149 153154
NH2
NH
OEt N
N
NH2
NCN
N N
NNH2
EtO
N
MeS SMe
CO2Et
N
N
NH2
MeO2CN
N N
NO
MeS
EtO2C
N
O
Me
N
N Br
NH
NC
Me
N
N N
NO
O
Me
Me
N
N
NH2
NCCl
N
N N
NNH2
NH2
NAr
Me
Cl n-C6H13
+
+
+
i- ArNHMe
ii- guanidine, 61-87%
Ar = ,
155156 157
158 159 160
161162 163
164165
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
212 www.scholarsresearchlibrary.com
2-aminopyrazine also reacted with isothiocyanates, isocyanates, or dithioketals to afford the corresponding pteridines. For example, with ethyl isothiocyanatoacetate, and ethyl isocyanatoacetate, the corresponding thioureidopyrazine and urethane derivatives, respectively, were obtained, which, on cyclization in the presence of sodium ethoxide, gave 2-thio and oxo-N-3-protected pteridines in good yields. on reaction with methyl iodide, afforded a 2-methylthiopteridine 171 was also obtained directly from by the condensation with ethyl N-[bis(methylthio)methylene]glycinate also reacted with phosphorusoxychloride to give a 2-chloro derivative 168, which was reacted with pyrrolidine, giving 2-pyrrolodinyl pteridine-4-one derivatives 169. Hydrazine hydrate reacted with 2-methylthioderivatives to give N-aminolactam derivatives 172 (Scheme 38) [74].
Scheme 38
N
N
N H 2
C O 2 M e
N
N
N H C X N H C H 2 C O O E t
C O 2 M eO O E tX C N
M e S S M e
N C O O E t
N
N
N
N
O
S M e
C O O E t
N
N
N
O
NN
O
N H 2
N H 2 N H 2 . H 2 O
N
N
NH
N
O
C O O E t
X
P O C l 3
N
N
N
N
O
C l
C O O E t N H 2 N H 2 . H 2 O
N
N
N
N
O
N R
C O O E t
N H - C 5 H 1 1
N
ON
M e I
N a O E t
a m in e s
a X = Sb X = O
a N R =
b N R =
c N R =
1 6 6
1 6 7
1 6 8
1 6 9
1 7 0
1 7 1
1 7 2
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
213 www.scholarsresearchlibrary.com
series of imino thioacetals [74] 2-(methylthio)-2-thiazoline 177a ,5,6-dihydro-2-(methylthio)-4H-1,3-thiazine 177b, 2-(methylthio)-2-imidazoline 173, 2-(methylthio)-1,4,5,6-tetrahydropyrimidine 175 and 2-(methylthio)-2-pyrazine 179 ,reacted readily with 2 aminopyrazine 159 to give the desired tricyclic fusion products, thiazolo[2,3-b]pteridine derivative 178a, thiazino[2,3-b]pteridine derivative178b [75,76] , imidazo[2,1-b]pteridine derivative 174, pyrimido[2,1-b]pteridine derivative 176 and pyrazino[2,1-b]pteridine derivative 180 respectively by one-step reaction (Scheme 39).
Scheme 39 6-anilinomethylpteridine derivatives 187 were prepared by the reaction of glycolic acid 182 with 5-metyl Pyrazine-2,3-dicarbonitrile 181 (Scheme 40) [72].
Scheme 40
N
N
NH2
CO2Me
(CH2)nN
NMeS
(CH2)n
N
N
N
N
N
O
N
N
Cl
N
N
N
O
N
N
N
N
SMe
N
N
N
O
N
N
(CH2)nN
SMeS
(CH2)n
S
N
N
N
N
O
159
173174
175
176
177178
179
180
178a; n=1178b; n=2
a; n=1b; n=2
N
N CN
CN
CH2OHCOOH
S2O8 , AgNO3
N
N
Me
CN
CN
HOH2CMnO2
PhNH2
N
N
Me
CN
CN
X
MeNH2
N
N
Me
CN
NHMe
PhNEt3SiH-CF3CO2H
N
N
Me
CN
NHMe
PhNHNH=C(NH2)2
N
N
Me
PhNH
N
N
NH
NH2
Me
+
2-
181 182 183 184
185186
187
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
214 www.scholarsresearchlibrary.com
The synthesis of 2-alkoxymethylpteridines has been achieved by the reaction of 3-aminopyrazine-2-carboxamide 130 with orthoesters 188 to give 2-alkoxymethylpteridine derivatives 191, which was synthesized by condensing 3-aminopyrazine-2-carbonitrile 156 with the acetoxyamidine 189 followed by the base hydrolysis (Scheme 41) [77].
Scheme 41 6-bromo-3-methyl amino Pyrazine-2-carbonitrile 162 underwent cross-coupling with propyne in the presence of bis(dibenzylidineacetone) palladium(0), tri-o-tolylphosphine, and copper (I) iodide to provide The pyrazines which was cyclized with methyl isocyanate to give corresponding pteridines 193 (Scheme 42) [78].
Scheme 42
Methyl-3-isothiocyanatopyrazine-2-carboxylate 194 reacted with (R)-(_)-2-amino-1-butanol 195 in the absence of base, which provided the pteridine derivative 196 and uncyclized pyrazine derivative 197 in similar amounts (Scheme 43) [79].
Scheme 43
N
N NH2
O
NH2
O
O
O
OR
Ac2O
N
NNH
N
O
RO
N
N NH2
CN
RONH2
NH
N
NN
N
NH2
RO
+
+
EtOH
aq.NaOH
130 188
156189
190
191
N
N Br
N
NC NEt3, MeCN
Pd(dba)2,P(o-tolyl)3,CuI
Me H N
N
N
NCMe
N
NMe
N
N
O
O
MeNCO
hydrolysis
162 192193
N
N COOMe
NCSNH2 CH2OH
EtN
NH
N
NO
S
EtOH
N
N COOMe
NH
NH
EtS
CH2OH+
THF, rt, 24h+
194 195 196 197
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
215 www.scholarsresearchlibrary.com
3.3. From different Heterocyclic compounds. Condensation of ethyl α-aminocyanoacetate 199 with diisonitrosoacetone 198 to give ethyl 2-amino-5-oximinomethylpyrazine-3-carboxylate1-oxide 200, which was cyclized with guanidine to pterin-6-carboxaldehyde oxime 8-oxide 201 direct hydrolysis of the oxime was not possible, but conversion to was achieved by reduction with sodium sulphite which gave 6-aminomethylpterin 202 followed by oxidation with iodine (Scheme 44) [80].
Scheme 44
Scheme 45
CH=NOH
CH=NOHO
NH2
CNEtOOC
N
N CH=NOH
NH2
EtOOC
O N
N CH=NOH
O
N
N
OH
NH2
Na2SO4
I2
N
NN
N
OH
NH2
CHO
+ +
-+
-
guan.
198 199200
201
202
NH2
CN
RO2CRO
NOH
N
N
O
RRO2C
NH2 N
N
O
RNH
N
O
NH2NH
N RNH
N
O
NH2
N
N RNH
N
O
NH2
NH2
CN
NCCH2Cl
NOH
OHC
N
N
ONH2
NC
CH2Cl N
N
OCH2Cl
N
N
NH2
NH2 N
N
CH2Cl
N
N
NH2
NH2
N
N
CH=CHPh
N
N
NH2
NH2
+ +
-+
-
++
-
+
-
203 204 205 206 207
208
209 210 211 212 213
214
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
216 www.scholarsresearchlibrary.com
Reaction of 3,3-dimethoxy- 1-pyrrolidinopropene 215 with nitrosyl chloride and addition of aminomalononitrile tosylate to the resulting oxime gave 2-amino-3-cyano-5-(dimethoxymethy1)pyrazine-1-oxide 217 which was deoxygenated to dimethylaceta with trimethyl phosphate then produce 6-aminomethylpterin 221 (Scheme 46) [85].
Scheme 46
2,4-Diaminopteridine-6-carboxlic acid 229 was prepared by base catalyzed condensation of 2-acetyl furan 222 and 2-furoyl chloride 223 to yield β-keto ester which by hydrolysis in KOH aqueous furnished the β-carboxlic acids which was treated with sodium nitrite and acidified leading to oximinoketone, Condensation of oximinoketone with malanonitrile tosylate in 2-propanol was gave the Pyrazine-N-oxide 226. The latter was deoxygenated giving aminocyanopyrazine 227 which cyclized readily with guanidine to give 2,4-diaminopeteridines 228 then oxidation to yield 2,4-diaminopeteridine-6-carboxlic acid 229 (Scheme 47) [86].
Scheme 47 5,8-dichloro-2,3-dicyanoquinoxaline 233 was prepared by reaction of 3,3,6,6- tetrachloro-1,2-cyclohexanedione 230 with diaminomaleonitrile 231 followed by treatment with pyridine then treated with an equimolar amount of
N
O CH(OMe)2
HON=CHCOCH(OMe)2
NH2
CNNC
N
N CH(OMe)2
NH2
O
NC
N
N CH(OMe)2
NH2
NC
N
N CH(OMe)2N
N
NH2
NH2N
N CH(OMe)2N
N
OH
NH2
N
NN
N
OH
NH2
CHO
NOCl. TsOH
+
-
215 216 217
218219220
221
OO
OO
Cl
OO
OC2H5
O OO
H
N
OH
ON
NNH2
NC
O
ON
NNH2
NC
N
N N
N O
NH2
NH2
N
N N
NNH2
NH2
CO2H
+
-
222
223
224225
226
227
228229
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
217 www.scholarsresearchlibrary.com
benzamidine in the presence of triethylamine to produce 4-amino-2-aryl-6,9-dichlorobenzo[g]pteridine 233 (Scheme 48) [87].
Scheme 48
CONCLUSION
Taken together, we have described some recent advances in the synthesis of pteridines derivatives from heterocyclic compounds. This review showed the significant development in pteridines synthetic methods, however, these derivatives are now being more popular because of its efficiency, and many new methods will probably be developed. Acknowledgment The authors are gratefully indebted to Dr. Emadeldin M. Kamel, Chemistry department, Faculty of science, Beni Suef University for his help.
REFERENCES [1] Vachala S. D., Der Pharma Chemica, 2012, 4, 255. [2] Hahn, F.E. and Jahnke, M.C. Angew. Chem. Int. Ed., 2008, 47, 3122. [3] Delgado JN and Remers WA, Wilson and Giswold’s-Textbook of Organic Chemistry Medicinal and Pharmaceutical Chemistry, 10th ed. Philadelphia:Lippincott Raven, 1998. [4] Milstien, S., Kapatos, G., Levine, R.A., Shane, B, Chemistry and Biology of Pteridines and Folates, Proceedings of the 12th International Symposium on Pteridines and Folates, National Institutes of Health, Bethesda, Maryland, 2002, XXIII, 677 p. [5] Sasada, T.; Kobayashi, F.; Sakai, N. and Konakahara, T. Organic Letters, 2009, 11, 2161. [6] Voet, D.; Voet, J.G. (2004). Biochemistry (3rd ed.). John Wiley & Sons.
[7] Enzinger C, Wirleitner B, Spöttl N, Böck G, Fuchs D, Baier-Bitterlich G. Reduced pteridine derivatives induce apoptosis in PC12 cells. Neurochem Int. 2002. [8] Negishi, E.; Hu, Q.; Huang, Z.; Qian, M. and Wang, G. Aldrichimica Acta, 2005, 38, 71. [9] Lehbauer, J. and Pfleiderer, W. Nucleosides Nucleotides 1997, 16, 869. [10] Purrmann, R. Justus Liebigs Ann. Chem., 1941, 548, 284. [11] Sen S. E. and Roach, S. L. Synthesis 1995, 756. [12] Elion, G.B.; Hitchings, G.H. and Russell, P.B. J. Am. Chem. Soc., 1950, 72, 78. [13] Marchal, A.; Melguizo, M.; Nogueras, M.; Sanchez, A. and Low, J. N. Synlett 2002, 255. [14] Forrest, H.S. and Walker, J. J. Chem. Soc. 1949, 79. [15] Pfleiderer, W.; Zondler, H. and Mengel, R. Justus Liebigs Ann. Chem., 1970, 741, 64. [16] Timmis, G.M. Nature, 1949, 164,139. [17] Steinlin, T. and Vasella, A. Helv. Chim. Acta, 2008, 91,435. [18] Pachter, I. J.; Nemeth, P. E. and Villani, A. J. J. Org. Chem., 1963, 28, 1197. [19] Pachter, I. J.; Nemeth, P. E. J. Org. Chem., 1963, 28, 1187. [20] Pachter, I. J.; Nemeth, P. E. J. Org. Chem., 1963, 28, 1203. [21] Pachter, I. J. J. Org. Chem., 1963, 28, 1191. [22] Xu, M. and Vasella, A. Helv. Chim. Acta, 2006, 89, 1140. [23] Taylor, E. C.; Takahashi, M. and Kobayashi, N. Heterocycles, 1996, 43, 437. [24] Baur, R.; Sugimoto, T. and Pfleiderer, W. Helv. Chim. Acta, 1988, 71, 53. [25] Greenber, S. and Moffatt, J. G. J. Am. Chem. Soc. 1973, 95, 4016.
Cl Cl
Cl Cl
O
O
NH2
NH2
CN
CNN
NCl
Cl
CN
CN
AR
NH2
NH
N
N
N
N
Cl
Cl
NH2
AR
+
230 231 232 233
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
218 www.scholarsresearchlibrary.com
[26] Mohit L. D, Pulak J. Bhuyan.,Synthetic Communications, 36: 3085–3090, 2006. [27] Abdel-Latif, E.; Mustafa, H. M.; Etman, H. A. and Fadda, A. A. Russian Journal of Organic Chemistry, 2007, 43, 443. [28] Forrest, H. S. and Walker, J. J. Chem. Soc. 1949, 2077. [29] Ivery, M. T. G. and Gready, J. E. Biol. Chem. Hoppe-Seyler, 1992, 373, 1125. [30] Waring, P. and Armarego, W. L. F. Aust. J. Chem., 1985, 38, 629. [31] Taghavi-Moghadam, S. and Pfleiderer, W. Tetrahedron Lett., 1997, 38, 6835. [32] Bergman, J.; Damberg, C. and Vallberg, H. Recl. Trav. Chim. Pays-Bas, 1996, 115, 31. [33] Molina, S.; Cobo, J.; Sanchez, A.; Nogueras, M. and De Clercq, E. J. Heterocycl. Chem., 1999, 36, 435. [34] Yamada, Y.; Yasuda, H.; Yoshihara, Y. and Yoshizawa, K. J. Heterocycl. Chem., 1999, 36, 1317. [35] Kim, Y.; Kang, Y. and Baek, D. Bull. Korean Chem. Soc., 2001, 22, 141. [36] Soyka, R.; Pfleiderer, W. and Prewo, R. Helv. Chim. Acta, 1990, 73, 808. [37] Abou-Hadeed, K. and Pfleiderer, W. Pteridines, 1998, 9, 175. [38] Singh, R. and Geetanjali, Russ. J. Org. Chem., 2006, 42, 136. [39] Dunn, C.; Gibson, C. L. and Suckling, C. J. Tetrahedron, 1996, 52, 13017. [40] Kolos, N. N.; Chebanov, V. A.; Orlov, V. D. and Surov, Y. N. Chem. Heterocycl. Compd., 2001, 37, 755. [41] Wamhoff, H. and Tzanova, M. Collect. Czech. Chem. Commun., 2003, 68, 965. [42] Boon, W. R.; Jones, W. G. M. and Ramage, G.R. J. Chem. Soc., 1951, 96. [43] Polonovski, M. and Jerome, H. Compt. Rend., 1950, 230, 392. [44] Bailey, S. W., Chandrasekaran, R. Y. and Ayling, J. E. J. Org. Chem., 1992, 57, 4470. [45] Bailey, S.W.; Rebrin, I.; Boerth, S.R. and Ayling, J.E. J. Am. Chem. Soc., 1995, 117, 10203. [46] Murata, S.; Sugimoto, T.; Ogiwara, S.; Mogi, K. and Wasada, H., Synthesis, 1992, 303. [47] Murata, S.; Kiguchi, K. and Sugimoto, T. Heterocycles, 1998, 48, 1255. [48] Lopez, M. D.; Quijano, M. L.; Sanchez, A.; Nogueras, M. and Low, J. N. J. Heterocycl. Chem., 2001, 38, 727. [49] Yao, Q. Z.; Zhang, Z. X. and Xiao, L. Acta Chim. Sin., 2002, 60, 343. [50] Guiney, D.; Gibson, C. L. and Suckling, C. J. Org. Biomol. Chem., 2003, 1, 664. [51] Gibson, C. L.; La Rosa, S. and Suckling, C. J. Tetrahedron Lett., 2003, 44, 1267. [52] Gibson, C. L.; La Rosa, S. and Suckling, C. J. Org. Biomol. Chem., 2003, 1, 1909. [53] Crean, C. W.; Camier, R.; Lawler, M.; Stevenson, C.; Davies, R. J. H.; Boyle, P. H. and Kelly, J. M. Org. Biomol. Chem., 2004, 2, 3588. [54] Adcock, J.; Gibson, C. L.; Huggan, J. K. and Suckling, C. J. Tetrahedron, 2011, 67, 3226. [55] Ikan R., Natural Products A laboratory guide; 2 nd ed. New Delhi Academic Press Elsevier; 2005: p 331-343. [56] Cain CK., US Patent. 2,667, 486 (Cl.260-251.5); 1954 Jan 26 US appl. 228, 139, 1951. May 24. [57] Sletzinger, M.; Reinhold, D.; Grier, J.; Beachem, M. and Tishler, M. J. Am. Chem. soc., 1955, 77, 6365. [58] Waller, C.W.; Hutchings, B.L.; Mowat, J.H.; Stokstad, E.L.R.; Boothe, J.H.; Angier, R.B.; Semb, J.; SubbaRow, Y.; Cosulich, D.B.; Fahrenbach, M. J.; Hultquist, M. E.; Kuh, E.; Northey, E. H.; Seeger, D. R.; Sickels, J. P. and Smith, J. M. J. Am. Chem. soc., 1948, 70, 19. [59] Boon, W. R. and Leigh, T. J. Chem. soc., 1951, 1497. [60] Martins Alho, M. A.; D’Accorso, N. B.; Ochoa, C.; Castro, A.; Calderón, F.; Chana, A.; Reviriego, F.; Páez, J. A.; Campillo, N. E.; Martínez-Grueiro, M.; López-Santa Cruz, A. M. and Martínez, A. R. Bioorg. Med. Chem., 2004, 12, 4431. [61] De Jonghe, S.; Marchand, A.; Gao, L.; Calleja, A.; Cuveliers, E.; Sienaert, I.; Herman, J.; Clydesdale, G.; Sefrioui, H.; Lin, Y.; Pfleiderer, W.; Waer, M. and Herdewijn, P. Bioorg. Med. Chem. Lett., 2011, 21, 145. [62] Pfleiderer, W. and Lohrmann, R. Chem. Ber. 1961, 94, 12. [63] Mohr, D.; Kazimierczuk, Z. and Pfleiderer, W. Helv. Chim. Acta, 1992, 75, 2317. [64] Albert; Brown and Cheeseman, J. chem. Soc., 1951, 474. [65] Gabriel, S. and Sonn, A. Ber., 1907, 40, 4850. [66] Taylor, E.C.; Henrie, R. N. and Portnoy, R.C. J. Org. Chem., 1978, 43, 736. [67] Albert and Okta, K. J. chem. Soc. C, 1971, 2357. [68] Okawa, T.; Eguchi, S. and Kakehi, A. J. Chem.Soc.,Perkin Trans.1, 1996, 247. [69] Okawa, T.; Kawase, M. and Eguchi, S. Synthesis, 1998, 1185. [70] Dick and Wood, J. chem. Soc., 1955, 1379. [71] Brown, D. J. and Jacobsen, N. W. ibid, 1961, 4413. [72] Tada, M.; Asawa, Y. and Igarashi, M. J. Heterocycl. Chem., 1997, 34, 973. [73] Rosowsky, A.; Wright, J. E.; Vaidya, C. M.; Forsch, R. A. and Bader, H. J. Med. Chem., 2000, 43, 1620. [74] Chowdhury, A.; Shibata, Y.; Morita, M.; Kaya, K. and Hiratani, K. J. Heterocycl. Chem., 2001, 38, 1173.
Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 _____________________________________________________________________________
219 www.scholarsresearchlibrary.com
[75] Southon, I. W. and Pfleiderer, W. Chem. Ber., 1978, 111, 971. [76] Falch, E. Acta Chem. Scand. B., 1977, 31, 167. [77] Ferrand, G.; Dumas, H.; Depin, J. C. and Quentin, Y. Eur. J. Med. Chem., 1996, 31, 273. [78] Sato, N. and Fukuya, S. J. Chem. Soc., Perkin Trans. 1, 2000, 89. [79] Urleb, U. J. Heterocycl. Chem., 1998, 35, 693. [80] Taylor, E.C. and Lenard, K. Liebigs Ann. Chem., 1969, 726, 100. [81] Taylor and Paudler, W. W. Chem. and Ind, 1955, 1061. [82] Taylor and Lenard, K. J. Amer. chem. Soc., 1968, 90, 2424. [83] Taylor, E. C.; Perlman, K. L.; Sword, I. P.; Sequin-Frey, M. and Jacobi, P. A. J. Amer. chem. Soc., 1973, 95, 6407. [84] Taylor and Kobayashi, T. J. org. Chem., 1973, 38, 2817. [85] Taylor, E.C. and Dumas, D. J. J. Org. Chem., 1981, 46, 1394. [86] Sato, N. and Saito, N. J. Heterocyclic Chem., 1988, 25, 1737. [87] Guirado, A.; López Sánchez, J. I.; Ruiz-Alcaraz A. J.; García-Peñarrubia, P.; Bautista, D. and Gálve, J. Eur. J. Med. Chem., 2013, 66, 269.