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1
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities M.S. Mohamed1 and S.S. Fathallah1* 1
Helwan University, Faculty of Pharmacy, Department of Pharmaceutical Organic Chemistry, Ein-Helwan,Cairo, Egypt Abstract: For several decades, interest in pyrrole derivatives increases due to their pharmaceutical importance, such as antimicrobial, anti-inflammatory, analgesic, anti-tumor, anti-epileptic, anti-viral, anti-hypertensive, and anti-diabetic agents. These huge therapeutic applications have motivated new efforts in searching for novel derivatives with improved biological activity and diverse applications in pharmaceutical industry. Motivated by the importance of this system, and in continuation of our research efforts, we have tried to highlight aspects reported on the chemistry and biological activity of pyrrole and its fused derivatives during the past years (till 2012).
Keywords: Pyrrole, fused pyrrole, pyrrolopyrimidine, synthesis, biological activities and drugs. INTRODUCTION The key roles played by purines and pyrimidines in cellular processes have made them valuable guide to drug discovery. Pyrrolo[3,2-d]pyrimidines, a class of 7-deazapurine analogs, exhibit remarkable biological activity in part due to their resemblance to pyrimidines and purines. Pyrroles as important class of heterocyclic compounds, are often found in naturally occurring products as in: Porphyrins; porphin (heam), chlorine (chlorophyll) and corrins (vitamin B12). Some bile pigments; biliverdin and bilirubin.
A) Paal-Knorr synthesis of pyrrole.
Owing to the importance of this system, we have tried in this review to explain the main aspects of the chemistry in historical aspect and biological properties of this heterocyclic core during the past years (till 2012).
B) Hantzsch synthesis of pyrrole.
O
Cl
+ H3 C
O
I) Synthesis of Pyrrole Ring Several methods have been reported for the preparation of pyrrole derivatives. The two main methods, that have been mainly utilized, are: A) Synthesis of pyrrole ring or B) Ring transformation to pyrrole. The following are some selected examples of special interest. A) Synthesis of Pyrrole Ring In 1885 Paal and Knorr reported [1] the formation of pyrroles1 via cyclization of 1,4-dicarbonyl compounds with ammonia or primary amines. In 1890 Hantzsch prepared 2 pyrrole derivatives 2 from α-halogenated ketones and 1,3dicarbonyl compound in the presence of ammonia [2] (Scheme 1a,b).
NH3
O
H3 C
CH3
N H 2
OC2H5
Scheme 1.
O
Cl
SYNTHETIC PROCEDURES FOR PYRROLES AND FUSED PYRROLE DERIVATIVES
COOC2H5
CH3
+ H3C
2
O
CH3
Pyridine
COOC2H5
H3C
CH3
O 3
O
COOC2H5
NH3
OC2H5
Pyridine
H3C
CH3
N H
4
Scheme 2. Pyrrole derivatives as secondary products.
compounds in the presence of pyridine. When ammonia is used as the condensing agent, pyrrole derivatives 4 produced as secondary products (Scheme 2). The reaction of acetoin, 2-hydroxy cyclohexanone or benzoin with malononitrile, alkylcyanoacetate or alkylsulphonyl acetonitrile with suitable amine, is reported [4-9] to afford 2-aminopyrrole 5 (Scheme 3).
Feist and Bénary reported [3] the formation of furans 3 from α-halogenated ketones 2 and 1,3-dicarbonyl
In 1969, Gewald et al., reported [10] the reaction of diazoketones with alkylidenemalonitrile in basic medium, to give 1,2-diamino-3-cyano-pyrroles 6 (Scheme 4).
*Address correspondence to this author at the Helwan University, Faculty of Pharmacy, Department of Pharmaceutical Organic Chemistry, Ein-Helwan, Cairo, Egypt; Tel & Fax: +202-25541-601; E-mail:
[email protected]
On heating [11, 12] pyrimidine derivative 7 or 8 with acids at higher temperature, cyclization took place, derivative 9 are obtained (Scheme 5).
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Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
R'
O
+
R-N H2
+
H2C
OH
R1
Mohamed and Fathallah
CN
R'
R'
O
Y
R1
N
NH
Y
Y N
R1
NHAc
YCH2CN R1
NH2
COR'
R 5
R R1
R’
R
Y
R1
R’
R
Y
Ph!
Ph!
Me!
CN
Me!
Me!
-CH2Ph!
CO2C4H9t
Ph!
Ph!
-CH2Ph!
CN
Me!
Me!
CH2-CH 2Ph!
CO2C4H9t
-(CH2)4!
-C6H4CH(CH3) 2!
CN
Me!
Me!
-CH2Ph!
CO2C4H9t
-(CH2)4!
4-ClC6H4!
CN
Me!
Me!
-c-C6H11!
SO2CH2CN
Scheme 3. Synthesis of 2-aminopyrrole.
NC
CN
R2
Et3N
N=N-CHCOR3
+ R1CH2
-
+
N
R1
R1,R2= H, Ph, (CH2)4
R2
CN NH2 N=CHCOR3
R3= OEt, Ph, p-C6H4NO2
6 Scheme 4. Synthesis of 1,2-diaminopyrrole.
In 1976 Gewald et al., reported [13] that condensation of (2-bromo-1-arylalkylidene) propanedinitriles 10 with various aromatic amines under mild Gewald reaction conditions, afforded 1,4,5-trisubstituted-2-aminopyrrolo-3-carbonitrile 11 [14, 15] (Scheme 6).
NH2
Cl
N RHN
H
+
NH2
N
N
7 H
NH2
R'HN
The Piloty-Robinson synthesis, one of the ring closure methods for pyrrole synthesis, by treating ketazine 12 with strong acid gives pyrrole 14 through rearrangement of divinyl hydrazine 13 [16-18] (Scheme 7).
N
9
R' R= alkyl
N HO
N
+
In 1980, Padwa et al., reported [19] the condensation of ethyl cyanoacetate with aldehydes in 2:1 ratio, afforded pyrrole derivative 15 (Scheme 8a). In 1982, Haddadin et al., reported [20] the base catalyzed condensation of α-diketones with secondary amines, afforded 2-cyanopyrrole 16 (Scheme 8b). In the same year, Mataka et al., reported [21] the reaction of 1,3-dicarbonyl with ethyl glycinate HCl afforded ethyl pyrrole-2-carboxylate 17 (Scheme 8c).
R'= alkyl , aryl
N
8 Scheme 5. Synthesis of 4-aminopyrrolopyrimidine. NC
NH2
CN
R
+
NH2
R2
R'
10
N
R'
Br
R
CN
Khachatryan et al., reported [22] that bromination of the allyl aminopyrimidines 18 afforded the corresponding dibromopropylpyrimidine 19, that upon ring closure afforded pyrrolopyrimidine derivative 20 (Scheme 9).
R1 R= Ph, (CH2)4, p-C6H4OMe, p-C6H4Cl R'= H, NCS, OMe R1= Me, OMe, F, Cl R2= H, Cl
R2
Toja and Tuan reported [23, 24] the condensation of ethoxycarbonyl acetamidine 21 with α-haloketones, also Basyouni et al., reported [25] the reaction of primary amines,
R1 11
Scheme 6. Synthesis of 2-aminopyrrole.
benzene R1
R1 N N 12
R1
R1
Pyridine R1, R2= H, Me, Et, Ph
Scheme 7. Piloty-Robinson synthesis of pyrrole.
H
+
R1
R1 N N
N N H
13
H
H
H
R2
R2
R2
R2
R2
R2
R2
R2
xylene -NH3
R1
N H
14
R1
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
H5C2O2C RCH=O
3
R
CO2C2H5
+ 2 H 2C
R= H, Me, Et, Ph
CN
CO2C2H5
N H
15 a) Synthesis of pyrrole derivative 15.
O Ph
O
+
Ph
RH2C
N
CH2R
(CH3)3CO-K
R
R= CN, CO2Et
H
Ph
Ph
- +
N
R
H
16 b) Synthesis of 2-cyanopyrrole 16.
O
R1
O
R2
R1
+
DMF
H2NCH2CO2C2H5
C2H5O2C
R1=Ph, Me R2=Ph
N
R2
H
17
c) Synthesis of ethyl pyrrole-2-carboxylates 17. Scheme 8.
CH3
H2C=CHCH2
Br2
N
RHN
N
18
CH3
CH3
CH3
BrCH2CHBrH2C
N
N
R= H,CH3,C6H5CH2, RHN CH2CHOH
N
CH3
19
BrH2C
N
N
R
20
CH3
Scheme 9. Synthesis of pyrrole 20 from allyl aminopyrimidines.
CH2CO2C2H5
H2N R'
Br
R''
O
NH
NCCH2CN
21
R-NH2
R'
R''
Y
N R
NH2
Y= CO2Et, CN R= H, Me, p-C6H4CH3 R'= Me, Ph, p-C6H4Cl R''= Me, Ph, H
22
Scheme 10. Synthesis of pyrrole 22 from α-haloketones.
α-haloketones with malononitrile in sodium ethoxide, afforded 1-substituted-2-aminopyrrole derivative 22 (Scheme 10). Hilmy et al., reported [26] the formation of pyrroles derivative 23 via reaction of phenacylmalononitrile with primary amines using catalytic amounts of HCl (Scheme 11a). In 1989, Abdel-Hamid et al., reported [27] reaction of phenacylmalononitrile with acetic acid/ HCl (3:1), gives 2aminofuran 24. This on reacting with N-arylmaleimides afforded the isoindoline-1, 3-dione 25 (Scheme 11b). Krutosiková et al., reported [28] that the formation of pyrroles derivative28 via reaction of 3-furancarboxaldehyde 26 with methylazidoacetate in the presence of sodium methoxide. The reaction proceeded smoothly to give the azide 27, and also,compound 28 in refluxing toluene is formed (Scheme 12).
In 2000, Dannhardt et al. [29] reported that the reaction of chalcone 29 with tosyl methyl isocyanide (TOSMIC) afforded substituted pyrrole 30 (Scheme 13a). Also, Barnett et al., reported [30] that the condensation of 2,4-diaminopyrimidin-6-one 31 with bromoaldehyde, afforded pyrrolopyrimidine 32 (Scheme 13b). In the same year, Tumkevicius et al., reported [31] that the cyclization of N[(4-substituted amino)-5-cyano-2-methylthiopyrimidin-6yl]amino acids 33 afforded the methyl esters of 5-amino-4(substituted amino)pyrrolo[2,3-d]pyrimidine-6-carboxylic acids 34 (Scheme 13c). In 2003, Tumkevicius reported [32] that the reaction of pyrimidine derivatives 35 with triethylamine afforded pyrrolo[2,3-d]pyrimidine derivative 36 (Scheme 14a). Also, Iwao et al., reported [33] that the condensation of iminodiacetates 37 with oxalic acid derivatives using
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Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
NC
Mohamed and Fathallah
NH2
CN
H2C
CN
+
O
Ph
N
NH2
R= F,Cl,Br,CH3
Ph R
23
R a) Synthesis of pyrrole 23 from phenacyl malononitrile.
NC
CN
H2C
O
+ O
Ph
Ph
NH2 O
O
CN
AcOH/ HCl
NC
NAr
NH2
NAr
O
24
O
Ph 25
b) Synthesis of isoindoline-1,3-dione 25. Scheme 11.
CO2CH3 Toluene
CHO N3CH2CO2CH3
CO2CH3
N3
N
O
O 27
O 26
28
Scheme12. Synthesis of pyrrole 28 from azide 27.
H
O
O
Ar1
+
O
O
KOH,MeOH Ar2
H3C
(B)
O
N
31
CH3CN ,NaOAc
O
+ NH2
CN
N
(C)
N
NH N H
MeO2C
CO2Me
NHR
CH3S
30
Br NH
H2N
N H
29
(A)
O
Ar2
Ar2
Ar1
Ar1, Ar2=different aryl groups
TOSMIC Ar1
NHR H2NCH2CO2CH3
Cl
MeOH
CH3S
R=Bu, Me
N
33
NaOCH3/MeOH
NHCH2CO2CH3
CH3S
NH2
N N
34
NH2
32
NHR CN
N
N
N H
CO2CH3
Scheme 13. Synthesis of pyrrole 30,32,34.
NaOMe as a base afforded 3,4-dihydroxypyrrole-2,5dicarboxylates 38 (Scheme 14b).
closure of {[2-cyano-2-([het]aryl)vinyl] malonate 42 (Scheme 16).
Many researchers reported [34-36] the synthesis of 3,4,5triaryl-1H-pyrrole derivative 39 through refluxing a mixture of benzoin, ketone and ammonium acetate in acetic acid (Scheme 15a), and the synthesis [35, 36] of 2-amino,3cyanopyrrole derivative 40 by refluxing a mixture of benzoin, arylamines and malononitrile in presence of PTSA (Scheme 15b).
Paal-Knorr reaction [38] was modified by Banik et al. in 2005 by mixing bismuth nitrate (5 mol%) in the presence of dichloro methane with amine and ketone at room temperature to afford pyrrole derivatives 43 (Scheme 17a). Another Paal-Knorr modification is reported [39] in the same year by Demir et al., for the preparation of 1,2,4-substituted pyrroles 45 from chloropentenone 44 and amines, amino alcohols and esters of amino acids (Scheme 17b).
Rochais et al., reported [37] the formation of ethyl-3amino-4-(het)aryl-1H-pyrrole-2-carboxylates 41 through ring
amino}-diethyl
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
SCH2CO2CH3
SCH2CO2CH3 NC N
H3CO2C
N
CH3
H2N
Et3N
N
5
H3CO2C
SCH3
N N
N
CH3
35
SCH3
36
a) Synthesis of pyrrole 36 from pyrimidine 35.
b) Synthesis of pyrrole 38 from pyrimidine 37. Scheme 14. R OH
X
O
+
R'
X R R' F H H H H CF3 OMe F H Cl F H
X
R CH3CO2NH4 AcOH
O
X
R' N H
X
39 a) Synthesis of 3,4,5-triaryl-1H-pyrrole derivatives 39.
Ph
O OH
Ph
+ RNH 2
Ph
O
Ph
NHR
PTSA / benzene reflux
NCCH2CN
Ph Ph
CN N
NH2
R
R= CH2Ph, -CH2CH2N(CH3)2
40
b) Synthesis of2-amino,3-cyanopyrrole derivatives 40. Scheme15.
EtO2C EtO2C
CN
N H
Ar
41
EtO2C EtO2C
CN
N
Ar=aryl group
Ar
EtO2C CN EtO2C
N H
Ar
H2N EtO2C
Ar N H 42
Scheme 16. Synthesis of pyrrole 42.
In the same year, Mathew et al., reported [40] that N,Sketal 46 experienced smooth cyclization to afford 3,4-diaryl pyrroles 47 (Scheme 18).
corresponding vinyl ether 49, that is cyclized to provide pyrrolopyrimidine derivative 50 upon treatment with hydrochloric acid (Scheme 19).
In 2006, Choi et al., reported [41] the Palladiumcatalyzed cross coupling of 4-amino-5-bromo-2chloropyrimidine 48 with vinyl stannane afforded the
In 2007, Simon et al., reported [42] the Rutheniumcatalysed conversion of 1,4-alkynediols 51 into pyrroles 52 (Scheme 20a). Also, Aydogan et al., reported [43] the
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Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
O RNH2
+
silica gel to afford pyrroles 54 (Scheme 20b).
Bi(NO3)3.(H2O)5 R'
O
Mohamed and Fathallah
CH2Cl2
N
R= Ph,naphtayl,pyridyl
R
R'= Ph, CH3
In the same year, Abid et al., reported [44] that the reaction of benzene sulfonamide with 1,4-butanedial afforded N-sulfonyl pyrrole 55 (Scheme 21a). Also, Joshi et al., reported [45] that the reaction of acetonyl acetone with a derivative of benzoic acid hydrazide 56 afforded pyrrole derivative 57 (Scheme 21b).
R'
43
a) Paal-Knorr modification using bismuth nitrate. O Cl
NH2
+ R
44
Baylis-Hillman adducts 58 was condensed [46] with phenacyl bromide followed by Michael addition at the conjugated vinyl moiety of the corresponding intermediate and afforded 2,3,5-trisubstituted pyrrole 59 (Scheme 22).
Et3N N
R'
R=CH3, CO2Et
R
R'= Ph, CO2Et, CH(OH)Ph
Teno et al., reported [47] the condensation of bromo pyrimidine derivative 60 with prop-2-ynylbenzene to afford pyrrolo[2,3-d]pyrimidine derivative 61 (Scheme 23).
R' 45
b) Paal-Knorr modification using chloropentenones. Scheme 17.
In the same year, Wu et al., reported [48] the preparation of the 2-thioxopyrrolo[2,3-d]pyrimidinone 63 from the appropriately substituted cyanoacetate 62 (Scheme 24).
condensation of 1,4-dichloro-2-butene 53 with various amines,or amino acid esters under microwave irradiation on
Krishna et al., reported [49] the condensation of 2-
R1 R1
R1 R1 POCl3 DMF
O HN R2O
R 2O
R1=H,Cl,CH3
SCH3
N O
H
R2, R3=CH3,C2H5
46
SCH3
47
O Scheme 18. N,S-ketal cyclization to give pyrrole. EtO Br
EtOCHCHSnBu3
N N
H2N
Pd(PPh3)4
Cl
H2N
48
N
HCl
N N
N H
Cl
49
N
50
Scheme 19. Palladium-catalyzed synthesis of pyrrole.
R1 OH
Ru Cat.
R2
R3NH2
OH
R1
N
R2
R3
52
51
a) The Ruthenium-catalysed synthesis of pyrrole.
NH2 Cl
53
Cl
+
R1
SiO2 R2
R1 , R2=CH3,Ph,CO2CH3,CO2C2H5,CH(CH3)2,CH2OH b) Microwave irradiation on silica gel to afford pyrroles. Scheme 20.
N
MWV R2
54
R1
Cl
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
OHC
CHO
+
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
7
NH2-SO2-Ph N SO2Ph
55
a) Synthesis of N-sulfonyl pyrrole. N
O N
+
CH3
CH3
CONHNH2
56
CONH
O
57
N
H3C
CH3
b) Synthesis of pyrrole derivative. Scheme 21. O TS
H N
R2 O
O
Br K2CO3
+
58
R1
TS
DMF
R2
DBu
N
N
CH3CN
R1=H, CH3, Cl R2=CH3, OC2H5
H
O R2
R1
O
R1
59
Scheme 22. Synthesis of pyrrole via Michael addition.
Br HN
PhCH2C CH
N
CuI, Et3N
CN
N
N
PhCH2 N
CN
N
61
60
Scheme 23. Synthesis of pyrrole from bromo pyrimidine derivative.
O O
Me
S
OEt EtO CN
OEt
+HN 2
Me
O H
HN NH2
OEt S
N H
NH2
62
Me
OEt +
HN S
N H
N
63
H
Scheme 24. 2-thioxo pyrrolo[2,3-d] pyrimidinone.
furanyl-2-propeonates with tosyl methyl isocyanide (TOSMIC), pyrrole-3-carboxylate 64 were formed (Scheme 25a). Tosyl methyl isocyanide (TOSMIC) also is condensed with chromone-3- carboxaldehydes 65 afforded 2-tosyl-4(2hydroxy-benzoyl) pyrroles 66. This reaction was reported [50] by Terzidis, et al., in 2007 (Scheme 25b). Pfefferkorn et al., reported [51] that 1-fluoro-4-(1-nitro2-phenyl-vinyl)-benzene reacted with ethyl isocyanoacetate in the presence of DBU produced pyrrole 67 (Scheme 26a). In the same year, Elmegeed et al., reported [52] the preparation of pyrrolo[1,2-a]indole derivatives 69 via the reaction of melatonin 68 with diethylmalonate and/or ethyl acetoacetate in absolute ethanol in presence of piperidine (Scheme 26b). Pujol et al., reported [53a] the preparation of
a pyrrole 71 via the reaction of 1,4-benzodioxian-6-amine 70 with the 2,5-dimethoxytetrahydrofuran [53] (Scheme 26c). In 2008, Majumdar et al., reported [54] the reaction of the bromo amino derivative 72 with trimethyl silyl acetylene (TMSA) afforded the acetylenic amine, that was cyclized by DMF to pyrrolo[3,2-f]quinolone or coumarin 73 (Scheme 27). The formation of N-benzoyl-3-difluoro-and 3chlorodifluoro methyl pyrroles 74 through N-benzoylation followed by ring closure of amino alcohols, was reported [55] by Shaitanova et al. (Scheme 28). In 2008, Abodel-Ella et al., reported [56] the synthesis of 2-amino-3-cyano-pyrrole 75 via the reaction of 4-(2-oxo-2-
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Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
Mohamed and Fathallah
CO2Et
BnO
O
EtO2C
BnO
TosCH2 N CH
O
NH
n-BuLi, THF MeO
MeO
64
a) Synthesis of pyrrole-3-carboxylate.
TosCH2 N CH
O
R1
Base
H O
R2
CHO
R2
O
R1
65 O N
R1=H,CH3,NO2,Cl
Tos
H
R2=H,CH3
66
b) Synthesis of 2-tosyl-4(2-hydroxy-benzoyl) pyrroles. Scheme 25.
F
H N
EtO2C NCCH2CO2Et
NO2
DBU/THF
F
F
67
F a) Synthesis of pyrrole-2-carboxylate.
(CH2)2NHAc
CH3O
(CH2)2NHAc
CH3O
Y
EtOOCCH2COX N H
N
X= CH3 ,OEt Y=CH3, OH
O
69
68 b) Synthesis of pyrrolo[1,2-a]indole.
O
O
DMTHF
O
70
OH
O
NH2
N
71
DMTHF = MeO
O
OMe
c) Synthesis of pyrrole from 1,4-benzodioxian-6-amine. Scheme 26.
NHR TMSA X O
Br
R
NHR R=H,CH3,C2H5 X=O,N-CH3
72
Scheme 27. Synthesis of pyrrolo[3,2-f]quinolone.
N
DMF,CuI X O
X TMS
O
73
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
EtO
NH2 HO
R
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
PhCOCl,Et3N,CH2Cl2
EtO
R
MeCN
NH-COPh HO R
R=CF3,CHF2,CF2Cl,C2F5
9
N COPh
74 Scheme 28. Synthesis of N-benzoyl pyrrole.
O
+
CN
Ph
Ph
HN
CN
NaOEt
NH2
N
CN SO2NH2
75 SO2NH2
a) Synthesis of 2-amino pyrrole.
NC
NC CN P-Anisidine
NC
Y
CN
CN
NC
NH2
X
EtO
NH
N
OMe
OMe
Y
N
Y
X= Cl , Br
OMe
76
b) Synthesis of 3-amino pyrrole.
O
O EtO N
COOEt
NH2
Br
Cl c) Synthesis of 2-amino,3-carboxylate pyrrole. Scheme 29.
phenyl-ethylamino)-benzene sulfonamide with malononitrile (Scheme 29a). Also, Salaheldin et al., reported [57] that 3Aminopyrrole derivatives 76 are synthesized from 3-anilino2-cyanoacrylonitrile by reaction with α-haloketones under basic conditions, using a Thorpe-Ziegler cyclization (Scheme 29b). In the same year, Schlapbach et al., reported [58] that the reaction of α- bromoketone with ethyl 3, 3diaminoacrylates yielded the 2-amino-pyrrole 77 (Scheme 29c). The preparation of the pyrrolopyrimidine 78 from cyanopyrimidine with prop-2-ynyl-p-chlorobenzene using catalytic amounts of Pd(PPh3)2Cl2 and CuI, is reported [59] by Irie et al (Scheme 30a). In 2009, Bernotas et al., reported [60] the synthesis of pyrrolo[3,2-b]pyridine 79 from 2chloro-3-nitropyridine. They described the introduction of tert-butyl cyanoacetate under basic conditions followed by decarboxylation and hydrogenation to give 79 (Scheme 30b). In the same year, Pudziuvelyte et al., reported [61] the preparation of 2,4-disubstituted 6-arylpyrrolo[3,2d]pyrimidin-7-one 5-oxides 80, via pyridine initiated smooth cycloisomerization of 2,4-disubstituted 5-nitro-6-arylethynylpyrimidines. Reactions are performed in boiling 2-
NH2
N H
N Cl
NH2
77
propanol and the resulting compounds 80 are obtained in high yields (Scheme 30c). Diana et al., reported [62] the reaction of 2-chloro-3-nitropyridine and the potassium enolate of ethyl cyanoacetate to give 3-nitropyridine derivative, that on reducing with iron and acetic acid, yielded the 2-amino-3-ethoxycarbonyl-pyrrolo[3,2-b]pyridine 81 (Scheme 30d). In 2010, Zbancioc et al., reported [63] the preparation of highly fluorescent derivatives containing the pyrrolodiazine 82a,b using microwave (MW) irradiation. The reaction mechanism occurred initially N-alkylation of the phthalazine, followed by a typical Huisgen [3+2] dipolar cycloaddition of diazinium ylides to the dipolarophiles (Scheme 31). In the same year, Keivanloo et al., reported [64] the reaction of N-alkyl-3-chloroquinoxaline-2-amines with 1alkynes, catalyzed by Pd-Cu, in the presence of sodium lauryl sulfate as the surfactant in water, led to the one-pot formation of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines 83 in good-to-high yields (Scheme 32a). Also, Zeeshan et al., reported [65] the base-mediated cyclocondensation of 1,3-dicarbonyl compounds with 4-chloro-3-nitrocoumarin
10 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
Br N
N
Cl
N
H2N
Mohamed and Fathallah
N
N H
CN
CN
78 Cl
a) Synthesis of 2-cyano pyrrolopyrimidine. NO2 N
NO2
NCCH2CO2tBu
Cl
H N
Pd/AcOH
CN
N
N
CO2tBu
79
b) Synthesis of pyrrolopyridine. NH2 NO2
N N
R
O
NH2 Pyridine 2-PrOH
N
N
Ph N
R
Ph
80
R= H, SCH3
c) Synthesis of N-oxide pyrrolopyrimidine. N
Cl
O
CN
+
Fe/AcOH
N
CO2Et
NO2
OEt
t-BuOK/ t-BuOH
CO2Et
N
CN NO2
81
NH2
N H
d) Synthesis of 6-amino pyrrolopyridine. Scheme 30. N N
BrCH2COR
N
R=NH2, OMe
N
Br
+
Et3N
N N
CH2COR
N N
-
+
CHCOR
CN NC
CO2Me N N
MeO2C
COR
82a
COR
82b
Scheme 31. Huisgen [3+2] dipolar cycloaddition. Cl
N
+
R'
R=Me,Bn,n-Pr R'=Ph, n-C3H7
NH
N
N
PdCl2/ PPh3/CuI/SDS
R'
R
N
83
N R
a) One-pot formation of pyrrolo[2,3-b]quinoxalines. Cl NO2 O
O
O R1
O
O R2
R1=OCH3,OEt,CH3,Ph R2=Ph,Me,Et
b) Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones. Scheme 32.
O
O
R1
R2 NO2 O
O
R1 H2/Pd
R2 NH
O
84
O
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
provided a convenient approach to various chromeno[3,4b]pyrrol-4(3H)-ones 84 (Scheme 32b).
either sulfathiazole or sulfapyridine moieties (Scheme 35a). Also, Mohamed et al., reported [69] the synthesis of 2amino-3-cyano-pyrrole 88 via the reaction of α-(arylphenylamino)-acetophenone with malononitrile in sodium ethoxide (Scheme 35b).
Moon et al., reported [66] the preparation of 1H-pyrrole2,5-dione 85 via the condensation of phenylacetamide with ethyl 4-methanesulfanylbenzoylformate (Scheme 33).
CH2CONH2
H N
O
CO-CO2Et
Takayama et al., reported [70] the preparation of Pyrrole derivatives 89 from 4-phenoxybenzoic acid (Scheme 36).
O
In 2011, Rudolph et al., reported [71] the treatment of 4oxo-piperidine-1-carboxylic acid tert-butyl ester with primary amine, generates the iminium/enamine intermediate which in turn trapped by nitrostyrenes to afford the Bocprotected tetrahydropyrido[3,2-c]pyrroles 90 (Scheme 37).
NaH/THF
+ SMe
85
SMe
In 2011, Yavari et al. [72] reported a simple synthesis of tetrasubstituted pyrrole derivatives 91 from the reaction of enaminone with α-haloketones under solvent-free conditions (Scheme 38a). A modification is reported [73] in 2012 by Nishida et.al, that condensation of α-bromoacetophenone with ethyl cyanoacetate afforded compound 92, that is cyclized under acidic condition to afford pyrrole derivative 93 (Scheme 38b). Also, Korotaev et al. reported [74] that the reaction of nitrobutene with 1,3-dicarbonyls (ethyl acetoacetate, acetylacetone and benzoylacetone) and primary
Scheme 33. Synthesis of 1H-pyrrole-2,5-dione 85.
Glotova et al., reported [67] that on heating O-2(Acyl)vinylketoximes 2- or 3-acylpyrroles 86a,b, are produced, wherein the positions of the acyl substituents did not correspond to known O-vinyloxime rearrangements; the chemo- and regioselectivity of the rearrangements depended on the reaction conditions (Scheme 34). Ghorab et al., reported [68] the preparation of series of novel 2-substituted-3-cyano-4-phenyl-pyrrole 87, bearing Ph
R'
R'
R HO
N
O
O
R
Ph3P
+
O O
N
Ph
R=R'= (CH2)4
O
O
Ph
R'
R' O N H
O O
O
R
R' R
N
O
R=Ph R'=H
Ph
R
Ph
86a
N H
86b
O
Scheme 34. Synthesis of 2- or 3-acylpyrroles.
CNCH2CN
BrCH2COPh
CN
Ph
NHCH2COPh
NH2
N
NH2
EtOH SO2NHR
SO2NHR R=
87
N S
SO2NHR
N
a) Synthesis of pyrrole bearing sulfathiazole.
Ph
Ph
O CH2(CN)2 NaOEt
NH
CN N
NH2
R= Cl, H
R b) Synthesis of 2-amino-3-cyano-pyrrole. Scheme 35.
11
88 R
12 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
OPh
Mohamed and Fathallah
SO2Cl
OPh
OPh
OPh
NH2CH2(C6H4)-p-OMe
(CH3)2SO2
(CN)2CH2 O
BrCH2COPh NC
NC
OH
OH
NC
CN
CN
OMe
N
OMe H2N
COPh 89
Scheme 36. Synthesis of 3-amino-4-cyanopyrrole.
O
CH=CH-NO2
+
N
PhCH2NH2
N boc
mechanism for the above transformation (Scheme 39).
CH2Ph
N boc
R
R= CF3,CH3,H,Cl,NO2
90
R
Scheme 37. Synthesis of Bocprotected tetrahydropyrido[3,2-c] pyrroles.
aliphatic amines afforded pyrrole derivatives 94 (Scheme 38c). B) Transformation/Ring Annulations Approached to Pyrrole Ring Pyrrole ring could be formed through the ring transformation of other heterocyclic compounds: Unexpected ring transformation, ring annulations occurred [75, 76] to 2-aminofuran-3-carbonitriles 95, to afford pyrrolo[2,3-d]pyrimidines 96 rather than furano[2,3d]pyrimidines. Michael addition could be the possible
amidine
Thermal isomerization of 2,3-dihydroisoxazoles 99 to 2acylaziridines are reported [78] by Lopes et al. The azomethine ylides generated via conrotatory aziridine ring opening that can undergo a proton shift followed by cyclization leading to pyrroles 100 (Scheme 40b). Also, Coskun and Cetin reported [79] the methoxideinduced diastereoselective rearrangement of isoxazolines 101 into 3-methoxy-7-(methoxycarbonyl)-2,7a-diaryl-5-oxo2,3,5,7a-tetrahydro-1H-pyrrolo[1,2-e]imidazol-6-olates, that on reacting with H3O+, it is converted to the corresponding methyl 1-formyl-4-hydroxy-5-oxo-2-phenyl-2-((arylamino)
O
NHR' +
R
O solvent-free
Br
R''
R''
R'= c-hexyl, n-Bu R= CH3, OC2H5 R''= 4-Br-C6H4, CO2C2H5, 4-CH3O-C6H4
N
91
R'
a) Synthesis of tetrasubstituted pyrrole.
O Br + NC
Ph
O
K2CO3 OEt acetone
O Ph
92
CN
EtO2C HCl Cl
CO2Et
N H
Ph
93
b) Cyclization under acidic condition.
CF3 O
+ R'NH2
H3C O c) Synthesis of 4-acyl pyrrole. Scheme 38.
R
R EtOH
H3C
O H3C
R= Me, Ph, OEt R'= H, Me, Et, Ph (CH2)2
ring
Hershenson and Pavia reported [77] the use of azalactone (2-oxazolin-5-one) 97 in 1,3-dipolar cycloaddition provided a synthetic route to pyrroles 98 in good yield, Where in situ alkylation of 97 with highly reactive alkylating agents, such as methyl trifluoromethanesulfonate or triethyloxonium tetrafluoroborate, and the presence of dimethyl acetylenedicarboxylate as the dipolarophile offered pyrroles 98 (Scheme 40a).
R O
mediated
NH R'
NO2
R CF3
O H3C
N R'
94
CH3
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
NC
R O
R
NH2
O
N
R
N H
R'
R= Me, Ph, Et R'= H, Me, Ph R''=NH2, MeS, (Me)2N
N
96
R
NC
R'
R' HN
NH R''
N
95
NC H 2N
R''
R'
NH2
R
NH
+ H2N
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
HN
R'
NHO 2
HN
R''
NH2
NH2O
HN R''
Scheme 39. From furan to pyrrolo pyrimidine.
O O
Ph
H3CO2C
CO2CH3 RX
+
N
CO2CH3
Ph
N R
CO2CH3 RX= EtOBF4, MeOSO2CF3 R= Et, Me
97
98
a) From azalactone to pyrrole.
O
CO2Bn
CO2Me Toluene Me
MeO2C N Me
Me
CH2CO2Bn
N Me
COCO2Me CO2Me
BnO2C
O
CO2Me
Me
N
CO2Me
Me
99
5-exo-trig cyclization BnO2C Me
CO2Me N Me
CO2Me
BnO2C
Toluene -H2O
CO2Me
Me
N Me
OH CO2Me
100 b) Aziridine ring convert to pyrrole.
Ph
Ar
N
N
CO2Me
O
Ph MeONa Ar
CO2Me
N
CO2Me
N
O
OMe O
101
H3O+ Ph ArHN
OH O
102 c) Rearrangement of isoxazolines to pyrrole. Scheme 40.
DMSO
HN
CHO
Ph
CO2Me
+
CO2Me
N
ArH2N O
OH O
R''
13
14 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
O
N
OH H
PhH2C
O
N
103
Mohamed and Fathallah
N
PhCH2NH2
N
O N
Ph
O
H
Ph
O
C-4 Attack PhH2C OH H N N O
CH2-Ph N
O
N N
104
-H2
N
- H2O
Ph
H
O
H
Ph
O
a) Thermal cyclization of furan to pyrrole.
DMAD R
O
E= CO2Me
105
E O E R
+ Ph
106
R'
CO2Me
E
R CO2Me NH
N R= CH2C6H4OBn
E
107
Ph
b) Thermal retro-DielseAlder of furan to pyrrole. Scheme 41.
methyl)-2,5-dihydro-1H-pyrrole-3-carboxylates 102 (Scheme 40c). Ring-transformation of furano[2,3-d]pyrimidinones 103 to pyrrolo[2,3-d] pyrimidinones 104 occurred [80] by the reaction of 103 with benzyl amine to cause ring closure, which undergo thermal cyclization in 1,4-dioxane and afford compound 104 (Scheme 41a). The preparation of 3-pyrrolines 107 are reported [81] in 2011by Soret et al., via metal salt/base-catalyzed cycloadditions of azomethine ylides generated from N-arylideneα-amino esters with a dimethyl 7-oxabicyclo[2.2.1]hepta2,5-diene-2,3-dicarboxylate derivative 106 and a subsequent thermal retro-Diels–Alder reaction (rDA). Compound 107, prepared by reaction of dimethyl acetylenedicarboxylate (DMAD) with furan derivatives 105, appeared like a masked form of the acetylenic reagent (Scheme 41b). In 2007, Kathriarachchi et al., reported [82] the reaction of 1-benzyl-2-methyleneaziridine 108 and 2,4-pentanedione in the presence of Pd(PPh3)4 afforded pyrrole derivative 109 (Scheme 42a). In 2010, Ribeiro Laia et al., reported [83] the formation of pyrroles 111a,b via thermolysis of aziridine 110 in the presence of benzyl buta-2,3-dienoate in refluxing toluene (Scheme 42b). In 2012, Auricchio et al., reported [84] that 2H-azirines react with enaminones and enaminoesters in the presence of metal salts to afford pyrrole derivatives 112a,b. The role of metal salts is investigated as they could act as Lewis acids. Authors suggested [84] that the azirine complex carried out nucleophilic attacked by the enaminic double bond to give intermediates, that can afford the different products depending upon the different intramolecular linkage with nitrogen or oxygen (Scheme 42c).
II) Sythesis of Fused Pyrroles from Pyrrole Derivatives A) Synthesis of Pyrrolopyrimidine Derivatives Treatment of compounds 113 successively with triethyl orthoformate then with ammonia, afforded the amidines 114 [6, 9] that are cyclized in sodium ethoxide/pyridine and afforded 7H-pyrrolo[2,3-d]pyrimidines 115. Also, when compounds 113 are treated [85-87] with triethyl orthoformate followed by ammonia, afforded pyrrolo[2,3d]pyrimidin-4-amine derivatives 115 without separation of the amidines 114.(Scheme 43a) When pyrroline derivative 116 is treated [68, 88, 89] with thiourea, gaunidine, urea, acetamidine or S-methylthiourea, the corresponding 4hydroxypyrrolo[2,3-d]pyrimidines 117 with various substitutions in the 2-position, are afforded (Scheme 43b). On heating compounds 118 with either formic acid, [7c, 25, 68, 90-92] or a mixture of dimethyl formamide/formic acid, [16] the corresponding pyrrolo[2,3-d]pyrimidin-4(3H)-ones 119 produced (Scheme 43c). Treatment [93, 94] of the acyl pyrrole derivatives 120 with phosphorous pentoxide and N,N-dimethylcyclohexylamine, afforded the pyrrolo[2,3-d]pyrimidin-4(3H)ones 121 (Scheme 44a). Treatment of the pyrrole-3carboxylates 122 with phenyl isothiocyanates [93] afforded pyrrole [2,3-d]pyrimidinones 123 (Scheme 44b). When compounds 124 reacted [67, 92, 95, 96] with formamide, the corresponding pyrrolo[2,3-d]pyrimidin-4amines 125 produced (Scheme 45a). Also, pyrrole-3carboxamides 126 reacted [86] with carbon disulphide in alcoholic sodium hydroxide in the presence of hydrogen peroxide, followed by treatment with ammonia, to form pyrrolo[2,3-d] pyrimidin-4(3H)-ones 127 (Scheme 45b). 2Aminopyrrole-3-carbonitrile 128 reacted [97] with some aryl isothiocyanates to give the corresponding 4-aminopyrrolo [2,3-d] pyrimidine-2(1H)-thiones 129 (Scheme 45c).
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
15
O CH2-Ph N +
O
O
Pd(PPh3)4
O
CH2-Ph
O OPd
CH2-Ph
O
N
H3C
N
CH3 CH3 N CH2-Ph
108
109 a) Aziridine to pyrrole using Pd(PPh3)4.
Bn +
N Ph
110
R
R
Bn
CO2Bn
Bn
R
BnO2C
BnO2C
R
Bn
Ph
111a OH
N
retro-aldo type fragmentation
Ph
COPh
Ph
-
- PhCHO
N
Bn N
+
BnO2C
R= H,Me,Ph
R
N
Toluene
COPh
COPh
BnO2C
111b
Ph Ph
b) Thermolysis of aziridine to pyrrole. R
R' Ph
R''
R +
N
R'
MCln M= Fe, Al n=2, 3
NH2 O
Ph
O
Ph
O
+ R
N H
R''
R'
112a
N H
R''
112b
c) Aziridine to pyrrole using Lewis acids. Scheme 42. CN
R R'
R'
NH2
N R'' 113
NaOEt
TEOF NH3
N R'
N
N
N
O
N=CH-NH2
R'' 114
NH2
R
CN
R
TEOF/NH3
R" R*
R' N R
R=Ph, Me,CN R'=H,SCH3 R''=H, -CH2OCH(CH2OH)2
R'' 115
R"
NHCOR1
120 50
COOC2H5 N
H2NCXNH2
H3C
N
OC2H5
H
X= SH,NH2,OH,SCH3,CH3
116
H 3C
N N
CO2C(CH3)3
R'
N
NH R'
R',R''= Me, Ph
R
N R
118 R= CH(Me)Ph, CH2Ph, CH2C6H4Br 119 Antipyrine, C6H3(Cl)3,4
c) Pyrrolo pyrimidin4-one. Scheme 43.
PhNCS R = Pyridylmethyl
H3C
122
Scheme 44.
R''
NH2
NH2
117
HCO2H N
R
R1
N
121
O
b) 2-thiopyrrolopyrimidine-4-one using PhNCS.
O
CN
N
H 3C
H
b) 2,4-disub- pyrrolopyrimidine. R''
N R
X
R* R1= Me, Ph R'= CN, CONH2 R,R'', R*= CH(Me)Ph, H
H
a) Pyrrolopyrimidine-4-one using P2O5.
a) 4-amino pyrrolopyrimidine. OH
N
P2O5
N N
N
Ph
SH
R
123
Reaction [98] of pyrroles or indoles 130 with N[bis(methylthio)- methylene]amino moiety (BMMAs), allowed one pot synthesis of the condensed pyrimidine 131. Yet, the reaction of pyrroles derivatives 130 with BMMAs in acetic acid, followed by treatment with sodium carbonate 98,imidazo[1,2-c] pyrrolo[3,2-e]pyrimidin-2(7H)ones 132 are produced (Scheme 46a). On refluxing [99] pyrroles 133 with TMOF imidic ethers produced, when reacted with acid hydrazides, afforded pyrrolotriazolopyrimidines 134. This transformation deserved attention because the formation of
16 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
R R'
Mohamed and Fathallah
CN
HCONH2
NH2
N
NH2
R
N
N R= Me,Ph, p-ClPh R' R'= H,Me, Ph R'' R''=Ph,benzyl, Antipyrinyl 125 aryl, Pyridyl
R'' 124
N
a) 4-amino pyrrolopyrimidine using HCONH2. NH2 OC
O
CONH2
NH2OC
NH
CS2 / H2 O2, NH3 R
N
NH2
R= CH 3 R'= CH 2 OH(CHOH)
R'
126
R
N
2
127
b) Pyrrolopyrimidine-2-one using NH3/CS2. H3 C Ph
CN NH2
N H
NH2
H3 C
RNCS
N
R'
N
R = C 6 H5 , 3-ClC 6 H4 Ph 2,3-(CH 3)2C 6H3
N
N
R S
H
128
129
c) 4-amino-2-thione pyrrolopyrimidine using RNCS. Scheme 45.
O R R
Y
N
+ N
R'
NH2 H3CS
NCH2CO2Et N
R'
Y= CO2Et
R= CH3 , C6H5, H R=R'= C4H4 R''=H,CH2Ph
SCH3
N
R AcOH Y=CN
N
R'' 131 O
SCH3
R''
130
CH2CO2C2H5
N N
R'
R''
N
SCH3
132
a) Synthesis of imidazopyrrolopyrimidinones.
R'' HN CN
R R
N
TMOF
NH2
CN
R
R
R'
133
N R'
R
R''CONHNH2
NH=CHOMe
R
N
NHCOR''
R
N N
R' R=CH3,Ph R'= Bn, 3-Pyridyl, 2-Furfuryl R''= PhCOCH2 , 4-Pyridyl
N
R
N N
N
N
R'
134
b) Synthesis of triazolopyrrolopyrimidine. Scheme 46.
the pyrimidine and triazole rings occurred as one-pot reaction (Scheme 46b).
(IDA)] for facile reaction with 1,3,5-triazine and generated various pyrrolo[2,3-d] pyrimidines 136 (Scheme 47a).
It was reported [100] that the reaction of 2-aminopyrrole4-carbonitriles 135 with 1,3,5-triazines, afforded the pyrrolo[2,3-d]pyrimidines 136. Pyrroles 135 are proved to be effective dienophiles [inverse electron demand Diels-Alder
3-Aryl-3,4,7-trihydropyrrolo[2,3-d]pyrimidin-4-amines 138 are synthesized [100] from the reaction of 137 and arylamines using phosphorus pentoxide (Scheme 47b). Treatment of compounds 139 with triethylorthoformate in
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
CO2Et
CN N
+ N R
H2N
EtO2C
135
N
CO2Et
NC
R=Benzyl, Cyclopentyl
N
N N N R 136
CO2Et
[4+2]
CN CO2Et
H CO2Et
NC
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
H
NC
N N N CO2Et R N H2N CO2Et
CO2Et
CO2Et NH3
N N N NH R 2
CO2Et
a) Inverse electron demand Diels-Alder (IDA) reaction.
CN
R3 R2
NHCOCH3
N R
R,R1= H,CH3,Cl
137
N
R2 N R
R2= H,CH3 R3= CH2Ph,Et,CH3,H
R
NH
R3
Ar-NH2 / P2O5
R
N
138
b) Synthesis of 4-imino pyrrolopyrimidine from ArNH2.
HN CN
Ph
CN
Ph
R-NH2
TEOF/Ac2O N
NH2 R=NH2, Et,(CH2)2OH, (CH2)3OH, CH2Ph
SO2NH2
Ph
N=CH-OC2H5
N
N
N
SO2NH2
139
N-R
SO2NH2
139a
140
c) Synthesis of 4-imino pyrrolopyrimidine from amidinesm using TEOf (triethylorthoformate).
O
.. CONH2
H3C R2
1-octanol
N-COOC2H5 R1
N H
141
reflux
R2
R2=Me, Et, Ph, CH2Ph,
N N R1
N H MeOH R1=H O
H3C H3C
a- KOC(CH3)3 b- (Me)2SO2 H
N N H
d) Synthesis of pyrrolopyrimidinediones via cyclization in strong Basic medium.
O
142a
a-KOC(CH3)3 THF b- (Me)2SO2 R1=H - HOC2H5
R1= H,CH3
H
H3C
N CH3
142b
O
17
18 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
Mohamed and Fathallah
O O
O O
R
143
Ph
R= OCH3,CH3,Cl,H
N
R
O
N
O
N
O
N H
N H
NH(CH2)2Cl O Phenyl piperazine
R
NH2
N H
NH
N H
ClCH2CH2NCO
O
MeOH R'=
144
PhN
NH
N H
KOH R
NH(CH2)2R'
O
NH
e) Synthesis of pyrrolopyrimidinediones using Phenylpiperazine.
NH2
S N H
NH4CHO/ HCONH2
CO2Et
145
N
S
NH N H
O
146
f) Synthesis of thienopyrrolopyrimidine. Scheme 47.
acetic anhydride afforded the amidines 139a [56], and afforded 4-imino-pyrrolo[2,3-d]pyrimidine 140 (Scheme 47c). Refluxing [101] the suspension of 2-carbethoxyamido-3carbamyl-4-methyl-5-substituted pyrroles 141 in 1-octanol afforded 5-methyl-6-substituted pyrrolo[2,3-d]pyrimidin2,4diones 142a, which on treating 142a(R1=H) with potassium t-butoxide in absolute methanol followed by alkylation using dimethylsulfate, 142b was afforded (Scheme 47d). Reaction [102] of the pyrrole esters 143 with 2-chloroethyl isocyanate afforded ureas, are reacted with phenyl piperazine, to afford pyrrolopyrimidine 144 (Scheme 47e). Condensation [103] of pyrrole carboxylate 145 with ammonium formate and formamide at elevated temperature, afforded thienopyrrolopyrimidine derivative 146 (Scheme 47f). B) Synthesis of Pyrrolopyridine Derivatives Treatment [26b, 104] of the 2-amino-pyrrolo-3-carbonitriles 147 with ethyl acetoacetate in dry toluene and PTSA, the products yielded are identified as propenylaminopyrroles 148, which cyclized in Na/EtOH to pyrrolepyridines 149. (Scheme 48a) Refluxing [105] the pyrrole derivatives 150 with methyl 3-methoxycrotonate, yielded the pyrrolopyridines 151 (Scheme 48b). The indole NH group of melatonin reacted [52] readily with phenacyl bromide, to afford 1-benzoyl methinomelatonin derivative, which on reacting with either malononitrile or ethyl cyanoacetate resulted in the corresponding iminopyrido[1,2-a]indole derivatives 152 (Scheme 48c).
THE MEDICINAL VALUE OF PYRROLES AND THEIR FUSED HETEROCYCLIC DERIVATIVES For several decades, interest in pyrrole derivatives increases due to their pharmaceutical importance [106], such as antimicrobial, anti-inflammatory, analgesic, anti-tumor, anti-epileptic, anti-viral, hypotensive, and anti-diabetic agents. Pyrrole Derivatives as Analgesic and Anti-inflammatory Agents Due to their essential presence in the pharmacophore system of a number of NSAID’s, pyrroles are considered [107] as a reliable fundament for the design of new antiinflammatory and/or anti-nociceptive agents. The nonsteroidal anti-inflammatory drugs (NSAIDs) [108, 109] indomethacin (Indacin®) 153a, acemetacin (Emflex®) 153b, and etodolac (Etodine®) 153c are indole derivatives, tolmetin (Rumatol®) 154a and ketorolac (Ketolac®) 154b are pyrrole derivatives. These compounds block prostaglandin synthesis by nonselective inhibition of COX-1 and COX-2 (indomethacin, acemetacin, tolmetin, and ketorolac) or by selective inhibition of COX-2 (etodolac) (Fig. 1a) A series of N-pyrrolylcarboxylic acids [110] 155 and 1-methyl-4-(methylthio)-5-aroylpyrrole-2-acetic acids [111] 156 are cyclooxysagenase-2 (COX-2) inhibitors (Fig. 1a). Also,2-(N-(2-fluorophenyl)pyrrol-2-yl) acetic acid 157 and 2-[N-(2,3-dihydro-1,4-benzodioxin-6-yl)-pyrrol-2-yl] acetic acid 158 showed more anti-inflammatory activity [54]
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
CN
R
NH2 O
N R''
CN
CO2Et R p-TsOH
+ R'
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
CH3
R'
147
H2N
Na/ EtOH R CH3 R'
N H
N
R,R'=-(CH2)4,H,Ph
CO2Et
N
CH3
R'' 149
148
R''=Ph, CH2Ph
CO2Et
N
R''
19
a) Synthesis of Pyrrolopyridine.
CN
+ NH2
N
H2N
CO2Me
p-TsOH
O
H3C
Na/ EtOH
Me
R''
CO2Me
N
R''=Ph, CH2Ph
CH3
N
R''
151
150 b) Synthesis of Pyrrolopyridine in one pot reaction.
CH3O XCH2CN/B-
(CH2)2NHAc CH O 3 BrCH2COPh
CH3O
N H
(CH2)2NHAc
(CH2)2NHAc
NH N
X=CN or CO2Et N CH2COPh
Et3N
152
X Ph
c) Synthesis of iminopyridoindole. Scheme 48.
CH3
CH3O
CH3
CH3O
O
CH2CO2H
CO2CH2CO2H
N
N
O
Cl
O
153a
N H
153b
O
153c
Cl
CO2H N CH3
N O
H3C
CO2H
CO2H
154b
154a
Fig. (1a). Nonsteroidal anti-inflammatory drugs (NSAIDs).
than the known classical anti-inflammatory agent ibuprofen (Fig. 1b). 3-(4-Chlorophenyl)-4-(5-chlorothien-2-oyl)-1H-pyrrole and 3-(4-chloro- phenyl) -4-(thien-2-oyl)-1H-pyrrole 159, new template for anti-inflammatory drugs 35, are active compounds that showed a balanced inhibition of the COXisoenzymes and enhancing patient compliance (Fig. 1b). In 2008, Ushiyama et.al., reported [112] the 2-(4ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole 160 as novel cyclooxygenase-2 (COX-2) selective inhibitor. The selectivity ratio of this pyrrole derivative was higher than those of the conventional non-steroidal antiinflammatory drugs naproxen, indomethacin, and sodium diclofenate (Fig. 1b).
New generations [66] of anti-inflammatory drugs are developed to enhance the anti-inflammatory and analgesic activities of NSAIDs, and to reduce the adverse effects of these agents. 1H-3-(4-sulfamoylphenyl)-4-phenyl-pyrrole2,5-dione 85 match traditional NSAIDs in terms of efficacy, and are comparatively free of stomach-associated complications (Fig. 1b). Rutaecarpine 161 is a major quinazolinocarboline alkaloid isolated [113] from the well-known Chinese herbal drugs Wu-Chu-Yu1, and Shih-Hu. It exhibits a strong antiinflammatory activity, and shows a potent and selective inhibitory activity against COX-2. Quinazoline-benzothiazine; indole-7-azaindole 161a and amide moiety-pyrrole 161b bioisoster hybrid structures are prepared, through
20 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
COR'
R''
R
Mohamed and Fathallah
CO2H
CH3S
O
O
CH3
158
CH3
157 S
N
CO2H
156
Cl
155
F
N
O
R CO2H
CO2H
N
CH3
N
O
O
X
H N
O
N C2H5O N H
159
160
X=H,Cl
85
SMe
SO2NH2
Fig. (1b). Some Pyrrole and Pyrrole carboxylic acids showing anti-inflammatory activites.
O S O N
O N N
N H
N H
161
HO
161a
O S O N N
N H
HO
161b
Fig. (1c). Rutaecarpine (quinazolinocarboline) alkaloid.
synthetic modifications of the pentacyclic ring system, to modify the anti-inflammatory activity of 161 and eliminate its undesired side effects (Fig. 1c). Aminoalkylindoles (AAIs) 162, although structurally dissimilar from the classical cannabinoids, are known [114] to be capable of binding to cannabinoid receptors and are synthesized as cyclo-oxygenase inhibitors, but subsequently, they are also found to possess antinociceptive activity (Fig. 1d). OMe
N H3C O N
N
162
H 2N
A novel pyrrole-2-carboxamide 163a was discovered [115] to have anti-inflammatory activity through acting as p38α inhibitors. The p38α mitogen-activated protein kinase was identified in human monocytes as the target for a class of cytokine suppressive anti-inflammatory compounds. It regulates the expression of many pro-inflammatory cytokines including interleukin (IL-1)and IFNα and γ. Also, a group of Merck researchers reported [116] that L-167307 163b and pyrrole derivative 163c (diaryl-pyrrole derivatives possessing basic polar groups at β-position), showed more potent inhibitory activity of the proinflammatory cytokine TNFα (Fig. 1f).
OPh
Pyrrolo[2,3-d]pyrimidine 164 is a potent carbocyclic nucleoside adenosine kinase (AK) inhibitor, has therapeutic activity [117] as analgesic and anti-inflammatory agents (Fig. 1g).
N
PNU-142731A 165 is a novel [118], anti-inflammatory, pyrrolopyrimidine that inhibits the production of Th2 cytokines in vivo. It is a potent and efficacious inhibitor of eosinophilic lung inflammation and is in Phase II clinical evaluation for the potential treatment of asthma (Fig. 1h).
Fig. (1d). Aminoalkylindoles.
NC
(IL-2)and IFNγ. Therefore, an inhibitor against Lck could be a potential immunosuppressive agent for treatment of inflammatory diseases such as rheumatoid arthritis, atopic dermatitis, asthma, and organ transplant rejection (Fig. 1e).
COPh
OMe
89
Fig. (1e). Pyrrole as lymphocyte-specific kinase (Lck) inhibitors.
A novel series of pyrrole derivatives 89 are synthesized [71] as lymphocyte-specific kinase (Lck) inhibitors. Lck activity led to production of cytokines such as interleukin-2
Mohamed et.al., evaluated [92] a series of pyrrole and pyrrolopyrimidines compounds as potential antiinflammatory agents. Based on their structure, it was concluded that the best aromatic nucleus is the pyrrole with an N-benzyl substituent124a and a pyrazolyl subunit on the C-2,124b. In the pyrrolopyrimidine derivatives, the antiinflammatory activity also depends on the nature of the side
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
N
21
N
O
(CH2)2NH2 NH O
H3C
N H
O
N H
F
163a
S
O
H
163b
N H
F
163c
Fig. (1f). Pyrrole derivatives act as pro-inflammatory cytokines inhibitors. NH2
Br
(CH2)2NHAc
CH3O
NH
N
N N
X
N
152 Fig. (1j). Novel inflammatory.
OH
H2N
synthesized
melatonin
Cl
O
H
OH
Br
N H
O
R
N N
CH3 X, Y=H,Cl,F R=Heterocyclic moeity
Fig. (1h). PNU-142731A, pyrrolopyrimidine for treatment of asthma.
X
group on the C-2 at the heterocyclic system (compound 125a is more active than 1254b) (Fig. 1i). Pyrido[1,2-a]indole derivatives 152, are extended [53] to study the potential role of the novel synthesized melatonin analogs as anti-inflammatory and anti-nociceptive agents in comparison with melatonin (pineal hormone). It was found more potent in this respect than melatonin itself (Fig. 1j). Pyrrole Derivatives as Antimicrobial and Anti-viral Agents Pyrrole derivatives 166a,b are reported [119, 120] to have antimicrobial activity against S. aureus, B. subtilis
N R''
124a
NH2
Ph X
OH
Fig. (2a). Pyrrole derivatives as antimicrobial and antifungial.
N
Y
CN
O
166b
166a
N
X
Br
Br
N
N
165
anti-
Br
Cl
N
as
Br
Fig. (1g). Pyrrolopyrimidine as carbocyclic nucleoside adenosine kinase (AK) inhibitor.
Ph
analogs
164
OH
N
Ph
CN
N R''
124b
NH2
NHN=
N N
H2N
167 Fig. (2b). trisubstitutedpyrroles.
and E. coli., and antifungal activity against C. albicans (Fig. 2a). 2-methyl-1,3,5-trisubstitutedpyrroles 167 have significant activity [121, 122] against Mycobacterium tuberculosis (Fig. 2b). Jana et al., [123] reported that diguanidino 1-methyl-2,5diaryl-1H-pyrrole derivatives 168, demonstrated significant O
O
Ph N X
N R''
N
X= Ph or H 125a R''= CH2Ph, antipyrinyl, C6H3(Cl)3,4
Fig. (1i). Pyrrole and pyrrolopyrimine as anti-inflammatory.
Ph N S
X
N R''
N
125b
NHNH2
22 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
Mohamed and Fathallah
activity against Candida species. The antifungal activity of compound 168 (R= CH3) was better than that of fluconazole on C. albicans, C. krusei, and C. parapsilosis (Fig. 2c). R
R2
R1
NH
R
O
N
HN HN
O
NH
CH3 NH2
168
HN
NH2
Fig. (2f). Pyrrole as HIV-1 integrase inhibition.
NH2
R
The antimicrobial properties of the copper complexes of pyrrole-2-carbaldehyde and indole-3-carbaldehyde 169a,b are evaluated [124] against yeasts, moulds and gram-positive bacteria. The pyrrole derivative 169a proved to be a wide spectrum agent, showing a strong inhibition of the growth of gram-positive bacteria and fungi. In contrast, a selective effect is observed for indole 169b against fungi and grampositive bacteria (Fig. 2d).
HO
N N H
H N N
N
S
OH
NH2
N
170a-c
Fig. (2g). Pyrrolopyrimidine nucleoside antibiotics.
NH2
R
HO
N
O HO
OH
N
170a
Fig. (2h). Halogenated Tubercidin analogs.
NH2
169b
N
Fig. (2d). Pyrrole-2-carbaldehyde and indole-3-carbaldehyde.
S R
N
H3C
N H
N
R=3 Cl , 2,3-Cl2 , 2-OCH3 2,5-(OCH3)2 NH2
171
Fig. (2i). dihydrofolate reductase (DHFR) inhibitors.
CONH N
R= I (5-Iodotubericidin) Cl (5-Chlorotubericidin) Br (5-Bromotubericidin)
N
S
H
H2N
N
O HO
Pyrrole derivative 58 showed [45] very good antibacterial and antitubercular activities (Fig. 2e).
169a
R= a H (Tubericidin) b CN (Toyocamycin) c CONH2 (Sangivamycin)
N
Fig. (2c). Diguanidino pyrrole derivative.
H
R2= Me, Et,nPr, nBu
O
84
R= H, CH3, Cl, OCH3
N
R1= OCH3, OEt, Ph
CH3
58 Fig. (2e). Pyrrole as antibacterial and antitubercular.
Pyrrolocoumarins [63] are of considerable pharmacological relevance and occur in a variety of natural products.A chromeno[3,4-b]pyrrol-4(3H)-one 84 core structure occurs, for example, in the marine alkaloids ningalin B and lamellarin D which exhibit HIV-1 integrase inhibition, immunomodulatory activity and cytotoxicity (Fig. 2f). Tubercidin, Toyocamycin and Sangivamycin are naturally occurring pyrrolo[2,3-d]pyrimidine nucleoside antibiotics [125-128]. 170a-c are known for a long time as nucleoside analogs effective as antiviral agents [129, 130] (Fig. 2g). Tubercidin 170a is closely related in structure to adenosine and is rapidly converted [131, 132] to its 5'-
monophosphate by adenosine kinase and subsequently to the higher phosphatesm that assist in inhibition of RNA and DNA virus replication. For example, the related halogenated Tubercidin analogs [133, 134] such as 5-iodo, 5-bromo and 5-chloro were found to have cytotoxic effects and antiviral activities (Fig. 2h). 2,4-Diamino-5-methyl-6-substituted-pyrrolo[2,3-d]pyrimidines 171 [76] are potent and selective dihydrofolate reductase (DHFR) inhibitors against Pneumocystis carinii, Toxoplasma gondii and Mycobacterium avium (Fig. 2i). Pyrrolo[2,3-d]pyrimidine derivatives 172 are found [135] to be more effective, less toxic, and orally available compounds for the treatment of human cytomegalovirus (HCMV) infections. 2'-amino analogs 172a was the most active compound against HCMV (Fig. 2j). Antiviral activity of carbocyclic ring, replacing the sugar moiety, in Sangivamycin (R = CN), Toyocamycin (R = CONH2) and Tubercidin 173a,b is described [136]. Compounds 173a had activity against HBV that is separate from cytotoxicity, that compound 173b had no activity against HBV (Fig. 2k). When the sugar moiety of 170b,c are
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
NH2
R N
O X
N
N
R X a CN NH2 b CONH2 N3
X
172 for
treatment
of
N
H 2N
N
R= CN , CONH2 N
N
R
176 O
human
N
NH2
R
N
X= H,CH3 R= H, 2'-deoxyribose R1=SH, SCH3 R2= OH,Cl,NH2 R1
Fig. (2n). Pyrrolopyrimidines as anti- (HSV-2).
HO Fig. (2j). Pyrrolopyrimidines cytomegalovirus.
N
N
N
R1 Fig. (2o). Pyrrolopyrimidinones as anti- (HSV-2).
173b
H
Fig. (2k). Antiviral activity of carbocyclic ring.
CH3O
N
N
174a
N
N
N
HO
OH
N OH
replaced by a benzyl moiety, these compounds 174a and 174b are turned into specific inhibitors of (HCMV) replication. They are found [137] to interfere with an early step of HCMV replicate cycle (Fig. 2l). Hepatitis C virus is the most common blood-borne infection and a major cause of chronic liver disease. Compounds 175a,b are showen [138] excellent anti-HCV activities through inhibition of HCV RNA replication (Fig. 2m). Pyrrolopyrimidines (2'-deoxyribonucleosides) 176 are proven [125] to have significant activity against herpes simplex type 2 (HSV-2) (Fig. 2n). Hilmy,[139] synthesized a series of some novel pyrrolo[2,3-d]pyrimidin-4-ones 177 as new antiviral agent, that inhibit the replication of herpes simplex virus type-2 (HSV-2) (Fig. 2o). OH
HO HO
N HO
O
HO
OH
Fig. (2m). Sugar derivatives as HCV RNA replication inhibitors.
a= b= HN(CH2)3N
179
O
CN HOHN-C=NH
Fig. (2q). Toyocamycin as HCV-RNA inhibitors.
A pyrrolopyrimidine derivative, 9-deazaneplanocin 178 is discovered [140] to have anti-HIV activity (Fig. 2p). Several Toyocamycin (170b) analogs are examined [141] for their ability to inhibit HCV-RNA in a replicon assay. Among the compounds examined 4-methylthio and 5carboxamide oxime derivatives 179a,b of Toyocamycin are found to have good activity and selectivity (Fig. 2q). R1
N R1= NHCH3 , N(CH3)2
N
N
175a
N
N
HO
X=
R=
N
R S R
N
OH
NHR
X
H2NOC
R N
178
Fig. (2p). 9-deazaneplanocin as anti-HIV.
Fig. (2l). Benzyl derivatives as (HCMV) replication inhibitors.
R= CN , CONH2
N
174b
H 3C
NH2
N
NH2
NC
NH2
N
R1= H, Cl, F R2= CH(CH3)2, CH3CHC2H5 CH2C6H5
177
HO
173a
R2
N
N N
N
HO
H2NSC
23
R2
N
HO
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
OH HO
175b
24 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
CO2Et
HO O
Mohamed and Fathallah
N
O
N
CONHOH
N
180
CH3
N OMe
182
Fig. (3a). Pyrrole as antiproliferative.
O Fig. (2r). Antimicrobial activity of the indole nucleus.
N NC EtO
N
181
N
R N
R'
R= OH, Cl, SH
R
N CH3
R= CH3 , C6H5, H R=R'= C4H4 R''=H,CH2Ph
N
N N
R''
SCH3
132 Fig. (3b). Tricyclic pyrrole as antiproliferative.
Fig. (2s). (7-azaindole) as antivirus.
O
It is reported [142] that the combinations of the pyrazole moiety with the indole nucleus 180 enhance the antimicrobial activity of the indole nucleus (Fig. 2r).
O N
Pyrrolopyridines 181 have attracted [143] considerable attention as an analogs of indole nucleus(7-azaindole) that exhibit antiviral properties. They also exhibited a remarkable antimicrobial activity against S. aureus and a moderate activity against E. coli and S. marcescens (Fig. 2s).
183 Fig. (3c). Pyrroloindoleone as antitumor.
blood toxicity. The 3-formyl compound (184b), one of such analogs, showed stronger antitumor activity with lower toxicity (Fig. 3d).
Pyrrole Derivatives as Anti-cancer Agents 3-[1-Methyl-4-phenylacetyl-1H-pyrrol-2-yl]-N-hydroxy2-propenamide (182) showed [144] antiproliferative and cyto differentiating effect in erythro leukemia (Fig. 3a). Several tricyclic and tetracyclic heterocycles incorporate the pyrrole are reported to have antiproliferative activity [94, 133, 137] (Fig. 3b). Compounds 132 as derivatives of these systems possess the steric requisite to interact with DNA and could constitute suitable compounds for new anticancer agents. A new tricycle, tetrahydropyrrolo[1,2-a]indole-1,8-dione (183), has been shown [145], to have a potential anti-tumor activities (Fig. 3c).
Farghaly has recently reported [142a] the synthesis and antitumor activity of some indole derivatives 185, containing 1,3,4-oxadiazole and/or 1,2,4-triazole. Some of the analogs are potent [142b] and selective against various cancer cell lines (Fig. 3e). Pyrrolopyrimidine 186a [76, 147] as folate antimetabolites, Pemetrexed (Alimta®), function as potent inhibitors of thymidylate synthetase (TS), blocked de novo DNA biosynthesis. It exhibits [148] potent in vitro and in vivo activities against a broad variety of solid tumors. Also, Compound 186b prepared [33, 149] by Miwa et.al., at Takeda Industries is representative of a new class of dihydrofolate reductase (DHFR) inhibitors (Fig. 3f).
A series of 3-substituted pyrrole compounds of duocarmycin (DUM), (184a) as novel antitumor antibiotics, are synthesized [146] and evaluated for in vivo antitumor activity against murine sarcoma. Several analogs showed remarkably potent antitumor activity with low peripheral
A series of analogs of Toyocamycin (170b) and Sangivamycin (170c) are reported [149, 150] as ATPSeg-B(=TMI)
O
Duocarmycin A OMe
H3CO2C H3C HN O
CHO OMe
N O
Seg-A
184a Fig. (3d). Duocarmycin (DUM) as antitumor antibiotics.
N H
OMe
H3C HN N
O
184b
Seg-B(TMI)
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
N N
NH2
X
O
NH2
N
Br N
N
N
25
188 OMe
X= O, N-NH2
Fig. (3i). MCS-C2 as anti-proliferative.
185 Fig. (3e). indole as antitumor.
HO2C
R
HNOC
HO2CH2CH2C
H
N
N
NH2
S
N
N H
N
H2N
N R= a= OH b= NH2
O
R= H, Me,OMe
189 Fig. (3j). Thiopyrrolopyrimidines as (DHFR) inhibitors.
Fig. (3f). Pyrrolopyrimidines as (DHFR) inhibitors.
HO
O HO
N
OH
O
NH2 N N
CH3
H
186
R
R
HN
R= b CN (Toyocamycin) c CONH2 (Sangivamycin)
N N
R'
190
N H
R
R= m-C6H4OMe, p-C6H4OMe, m-C6H4 R'= H, NH2, CF3, Me, CH2Ph
170
Fig. (3g). Toyocamycin as PKC inhibitors.
Fig. (3k). Pyrrolopyrimidinones as MK2 inhibitors.
competitive inhibitors as inhibitors of protein kinase C (PKC) and /or protein kinase A (PKA) (Fig. 3g).
A series of novel 2-amino-4-oxo-5-[(substituted phenyl)thio]pyrrolo[2,3-d]pyrimidines (189) are synthesized [147] as potential inhibitors of thymidylate synthetase (TS) and as dihydrofolate reductase (DHFR) inhibitors (Fig. 3j). Pyrrolo-pyrimidones of the general structure 190 are evaluated [58] for their potential as MK2 (mitogen-activated protein kinase activated protein kinase 2) inhibitors, that is shown to play a critical role in TNFα signalin(tumor necrosis factor alpha) (Fig. 3k).
Modified nucleosides are incorporated into the polynucleotide chain by specific RNA-modifying enzymes during all stages of the post-transcriptional processing of nascent RNA transcripts [151]. Of the known t RNA modifications queuosine 187a and archaeosine 187b. Each of these modifications arised through the replacement of a genetically encoded guanine 187c in a reaction that is catalyzed by the enzyme tRNA guanine transglycosylase (Fig. 3h). MCS-C2 188 a novel synthetic analogs of toyocamycin and sangivamycin, have high activity as anti-proliferative in human promyelocytic leukemia [152] (Fig. 3i).
The evaluation [153] of a series of 4,6-bis-anilino-1Hpyrrolo[2,3-d]pyrimidines(191) as inhibitors of the IGF-1R (IGF-IR) receptor tyrosine kinase is reported. Inhibition of IGF-1R signaling using a variety of approaches has resulted in decreasing proliferation and survival of tumor cells (Fig. 3l).
OH OH
NH
O
H2N N
N
HN
N N H
O
O
NH2
187a Fig. (3h). queuosine a and archaeosine b as antitumor antibiotics.
N N H
187b
N
NH2
N N H
N
187c
NH2
26 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1
Mohamed and Fathallah
F
H2NOC R=
R'
HN
(CH2)2N
N RHN
X
N
N H
X= Me, H, F, CF3 R'= H, F
191
Fig. (3l). Pyrrolopyrimidines as IGF-1R inhibitors.
O
F
O
O
N H N H
N
The discovery of pyrrolopyrimidine192 based protein kinase B (PKB) (Pkb/Akt a serine-threonine kinase that play a central role in the regulation of cell survival and proliferation) inhibitor is reported [154]. These compounds demonstrate potent inhibiting Akt activity as a novel therapeutic approach to cancer treatment (Fig. 3m).
193 Fig. (3n). Toyocamycin as Met kinase inhibitors.
X N
N
R= H,F, R'= H,CF3 R''= H, F, NH2
H
N
194 N
N
H
192
R
X=
O
N
R'
R''
NH2
N
N H
NH O
N H
Fig. (3o). Pyrrolopyridines as IGF-1R inhibitors.
Cl
F
Fig. (3m). Pyrrolopyrimidines as PKB inhibitors. 2+
A series of acylurea analogs derived from pyrrolopyridine 193 are identified [155] as potent inhibitors of Met kinase activity (a receptor tyrosine kinase protein), inhibition of Met kinase activity blocks tumor cell growth (Fig. 3n). A series of 3,5-disubstituted-1H-pyrrolo[2,3b]pyridines194 are discovered [156] as a novel inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase, that is associated with various cancers (Fig. 3o). Pyrrole Derivatives as Anti-hyperLipidemic Agents Atorvastatin calcium (195) (Lipitor®) [157] is a synthetic lipid-lowering agent. It is an inhibitor of 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis (Scheme 4a).
N CH2(CH2CH(OH))2CH2COO Ca 3 H2O PhNHOC
195 Fig. (4a). (Lipitor®).
4-Sulfamoyl pyrroles 196 are designed [158] as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. These compounds are found to have a greater selectivity for hepatocytes than atorvastatin. A number of analogs are effective cholesterol reducing agents in acute and chronic in vivo models (Scheme 4b). Pyrrole Derivatives as Anti-depressant Agents Arylpiperzine-containing pyrrole 3-carboxamide derivatives (197) are efficiently [159] bio-assayed for
F N R= OH N
- +
CO2Na
RO2S
OH
196 Fig. (4b). Sulfamoyl pyrroles as HMG reductase inhibitors.
2
N
N O
Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities
binding to 5-HT2A, 5-HT2C receptor, and 5-HT transporter. Based on their in vitro and in vivo activities as well as selectivity over other neurotransmitter receptors and PK profiles, 197 are identified as lead compounds (Scheme 5a). O
Ph
N
H N N
Me
R
R= H,Me, Et, Pr R', R''= H, Cl, Br
N R'
197
Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1
Pyrrole Derivatives as Anti-allergic Agent Pyrrolo[2,3-d]pyrimidine derivative 199 is reported as potent Signal transducers and activators of transcription 6 (STAT6) inhibitor [41]. STAT6 is an important transcription factor in interleukin (IL)-4 signaling pathway and a key regulator of the type 2 helper T (Th2) cell immune response. Therefore, STAT6 may be an excellent therapeutic target for allergic conditions, including asthma and atopic diseases (Scheme 8).
R''
N
Fig. (5a). Arylpiperzine-containing pyrrole.
N
A novel series of tetrahydropyrido[3,2-c]pyrroles 198 is described [71] to have a high binding affinity at the 5-HT7 receptor (the most recently described member of the 5-HT receptor family). A representative set of compounds are shown to be functional antagonists of the 5-HT7 receptor (classical serotonin reuptake inhibitors) (Scheme 5b).
N
H N
F N F
199
N H2N
R N
90
CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS
Fig. (5b). Tetrahydropyridopyrroles.
Declared none.
Pyrrole Derivatives as Anti-hyperglycemic Agents 2,3,4-Triaryl-1H-pyrrole derivatives 39 are reported [34] to have significant hepatic glucose lowering properties by acting as inhibitors of glucagon receptor (Scheme 6). R X R F H H H OMe F Cl F
X R'
X N H
R' H CF3 H H
REFERENCE [1] [2] [3] [4]
39
Fig. (6). Triarylpyrrole derivatives.
[5]
Pyrrole Derivatives as Anti-convulsant Agents Patil et al. reported [160] that two pyrrole derivatives 198 have potential anti-convulsant activity (Scheme 7). [6]
H3C
N
CH3
[7]
X X= H, OH Y= I, H Y
O
Fig. (8). Pyrrolopyrimidines as (STAT6) inhibitor.
R= H, 4-Cl, 4-Me, 4-CF3 4-OCF3, 3-Cl, 3-F N H
27
198
Fig. (7). Arylpyrrole derivatives as anti-convulsant.
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