Pyrroles and Fused Pyrroles: Synthesis and

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Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1 9. NH2. HO. R. PhCOCl,Et3N,CH2Cl2. N. R. COPh. MeCN. EtO. R=CF3,CHF2,CF2Cl,C2F5. NH-COPh.

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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.

Paal, C. Formation of pyrroles via cyclization of 1, 4-dicarbonyl compounds with ammonia or primary amines. Biomed. Engineer. Res., 1885, 18, 367. Hantzsch, A. Formation of pyrrole derivatives from α-chloromethyl ketones, β-keto esters and ammonia or amines. Biomed. Engineer. Res., 1890, 23, 1474. Feist, F. Formation of furans from α-halogenated ketones or ethers and 1, 3-dicarbonyl compounds in the presence of pyridine. Biomed. Engineer. Res., 1902, 35, 1537-1545. a) Taylor, E.C.; Hendress, R.W. Synthesis of 4-Amino-5cyanopyrrolo [2, 3-d]pyrimidine, the Aglycone of Toyocamcin. J. Am. Chem. Soc., 1964, 86, 951-952. b) Taylor, E.C.; Hendress, R.W. Synthesis of Pyrrolo[2, 3-d]pyrimidines. The Aglycone of Toyocamycin. J. Am. Chem. Soc., 1965, 85, 1995-1996. a) Wamhoff, H.; Wehling, B. Heterocyclische β-Enamino-ester; XI1. Synthese von 3-Alkoxycarbonyl-2-amino-1-tosyl-Δ2pyrrolinen. Synthesis, 1973, 546. b) Roth, H.J.; Eger, K. Synthesis of 2-Amino-3-cyano-pyrroles. Arch. Pharmaz., 1975, 308, 179185. c) Wamhoff, H.; Wehling, B. Heterocyclic β-enaminoesters; 181. For the synthesis of 2-aminopyrrole-3-carboxylic acid derivatives. Synthesis, 1976, 51. Mattson, R.J.; Wang, L.C.; Sowell, J.W. Synthesis of substituted 2amino-3-cyano-4-methylpyrroles. J. Heterocycl. Chem., 1977, 14, 383-385. a) Laks, J.S.; Ross, J.R.; Bayomi, S.M. Synthesis of N-1Substituted 2-Amino-3-t-butoxycarbonyl-4, 5- dimethylpyrroles. Synthesis, 1985, 291-293. b) Muller, C.E.; Daly, J.W.; Eger, K. 7Deaza-2-phenyladenines: structure-activity relationships of potent A1 selective adenosine receptor antagonists. J. Med. Chem., 1990, 33, 2822-2828. c) Eger, K.; Lanzner, W.; Rothenhausler, K. Synthesis of Substituted Indoles and Pyrimido[4, 5-b] indoles by Dehydrogenation of Tetrahydroindoles and Tetrahydropyrimidoindoles. Lieb. Ann. Chem., 1993, 465-470.

28 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 [8] [9] [10] [11] [12] [13] [14]

[15] [16] [17] [18]

[19]

[20] [21]

[22] [23] [24] [25]

[26]

[27]

[28] [29] [30] [31] [32]

Traxler, P.M.; Furet, P. 4-(Phenylamino)pyrrolopyrimidines: Potent and Selective, ATP Site Directed Inhibitors of the EGF-Receptor Protein Tyrosine Kinase. J. Med. Chem., 1996, 39, 2285-2292. Fischer, R.W.; Misun, M. Large-Scale Synthesis of a Pyrrolo[2, 3d] pyrimidine via Dakin-West Reaction and Dimroth Rearrangement. Org. Pro. Res. Dev., 2001, 5, 581-586. Gewald, K.; Wagner, K.; Putsch, K.; Fanghanel, V.E. The Reaction of diazocarbonyl compounds with Alkylidenmalonitrilen and cyanoacetic esters. J. Prackt. Chem., 1969, 311, 388-394. Chkhikvadze, K.A.; Rodnyanskaya, N.S. Khim. Farm. Zh., 1968, 34, 2577. Ordzhhonikidize, S.; Chkhikvadze K.A.; Rodnyanskaya, N.S.U.S.S.R. Patent, 1967, 29, Chem. Abstr., 1968, 27444. Gewald, K.; Hentschel, M. Reaction of γ-halo-α-cyano crotonic acid nitriles with amines. J. Prackt. Chem., 1976, 318, 663-670. Abdelrazek, F.M.; Bahbouh, M.S. Heterocyclic synthesis within nitriles: Synthesis of some novel Pyrrole, Pyrrolo[1, 2a]quinazoline and pyrrolo[1, 2-a]triazine derivatives. Phosphor. Sulfur Silic., 1996, 116, 235-241. Dave, C.G.; Desai, N.D. Synthesis and reactions of fluoroaryl substituted 2-amino-3-cyanopyrroles and pyrrolo[2, 3d]pyrimidines . J. Heterocycl. Chem., 1999, 36, 729-733. Chambers, R.D.; Maslakiewicz, J.R.; Srivastava, K.C. Chem. Soc. Perkin. Trans., 1975, 1, 1130. Barlin, G.B.; Yap, C.Y. Some 3-halogenopyridazines. Aust. J. Chem., 1977, 30, 2319-2322. Coats, W.J.; Mckillop, A. Reinvestigation and extension of the aluminum chloride induced reactions of resorcinol and hydroquinone with 3, 6-dichloropyridazine. J. Org. Chem., 1990, 55, 5418-5420. Padwa, A.; Gingrich, H.L.; Lim, R. Regiochemical aspects associated with the intramolecular 1, 3-dipolar cycloaddition reactions of munchnone derivatives. Tetrahedr. Lett., 1980, 34193422. Haddadin, M.J.; Kattan, A.M.; Freeman, J.P. Novel synthesis of the mesoionic system 1, 3-oxazolium-4-olate. J. Org. Chem., 1982, 47, 723-725. Mataka, S.; Takahashi, K.; Tsuda, Y.; Tashiro, M. Preparation of Ethyl 3, 5-Disubstituted Pyrrole-2-carboxylates from 1, 3Diketones and Ethyl Glycinate Hydrochloride. Synthesis, 1982, 2, 157-159. Khachatryan, V.E.; Mirzoyan, V.S. Khim. Geterotisk Soedin., 1982, 12, 1686-1689. Toja, E.; Tarzia, G.; Tuan, G. Pyrrolopyridine analogs of nalidixic acid. Pyrrolo[2, 3-b]pyridines. J. Heterocycl. Chem., 1986, 23, 1555-1560. Toja, E.; DePaoli, A.; Tuan, G. Synthesis of 2-Amino-3ethoxycarbonylpyrroles. Synthesis, 1987, 272-274. Basyouni, W.M.; Hosni, H.M.; Elbayouki, K.A.M. Pyrrolo[2, 3-d] pyrimidines. Part 3. Synthesis of Some Novel 4-Substituted Pyrrolo[2, 3-d] pyrimidines and Their Related Triazolo Derivatives. J. Chem. Res., 1997, 29, 452-453. a) Hilmy, K.M.H.; Pedersen, E.B. Nitriles in Heterocyclic Synthesis: A Novel Synthesis of 2-Amino-3-pyrrolecarbonitriles. Liebigs Ann. Chem., 1989, 1145-1146. b) Hilmy, K.M.H. Synthesis of New Pyrrolo[2, 3-b]pyridines as a Potent Inhibitor of Tumour Necrosis Factor Alpha. Arch. Pharm. Pharm. Med. Chem., 2004, 337, 15-19. Abdel-Hamid, A.O.; Negm, A.M.; Abbas, I.M. New syntheses of pyrazolo[3, 4-d]pyrimidine, pyrazolo[3, 4-d]pyridazine, isoindolinedione and pyrazole derivatives. J. Prackt. Chem., 1989, 331, 31-36. Krutosiková1, A.; Ramsden, C.A.; Dandárová1, M.; Lycka, A. Synthesis and Reactions of Furo[2, 3-b]pyrroles. Molecules, 1997, 2, 69-79. Dannhardt, G.; Kiefer, W. Kramer, G.; Maehrlein, S.; Noure, U.; Fiebich, B. The pyrrole moiety as a template for COX-1/COX-2 inhibitors. Eur. J. Med. Chem., 2000, 35, 499-510. Barnett, C.J.; Grubb, L.M. Synthesis of pyrrolo[2, 3-d]pyrimidines via cyclocondensation of β-alkoxyand β-amino-αbromoaldehydes. Tetrahedron Lett., 2000, 41, 9741-9745. Tumkevicius, S.; Urbonas, A.; Vainilavicius, P. Chem. Heterocyc. Comp., 2000, 36(7), 841-846. Tumkevicius, S. Synthesis of Novel Thieno- and Pyrrolo[2, 3-d] pyrimidines peri-Fused with Pyrimidine, 1, 4-Diazepine and 1, 4Thiazepine Rings. Synthesis, 2003, 9, 1377-1382.

Mohamed and Fathallah [33]

[34]

[35] [36] [37]

[38] [39] [40] [41]

[42] [43] [44]

[45]

[46] [47] [48] [49] [50] [51]

[52]

[53]

Iwao, M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi, F. Short and flexible route to 3, 4-diarylpyrrole marine alkaloids: syntheses of permethyl storniamide A, ningalin B, and lamellarin G trimethyl ether. Tetrahedron Lett., 2003, 44, 4443-4446. Goel, A.; Agarwal, N.; Singh, F.V.; Sharon, A.; Tiwari, P.; Dixit, M.; Pratap, R.; Srivastava, A.K.; Maulik, P.R.; Ram, V. J. Antihyperglycemic activity of 2-methyl-3, 4, 5-triaryl-1H-pyrroles in SLM and STZ models. Biorg. Med. Chem. Lett., 2004, 14, 10891092. Mohamed, M.S.; Rashad, A.E.; Zaki, M.E.A.; Fatahala, S.S. Synthesis and antimicrobial screening of some fused heterocyclic pyrroles. Acta Pharm., 2005, 55, 237-249. Mohamed, M.S.; Rashad, A.E.; Zaki, M.E.A.; Fatahala, S.S. Synthesis and Biological Evaluation of Some Pyrrolo[2, 3d]pyrimidines. Arch. Pharm. Chem. Life Sci., 2006, 339, 664 - 669. Rochais, C.; Lisowski, V.; Dallemagne, P.; Rault, S. First synthesis of methyl 3-amino-4-(het)aryl-1H-pyrrole-2-carboxylates as useful scaffolds in medicinal chemistry. Tetrahedron, 2004, 60, 22672270. Banik, B.K.; Banik, I.; Renteria, M.; Dasgupta, S.K. A straightforward highly efficient Paal-Knorr synthesis of pyrroles. Tetrahedron Lett., 2005, 46, 2643-2645. Demir, A.S.; Igdir, A.C.; Gunay, N.B. Amination/annulation of chlorobutenones with chiral amine compounds: synthesis of 1, 2, 4trisubstituted pyrroles. Tetrahedron Asy., 2005, 16, 3170-3175. Mathew, P.; Asokan, C.V. Cyclization of functionalized ketene-N, S-acetals to substituted pyrroles: applications in the synthesis of marine pyrrole alkaloids. Tetrahedron Lett., 2005, 46, 475-478. Choi, H.S.; Wang, Z.; Richmond, W.; He, X.; Caldwell, J.; Gray, N.; He, Y. Design and synthesis of 7H-pyrrolo[2, 3-d]pyrimidines as focal adhesion kinase inhibitors. Part 1, Bioorg. Med. Chem. Lett. 2006, 16, 2173. Pridmore, S.J.; Slatford, P.A.; Daniel, A.; Whittlesey, M.K.; Williams, J.M. Ruthenium-catalysed conversion of 1, 4-alkynediols into pyrroles. Tetrahedron Lett., 2007, 48, 5115-5120. Aydogan, F.; Basarir, M.; Yolacan, C.; Demir, A.S. New and clean synthesis of N-substituted pyrroles under microwave irradiation. Tetrahedron, 2007, 63, 9746-9750. Abid, M.; Teixeira, L.; Torok, B. Triflic acid controlled successive annelation of aromatic sulfonamides: an efficient one-pot synthesis of N-sulfonyl pyrroles, indoles and carbazoles. Tetrahedron Lett., 2007, 48, 4047-4050. Joshi, S.D.; Vagdevi, H.M.; Vaidya, V.P.; Gadaginamath, G.S. Synthesis, biological activity and molecular modelling of new trisubstituted 8-azaadenines with high affinity for A1adenosine receptors. Euro. J. Med. Chem., 2007, 42, 3-9. Lee, H.S.; Kim, J.M.; Kim, J.N. Synthesis of poly-substituted pyrroles starting from the Baylis-Hillman adducts. Tetrahedron Lett., 2007, 48, 4119-4122. Teno, N.; Miyake, T.; Ehara, T.; Missbach, M.; Lattmann, R.; Betschart, C. Novel scaffold for cathepsin K inhibitors. Bioorg. Med. Chem. Lett., 2007, 17, 6096-6100. Kanamarlapudi, R.C.; Bednarz, M.; Wu, W.; Keyes, P. One-Pot Synthesis of 5-Methyl-3H-pyrrolo[2, 3-d]pyrimidin-4(7H)-one. Org. Pro. Res. Dev., 2007, 11, 86-89. Krishna, P.R.; Reddy, V.R.; Srinivas, R. A new synthetic route to oxazole and pyrrole 2-deoxy-C-ribosides, Tetrahedron, 2007, 63, 9871-9880. Terzidis, M.; Tsoleridis, C.A.; Stephanatou, J.S. Reaction of chromone-3-carboxaldehydes with TOSMIC: synthesis of 4-(2hydroxybenzoyl) pyrroles. Tetrahedron, 2007, 63, 7828-7832. Pfefferkorn, J.A.; Bowles, D.M.; Kissel, W.; Boyles, D.C.; Choi, C.; Larsen, S.D.; Song, Y.; Sun, K.L.; Miller, S.R.; Trivedi, B.K. Development of a practical synthesis of novel, pyrrole-based HMG-CoA reductase inhibitors. Tetrahedron, 2007, 63, 81248134. Elmegeed, G.A.; Baiuomy, A.R.; Abdel-Salam, O.M.E. Evaluation of the anti-inflammatory and anti-nociceptive activities of novel synthesized melatonin analogues. Eur. J. Med. Chem., 2007, 42, 1285-1292. a) Harrak, Y.; Rosell, G.; Daidone, G.; Plescia, S.; Schillaci, D.; Pujola, M.D. Synthesis and biological activity of new antiinflammatory compounds containing the 1, 4-benzodioxine and/or pyrrole system. Bioorg. Med. Chem., 2007, 15, 4876-4890. b) Rivera, S.; Bandyopadhyay, D.; Banik, B.K. Facile synthesis of Nsubstituted pyrroles via microwave-induced bismuth nitrate-

Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities

[54]

[55] [56]

[57]

[58]

[59]

[60]

[61]

[62]

[63] [64]

[65]

[66]

[67]

[68]

[69]

catalyzed reaction, Tetrahedron Letters, 2009, 50, 5445-5448. C) Bandyopadhyay, D.; Mukherjee, S.; Granados, J.C.; Short, J.D.; Banik, B.K. Ultrasound-assisted bismuth nitrate-induced green synthesis of novel pyrrole derivatives and their biological evaluation as anticancer agents, Eur. J. Med. Chem., 2012, 50, 209215. Majumdar, K.C.; Mondal, S. A new strategy for the synthesis of coumarin- and quinolone-annulated pyrroles via Pd(0) mediated cross-coupling followed by Cu(I) catalyzed heteroannulation. Tetrahedron Lett., 2008, 49, 2418-2420. Shaitanova, E.N.; Gerus, I.I.; Kukhar, V.P. A new synthetic route to 3-polyfluoroalkyl-containing pyrroles. Tetrahedron Lett, 2008, 49, 1184-1187. Abdel-Ella, D.A.; Ghorab, M.M.; Noaman, E.; Heiba, H.I.; Khalil, A.I. Molecular modeling study and synthesis of novel pyrrolo[2, 3d]pyrimidines and pyrrolotriazolopyrimidines of expected antitumor and radioprotective activities. Bioorg. Med. Chem., 2008, 16, 2391-2402. Salaheldin, A.M.; Oliveira-Campos, A.M.F.; Rodrigues, L.M. 3Aminopyrroles and their application in the synthesis of pyrrolo[3, 2-d] pyrimidine (9-deazapurine) derivatives. Arkivoc, 2008, xiv, 180-190. Schlapbach, A.; Feifel, R.; Hawtin, S.; Heng, R.; Koch, G.; Moebitz, H.; Revesz, L.; Scheufler, C.; Velcicky, J.; Waelchli, R.; Huppertz, C. Pyrrolo-pyrimidones: A novel class of MK2 inhibitors with potent cellular activity. Bioorg. Med. Chem. Lett., 2008, 18, 6142-6146. Irie, O.; Ehara, T.; Iwasaki, A.; Yokokawa, F.; Sakaki, J.; Hirao, H.; Kanazawa, T.; Teno, N.; Horiuchi, M.; Umemura, I.; Gunji, H.;. Masuya, K; Hitomi, Y.; Iwasaki, G.; Nonomura, K.; Tanabe, K.; Fukaya, H.; Kosaka, T.; Snell, C.R.; Hallett, A. Discovery of selective and nonpeptidic cathepsin S inhibitors. Bioorg. Med. Chem. Lett., 2008, 18, 3959-3962. Bernotas, R.C.; Antane, S.A.; Lenicek, S.E.; Haydar, S.N.; Robichaud, A.J.; Harrison, B.L.; Zhang, G.M.; Smith, D.; Coupet, J.; Schechter, L.E. 1-(2-Aminoethyl)-3-(arylsulfonyl)-1Hpyrrolopyridines are 5-HT6 receptor ligands. Bioorg. Med. Chem. Lett., 2009, 19, 6935-6938. Pudziuvelyte, E.; Ríos-Luci, C.; León, L.G.; Cikotien, I.; Padrón, J.M. Synthesis and antiproliferative activity of 2, 4-disubstituted 6aryl-7H-pyrrolo[3, 2-d]pyrimidin-7-one 5-oxides. Bioorg. Med. Chem., 2009, 17, 4955-4960. Diana, P.; Stagno, A.; Barraja, P.; Montalbano, A.; Martorana, A.; Carbone, A.; Dattolo, G.; Cirrincione, G. Pyrido[2’, 3’:4, 5]pyrrolo[2, 1-d][1, 2, 3, 5]tetrazine-4(3H)-ones, a new class of temozolomide heteroanalogues (NV-3678JP). Arkivoc, 2009, viii, 177-186. Zbancioc, G.N.; Huhn, T.; Groth, U.; Deleanu, C.; Mangalagiu, I.I. Pyrrolodiazine derivatives as blue organic luminophores: synthesis and properties. Part 3. Tetrahedron, 2010, 66, 4298-4306. Keivanloo, A.; Bakherad, M.; Rahimi, A.; Taheri.; S.A.N. One-pot synthesis of 1, 2-disubstituted pyrrolo[2, 3-b]quinoxalines via palladium-catalyzed heteroannulation in water. Tetrahedron Lett., 2010, 51, 2409-2412. Zeeshan, M.; Iaroshenko, V.O.; Dudkin, S.; Volochnyuk, D.M.; Langer, P. Synthesis of chromeno[3, 4-b]pyrrol-4(3H)-ones by cyclo-condensation of 1, 3-dicarbonyl compounds with 4-chloro-3nitrocoumarin. Tetrahedron Lett., 2010, 51, 3897-3898. Moon, J.T.; Jeon, J.Y.; Park, H.A.; Noh, Y.S.; Lee, K.T.; Kim, J.; Choo, D.J.; Lee, J.Y. Synthesis and PGE2 production inhibition of 1H-furan-2, 5-dione and 1H-pyrrole-2, 5-dione derivatives. Bioorg. Med. Chem. Lett., 2010, 20, 734-737. Glotova, T.E.; Schmidt, E.Y.; Dvorko, M.Y.; Ushakov, I.A.; Mikhaleva, A.I.; Trofimov, B.A. Synthesis of О-2(acyl)vinylketoximes and their unusual rearrangements into 2- and 3-acyl-substituted pyrroles. Tetrahedron Lett., 2010, 51, 61896191. Ghorab, M.M.; Ragab, F.A.; Heiba, H.I.; Youssef, H.A.; ElGazzar, M.G. Synthesis of novel pyrrole and pyrrolo[2, 3d]pyrimidine derivatives bearing sulfonamide moiety for evaluation as anticancer and radiosensitizing agents. Bioorg. Med. Chem. Lett., 2010, 20, 6316-6320. Mohamed, M.S.; Kamel, R.; Fatahala, S.S. Synthesis and biological evaluation of some thio containing pyrrolo [2, 3-d]Pyrimidine derivatives for their anti-inflammatory and anti-microbial activities, Eur. J. Med. Chem., 2010, 45, 2994-3004.

Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1 [70]

[71]

[72]

[73]

[74]

[75]

[76]

[77] [78] [79]

[80]

[81] [82]

[83]

[84]

[85] [86]

[87] [88] [89]

29

Takayama, T.; Umemiya, H.; Amada, H.; Yabuuchi, T.; Shiozawa, F.; Katakai, H.; Takaoka, A.; Yamaguchi, A.; Endo, M.; Sato, M. Pyrrole derivatives as potent inhibitors of lymphocyte-specific kinase: Structure, synthesis, and SAR. Bioorg. Med. Chem. Lett., 2010, 20, 108-111. Rudolph, D.A.; Dvorak, C.A.; Dvorak, L.; Nepomuceno, D.; Bonaventure, P.; Lovenberg, T.W.; Carruthers, N.I. Novel tetrahydropyrido[3, 2-c]pyrroles as 5-HT7 antagonists. Bioorg. Med. Chem. Lett., 2011, 21, 42-44. Yavari, I.; Ghazvini, M.; Azad, L.; Sanaeishoar, T. A solvent-free synthesis of 1, 2, 3, 5-tetrasubstituted pyrroles from enaminones and α-haloketones, Chinese Chemical Letters, 2011, 22(10), 12191222. Nishida, H.; Hasuoka, A.; Arikawa, Y.; Kurasawa, O.; Hirase, K.; Inatomi, N.; Hori, Y.; Sato, F.; Tarui, N.; Imanishi, A.; Kondo, M.; Takagi, T.; Kajino, M. Discovery, synthesis, and biological evaluation of novel pyrrole derivatives as highly selective potassium-competitive acid blockers, Bioorg. Med. Chem., 2012, 20, 3925-3938. Korotaev, V. Yu.; Barkov, A. Yu.; Kotovich, I.V.; Sosnovskikh, V.Y. Three-component synthesis of substituted b(trifluoromethyl)pyrroles via Grob cyclization of 1, 1, 1-trifluoro-3nitrobut-2-ene with 1, 3-dicarbonylic compounds and ammonia or primary amines, Journal of Fluorine Chemistry, 2012, 138, 42-47. Taylor, E.C.; Junt, J.G. A One-Step Ring Transformation/Ring Annulation Approach to Pyrrolo[2, 3-d]pyrimidines. A New Synthesis of the Potent Dihydrofolate Reductase Inhibitor TNP351. J. Org. Chem., 1995, 60, 6684-6687. Gangjee, A.; Lin, X.; Queener, S.F. Design, Synthesis, and Biological Evaluation of 2, 4-Diamino-5-methyl-6-substitutedpyrrolo[2, 3-d] pyrimidines as Dihydrofolate Reductase Inhibitors. J. Med. Chem., 2004, 47, 3689-3692. Hershenson, F.M.; Pavia, M. Synthesis of N-Substituted Pyrroles From Azlactones via 1, 3-Oxazolium 5-Oxides. Synthesis, 1988, 999-1001. Lopes, S.M.M.; Nunes, C.M.; Pinho e Melo, T.M.V.D. 4Isoxazolines and pyrroles from allenoates. Tetrahedron, 2010, 66, 6078-6084. Coskun, N.; Cetin, M. Rearrangements of tetrahydroimidazo[1, 5b] isoxazole-2, 3-dicarboxylates to pyrrolo[1, 2-e]imidazol-6-ols, precursors of 2, 5-dihydro-1H-pyrrole derivatives. Tetrahedron, 2009, 65, 648-658. Naya, S.; Iida, Y.; Nitta, M. Alternative synthesis and novel oxidizing ability of 6, 9-disubstituted cyclohepta[b]pyrimido[5, 4d]pyrrole-8(6H), 10(9H)-dione derivatives. Tetrahedron, 2004, 60, 459-467. Soret, A.; Muller, C.; Guillot, R.; Blanco, L.; Deloisy, S. Short and efficient synthesis of 2H-pyrroles from 7-oxanorbornadiene derivatives. Tetrahedron, 2011, 67, 698-705. Kathriarachchi, K.K.; Siriwardana, A.I.; Nakamura, I.; Yamamoto, Y. Synthesis of 1, 2, 3, 4-tetrasubstituted pyrrole derivatives via the palladium-catalyzed reaction of 1, 3-diketones with methyleneaziridines. Tetrahedron Lett., 2007, 48, 2267-2270. Ribeiro Laia, F.M.; Cardoso, A.L.; Beja, A.M.; Silva, M.R.; Pinho e Melo, T.M.V.D. Reactivity of allenoates towards aziridines: synthesis of functionalized methylene pyrrolidines and pyrroles. Tetrahedron, 2010, 66, 8815-8822. Auricchio, S.; Truscello, A.M.; Lauria, M.; Meille, S.V.A. Ambivalent role of metal chlorides in ring opening reactions of 2Hazirines: synthesis of imidazoles, pyrroles and pyrrolinones. Tetrahedron, 2012, 68, 7441-7449. Dave, C.G.; Gandi, T. P and Shah, R.D. Synthesis & Biological Activity of Pyrrolo[2, 3-d]pyrimidine. Indian J. Chem., 1988, 27B, 779-780. Bennett, S.M.; Naguden, B.N.; Olgilive, K.K. Synthesis and antiviral activity of some acyclic and C-acyclic pyrrolo[2, 3d]pyrimidine nucleoside analogs. J. Med. Chem., 1990, 33, 21622173. Dave, C.G.; Shah, R.D. Synthesis of isomeric triazolopyrrolopyrimidines. J. Heterocycl. Chem., 2000, 37, 757-761. Granik, V.G. Khim. Farm. Zh., 1967, (1), 16, ; Chem. Abstr., 1968, 68, 12941. Taylor, E.C.; Liu, B. A New Route to 7-Substituted Derivatives of N-{4-[2-(2-Amino-3, 4-dihydro-4-oxo-7H-pyrrolo[2, 3d]pyrimidin-5-yl)- ethyl]benzoyl}-l-glutamic Acid [ALIMTA (LY231514, MTA)]. J. Org. Chem., 2001, 66, 3726-3738.

30 Mini-Reviews in Organic Chemistry, 2014, Vol. 11, No. 1 [90]

[91]

[92]

[93] [94]

[95] [96]

[97] [98]

[99] [100]

[101] [102] [103]

[104] [105] [106]

[107]

Milne, J.H.; Tolman, R.L.; Robins, R.K.; Townsend, L.B. The synthesis of 2-amino-7-(β-D-ribofuranosyl)pyrrolo[2, 3-d]pyrimidin-4-one (7-deazaguanosine), a nucleoside Q and Q* analog. J. Heterocycl. Chem., 1976, 13, 1363-1368. Jorgenese, A.; El-Bayouki, K.; Pedersen, E.B. Phosphorus pentoxide in organic synthesis. XX. Synthesis of N-aryl-7Hpyrrolo[2, 3-d]pyrimidin-4-amines. J. Heterocycl. Chem., 1985, 22, 859-865. a) Mohamed, M.S.; Kamel, R.; Fatahala, S.S. New condensed pyrroles of potential biological interest Synthesis and structureactivity relationship studies'' Eur. J. Med. Chem. 2011, 46, 30223029. b) Mohamed, M.S.; Kamel, R.; Fatahala, S.S. Synthesis of New Pyrroles of Potential Anti-InflammatoryActivity. Arch. Pharm. Chem. Life Sci, 2011, 344(12), 830-839. c) Hussein, W.M.; Fatahala, S.S.; Mohamed, Z.M.; McGeary, R.P.; Schenk, G.; Olli, D.L.; Mohamed, M.S. Synthesis and Kinetic Testing of Tetrahydropyrimidine-2-thione and Pyrrole Derivatives as Inhibitors of the Metallo-blactamase from Klebsiella pneumonia and Pseudomonas aeruginosa. Chem Biol Drug Des 2012, 80, 500515. Girgis, N.S.; Anker, J.; Erik, B.P. Phosphorus Pentoxide in Organic Synthesis, ; XI 1. A new synthetic approach to 7deazahypoxanthines. Synthesis, 1985, 1, 101-104. Lauriary, A.; Bruno, M.; Almerico, A.M. Annelated pyrrolopyrimidines from amino-cyanopyrroles andBMMAs as leads for new DNA-interactive ring systemsBioorg. Med. Chem. 2005, 13, 1545-1553. Mohamed, M.S.; El-Domany, R.A.; Abd El-Hamide, R.H. Synthesis of certain pyrrole derivatives as antimicrobial agents. Acta Pharm. 2009, 59, 145-158. El-Gabya, M.S.A.; Gaber, A.M.; Atalla, A.A. Novel synthesis and antifungal activity of pyrrole and pyrrolo[2, 3-d]pyrimidine derivatives containing sulfonamide moieties. IL Farmaco, 2002, 57, 613-617. Dave, C.G.; Gandi, T.P.; Shah, R.D. J. Indian Chem. Soc., 1987, LXIV, 713-718. Lauria, A.; Diana, P.; Barraja, P.; Montalbano, A.; Dattolo, G.; Cirrincione, G.; Almerico, A.M. Docking of indolo- and pyrrolopyrimidines to DNA. New DNA-interactive polycycles from amino-indoles/pyrroles and BMMA (VT-1079LP). Arkivoc, 2004, v, 263-271. Vorob´ev, E.V.; Kurbatov, E.S.; Krasnikov, V.V.; Mezheritskii, V.V.; Usova, E.V. Russ. Chem. Bull., Int. Ed., 2006, 55, 14921497. Dang, Q.; Gomez-Galeno, J.E. An Efficient Synthesis of Pyrrolo[2, 3-d] pyrimidines via Inverse Electron Demand Diels-Alder Reactions of 2-Amino-4-cyanopyrroles with 1, 3, 5-Triazines. J. Org. Chem., 2002, 67, 8703-8705. Etson, S.R.; Mattson, R.J.; Sowell, J.W. Synthesis of substituted pyrrolo[2, 3-d]pyrimidine-2, 4-diones. J. Heterocycl. Chem., 1979, 16, 929-933. Pittala, V.; Romeo, G.; Salerno, L.; Siracusa, M.A.; Modica, M.; Materia, L.; Angeli, P.; Russo, F. Biorg. Med. Chem. Lett., 2006, 16, 150-158. Jiang, J.k.; Boxer, M.B.; Heiden, M.G.V.; Shen, M.; Skoumbourdis, A.P.; Southall, N.; Veith, H.; Leister, W.; Austin, C.P.; Park, H.W.; Inglese, J.; Cantley, L.C.; Auld, D.S.; Thomas, C. J. Biorg. Med. Chem. Lett., 2010, 20, 3387-3393. Zimmermann, W.; Eger, K.; Roth, H. J. Pyrrolo[2, 3-b]pyridine . Arch. Pharm., 1976, 309, 597-560. Forbes, I.T.; Johnoson, C.N.; Thompson, M. J. Chem. Soc. Perkin Trans. 1992, 1, 275-281. a) Wang, S.; Folkes, A. Studies on Pyrrolopyrimidines as Selective Inhibitors of Multidrug-Resistance- Associated Protein in Multidrug Resistance. J. Med. Chem., 2004, 47, 1329-1338. b) Smith, K.L.; Vicky Lai, C.H. Biorg. Med. Chem. Lett., 2004, 14, 3517-3520. c) Chien, T.C.; Townsend, L.B. Org. let., 2004, 6, 2857-2859. d) Obniska, J.; Kulig, K.; Zejc, A. Acta Pol. Pharm., 1998, 55, 223-231. a) Zhang, C.; Dong, J.; Cheng, T.; Li, R. Y(OTf) 3-catalyzed novel Mannich reaction of N-alkoxycarbonylpyrroles, formaldehyde and primary amine hydrochlorides. Tetrahedron Lett., 2001, 42, 461463. b) G. Murineddu, ; Loriga, G.; Gavini E.; Peana, T.; Mul A.C.; Pinna, G.A. Synthesis and analgesic-antiinflammatory activities of novel acylarylhydrazones with a 5-phenyl-4-R-3-pyrrolyl-acyl moiety. Arch. Pharm., 2001, 334, 393-398. c) Micheli, F.; Di

Mohamed and Fathallah

[108]

[109]

[110]

[111]

[112]

[113]

[114] [115]

[116] [117] [118]

[119]

[120]

[121] [122]

[123] [124] [125]

[126]

Fabio, R.; Bordi, F.; Cavallini, P.; Cavanni, P.; Donati, D.; Faedo, S.; Maffeis, M.; Sabbatini, F.M.; Tarzia, G.; Tranquillini, M.E. Bioorg. Med. Chem. Lett., 2003, 13, 2113-2118. Fernandes, E.; Costa, D.; Toste, S.A.; Reis, S. In Vitro Scavenging Activity for Reactive Oxygen and Nitrogen Species by Nonsteroidal Anti-Inflammatory Indole, Pyrrole, and Oxazole Derivative Drugs. Free Radical Biology & Medicine, 2004, 37, 1895-1905. Etcheverry, S.B.; Barrioa, D.A.; Cortizoa, A.M.; Williamsb, P.A.M. Three new vanadyl(IV) complexes with non-steroidal antiinflammatory drugs (Ibuprofen, Naproxen and Tolmetin). Bioactivity on osteoblast-like cells in culture. J. Inorg. Biochem., 2002, 88, 94-99. Bocheva, A.; Bijev, A.; Nankov, A. Further Evaluation of a Series of Anti-Inflammatory N-Pyrrolylcarboxylic Acids: Effects on the Nociception in Rats. Arch. Pharm. Chem. Life Sci., 2006, 339, 141 - 144. Lessigiarska, I.; Nankov, A.; Bocheva, A.; Pajeva, I.; Bijev, A. 3DQSAR and preliminary evaluation of anti-inflammatory activity of series of N-pyrrolylcarboxylic acids. Il Farmaco, 2005, 60, 209218. Ushiyama, S.; Yamada, T.; Murakami, Y.; Kumakura, S.; Kimura, T. Preclinical pharmacology profile of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects. Eur. J. Pharmacology, 2008, 578, 76-82. Bubenyak, M.; Noszal, B.; Koczian, K.; Takacs, M.; Beni, S.; Hermecz, I.; Kokosi, J. Bioisosteric hybrids of two antiinflammatory agents, rutaecarpine and piroxicam, Tetrahedron Lett., 2008, 49, 5711-5713. Mazzoni1, O.; Diurno1, M.V.; di Bosco1, A.M.; Novellino1, E.; Grieco, P.; Esposito, G.; Bertamino, A.; Calignano, A.; Russo, R. Chem. Biol. Drug Des., 2010, 75, 106-111. Downa, K.; Bamborough, P.; Alder, C.; Campbell, A.; Christopher, J.A.; Gerelle, M.; Ludbrook, S.; Mallett, D.; Mellor, G.; Miller, D.D.; Pearson, R.; Ray, K.; Solanke, Y.; Somers, D. Bioorg. Med. Chem. Lett., 2010, 20, 3936-3940. Nakao, A.; Ohkawa, N.; Nagasaki, T.; Kagari, T.; Doi, H.; Shimozato, T.; Ushiyama, S.; Aoki, K. Bioorg. Med. Chem. Lett., 2009, 19, 4607-4610. Jarvis, M.F.; Yu, H.; Cox B.F.; Polakowski, J. Analgesic and antiinflammatory effects of A-286501, a novel orally active adenosine kinase inhibitor, Pain, 2002, 96, 107-118. Banitt, J.L.S.; Bundy, G.L.; Richards, I.M. Preclinical Evaluation of Anti-inflammatory Activities of the Novel Pyrrolopyrimidine PNU-142731A, a Potential Treatment for Asthma. J. Pharm. Exp. Ther., 1999, 290, 188-195. Petruso, S.; Bonanno, S.; Caronna, S.; Ciofalo, M.; Maggi, B.; Schillaci, D. Oxidative halogenation of substituted pyrroles with Cu(II). Part IV. Bromination of 2-(2′-hydroxybenzoyl)pyrrole. A new synthesis of bioactive analogs of monodeoxypyoluteorin. J. Heterocycl. Chem., 1994, 31, 941-947. Raimondi, M.V.; Cascioferro, S.; Schillaci, D.; Petruso, S. Synthesis and antimicrobial activity of new bromine-rich pyrrole derivatives related to monodeoxypyoluteorin. Eur. J. Med. Chem., 2006, 41, 1439-1445. Biava, M.; Fioravanti, R.; Porretta, G.C.; Deidda, D.; Maullu, C.; Pompei, R. New pyrrole derivatives as antimycobacterial agents analogs of BM212. Bioorg. Med. Chem. Lett., 1999, 9, 2983-2988. Biava, M.; Porretta, G.C.; Deidda, D.; Pompei, R.; Tafic, A.; Manettic, F. Importance of the thiomorpholine introduction in new pyrrole derivatives as antimycobacterial agents analogues of BM 212. Bioorg. Med. Chem., 2003, 11, 515-519. Jana, G.H.; Jain, S.; Arora, S.K.; Sinha, N. Synthesis of some diguanidino 1-methyl-2, 5-diaryl-1H-pyrroles as antifungal agents. Biorg. Med. Chem. Lett., 2005, 15, 3592-3595. Rodriguez-Arguelles, M.C.; Lopez-Silva, E.C.; Sanmartin, J.; Pelagatti, P.; Zani, F. J. Inorg. Biochem., 2005, 99, 2231-2239. Cottam, B.H.; Kazimierczuk, Z.; Geary, S.; McKernan, P. Synthesis and Biological Activity of Certain 6-Substituted and 2, 6Disubstituted 2’-Deoxytubercidins Prepared via the Stereospecific Sodium Salt Glycosylation Procedure. J. Med. Chem., 1985, 28, 1461-1467. Ding, Y.; An, H.; Hong, Z.; Luc Girardet, J. Synthesis of 2′-β-Cmethyl toyocamycin and sangivamycin analogues as potential HCV inhibitors Biorg. Med. Chem. Lett., 2005, 15, 725-727.

Pyrroles and Fused Pyrroles: Synthesis and Therapeutic Activities [127]

[128]

[129]

[130] [131] [132]

[133]

[134] [135]

[136] [137] [138] [139] [140] [141]

[142]

[143] [144]

Mini-Reviews in Organic Chemistry, 2013, Vol. 11, No. 1

Tolman, R.L.; Robins R.K.; Townsend, L.B. Pyrrolopyrimidine nucleosides. III. Total synthesis of toyocamycin, sangivamycin, tubercidin, and related derivatives. J. Am. Chem. Soc., 1969, 91, 2102-2108. Supuran, C.T.; Scozzafava, A.; Jurca B.C.; Iiies, M.A. Carbonic anhydrase inhibitors - Part 49: Synthesis of substituted ureido and thioureido derivatives of aromatic/heterocyclic sulfonamides with increased affinities for isozyme I. Eur. J. Med. Chem., 1998, 33, 83-93. De Clercq, E.; Balzarini, J.; Robins, M. J. Nucleic acid related compounds. 51. Synthesis and biological properties of sugarmodified analogues of the nucleoside antibiotics tubercidin, toyocamycin, sangivamycin, and formycin J. Med. Chem., 1987, 30, 481-486. Gupta P.K.; Drach, J.C. J. Med. Chem., 1989, 32, 402-408. Clercq E. De and Robins, M. J. Antimicrob. Agents Chemother., 1986, 30, 719-724. Migawa, M.T.; Drach J.C.; Townsend, L.B. Design, Synthesis and Antiviral Activity of Novel 4, 5-Disubstituted 7-(β-DRibofuranosyl) pyrrolo[2, 3-d][1, 2, 3]triazines and the Novel3Amino-5-methyl-1-(β-D-ribofuranosyl)-and 3-Amino-5-methyl-1(2-deoxy- β -D-ribofuranosyl)-1, 5-dihydro-1, 4, 5, 6, 7, 8hexaazaacenaphthylene as Analogues of Triciribine. J. Med. Chem., 2005, 48, 3840-3851. Ugarkar, B.G.; Da Re J.M.; Browne, C.E. Adenosine kinase inhibitors. 1. Synthesis, enzyme inhibition, and antiseizure activity of 5-iodotubercidin analogues, J. Med. Chem., 2000, 43, 28832893. Wang, X.; Seth P.P.; Migawa, M.T. Synthesis and Biological Activity of 5-Fluorotubercidin. Nucleosides and Nucleotides, 2004, 23, 161-170. Krawczyk, S.H.; Bernier-Rodriguez, M.; Townsend, L.B. Arabinofuranosylpyrrolo[2, 3-d]pyrimidines as Potential Agents for HumanbCytomegalovirus Infections, J. Med. Chem., 1990, 33, 3160-3169. Gudmunds son, K.S.; Wang Z.; Feldman, P.L. Nucleosides and Nucleotides, 2001, 20, 1823-1830. De Clercq, E. Nucleoside Analogues Exerting Antiviral Activity Through a Non-nucleoside Mechanism. Nucleosides and Nucleotides, 2004, 23, 457-470. Howard, B.; Kazimierczuk, Z.; Geary S.; McKernan, P. J. Med. Chem., 1985, 28, 1461-1467. Hilmy, K.M.H. Synthesis of Non-Nucleosides: 7- and 1, 3Substituents of New Pyrrolo[2, 3-d]pyrimidin-4-ones on Antiviral Activity. Arch. Pharm., 2006, 339, 174-181. Rao, J.R.; Schinazib R.F.; Chua, C.K. Enantioselective synthesis and antiviral activity of purine and pyrimidine cyclopentenyl Cnucleosides Bioorg. Med. Chem., 2007, 15, 839-843. Varaprasad, C.V.N.S.; Ramasamy, K.S.; Girardet, J.L.; Gunic, E.; Lai, V.; Zhong, W.; An H.; Hong, Z. Synthesis of pyrrolo[2, 3d]pyrimidine nucleoside derivatives as potential anti-HCV agents. Bioorg. Chem., 2007, 35, 25-34. a) Farghaly, A.R. Synthesis of some new indole derivatives containing pyrazoles with potential antitumor activity (105525VP) Arkivoc, 2010, xi, 177-187. b) Farghaly, A.; De-clercq E.; El-Kashef, H. Synthesis and antiviral activity of novel [1, 2, 4]triazolo[3, 4-b][1, 3, 4]thiadiazoles, [1, 2, 4] triazolo[3, 4-b][1, 3, 4]thiadiazines and [1, 2, 4]triazolo[3, 4-b][1, 3, 4] thiadiazepines (06-1833CP) Arkivoc 2006, x, 137-147. Abdel-Mohsen S.A.; Geies, A.A. Monatsh Chem., 2008, 139, 1233-1240. Mai, A.; Massa, S.; Ragno, R.; Cerbara, I.; Jesacher F.; Loidl, P. 3(4-Aroyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-alkylamides as a new class of synthetic histone deacetylase inhibitors. 1. Design, synthesis, biological evaluation, and binding mode studies performed through three different docking procedures. J. Med. Chem., 2003, 46, 512-517.

Received: February 23, 2013

[145]

[146] [147] [148] [149] [150] [151] [152]

[153]

[154]

[155]

[156]

[157] [158]

[159]

[160]

Revised: June 05, 2013

31

Sechi, M.; Mura, A.; Sannia, L.; Orecchioni M.; Paglietti, G. Synthesis of pyrrol-[1, 2-a]indole-1, 8(5H)-diones as new synthones for developing novel tryciclic compounds of pharmaceutical interest (VT-1012LP). Arkivoc, 2004, v, 97-106. Amishiro, N.; Okamoto, A.; Murakata, C.; Tamaoki, T.; Okabe M.; Saito, H. J. Med. Chem., 1999, 42, 2946-2960. Hazarika, M.; White R.; Johnson, J.R. FDA Drug Approval Summaries: Pemetrexed (Alimta®). The Oncologist, 2004, 9, 482488. Taylor, E.C.; Kuhnt, D.; Shih C.; Barredo, J. J. Med. Chem., 1992, 35, 4450-4458. Miwa, T.; Hitaka, T.; Akimoto H.; Nomura, H. J. Med. Chem., 1991, 34, 555-561. Huang B.; Bobek, M. Synthesis and in vitro antitumor activity of some amino-deoxy 7-hexofuranosylpyrrolo[2, 3-d]pyrimidines, Carbohyd. Res., 1998, 308, 319-328. Garcia G.A.; Kittendorf, J.D. Transglycosylation: A mechanism for RNA modification (and editing). Biorg. Chem., 2005, 33, 229-251. Gangjee, A.; Jaina H.D.; Kisliuk, R.L. Novel 2-amino-4-oxo-5arylthio-substituted-pyrrolo[2, 3-d]pyrimidines as nonclassical antifolate inhibitors of thymidylate synthase, Bioorg. Med. Chem. Lett., ; 2005, 15, 2225-2230. Chamberlain, S.D.; Wilson, J.W.; Deanda, F.; Patnaik, S.; Redman, A.M.; Yang, B.; Shewchuk, L.; Sabbatini, P.; Leesnitzer, M.A.; Shotwell, J.B. Discovery of 4, 6-bis-anilino-1H-pyrrolo[2, 3d]pyrimidines: Potent inhibitors of the IGF-1R receptor tyrosine kinase. Bioorg. Med. Chem. Lett., 2009, 19, 469-473. Blake, J.F.; Kallan, N.C.; Xiao, D.; Xu, R.; Bencsik, J.R.; Skelton, N.J.; Spencer, K.L.; Mitchell, I.S.; Woessner, R.D.; Vigers G.P.A.; Brandhuber, B. J. Discovery of pyrrolopyrimidine inhibitors of Akt. Bioorg. Med. Chem. Lett., 2010, 20, 5607-5612. Cai, Z.; Wei, D.; Schroeder, G.M.; Cornelius, L.A.M.; Kim, K.; Chen, X. T; Schmidt, R.J.; Williams, D.K.; Tokarski, J.S.; Marathe, P.; Hunt, J.T.; Lombardo, L.J.; Fargnoli J.; Borzilleri, R.M. Discovery of orally active pyrrolopyridine- and aminopyridinebased Met kinase inhibitors. Bioorg. Med. Chem. Lett., 2008, 18, 3224-3229. Patnaik, S.; Steven, K.L.; Gerding, R.; Deanda, F.; Shotwell, J.B.; Tang, J.; Hamajima, T.; Nakamura, H.; Leesnitzer, M.A.; Hassell, A.M.; Shewchuck, L.M.; Kumar, R.; Lei H.; Chamberlain, S.D. Discovery of 3, 5-disubstituted-1H-pyrrolo[2, 3-b]pyridines as potent inhibitors of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase. Bioorg. Med. Chem. Lett., 2009, 19, 31363140. Lipitor®, LAB-0021-7. 0, Pfizer Ireland Pharmaceuticals, 2004. Park, W.K.C.; Kennedy, R.M.; Larsen, S.D.; Miller, S.; Roth, B.D.; Song, Y.; Steinbaugh, B.A.; Sun, K.; Tait, B.D.; Kowala, M.C.; Trivedi, B.K.; Auerbach, B.; Askew, V.; Dillon, L.; Hanselman, J.C.; Lin, Z.; Lu, G.H.; Robertson, A.; Sekerke, C. Hepatoselectivity of statins: Design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors Bioorg. Med. Chem. Lett., 2008, 18, 1151-1156. a) Kang, S.Y.; Park E., ; Park, W.; Kim, H.J.; Choi, G.; Jung, M.E.; Seo, H.J.; Kim, M.J.; Pae, A.N.; Kim J.; Lee, J. Bioorg. Med. Chem., Further optimization of novel pyrrole 3-carboxamides for targeting serotonin 5-HT2A, 5-HT2C, and the serotonin transporter as a potential antidepressant,, 18, 6156-6169. b) Kang, S.Y.; Park, E.; Park, W.; Kim, H.J.; Jeong, D.; Jung, M.E.; Song, K.; Lee, S.H.; Seo, H.J.; Kim, M.J.; Lee, M.W.; Han, H.; Son, E.; Pae, A.N.; Kim J.; Lee, J. Arylpiperazine-containing pyrrole 3-carboxamide derivativestargeting serotonin 5-HT2A, 5-HT2C, and the serotonin transporter as a potential antidepressant. Bioorg. Med. Chem. Lett., 2010, 20, 1705-1711. Patil, V.M.; Sinha, R.; Masand, N.; Jain, J. Synthesis and anticonvulsant activities of small N-substituted 2, 5-dimethyl pyrrole and bipyrrole, Digest. J. of Nanomaterials and Biostructures, 2009, 4, 471-477. Accepted: June 07, 2013

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