Synthesis and Evaluation of Novel Pyrroles and ......Synthesis and Evaluation of Novel Pyrroles and...

Research ArticleSynthesis and Evaluation of Novel Pyrroles andPyrrolopyrimidines as Anti-Hyperglycemic Agents

M S Mohamed1 S A Ali2 D H A Abdelaziz2 and Samar S Fathallah1

1 Pharmaceutical Organic Chemistry Department Faculty of Pharmacy Helwan University Ein-Helwan Helwan Cairo 11795 Egypt2 Biochemistry and Molecular Biology Department Faculty of Pharmacy Helwan University Ein-Helwan Helwan Cairo 11795 Egypt

Correspondence should be addressed to Samar S Fathallah ssfathallahyahoocom

Received 12 February 2014 Revised 16 May 2014 Accepted 22 May 2014 Published 26 June 2014

Academic Editor Paul M Tulkens

Copyright copy 2014 M S Mohamed et alThis is an open access article distributed under the Creative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

A series of pyrrole and pyrrolopyrimidine derivatives were examined for their in vivo antihyperglycemic activity CompoundsIandashce and IVg showed promising antihyperglycemic activity equivalent to a well-known standard antihyperglycemic drugGlimepiride (Amaryl 4mgkg) In this paper we examine and discuss the structure-activity relationships and antihyperglycemicactivity of these compounds

1 Introduction

For several decades interest in pyrrole derivatives increasesdue to their pharmaceutical importance [1ndash3] such as antimi-crobial [4ndash8] antiviral [9 10] anti-inflammatory [11ndash13]analgesic [14] antitumor [15 16] antihyperlipidemic [17]anticonvulsant [18] and antihyperglycemic agents [19 20] asshown in Figures 1 and 2(a)

Likewise the key roles played by purines and pyrimidinesin cellular processes have made them valuable lead for drugdiscovery among these pyrrolo[32-d]pyrimidines a class of7-deazapurine analogs exhibit interesting biological activityin part due to their resemblance to pyrimidines and purinesThese huge therapeutic applications have motivated newefforts in the search for novel derivatives with improved bio-logical activity and diverse applications in the pharmaceuticalindustry [1ndash4 19 20]

Diabetes mellitus (DM) is a severe metabolic disorderthat has a significant impact on the health and quality ofpatientsrsquo life Treatment of diabetic patients has been focusedon dietary management and oral antidiabetics among thesesulfonylureas metformin acarbose and others Howeversome of the currently used antihyperglycemic have severaladverse side effects like hepatotoxicity weight gain andhypoglycemia

This situation emphasized the need to develop novelantihyperglycemic agents [21] Glimepiride (Amaryl) is asulfonylurea containing a pyrrole group acting as antihyper-glycemic drug [22] It is sometimes classified either as thefirst third-generation sulfonylurea or as second-generationGlimepiride is indicated to treat type 2 diabetes mellitusits mode of action is to increase insulin production by thepancreas as shown in Figure 2(b)

Recently dipeptidyl peptidase IV (DPP-IV) inhibitors[23ndash25] have been shown to be effective and safe compoundsthat control blood glucose Improvement of the inhibitoryactivity and chemical stability of a series of substitutedpiperidinyl glycine 2-cyano-45-methano pyrroline (DPP-IV) inhibitors was respectively achieved by the introduc-tion of pyrroline moiety at the 4 position and 1 positionof the piperidinyl glycine leading to a series of potentand stable DPP-IV inhibitors [25] Two important DPP-IVinhibitors having a pyrrole and fused pyrrole vildaglipinand saxagliptin [24 25] are on themarket inmany countriesas shown in Figure 2(b)

A highly potent DPP-IV inhibitor thienopyrimidine wasalso reported [24] While trying to maintain consistencyof in vitro and in vivo biological activity a simple scaffoldreplacement of thienopyrimidine with pyrrolopyrimidinelead to significantly improved metabolic stability [22ndash24] asshown in Figure 2(c)

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 249780 13 pageshttpdxdoiorg1011552014249780

2 BioMed Research International

NH N N

H

H2NS

integrase inhibition [4ndash8]Pyrrole as antibacterial and as HIV-1

Pyrrole-2-carbaldehyde

(a)

N

CH3

CO2H

CO2H

O

ON

Ketorolac (ketorolac)Tolmetin (rumatol)

Pyrroles as nonsteroidal anti-inflammatory

H3C

drugs (NSAIDs) [11ndash13]

(b)

Figure 1 Pyrrole as valuable leads in the drug discovery field

NH

R998400

R998400

RR

X

X XF

FF

HH H

HH

HOMeCl

CF3

Triarylpyrrole derivatives

(a)

O HN

HNS

O

HN

N

O

O

O

Glimepiride

HOHN N

OCN

VildagliptinEMEA approved

HO N

OCN

NH2

SaxagliptinEMEAFDA approved

(b)

NH2 NH2

N

N N

OR3

R2

R1

R1 = H CH3

R2 R3 = H CH3 Br

N

CN

Pyrrolopyrimidines

N N

S

O

N

CN

Thienopyrimidines

(c)

Figure 2 (a) Pyrroles as antihyperglycemic agents [19 20] (b) Amaryl standard antihyperglycemic drug [21 22] and approved DPP-IVinhibitors [23ndash25] as type 2 diabetes medications containing a pyrrole moiety (c) Thieno and Pyrrolo-pyrimidines as DPP-IV inhibitors

BioMed Research International 3

Motivated by the importance of this system and in con-tinuation of our research efforts [26ndash30] we try to highlightaspects reported on the chemistry of some newly synthesizedpyrrole and pyrrolopyrimidine derivatives and evaluate themfor the antihyperglycemic activities The synthetic pathwaysadopted for the synthesis of these compounds are registeredin Schemes 1ndash3

2 Materials and Methods

21 Chemistry Allmelting pointswere uncorrected andmea-sured using Electrothermal IA 9100 apparatus (ShimadzuJapan) IR spectra were recorded as potassium bromidepellets on a Perkin-Elmer 1650 spectrophotometer (USA)Faculty of Science Cairo University Cairo Egypt 1H NMRand 13CNMR spectra were performed on JOEL NMR FXQ-300MHz and JOELNMR FXQ-500MHz spand chemicalshifts were expressed as ppm against TMS as internal ref-erence (Faculty of Science Cairo University Cairo Egypt)Mass spectra were recorded at 70 eV EIMs-QP 1000 EX (Shi-madzu Japan) Faculty of Science Cairo University CairoEgypt Microanalyses were operated using Vario Elementarapparatus (Shimadzu Japan) Organic Microanalysis UnitFaculty of Science Cairo University Cairo Egypt Columnchromatography was performed on (Merck) silica gel 60(particle size 006ndash020mm) Compounds Iandashc fndashh kndashmIIandashc fndashh IIIandashc fndashh IVandashc Vandashc VIandashc VIIandashcandVIIIandashc were prepared as reported in the literature [26ndash31]All new compounds yielded spectral data consistent with theproposed structure and microanalysis withinplusmn 04 of thetheoretical values

211 2-Amino-1-(34-dichlorophenyl)-45-diphenyl-1H-pyr-role-3-carbonitrile Id (Scheme 1) A mixture of benzoin (2 g001mol) 34-dichlorophenyl amine (16 g 001mol) in drybenzene (50mL) was kept at 80∘C for 9 h The reactionmixture was cooled then malononitrile (066mg 001mol)was added followed by catalytic amount of pyridine (2mL)portion wise and left to reflex till solid formed The solventwas evaporated under reduced pressure and the residue wasrecrystallized from methanol to give Id Yield 45 MP118ndash122∘C 1H NMR (DMSO-119889

6 300MHz) 120575 (ppm) 521

(brs 2H NH2 D2O exchangeable) 70ndash78 (m 13H Ar-H)

13C NMR (DMSO-1198896) 120575 11433 11824 11937 1258 12618

12780 12845 12984 13029 13216 13270 13362 1349614205 ppm IR (KBr) 120592 (cmminus1) 3410 3370 (NH

2) 2220

(CequivN) MS (EI) mz 403 (M+ 14) 405 (M++ 2 875)407 (M++ 4 11) Anal Calcd for C

23H15Cl2N3(40306) C

6833 H 374 Cl 1754 N 1039 Found C 6855 H 392Cl 1723 N 1072

212 2-Amino-1-(15-dimethyl-3-oxo-2-phenyl-23-dihydro-1H-pyrazol-4-yl)-4-phenyl-1H-pyrrole-3-carbonitrile Ie (Scheme1) 15-Dimethyl-4-(2-oxo-2-phenylethylamino)-2-phenyl-1H-pyrazol-3(2H)-one [27ndash30](322 g 001mol) wasdissolved in dry ethanol (20mL) then malononitrile (066 g001mol) was added followed by sodium ethoxide (001mol)portion wise and left to reflux till solid formed The solvent

was evaporated under reduced pressure and the residue wasrecrystallized from methanol to give Ie Yield 66 MP163ndash166∘C1H NMR (DMSO-119889

6 300MHz) 120575 (ppm) 243

(s 3H CH3) 312 (s 3H N-CH

3) 613 (brs 2H NH

2 D2O

exchangeable) 68ndash78 (m 10H Ar-H and 1H C6-H) IR

(KBr) 120592 (cmminus1) 3410 3350 (NH2) 2210 (CequivN) 1703 (C=O)

MS (EI) mz 369 (M+ 23) 370 (M++ 1 61) Anal Calcdfor C22H19N5O (36916) C 7153 H 518 N 1896 O 433

Found C 7155 H 526 N 1870 O 305

213 2-Ethoxymethylenamino-15-disubstituted-4-phenyl-1H-pyrrole-3-carbonitriles Iij (Scheme 1) Compound I d or e(001mol) in triethyl orthoformate (20mL) was refluxed for9 hThe solvent was removed under reduced pressure and theresidue was recrystallized from methanolwater to give thetarget compounds Ii j

214 Ethyl N-3-Cyano-1-(34-dichlorophenyl)-45-diphenyl-1H-pyrrol-2-ylformimidate Ii Yield 60MP 120ndash122∘C 1HNMR (DMSO-119889

6 300MHz) 120575 (ppm) 130 (t 3H J = 71Hz

CH3) 42 (q 2H J = 71Hz OCH

2) 69ndash78 (m 14H Ar-H

and N=CH) IR (KBr) 120592 (cmminus1) 3070 2900(CH) 2310(CN)1620 (C=C) 1560 (C=N) MS (EI) mz 460 (M+ 135)462 (M++ 2 85) 464 (M++ 4 271) Anal Calcd forC26H19Cl2N3O (46035) C 6783 H 416 Cl 1540 N 913

O 348 Found C 6803 H 411 Cl 1563 N 891 O 369

215 Ethyl N-3-Cyano-1-(15-dimethyl-3-oxo-2-phenyl-23-dihydro-1H-pyrazol-4-yl)-4-phenyl-1H-pyrrol-2-ylacetimidateIj Yield 56 MP 120ndash122∘C 1H NMR (DMSO-119889

6

300MHz) 120575 (ppm) 120 (t 3H J = 72Hz CH3) 241 (s 3H

CH3) 31 (s 3H N-CH

3) 401 (q 2H J = 71Hz OCH

2)

69ndash78 (m 12H Ar-H C6-H and N=CH) IR (KBr) 120592 (cmminus1)

3030 2910(CH) 2240(CN) 1610 (C=C) 1570 (C=N) MS(EI)mz 425 (M+ 65) 426 (M++ 1 181) Anal Calcd forC26H23N5O2(42519) C 7057 H 545 N 1646 O 752

Found C 7021 H 517 N 1612 O 718

216 N-(4-Phenyl-135-trisubstituted-1H-pyrrol-2-yl)-aceta-mides I no (Scheme 1) Compound I d or e (001mol)in acetic anhydride (30mL) was refluxed for 2 h cooledpoured onto ice water neutralized with ammonia to give aprecipitate which was filtered off dried and recrystallizedfrom methanol to give the target compounds In o

217 N-(3-Cyano-1-(34-dichlorophenyl)-45-diphenyl-1H-pyrrol-2-yl) acetamide In Yield 66 MP 135ndash138∘C 1HNMR (DMSO-119889

6 300MHz) 120575 (ppm) 223 (s 3H CO-CH

3)

70ndash78 (m 13H Ar-H) 95 (s 1H NH D2O exchangeable)

IR (KBr) 120592 (cmminus1) 3430 (NH) 2330 (CequivN) 1710 (C=O) MS(EI) mz 445 (M+ 131) 447 (M+ + 2 79) 449 (M+ + 4091) Anal Calcd for C

25H17Cl2N3O (44507) C 6728 H

384 Cl 1589 N 941 O 358 Found C 6747 H 406 Cl1622 N 957 O 366

218 N-(3-Cyano-1-(15-dimethyl-3-oxo-2-phenyl-23-dihy-dro-1H-pyrazol-4-yl)-4-phenyl-1H-pyrrol-2-yl)acetamide Io


Ph Ph

PhPh

Ph

Ph

Ph

PhPh

O

O

O

O

O

O

1NH

2

CN

Ar

Ar

Ar

Ar

XX

NH2

5 6Y

NHX998400

Br 3 4

Ar =CH2C6H5

CH3

CH3

X = H Ph

Y = CN

HN

+ ArNH2

+ ArNH2

N

NN

N

Iandashe Ifndasho

34-(Cl)2C6H3

Scheme 1 Synthetic pathways for compounds Iandasho reagents and conditions (1) pyridinebenzene (2) CH2(CN)2 (3) NaHCO

3EtOH (4)

CH2(CN)2NaOEt (5) TEOF or (6) Ac

2O

PhPh

Ph

Ph

Ph Ph

Ph

Ph

XX

X

X X

X

XNN

N

N N

N N

N

NN N

N

N

N

N

N

NN

N

N

NH2

ArAr

Ar

Ar Ar

Ar

Ar

1 (Y = H)2 (Y = CH3)

Ιandashe ΙΙandashj

5

ΙVandashi

CI

Y Y Y

Y

6 6

Vandashi

NHNH2

NNH2 Ιfndashj

Dimrothrearrangement

S

VIandashf

3 (Y998400= H)

H2N

Y998400

IIIandashj

Ar =

CH2C6H5

CH3

CH3

X = H Ph

Y = H CH3

CNO

O

HHN

4 (Y998400= SH)

(X998400=

CHOEt)

Cl

7

(Y = H CH3)

34-(Cl)2C6H3Y998400

= HSH

Scheme 2 Synthetic pathways for compounds IndashVI reagents and conditions (1) HCO2H (2) AcOHHCl (3) HCONH

2 (4) NH

2CSNH

2

(5) POCl3 (6) N

2H4sdotH2O and (7) NH

2CSNH

2

Yield 72 MP 135ndash138∘C 1H NMR (DMSO-1198896 300MHz)

120575 (ppm) 223 (s 3H CO-CH3) 243 (s 3H CH

3) 312 (s

3H N-CH3) 70ndash78 (m 11H Ar-H and C

6-H) 94 (s 1H

NH D2O exchangeable) IR (KBr) 120592 (cmminus1) 3350 (NH)

2310 (CequivN) 1715 1705 (C=O) MS (EI)mz 411 (M+ 154)412 (M++ 1 373) Anal Calcd for C

24H21N5O2(41117) C

7006 H 514 N 1702 O 778 Found C 7037 H 545 N1734 O 795

219 7-(24-Dimethyl-5-oxo-1-phenyl-25-dihydro-1H-pyra-zol-3-yl)-56-diphenyl -3H-pyrrolo[23-d]pyrimidin-4(7H)-one IIde (Scheme 2) Compound Id or e (001mol) in formic


Ph Ph Ph

Ph

Ph

CN CN CN

CN

X X X

X

N N N

N

NN

N

N

NH2

Ar Ar Ar

Ar

1 2

3

Ιandashc

N2Cl NHN = C(Y)CN

VIIandashf

Ar =

CH2C6H5

CH3

CH3

X = H Ph

Y = CN CO2Et

H2N

NHN

Y998400998400

VIIIandashfO

minus+

34-(Cl)2C6H3Y998400998400

= NH2OH

Scheme 3 Synthetic pathways for compounds VIIndashVIII reagents and conditions (1) NaNO2HClStirring (75min) (2)

NCCH2YCH

3CO2NH4EtOH and (3) N

2H4sdotH2O

acid (20mL 85) was refluxed for 12 hThe reaction mixturewas cooled poured onto icewater to give a precipitate whichwas filtered dried and recrystallized from ethanol to givethe target compounds IId e

7-(34-Dichlorophenyl)-56-diphenyl-3H-pyrrolo[23-d]pyr-imidin-4(7H)-one IId Yield 56 MP 172ndash176∘C 1H NMR(DMSO-119889

6 300MHz) 120575 (ppm) 69ndash78 (m 13H Ar-H)

84 (s 1H C2-H) 1240 (s 1H NH D

2O exchangeable)

13C NMR (DMSO-1198896) 12057511824 11937 1258 12618 12780

12845 12984 13029 13216 13270 13362 13496 1382514205 1462 16315 ppm IR (KBr) 120592 (cmminus1) 3410 3350(NH2) 1720 1705 (C=O) 1550(C=N) MS (EI)mz 432 (M+

215) 434 (M++ 2 139) 436 (M++ 4 42) Anal Calcdfor C24H15Cl2N3O (43230) C 6668 H 350 Cl 1640 N

972 O 370 Found C 6632 H 318 Cl 1621 N 950 O346

7-(15-Dimethyl-3-oxo-2-phenyl-23-dihydro-1H-pyrazol-4-yl)-5-phenyl-3H-pyrrolo[23-d]pyrimidin-4(7H)-one IIe Yield65 MP 205ndash208∘C 1H NMR (DMSO-119889

6 300MHz) 120575

(ppm) 241 (s 3H CH3) 321 (s 3H N-CH

3) 69ndash78 (m

11H Ar-H and C6-H) 832 (s 1H C

2-H) 1232 (s 1H NH

D2O exchangeable) IR (KBr) 120592 (cmminus1) 3410 3320 (NH

2)

1720 1680 (C=O) 1560(C=N) and disappearance of the CNgroup MS (EI) mz 379 (M+ 235) 380 (M++ 1 71)Anal Calcd for C

23H19N5O2(37943) C 6951 H 482 N

1762 O 805 Found C 6989 H 516 N 1797 O 841

2110 7-Disubstituted-2-methyl-5-phenyl-7H-pyrrolo[23-d]pyrimidin-4(3H)-one IIi j (Scheme 2) Compound Id or e(001mol) in acetic acidHCl (3 1) (30mL) was refluxed for12 hThe reactionmixture was cooled poured onto icewaterneutralized with ammonia to give a precipitate which was

filtered dried and recrystallized from methanol to give thetarget compounds II i j

7-(34-Dichlorophenyl)-2-methyl-56-diphenyl-3H-pyrrolo[23-d]pyrimidin-4(7H)-one II i Yield 67 MP 200ndash202∘C1H NMR (DMSO-119889

6 300MHz) 120575 (ppm) 235 (s 3H

C2-CH3) 69ndash78 (m 13H Ar-H) 1240 (s 1H NH D

2O

exchangeable) IR (KBr) 120592 (cmminus1) 3430 3330 (NH2) 1710

(C=O) 1570 (C=N) MS (EI) mz 445 (M+ 262) 447(M++ 2 153) 449 (M++ 4 104) Anal Calcd forC25H17Cl2N3O (44507) C 6728 H 384 Cl 1589 N 941

O 358 Found C 6745 H 411 Cl 1622 N 974 O 382

7-(15-Dimethyl-3-oxo-2-phenyl-23-dihydro-1H-pyrazol-4-yl)-2-methyl-5-phenyl-3H-pyrrolo[23-d]pyrimidin-4(7H)-oneII j Yield 67 MP 225ndash227∘C 1H NMR (DMSO-119889

6

300MHz) 120575 (ppm) 232 (s 3H C2-CH3) 241 (s 3H CH

3)

322 (s 3H N-CH3) 7ndash78 (m 11H Ar-H and C

6-H) 1236 (s

1H NH D2O exchangeable) IR (KBr) 120592 (cmminus1) 3430 3330

(NH2) 1730 1700 (C=O) 1560 (C=N) MS (EI) mz 487

(M+ 45) 488 (M++ 1 152) Anal Calcd for C24H21N5O2

(41146) C 7006 H 514 N 1702 O 778 Found C 7024H 532 N 1731 O 796

2111 6 7-Disubstituted-5-phenyl-7H-pyrrolo[23-d]pyrim-idin-4-ylamines IIId e (Scheme 2) A suspension of theappropriate aminopyrrole I d or e (001mol) and formamide(30mL 0066mol) were heated under reflux for 9 h cooledpoured onto icewater to give precipitates which were filteredoff dried and recrystallized from ethanol to give the targetcompounds III d e

7-(34-Dichlorophenyl)-56-diphenyl-7H-pyrrolo[23-d]pyr-im-idin-4-amine III d Yield 63 MP 115ndash118∘C 1H NMR(DMSO-119889

6 300MHz) 120575 (ppm) 54 (brs 2H NH

2 D2O


exchangeable) 71ndash77 (m 13H Ar-H) 82 (s 1H C2-H) IR

(KBr) 120592 (cmminus1) 3440 3350 (NH2) 1570 (C=N) 1610 (C=C)

MS (EI)mz 430 (M+ 312) 432 (M++ 2 176) 434 (M++4 098) Anal Calcd for C

24H16Cl2N4(43008) C 6683

H 374 Cl 1644 N 1299 Found C 6707 H 511 Cl1681 N 1336

4-(4-Amino-5-phenyl-7H-pyrrolo[23-d]pyrimidin-7-yl)-15-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one III e Yield 69MP 152ndash155∘C 1H NMR (DMSO-119889

6 300MHz) 120575 (ppm)

241 (s 3H CH3) 314 (s 3H N-CH

3) 58 (brs 2H NH

2

D2O exchangeable) 71ndash78 (m 11H Ar-H and C

6-H) 83

(s 1H C2-H) IR (KBr) 120592 (cmminus1) 3430 3330 (NH NH

2)

1705 (C=O) 1600 (C=C) 1540 (C=N) MS (EI) mz 396(M+ 137) 397 (M++ 1 191) Anal Calcd for C

23H20N6O

(39644) C 6968 H 508 N 2120 O 404 Found C6942 H 492 N 2089 O 432

2112 5-(56-Diphenyl-4-thioxo-3H-pyrrolo[23-d]pyrimidin-7(4H)-yl)-14-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one IIIi j(Scheme 2) Compound I d or e (001mol) and thiourea(12 g 002mol) were refluxed in dry ethanol (20mL) for 12 hThe reactionmixture was evaporated under reduced pressureand the residues were recrystallized from methanol to givethe target compounds III i j

4-Amino-7-(34-dichlorophenyl)-56-diphenyl-1H-pyrrolo[23-d] pyrimidine-2(7H)-thione IIIi Yield 70 MP 90ndash95∘C1H NMR (DMSO-119889

6 300MHz) 120575 (ppm) 662 (s 2H NH

2

D2O exchangeable) 71ndash79 (m 13H Ar-H) 922 (s 1H NH


NH2) 1610 (NHndashC=S) MS (EI) mz 463 (M+ 2236)

465 (M++ 2 1423) 467 (M+ + 4 454) Anal Calcd forC24H16Cl2N4S (46338) C 6221 H 348 Cl 1530 N 1209

S 692 Found C 6245 H 362 Cl 1549 N 1241 S 721

4-(4-Amino-5-phenyl-2-thioxo-1H-pyrrolo[23-d]pyrimidin-7(2H)-yl)-15-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one IIIjYield 74 MP 172ndash174∘C 1H NMR (DMSO-119889

6 300MHz)

120575 (ppm) 234 (s 3H CH3) 311 (s 3H N-CH

3) 651 (brs 2H

NH2 D2O exchangeable) 71ndash78 (m 11H Ar-H and C

6-H)

83 (s 1H C2-H) 892 (s 1H NH D

2O exchangeable) IR

(KBr) 120592 (cmminus1) 3440 3370 (NH NH2) 1610 (C=C) 1600

(NHndashC=S) MS (EI) mz 428 (M+ 148) 429 (M+ + 1231) Anal Calcd for C

23H20N6OS (42851) C 6447 H

470 N 1961 O 373 S 748 Found C 6478 H 497 N1992 O 391 S 762

2113 General Procedure for the Preparation of 4-Chloropyrrolopyrimidines IVdndashj (Scheme 2) The appropriatecompound II (001mol) was refluxed in phosphorusoxychloride (30mL) for 12 h The solution was cooledand poured with stirring onto icewater and the formedprecipitated was filtered washed several times with waterdried and recrystallized from ethanol to give the targetcompounds IVdndashj

4-Chloro-7-(34-dichlorophenyl)-56-diphenyl-7H-pyrrolo[23-d]pyrimidine IVd Yield 76 MP 124ndash128∘C 1H NMR(DMSO-119889

6 300MHz) 120575 (ppm) 69ndash78 (m 13H Ar-H) 86

(s 1H C2-H) 13C NMR (DMSO-119889

6) 1205751175 1188 12618

12780 12845 12984 13021 13246 13264 13376 1348413827 14105 1502 15124 1538 ppm IR (KBr) 120592 (cmminus1)3080 2840(CH) 1612 (C=C) 1580 (C=N) MS (EI) mz 449(M+ 2998) 451 (M+ + 2 236) 453 (M+ + 4 69) 455(M+ + 6 066) Anal Calcd for C

24H14Cl3N3(44903) C

6395 H 313 Cl 2360 N 932 Found C 6423 H 342Cl 2391 N 949

4-(4-Chloro-5-phenyl-7H-pyrrolo[23-d]pyrimidin-7-yl)-15-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one IVe Yield 76MP 125ndash130∘C 1H NMR (DMSO-119889

6 300MHz) 120575 (ppm)

243 (s 3H CH3) 312 (s 3H N-CH


and C6-H) 85 (s 1H C

2-H) IR (KBr) 120592 (cmminus1) 3080 2840

(CH) 1730 (C=O) 1612 (C=C) 1580 (C=N) MS (EI)mz 415(M+ 20) 417 (M++ 2 55) Anal Calcd for C

23H18ClN5O

(41587) C 6643 H 436 Cl 852 N 1684 O 385Found C 6667 H 471 Cl 868 N 1694 O 399

7-Benzyl-4-chloro-2-methyl-56-diphenyl-7H-pyrrolo[23-d]pyrimidine IVf Yield 46 MP 120ndash124∘C 1H NMR(DMSO-119889

6 300MHz) 120575 (ppm) 232 (s 3H CH

3) 512 (s

2H Ph-CH2) 69ndash78 (m 15H Ar-H and C

6-H) IR (KBr)

120592 (cmminus1) 3080 2840 (CH) 1610 (C=C) 1560 (C=N) MS(EI) mz 409 (M+ 14) 411 (M+ + 2 45) Anal Calcd forC26H20ClN3(40991) C 7618 H 492 Cl 865 N 1025

Found C 7647 H 523 Cl 896 N 1059

4-(4-Chloro-2-methyl-56-diphenyl-7H-pyrrolo[23-d]pyrim-idin-7-yl)-15-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one IVgYield 42 MP 158ndash160∘C 1H NMR (DMSO-119889

6 300MHz)

120575 (ppm) 230ndash244 (s 6H2lowastCH3) 313 (s 3H N-CH

3)

69ndash78 (m 15H Ar-H) IR (KBr) 120592 (cmminus1) 3080 2840 (CH)1710 (C=O) 1605 (C=C) 1577 (C=N) MS (EI)mz 505 (M+13) 507 (M+ + 2 25) Anal Calcd for C

30H24ClN5O

(50517) C 7121 H 478 Cl 701 N 1384 O 316 FoundC 7102 H 497 Cl 723 N 1406 O 345

4-Chloro-7-(34-dichlorophenyl)-2-methyl-56-diphenyl-7H-pyrrolo[23-d]pyrimidine IVh Yield 45 MP 108ndash110∘C1H NMR (DMSO-119889

6 300MHz) 120575 (ppm) 236 (s 3H CH

3)

72ndash78 (m 13H Ar-H) IR (KBr) 120592 (cmminus1) 3080 2840 (CH)1600 (C=C) 1565 (C=N) MS (EI) mz 464 (M+ 11) 466(M+ + 2 65) 468 (M+ + 4 23) 394 (M+ + 6 088)Anal Calcd for C

25H16Cl3N3(46477) C 6461 H 347

Cl 2288 N 904 Found C 6499 H 373 Cl 2308 N929

4-(4-Chloro-2-methyl-5-phenyl-7H-pyrrolo[23-d]pyrimidin-7-yl)-15-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one IVi Yield42 MP 95-100∘C 1H NMR (DMSO-119889

6 300MHz) 120575

(ppm) 228ndash246 (s 6H 2lowastCH3) 327 (s 3H N-CH

3)

70ndash78 (m 11H Ar-H and C6-H) IR (KBr) 120592 (cmminus1) 3070

2850 (CH) 1700 (C=O) 1600 (C=C) 1570 (C=N) MS (EI)mz 429 (M+ 16) 431 (M+ + 2 47) Anal Calcd for


C24H20ClN5O (42990) C 6705 H 469 Cl 825 N 1629

O 372 Found C 6742 H 508 Cl 857 N 1665 O402

2114 General Procedure for the Preparation of 4-Hydrazino-pyrrolopyrimidines Vdndashi (Scheme 2)

Method A Compound IV (001mol) and hydrazine hydrate(8mL 0015mol 98) were refluxed in dry ethanol (30mL)for 12 hThe solventwas removed under reduced pressure andthe residues were recrystallized from methanol to give thetarget compounds V

Method B Compounds Ii j (001mol) in dry toluene (20mL)and hydrazine hydrate (5mL 0015mol 98) were addedwith stirring at room temperature for 14 h The solventwas removed under reduced pressure and the residue wasrecrystallized frommethanol to giveVd e CompoundsVd eprepared by this method are identical in all respects (physicaland spectral data) to that prepared fromMethod A

7-(34-Dichlorophenyl)-4-hydrazinyl-56-diphenyl-7H-pyrrolo[23-d]pyrimidine Vd Yield (A 68 B 56) MP 122ndash126∘C 1H NMR (DMSO-119889

6 300MHz) 120575 (ppm) 49ndash52

(brs 2H NH2 D2O exchangeable) 71ndash78 (m 14H Ar-H

and NH D2O exchangeable) 83 (s 1H C

2-H) 13C NMR

(DMSO-1198896) 12057511745 11869 12621 12747 1284 12974

1302 13239 13264 13376 13484 13827 14105 1532 153816871 ppm IR (KBr) 120592 (cmminus1) 3420 3350 (NH

2) 3210 (NH)

1610 (C=C) 1580 (C=N) MS (EI) mz 446 (M+ 23)448 (M+ + 2 14) 450 (M+ + 4 34) Anal Calcd forC24H17Cl2N5(44633) C 6458 H 384 Cl 1589 N 1569

Found C 6495 H 420 Cl 1623 N 1604

4-(4-Hydrazinyl-5-phenyl-7H-pyrrolo[23-d]pyrimidin-7-yl) -15-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one Ve Yield (A)71 (B) 60 MP 142ndash146∘C 1H NMR (DMSO-119889

6

300MHz) 120575 (ppm) 242 (s 3H CH3) 313 (s 3H N-CH

3)

48ndash51 (brs 2HNH2 D2Oexchangeable) 71ndash78 (m 11HAr-

H C6-H and NH D

2O exchangeable) 82 (s 1H C

2-H) IR

(KBr) 120592 (cmminus1) 3440 3330 (NH2) 3260 (NH) 1705 (C=O)

1600 (C=C) 1580 (C=N) MS (EI) mz 411 (M+ 28) 412(M+ + 1 65) Anal Calcd for C

23H21N7O (41146) C 6714

H 514 N 2383 O 389 Found C 6752 H 548 N 2415O 452

7-Benzyl-4-hydrazinyl-2-methyl-56-diphenyl-7H-pyrrolo[23-d] pyrimidine Vf Yield 67 MP 147ndash152∘C 1H NMR(DMSO-119889

6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 49ndash52

(brs 2H NH2 D2O exchangeable) 578 (s 2H Ph-CH

2)

723ndash78 (m 16H Ar-H and NH D2O exchangeable) IR

(KBr) 120592 (cmminus1) 3430 3350 (NH2) 3250 (NH) 1605 (C=C)

1570 (C=N) MS (EI) mz 405 (M+ 29) 406 (M+ + 141) Anal Calcd for C

26H23N5(40549) C 7701 H 572

N 1727 Found C 7738 H 605 N 1762

4-(4-Hydrazinyl-2-methyl-56-diphenyl-7H-pyrrolo[23-d]pyrimidin-7-yl)-15-dimethyl-2-phenyl-1H-pyrazol-3(2H)-oneVg Yield 68 MP 185ndash188∘C 1H NMR (DMSO-119889

6

300MHz) 120575 (ppm) 222ndash246 (s 6H 2lowastCH3) 311 (s 3H

N-CH3) 434ndash48 (brs 2H NH

2 D2O exchangeable) 72ndash78

(m 16H Ar-H and NH D2O exchangeable) IR (KBr) 120592

(cmminus1) 3420 3350 (NH2) 3240 (NH) 1700 (C=O) 1605

(C=C) 1560 (C=N) MS (EI) mz 501 (M+ 31) 502 (M++1 54) Anal Calcd for C

30H27N7O (50158) C 7184 H

543 N 1955 O 319 Found C 7220 H 581 N 1992 O355

7-(34-Dichlorophenyl)-4-hydrazinyl-2-methyl-56-diphenyl-7H-pyrrolo[23-d]pyrimidine Vh Yield 59 MP 142ndash146∘C 1H NMR (DMSO-119889

6 300MHz) 120575 (ppm) 225 (s 3H

CH3) 45ndash49 (brs 2H NH


(m 14H Ar-H NH D2O exchangeable) IR (KBr) 120592 (cmminus1)

3440 3360 (NH2) 3250 (NH) 1610 (C=C) 1560 (C=N) MS

(EI) mz 460 (M+ 31) 462 (M+ + 2 18) 464 (M+ + 449) Anal Calcd for C

25H19Cl2N5(46036) C 6522 H

416 Cl 1540 N 1521 Found C 6557 H 452 Cl 1578N 1556

4-(4-Hydrazinyl-2-methyl-5-phenyl-7H-pyrrolo[23-d]pyrimidin-7-yl)-15-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one Vi Yield 69 MP 148ndash150∘C 1H NMR (DMSO-119889

6




(m 12H Ar-H C6-H and NH D

2O exchangeable) IR (KBr)

120592 (cmminus1) 3430 3360 (NH2) 3250 (NH) 1705 (C=O) 1600

(C=C) 1580 (C=N) MS (EI) mz 501 (M+ 31) 502 (M+ +1 54) Anal Calcd for C

24H23N7O (42549) C 6775 H

545 N 2304 O 376 Found C 6812 H 576 N 2337O 411

2115 General Procedure for the Preparation of 4-Thien-opyrrolopyrimidine VI dndashf (Scheme 2) Compound III(001mol) and thiourea (12 g 002mol) were refluxed indry ethanol (20mL) for 14 h The reaction mixture wasevaporated under reduced pressure and the residues wererecrystallized from methanol to give the target compoundsVI

7-(34-Dichlorophenyl)-56-diphenyl-3H-pyrrolo[23-d]pyr-imidine-4(7H)-thione VId Yield 66 MP 142ndash166∘C 1HNMR (DMSO-119889

6 300MHz) 120575 (ppm) 73ndash78 (m 13H Ar-

H) 902 (s 1H C2-H) 1171 (s 1H NH D

2O exchangeable)

IR (KBr) 120592 (cmminus1) 3250 (NH) 1630 (NHndashC=S) 1560 (C=N)MS (EI)mz 447 (M+ 28) 449 (M+ + 2 18) 451 (M++ 4098) Anal Calcd for C

24H15Cl2N3S (44704) C 6429 H

337 Cl 1581 N 937 S 715 Found C 6464 H 374 Cl1614 N 973 S 752

15-Dimethyl-2-phenyl-4-(5-phenyl-4-thioxo-3H-pyrrolo[23-d]pyrimidin-7(4H)-yl)-1H-pyrazol-3(2H)-one VIe Yield61 MP 142ndash166∘C 1H NMR (DMSO-119889

6 300MHz) 120575

(ppm) 244 (s 3H CH3) 313 (s 3H N-CH

3) 72ndash78 (m


2-H) 1210 (s 1H NH

D2O exchangeable) IR (KBr) 120592 (cmminus1) 3230 (NH) 1700

(C=O) 1610 (NHndashC=S) 1550 (C=N) MS (EI) mz 413 (M+30) 414 (M+ + 1 84) Anal Calcd for C

23H19N5OS


(41349) C 6681 H 463 N 1694 O 387 S 775 FoundC 6716 H 498 N 1731 O 424 S 812

7-Benzyl-2-methyl-56-diphenyl-3H-pyrrolo[23-d]pyrimidine-4(7H)-thione VIf Yield 47 MP 165ndash167∘C 1H NMR(DMSO-119889

6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 578

(s 2H Ph-CH2) 723ndash78 (m 16H Ar-H and NH D

2O

exchangeable) IR (KBr) 120592 (cmminus1) 3250 (NH) 1605 (NHndashC=S) 1570 (C=N) MS (EI) mz 407 (M+ 26) 408 (M++1 391) 409 (M++ 2 081) Anal Calcd for C

26H21N3S

(40753) C 7663 H 519 N 1031 S 787 Found C 7656H 511 N 1026 S 780

2116 General Procedure for the Preparation of SubstitutedCarbonohydrazonoyl Derivatives VII (Scheme 3) A mixtureof I (001mol) in concentrated HCl (10ml) was cooledwith stirring to 0ndash5∘C under ice and cooled sodium nitritesolution (25 g in 10mL of water) was added to it dropwiseduring 30 minutes The reaction mixture was then stirred for30minutesWithout separation an ice-coldmixture of activemethylene compounds (malononitrile andor ethyl cyanoac-etate) (0015mol) and sodium acetate (410 g 005mole) inethanol (50mL) were added dropwise with stirring for 15min The stirring was continued for 30 minutes under iceand the reaction mixture was then left for 12 h at roomtemperatureTheprecipitatewas filtered off and recrystallizedfrom ethanolH

2O to give VII

(3-Cyano-1-(34-dichlorophenyl)-45-diphenyl-1H-pyrrol-2-yl)carbon-hydrazonoyl dicyanide VIId Yield 56 MP 102ndash106∘C 1H NMR (DMSO-119889

6 300MHz) 120575 (ppm) 671 (s 1H

NH hydrazone D2O exchangeable) 73ndash78 (m 13H Ar-H)

IR (KBr) 120592 (cmminus1) 3290 (NH) 2320 (CequivN) 1695 (C=O) 1585(C=N) MS (EI) mz 481 (M+ 19) 482 (M+ + 2 128)483 (M+ + 4 23) Anal Calcd for C

26H14Cl2N6(48133)

C 6488 H 293 Cl 1473 N 1746 Found C 6467 H278 Cl 1451 N 1712

(3-Cyano-1-(15-dimethyl-3-oxo-2-phenyl-23-dihydro-1H-pyrazol-4-yl)-4-phenyl-1H-pyrrol-2-yl)carbonohydrazonoyldicyanideVIIe Yield 51MP 110ndash114∘C 1HNMR (DMSO-1198896 300MHz) 120575 (ppm) 242 (s 3H CH

3) 311 (s 3H N-CH

3)

671 (s 1H NH hydrazone D2O exchangeable) 72ndash78 (m

11H Ar-H and C6-H) IR (KBr) 120592 (cmminus1) 3290 (NH) 2320

(CequivN) 1695 (C=O) 1585 (C=N) MS (EI) mz 446 (M+178) 447 (M+ + 1 821) Anal Calcd for C

25H18N8O

(44646) C 6725 H 406 N 2510 O 358 Found C6754 H 412 N 2523 O 369

Ethyl 2-(2-(1-Benzyl-3-cyano-45-diphenyl-1H-pyrrol-2-yl)hydrazono)-2-cyano-acetate VIIf Yield 48 MP 125ndash130∘C 1H NMR (DMSO-119889

6 300MHz) 120575 (ppm) 131 (t 3H

J = 68 CH2-CHlowast3) 44 (q 2H J = 68 O-CH

2) 562 (s 2H

Ph-CH2) 68 (s 1H NH hydrazone D

2O exchangeable)


(NH) 2320 (CequivN) 1695 (C=O) 1585 (C=N) MS (EI)mz 473 (M+ 18) 474 (M+ + 1 51) Anal Calcd for

C29H23N5O2(47353) C 7356 H 490 N 1479 O 676

Found C 7348 H 464 N 1463 O 670

2117 General Procedure for the Preparation of PyrazolylDerivatives VIII (Scheme 3) A mixture of compound VII(001mol) and hydrazine hydrate (064ml 002mole) inethanol (30mL) were heated under reflux for 8 h controlledby TLC The solvent was concentrated and the reactionproduct was allowed to cool then pour on acidified iceH

2O

The product was filtered off washed with water dried andrecrystallized from ethanol to give VIII

2-(2-(35-Diamino-4H-pyrazol-4-ylidene)hydrazinyl)-1-(34-dichloro phenyl)-45-diphenyl-1H-pyrrole-3-carbonitrileVIIId Yield 55 MP 120ndash124∘C 1H NMR (DMSO-119889

6

300MHz) 120575 (ppm) 65 (s 4H 2lowastNH2 D2O exchangeable)

72ndash8 (m 14HAr-H andNH hydrazone D2Oexchangeable)

IR (KBr) 120592 (cmminus1) 3350ndash3280 (broad NH and NH2) 2320

(CequivN) 1695 (C=O) 1585 (C=N) MS (EI) mz 513 (M+12) 515 (M+ + 2 78) 516 (M+ + 4 24) Anal Calcdfor C26H17Cl2N7O (51309) C 6071 H 333 Cl 1379 N

1906 O 311 Found C 6098 H 341 Cl 1395 N 1943O 327

2-(2-(35-Diamino-4H-pyrazol-4-ylidene)hydrazinyl)-1-(15-dimethyl-3-oxo-2-phenyl-23-dihydro-1H-pyrazol-4-yl)-4-phenyl-1H-pyrrole-3-carbonitrile VIIIe Yield 61 MP135ndash138∘C 1H NMR (DMSO-119889

6 300MHz) 120575 (ppm) 242

(s 3H CH3) 311 (s 3H N-CH

3) 648 (s 4H 2lowastNH

2

D2O exchangeable) 689 (s 1H NH hydrazone D

2O

exchangeable) 73ndash8 (m 11H Ar-H and C6-H) IR (KBr) 120592

(cmminus1) 3340ndash3290 (broad NH and NH2) 2320 (CequivN) 1695

(C=O) 1585 (C=N) MS (EI) mz 478 (M+ 152) 479 (M++ 1 446) Anal Calcd for C

25H22N10O (47851) C 6275

H 463 N 2927 O 334 Found C 6264 H 447 N2902 O 309

2-(2-(3-Amino-5-hydroxy-4H-pyrazol-4-ylidene)hydrazinyl)-1-benzyl-45-diphenyl-1H-pyrrole-3-carbonitrile VIIIf Yield56 MP 97ndash100∘C 1H NMR (DMSO-119889

6 300MHz)

120575 (ppm) 561 (s 2H CH2) 645 (s 4H 2lowastNH

2


2O

exchangeable) 72ndash79 (m 15H Ar-H) IR (KBr) 120592 (cmminus1)3340ndash3270 (broad NH and NH

2) 2310 (CequivN) 1690 (C=O)


27H21N7O (45950) C 7057 H

461 N 2134 O 348 Found C 7065 H 469 N 2107O 341

3 Biological Screening

31 Animals The complete course of the experiment wasconducted using male Wistar albino rats (200ndash250 g) rearedand maintained in the animal house of the institution andprovided free access to pelleted food and water ad libitumThe rats were maintained in a controlled environment (12 hlight and dark cycle) for about a week for acclimatizationThe protocol of the study was approved by the animal ethics


committee of the Faculty of Pharmacy Helwan University(10-01-2012)The studywas conducted in accordance with theEC directive 86609EEC for animal experiments

32 Dose Determination Glimepiride (Amaryl) was usedas a standard antidiabetic (4mgkg) in 1 gum acacia andadministered orally [32] Equivalent doses of all derivativeswere calculated according to their molecular weight [Msdotwt]

33 Sucrose-Loaded Model (SLM) Male Wistar rats werefasted overnight Blood was collected initially and then thecompounds were given to corresponding groups consistingof six rats each by oral gavage A sucrose load of (10 gmkg)body weight was given to each rat after half an hour posttesttreatment Bloodwas collected in 30 60 90 and 120min aftersucrose load [33]The percentages () fallen in blood glucoselevel were calculated according to the AUC method

34 Toxicity Study Thederivatives which showed antihyper-glycemic activity in this study were subjected to in vivo acutetoxicity study by testing their effect on serum liver and kidneymarkers

35 Induction of Experimental Diabetes Diabetes wasinduced in overnight fasted rats with a single intraperitonealinjection of streptozotocin (STZ) (Sigma-Aldrich Co StLouis USA Catalog number 1001062761) in a dose of65mgkg STZ was freshly dissolved in ice cold citrate buffer(001M pH 45) prior to injection [34] After 48 h ratsshowing blood glucose levelge 200mgdl were included inthe experiment [35]

36 Experimental Design Seventy-six rats (fourteen groupsof 5-6 rats each) were used to investigate the antihyper-glycemic effect of 12 pyrrole and pyrrolo pyrimidine deriva-tives Group 1 was diabetic control Group 2 diabetic +Glimepiride (Amaryl) (4mgkg) served as a reference antidi-abetic drug Groups (3ndash14) were given the various pyrrolederivatives (Iandashe IVg VIf VIIa b f and VIIIf a resp)The treated groups administered the Amaryl and differentderivatives orally

37 Methodology For each group blood glucose was esti-mated at zero one two four and six hours after oral admin-istration of derivatives using glucometer (Gluco Dr SuperSensor AllMedicus Co Ltd Anyang Gyeonggi Korea)

Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) activities in serum were measured accord-ing to the Reitman-Frankel calorimetric transaminase proce-dure [36] whereas alkaline phosphatase (ALP) was assayedby the kinetic enzymatic method by measuring the rate ofhydrolysis of p-nitrophenyl phosphate by ALP according toHenry [37] all were measured as indicators of hepatic injurySerum creatinine levels were assayed as an indicator for renalinjury in the samples by a calorimetric method [38] usingcommercial diagnostic kits (Diamond Diagnostics Egypt)

38 Statistical Analysis Data were represented as mean areaunder curve (AUC) plusmn SD Significant differences betweengroups was tested using GraphPad InStat (Graph softwareInc V 305 Ralph Stahlman Purdue University) Appropri-ate graphs were plotted using Microsoft Excel 2007 119875 valueless than 005 was considered statistically significant

4 Results and Discussion

41 Chemistry The target pyrrole o-amino carbonitriles Ia band d were prepared by the reaction [26ndash31] of benzoin withappropriate amines and malononitrile in nonpolar solventOn the other hand Ic and ewere obtained by condensation of120572-(arylamino)-acetophenone with malononitrile in sodiumethoxideethanol

Compounds Iandashewere utilized for the preparation of pyr-role derivatives Ifndasho using appropriate reagents and reactionconditions heating Iandashe with triethyl orthoformate (TEOF)afforded the corresponding 2-ethoxymethylamino derivativeIfndashj while on react with acetic anhydride the corresponding2-acetylamino Ikndasho were afforded as revealed in Scheme 1

On the other hand the pyrrole derivatives Iandashe wereconverted to the corresponding pyrrolo[23-d]pyrimidine-4-ones IIandashj via condensation with formic acid [39 40] andorAcOHHCl [28 41] as revealed in Scheme 2

Interaction [41] of Iandashe with formamide afforded thecorresponding 4-amino pyrrolo[23-d]pyrimidines IIIandashewhich can also be prepared via stirring of the imidate I fndashjwith ammonium hydroxide at room temperature as revealedin Scheme 2 The reaction of pyrrole o-amino carbonitrilesIandashe with thiourea in ethanol was reported [42] to afford thecorresponding 4-aminopyrimidine-2-thione IIIfndashj

Pyrrolopyrimidinones IIandashjwere converted [41 43 44] toits corresponding 4-chloro derivative IVandashj by refluxing withphosphorus oxychloride as revealed in Scheme 2

The 4-chloro IVandashj were utilized for the preparation ofpyrrolopyrimidine derivatives Vandashj and VIandashj using appro-priate reagents and reaction conditions [40 44] the synthesisof certain 4-hydrazino-7H-pyrrolo[23-d]pyrimidines Vandashjby hydrazinolysis of the corresponding 4-chloro analoguesYet when 4-chloro analogues IVandashj and thiourea wereheated [45] in absolute ethanol the pyrrolopyrimidine-4(3H)-thionesVIandashf were obtained as revealed in Scheme 2Diazotisation reaction of amino group in 2-amino-pyrrolefollowed by coupling of the diazonium salt with activemethylenes (ex malononitrile) has been reported [46ndash48]

Diazotization of Iandashe using a mixture of sodium nitriteand HCl (without acetic acid) at 0ndash5∘C without separationadding an active methylene compounds namely malonon-itrile andor ethyl cyanoacetate in ethanol in the presenceof sodium acetate afforded the corresponding hydrazonoderivatives VIIandashi This reaction could be explained via for-mation of the diazonium chlorides at first which in additionto malononitrile afforded VIIandashi Cyclization of hydrazonoderivatives 2 using hydrazine hydrate in boiling ethanolleads to the formation of the corresponding pyrazolin-5-onederivatives VIIIandashi as revealed in Scheme 3


Table 1 Effect of various treatments on the mean area under curve(AUC) of blood glucose levels in rats

Tested compound(s) reduction in blood glucose compared

to controlSLM STZ

Amaryl [Standard drug] 277a 304a

[Ia] 174a 333a

[Ib] 109a NA[Ic] 18a 353a

[Id] NA NA[Ie] 167a 295a

[IVg] 13a 112a

[VIf] NA NA[VIIa] NA NA[VIIb] NA NA[VIIf] NA NA[VIIIa] NA NA[VIIIf] NA NANA = not activeaConsidered significant compared to control (119875 le 005)SLM Sucrose-Loaded Model STZ Streptozotocin model of diabetes

42 Biological Activities Twelve of the synthesized Pyrrolesand pyrrolopyrimidines were evaluated for their antihyper-glycemic activity using both streptozotocin models of dia-betes and sucrose load model [32ndash35] The synthesized com-pounds were assessed for their antihyperglycemic activitywhich is comparable to Glimepiride (Amaryl) the standardantihyperglycemic drug by comparing the mean area underthe curve (AUC) for the blood glucose level between thedifferent studied groups The proved pyrrole derivativeswhich showedpromising decrease in the serumblood glucoselevel were subjected to test their toxicity in vivo on serumliver and kidney markers

The tested compounds were classified into 2 maingroups first the open form pyrrole derivatives namely Iandashe(pyrrole o-amino carbonitriles) hydrazone derivatives VIIab and f and pyrazolin-5-one derivatives VIIIa f secondthe pyrrolopyrimidines namely 4-chloro IVg and 4-thioderivatives VIf

Only the open form pyrrole derivatives namely I ac and e (pyrrole o-amino carbonitriles) induced a signif-icant decrease in blood glucose level in the sucrose loadmodel (174 18 and 167 respectively) compared to theuntreated normal controlMoreover they induced significantdecrease in blood glucose level in the STZ model of diabetes(333 353 and 295 respectively) compared to thediabetic control group as depicted in Table 1

Comparing the antihyperglycemic activity of the thesecompounds with that of the reference antidiabetic drug(Amaryl) showed that compounds Ia Ic and Ie showedsignificant decrease in the blood glucose level (10941162 and 97 respectively) when compared to the activityof Amaryl as shown in Figure 3

Among the pyrrolopyrimidines only the 4-chloro IVg(also bearing the antipyrine moiety at N-pyrrole) showed

1094311617

9699

3619 3938

100

0

20

40

60

80

100

120

140

Amaryl Ia Ic Ie Vg VIIb

Figure 3 Potency of antihyperglycemic derivatives compared toAmaryl

marked but not significant decrease in blood glucose level112 compared to the diabetic control group as shown inTable 1

Studying the acute toxicity of the promising antihyper-glycemic derivatives Ia c and e on the rats showed thatthe levels of sera ALT AST ALP and creatinine were notsignificantly changed from that of the control untreated groupand also the rats did not die or show any toxicity symptomsas shown in Table 2

To analyze structure-activity relationships three struc-tural components were considered the nature of the hetero-cycle nucleus the nature of the side chain of the heterocyclesystem and the function of the side chain as shown inFigure 4

First the influence of the nature of the heterocyclic systemwas easily observed as pyrrole (I a c and e) derivatives haveshow superior activity over pyrrolopyrimidines IVg andVIf

Regarding the side chain function for the pyrroles deriva-tives the free amino group in pyrrole o-amino carbonitrilesI a c and e conferred the greater activity over the hydrazonederivatives VIIa b and f which showed a marked activityover the pyrazolin-5-one derivatives VIIIa f which have noactivity For the pyrrolopyrimidines the 4-chloro IVg confersmarkedly but not significantly higher activity than the 4-thioderivatives VIf

Finally the influence of the nature of the side chain onthe heterocycle system among the active compounds theantipyrine bearing N7-pyrrole (I e and IVg) showing a goodactivity over the benzyl (VIf VIIa and VIIIa)

5 Conclusion

In the present study we described a straightforward andefficient synthesis of some pyrroles and pyrrolo[23-d]pyrimidine and alsowe examined their effects asantihperglycemic agents The structure-activity relationship(SAR) results indicated that the pyrroles Ia c and econtaining amino and cyano groups displayed good tomoderate antihyperglycemic activity profile compared tocontrol On diazotization of the amino group inVII andVIIIthis did not enhance the activity The introduction of chlorogroup to IVg resulted in an enhanced antihyperglycemicactivity of the pyrrolopyrimidine analogs over the hydrazinederivatives These results and others demonstrated that


Table 2 Effect of compounds Ia Ic and Ie on ALT AST ALP and creatinine

Parameter Control Ia Ic IeALT (UL) 226 plusmn 46 179 plusmn 27 2716 plusmn 63 205 plusmn 31AST (UL) 634 plusmn 146 694 plusmn 95 72 plusmn 78 627 plusmn 97ALP (UL) 706 plusmn 15 685 plusmn 123 638 plusmn 154 739 plusmn 132Creatinine (mgdL) 083 plusmn 013 08 plusmn 016 063 plusmn 009 077 plusmn 014

NAr

NH2

CNPh

Ph Ph

X

Anti AntiH H

Ar = CH2PhX = Ph

(Cl)2Ph (Cl)2Ph

Ia Ib Ic Id Ie

(a)

N

N

N

Ph

Ph

Cl

CH3

Anti

IVg

(b)

NN

NPh

PhCH3

HS

CH2PhVIf

(c)

N

Ar

CN

CN CNCN

Ph

Ph

Anti CH2PhAr = CH2PhR = CN

NHN=CHRR998400

COOEt

VIIa VIIb VIIf

R998400= CN

(d)

N NN

NH2

CNPh

Ph NHN=

Y

Y = NH2 OH

CH2Ph

VIIIa VIIIf

(e)

Figure 4 Pyrrole and Pyrrolopyrimidines derivatives evaluated as antihyperglycemic agents

the synthesized pyrrole and pyrrolopyrimidine compoundsare promising antihyperglycemic agents

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] S Wang N C Wan J Harrison et al ldquoDesign and syn-thesis of new templates derived from pyrrolopyrimidine asselective multidrug-resistance-associated protein inhibitors inmultidrug resistancerdquo Journal of Medicinal Chemistry vol 47no 6 pp 1339ndash1350 2004

[2] K L Smith V C H Lai B J Prigaro et al ldquoSynthesis of new 21015840-120573-C-methyl related triciribine analogues as anti-HCV agentsrdquoBioorganic amp Medicinal Chemistry Letters vol 14 no 13 pp3517ndash3520 2004

[3] T-C Chien E A Meade J M Hinkley and L B TownsendldquoFacile synthesis of 1-substituted 2-amino-3-cyanopyrrolesnew synthetic precursors for 56-unsubstituted pyrrolo[23-d]pyrimidinesrdquo Organic Letters vol 6 no 17 pp 2857ndash28592004

[4] A Budhiraja K Kadian M Kaur et al ldquoSynthesis and bio-logical evaluation of naphthalene furan and pyrrole based

chalcones as cytotoxic and antimicrobial agentsrdquo MedicinalChemistry Research vol 21 no 9 pp 2133ndash2140 2012

[5] M V Raimondi S Cascioferro D Schillaci and S PetrusoldquoSynthesis and antimicrobial activity of new bromine-rich pyr-role derivatives related to monodeoxypyoluteorinrdquo EuropeanJournal of Medicinal Chemistry vol 41 no 12 pp 1439ndash14452006

[6] M Biava R Fioravanti G C Porretta D Deidda C Maulluand R Pompei ldquoNew pyrrole derivatives as antimycobacterialagents analogs of BM212rdquo Bioorganic amp Medicinal ChemistryLetters vol 9 no 20 pp 2983ndash2988 1999

[7] M Biava G C Porretta D Deidda R Pompei A Tafi andF Manetti ldquoImportance of the thiomorpholine introduction innew pyrrole derivatives as antimycobacterial agents analoguesof BM 212rdquo Bioorganic ampMedicinal Chemistry vol 11 no 4 pp515ndash520 2003

[8] C Zhang J Dong T Cheng and R Li ldquoY(OTf)3-catalyzednovel Mannich reaction of N-alkoxycarbonylpyrrolesformaldehyde and primary amine hydrochloridesrdquo TetrahedronLetters vol 42 no 3 pp 461ndash463 2001

[9] U Ursic J Svete and B Stanovnik ldquoSynthesis of 4-(2-hydroxy-1-methyl-5-oxo-1H-imidazol-4(5H)-ylidene)-5-oxo-1-aryl-45-dihydro-1H-pyrrole-3-carboxylates a new triazafulvalenesystemrdquo Tetrahedron vol 66 no 24 pp 4346ndash4356 2010

[10] M C Rodrıguez-Arguelles E C Lopez-Silva J SanmartınP Pelagatti and F Zani ldquoCopper complexes of imidazole-2- pyrrole-2- and indol-3-carbaldehyde thiosemicarbazones


inhibitory activity against fungi and bacteriardquo Journal of Inor-ganic Biochemistry vol 99 no 11 pp 2231ndash2239 2005

[11] F Micheli R Di Fabio F Bordi et al ldquo24-Dicarboxy-pyrrolesas selective non-competitive mGluR1 antagonists further char-acterization of 35-dimethyl pyrrole-24-dicarboxylic acid 2-propyl ester 4-(122-trimethyl-propyl) ester and structure-activity relationshipsrdquo Bioorganic amp Medicinal Chemistry Let-ters vol 13 no 13 pp 2113ndash2118 2003

[12] E Fernandes D Costa S A Toste J L F C Lima and S ReisldquoIn vitro scavenging activity for reactive oxygen and nitrogenspecies by nonsteroidal anti-inflammatory indole pyrrole andoxazole derivative drugsrdquo Free Radical Biology amp Medicine vol37 no 11 pp 1895ndash1905 2004

[13] S B Etcheverry D A Barrio A M Cortizo and P AM Williams ldquoThree new vanadyl(IV) complexes with non-steroidal anti-inflammatory drugs (Ibuprofen Naproxen andTolmetin) bioactivity on osteoblast-like cells in culturerdquo Jour-nal of Inorganic Biochemistry vol 88 no 1 pp 94ndash100 2002

[14] I Lessigiarska A Nankov A Bocheva I Pajeva and A Bijevldquo3D-QSAR and preliminary evaluation of anti-inflammatoryactivity of series ofN-pyrrolylcarboxylic acidsrdquo Il Farmaco vol60 no 3 pp 209ndash218 2005

[15] A Mai S Valente D Rotili et al ldquoNovel pyrrole-containinghistone deacetylase inhibitors endowedwith cytodifferentiationactivityrdquo International Journal of Biochemistry and Cell Biologyvol 39 no 7-8 pp 1510ndash1522 2007

[16] M Sechi A Mura L Sannia M Orecchioni and G PagliettildquoSynthesis of pyrrolo[12-a]indole-18(5H)-diones as new syn-thons for developing novel tryciclic compounds of pharmaceu-tical interestrdquo Arkivoc vol 2004 no 5 pp 97ndash106 2004

[17] Lipitor LAB-0021-7 0 Pfizer Ireland Pharmaceuticals 2004[18] R N Madadi N R Penthala V Janganati and P A

Crooks ldquoSynthesis and anti-proliferative activity of aro-matic substituted 5-((1-benzyl-1H-indol-3-yl)methylene)-13-dimethylpyrimidine-2 4 6(1H3H5H)-trione analogs againsthuman tumor cell linesrdquo Bioorganic amp Medicinal ChemistryLetters vol 24 no 2 pp 601ndash603 2014

[19] T Hirose H Asakawa Y Itoh et al ldquoEfficacy of glimepiridein type 2 diabetic patients treated with glibenclamiderdquoDiabetesResearch and Clinical Practice vol 66 supplement 1 pp S129ndashS132 2004

[20] A Goel N Agarwal F V Singh et al ldquoAntihyperglycemicactivity of 2-methyl-345-triaryl-1H-pyrroles in SLM and STZmodelsrdquo Bioorganic amp Medicinal Chemistry Letters vol 14 no5 pp 1089ndash1092 2004

[21] H Xie L Zeng S Zeng et al ldquoNovel pyrrolopyrimidineanalogues as potent dipeptidyl peptidase IV inhibitors basedon pharmacokinetic property-driven optimizationrdquo EuropeanJournal of Medicinal Chemistry vol 52 pp 205ndash212 2012

[22] S Sancheti S Sancheti and S-Y Seo ldquoChaenomeles sinensis apotent 120572-and 120573-glucosidase inhibitorrdquoThe American Journal ofPharmacology and Toxicology vol 4 no 1 pp 8ndash11 2009

[23] J Deng L Peng G Zhang et al ldquoThe highly potent andselective dipeptidyl peptidase IV inhibitors bearing a thienopy-rimidine scaffold effectively treat type 2 diabetesrdquo EuropeanJournal of Medicinal Chemistry vol 46 no 1 pp 71ndash76 2011

[24] D J Augeri J A Robl D A Betebenner et al ldquoDiscovery andpreclinical profile of saxagliptin (BMS-477118) a highly potentlong-acting orally active dipeptidyl peptidase IV inhibitorfor the treatment of type 2 diabetesrdquo Journal of MedicinalChemistry vol 48 no 15 pp 5025ndash5037 2005

[25] G Zhao C Kwon A Wang et al ldquoSubstituted piperidinylglycinyl 2-cyano-45-methano pyrrolidines as potent and stabledipeptidyl peptidase IV inhibitorsrdquo Bioorganic amp MedicinalChemistry Letters vol 23 no 6 pp 1622ndash1625 2013

[26] M S Mohamed R Kamel and S S Fatahala ldquoSynthesis andbiological evaluation of some thio containing pyrrolo [23-d] pyrimidine derivatives for their anti-inflammator and anti-microbial activitiesrdquo European Journal of Medicinal Chemistryvol 45 no 7 pp 2994ndash3004 2010

[27] A E Rashad M S Mohamed M E A Zaki and S S Fata-hala ldquoSynthesis and biological evaluation of some pyrrolo[23-d]pyrimidinesrdquo Archiv der Pharmazie vol 339 no 12 pp 664ndash669 2006

[28] M S Mohamed R Kamel and S S Fathallah ldquoSynthesis ofnew pyrroles of potential anti-inflammatory activityrdquoArchiv derPharmazie vol 344 no 12 pp 830ndash839 2011

[29] M S Mohamed R Kamel and S S Fatahala ldquoNew con-densed pyrroles of potential biological interest syntheses andstructure-activity relationship studiesrdquo European Journal ofMedicinal Chemistry vol 46 no 7 pp 3022ndash3029 2011

[30] M SMohamed and S S Fatahala ldquoPyrroles and fused pyrrolessynthesis and therapeutic activitiesrdquo inMini-Reviews in OrganicChemistry 2014

[31] P M Traxler P Furet H Mett E Buchdunger T Meyerand N Lydon ldquo4-(Phenylamino)pyrrolopyrimidines potentand selective ATP site directed inhibitors of the EGF-receptorprotein tyrosine kinaserdquo Journal of Medicinal Chemistry vol 39no 12 pp 2285ndash2292 1996

[32] A Mowla M Alauddin M A Rahman and K Ahmed ldquoAnti-hyperglycemic effect of Trigonella foenum-graecum (fenugreek)seed extract in alloxan-induced diabetic rats and its use indiabetes mellitus A brief qualitative phytochemical and acutetoxicity test on the extractrdquo African Journal of TraditionalComplementary andAlternativeMedicines vol 6 no 3 pp 255ndash261 2009

[33] FV SinghA Parihar S Chaurasia et al ldquo56-Diarylanthranilo-13-dinitriles as a new class of antihyperglycemic agentsrdquo Bioor-ganicampMedicinal Chemistry Letters vol 19 no 8 pp 2158ndash21612009

[34] G DrsquoAndrea A R Lizzi F Brisdelli A M DrsquoAlessandroA Bozzi and A Oratore ldquoProtein glycans alteration and adifferentdistribution of some enzymatic activities involvedinthe glycan processing are found in AZT-treated K562 cellsrdquoMolecular and Cellular Biochemistry vol 252 no 1-2 pp 45ndash51 2003

[35] N N Kim M Stankovic T T Cushman I Goldstein RMunarriz and A M Traish ldquoStreptozotocin-induced diabetesin the rat is associated with changes in vaginal hemodynamicsmorphology and biochemical markersrdquo BMC Physiology vol 6article 4 2006

[36] S Reitman and S A Frankel ldquoA colorimetric method for thedetermination of serum glutamic oxalacetic and glutamic pyru-vic transaminasesrdquoThe American Journal of Clinical Pathologyvol 28 no 1 pp 56ndash63 1957

[37] R J Henry Clinical Chemistry Principles and TechniquesHarper amp Row New York NY USA 1964

[38] G Szasz U Boerner E W Busch and W Bablok ldquoEnzymaticassay of creatinine in serum comparison with Jaffe methodsrdquoJournal of Clinical Chemistry and Clinical Biochemistry vol 17no 11 pp 683ndash687 1979


[39] C G Dave and N D Desai ldquoSynthesis and reactions of flu-oroaryl substituted 2-amino-3-cyanopyrroles and pyrrolo[23-d]pyrimidinesrdquo Journal of Heterocyclic Chemistry vol 36 no 3pp 729ndash733 1999

[40] M M Ghorab F A Ragab H I Heiba H A Youssef andM G El-Gazzar ldquoSynthesis of novel pyrrole and pyrrolo[23-d]pyrimidine derivatives bearing sulfonamidemoiety for evalu-ation as anticancer and radiosensitizing agentsrdquo Bioorganic andMedicinal Chemistry Letters vol 20 no 21 pp 6316ndash6320 2010

[41] B S Holla M Mahalinga M S Karthikeyan P M Akber-ali and N S Shetty ldquoSynthesis of some novel pyrazolo[34-d]pyrimidine derivatives as potential antimicrobial agentsrdquoBioorganic ampMedicinal Chemistry vol 14 no 6 pp 2040ndash20472006

[42] M S A El-Gaby A M Gaber A A Atalla and K A Abd Al-Wahab ldquoNovel synthesis and antifungal activity of pyrrole andpyrrolo[23-d]pyrimidine derivatives containing sulfonamidomoietiesrdquo Il Farmaco vol 57 no 8 pp 613ndash617 2002

[43] C G Dave and R D Shah ldquoSynthesis of 7H-tetrazolo[15-c]pyrrolo[32-e]pyrimidines and their reductive ring cleavageto 4-aminopyrrolo[23-d]pyrimidinesrdquo Journal of HeterocyclicChemistry vol 35 no 6 pp 1295ndash1300 1998

[44] A M El-Ghanam ldquoSynthesis of some new spirothiopyranderivatives from the reaction of 4-thiopyrylidenemalononitrileswith bidentate and active methylene reagentsrdquo PhosphorusSulfur and Silicon and the Related Elements vol 178 no 4 pp863ndash868 2003

[45] A Lauria P Diana P Barraja et al ldquoNew tricyclic systemsof biological interest annelated 123-triazolo[15-a]pyrimidinesthrough domino reaction of 3-azidopyrroles and methyleneactive nitrilesrdquoTetrahedron vol 58 no 48 pp 9723ndash9727 2002

[46] A Lauria P Diana P Barraja et al ldquoPyrrolo[21-d][1235]tetrazine-4(3H)-ones a new class of azolotetrazineswith potent antitumor activityrdquo Bioorganic amp MedicinalChemistry vol 11 no 11 pp 2371ndash2380 2003

[47] M A Khan and A C C Freitas ldquoFused pyrazolopyrimidinesI Pyrazolo[4 3-e]-v-triazolo[1 5-a]pyrimidine a new hetero-cyclic systemrdquo Journal of Heterocyclic Chemistry vol 17 no 7pp 1603ndash1604 1980

[48] A P Freitas M Fernanda J R P Proenca and B L BoothldquoSynthesis of 5-azido-4-cyanoimidazole and its reaction withactive methylene compoundsrdquo Journal of Heterocyclic Chem-istry vol 32 no 2 pp 457ndash462 1995


NH N N

H

H2NS

integrase inhibition [4ndash8]Pyrrole as antibacterial and as HIV-1

Pyrrole-2-carbaldehyde

(a)

N

CH3

CO2H

CO2H

O

ON

Ketorolac (ketorolac)Tolmetin (rumatol)

Pyrroles as nonsteroidal anti-inflammatory

H3C

drugs (NSAIDs) [11ndash13]

(b)

Figure 1 Pyrrole as valuable leads in the drug discovery field

NH

R998400

R998400

RR

X

X XF

FF

HH H

HH

HOMeCl

CF3

Triarylpyrrole derivatives

(a)

O HN

HNS

O

HN

N

O

O

O

Glimepiride

HOHN N

OCN

VildagliptinEMEA approved

HO N

OCN

NH2

SaxagliptinEMEAFDA approved

(b)

NH2 NH2

N

N N

OR3

R2

R1

R1 = H CH3

R2 R3 = H CH3 Br

N

CN

Pyrrolopyrimidines

N N

S

O

N

CN

Thienopyrimidines

(c)

Figure 2 (a) Pyrroles as antihyperglycemic agents [19 20] (b) Amaryl standard antihyperglycemic drug [21 22] and approved DPP-IVinhibitors [23ndash25] as type 2 diabetes medications containing a pyrrole moiety (c) Thieno and Pyrrolo-pyrimidines as DPP-IV inhibitors






6 300MHz) 120575 (ppm) 521


13C NMR (DMSO-1198896) 120575 11433 11824 11937 1258 12618


2) 2220


23H15Cl2N3(40306) C

6833 H 374 Cl 1754 N 1039 Found C 6855 H 392Cl 1723 N 1072



6 300MHz) 120575 (ppm) 243

(s 3H CH3) 312 (s 3H N-CH

3) 613 (brs 2H NH

2 D2O




Found C 7155 H 526 N 1870 O 305



6 300MHz) 120575 (ppm) 130 (t 3H J = 71Hz

CH3) 42 (q 2H J = 71Hz OCH



O 348 Found C 6803 H 411 Cl 1563 N 891 O 369


6


CH3) 31 (s 3H N-CH

3) 401 (q 2H J = 71Hz OCH

2)



Found C 7021 H 517 N 1612 O 718



6 300MHz) 120575 (ppm) 223 (s 3H CO-CH

3)



25H17Cl2N3O (44507) C 6728 H




Ph Ph

PhPh

Ph

Ph

Ph

PhPh

O

O

O

O

O

O

1NH

2

CN

Ar

Ar

Ar

Ar

XX

NH2

5 6Y

NHX998400

Br 3 4

Ar =CH2C6H5

CH3

CH3

X = H Ph

Y = CN

HN

+ ArNH2

+ ArNH2

N

NN

N

Iandashe Ifndasho

34-(Cl)2C6H3


3EtOH (4)


2O

PhPh

Ph

Ph

Ph Ph

Ph

Ph

XX

X

X X

X

XNN

N

N N

N N

N

NN N

N

N

N

N

N

NN

N

N

NH2

ArAr

Ar

Ar Ar

Ar

Ar

1 (Y = H)2 (Y = CH3)


5

ΙVandashi

CI

Y Y Y

Y

6 6

Vandashi

NHNH2

NNH2 Ιfndashj


S

VIandashf

3 (Y998400= H)

H2N

Y998400

IIIandashj

Ar =

CH2C6H5

CH3

CH3

X = H Ph

Y = H CH3

CNO

O

HHN

4 (Y998400= SH)

(X998400=

CHOEt)

Cl

7

(Y = H CH3)

34-(Cl)2C6H3Y998400

= HSH


2 (4) NH

2CSNH

2

(5) POCl3 (6) N


2CSNH

2


120575 (ppm) 223 (s 3H CO-CH3) 243 (s 3H CH

3) 312 (s


6-H) 94 (s 1H



24H21N5O2(41117) C

7006 H 514 N 1702 O 778 Found C 7037 H 545 N1734 O 795



Ph Ph Ph

Ph

Ph

CN CN CN

CN

X X X

X

N N N

N

NN

N

N

NH2

Ar Ar Ar

Ar

1 2

3

Ιandashc

N2Cl NHN = C(Y)CN

VIIandashf

Ar =

CH2C6H5

CH3

CH3

X = H Ph

Y = CN CO2Et

H2N

NHN

Y998400998400

VIIIandashfO

minus+

34-(Cl)2C6H3Y998400998400

= NH2OH


NCCH2YCH


2H4sdotH2O




84 (s 1H C2-H) 1240 (s 1H NH D

2O exchangeable)

13C NMR (DMSO-1198896) 12057511824 11937 1258 12618 12780



972 O 370 Found C 6632 H 318 Cl 1621 N 950 O346


6 300MHz) 120575

(ppm) 241 (s 3H CH3) 321 (s 3H N-CH

3) 69ndash78 (m


2-H) 1232 (s 1H NH


2)


23H19N5O2(37943) C 6951 H 482 N

1762 O 805 Found C 6989 H 516 N 1797 O 841




6 300MHz) 120575 (ppm) 235 (s 3H


2O



O 358 Found C 6745 H 411 Cl 1622 N 974 O 382


6


3)


6-H) 1236 (s


(NH2) 1730 1700 (C=O) 1560 (C=N) MS (EI) mz 487


(41146) C 7006 H 514 N 1702 O 778 Found C 7024H 532 N 1731 O 796



6 300MHz) 120575 (ppm) 54 (brs 2H NH

2 D2O





24H16Cl2N4(43008) C 6683

H 374 Cl 1644 N 1299 Found C 6707 H 511 Cl1681 N 1336


6 300MHz) 120575 (ppm)

241 (s 3H CH3) 314 (s 3H N-CH

3) 58 (brs 2H NH

2


6-H) 83


2)


23H20N6O

(39644) C 6968 H 508 N 2120 O 404 Found C6942 H 492 N 2089 O 432



6 300MHz) 120575 (ppm) 662 (s 2H NH

2





S 692 Found C 6245 H 362 Cl 1549 N 1241 S 721


6 300MHz)

120575 (ppm) 234 (s 3H CH3) 311 (s 3H N-CH

3) 651 (brs 2H


6-H)

83 (s 1H C2-H) 892 (s 1H NH D

2O exchangeable) IR



23H20N6OS (42851) C 6447 H

470 N 1961 O 373 S 748 Found C 6478 H 497 N1992 O 391 S 762




(s 1H C2-H) 13C NMR (DMSO-119889

6) 1205751175 1188 12618


24H14Cl3N3(44903) C

6395 H 313 Cl 2360 N 932 Found C 6423 H 342Cl 2391 N 949


6 300MHz) 120575 (ppm)

243 (s 3H CH3) 312 (s 3H N-CH



2-H) IR (KBr) 120592 (cmminus1) 3080 2840


23H18ClN5O



6 300MHz) 120575 (ppm) 232 (s 3H CH

3) 512 (s


6-H) IR (KBr)


Found C 7647 H 523 Cl 896 N 1059


6 300MHz)


3)


30H24ClN5O



6 300MHz) 120575 (ppm) 236 (s 3H CH

3)


25H16Cl3N3(46477) C 6461 H 347

Cl 2288 N 904 Found C 6499 H 373 Cl 2308 N929


6 300MHz) 120575


3)




C24H20ClN5O (42990) C 6705 H 469 Cl 825 N 1629

O 372 Found C 6742 H 508 Cl 857 N 1665 O402





6 300MHz) 120575 (ppm) 49ndash52



2-H) 13C NMR

(DMSO-1198896) 12057511745 11869 12621 12747 1284 12974


2) 3210 (NH)


Found C 6495 H 420 Cl 1623 N 1604


6


3)


H C6-H and NH D


2-H) IR



23H21N7O (41146) C 6714

H 514 N 2383 O 389 Found C 6752 H 548 N 2415O 452


6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 49ndash52


2)




26H23N5(40549) C 7701 H 572

N 1727 Found C 7738 H 605 N 1762


6





(cmminus1) 3420 3350 (NH2) 3240 (NH) 1700 (C=O) 1605


30H27N7O (50158) C 7184 H

543 N 1955 O 319 Found C 7220 H 581 N 1992 O355


6 300MHz) 120575 (ppm) 225 (s 3H




3440 3360 (NH2) 3250 (NH) 1610 (C=C) 1560 (C=N) MS


25H19Cl2N5(46036) C 6522 H

416 Cl 1540 N 1521 Found C 6557 H 452 Cl 1578N 1556


6






120592 (cmminus1) 3430 3360 (NH2) 3250 (NH) 1705 (C=O) 1600


24H23N7O (42549) C 6775 H

545 N 2304 O 376 Found C 6812 H 576 N 2337O 411




H) 902 (s 1H C2-H) 1171 (s 1H NH D

2O exchangeable)


24H15Cl2N3S (44704) C 6429 H



6 300MHz) 120575

(ppm) 244 (s 3H CH3) 313 (s 3H N-CH

3) 72ndash78 (m


2-H) 1210 (s 1H NH



23H19N5OS




6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 578


2O


26H21N3S

(40753) C 7663 H 519 N 1031 S 787 Found C 7656H 511 N 1026 S 780


2O to give VII


6 300MHz) 120575 (ppm) 671 (s 1H



26H14Cl2N6(48133)



3) 311 (s 3H N-CH

3)




25H18N8O

(44646) C 6725 H 406 N 2510 O 358 Found C6754 H 412 N 2523 O 369


6 300MHz) 120575 (ppm) 131 (t 3H


2) 562 (s 2H


2O exchangeable)



C29H23N5O2(47353) C 7356 H 490 N 1479 O 676

Found C 7348 H 464 N 1463 O 670


2O



6





1906 O 311 Found C 6098 H 341 Cl 1395 N 1943O 327


6 300MHz) 120575 (ppm) 242

(s 3H CH3) 311 (s 3H N-CH


2


2O




25H22N10O (47851) C 6275

H 463 N 2927 O 334 Found C 6264 H 447 N2902 O 309


6 300MHz)


2


2O


2) 2310 (CequivN) 1690 (C=O)


27H21N7O (45950) C 7057 H

461 N 2134 O 348 Found C 7065 H 469 N 2107O 341
























to controlSLM STZ


[Ia] 174a 333a

[Ib] 109a NA[Ic] 18a 353a


[IVg] 13a 112a







1094311617

9699

3619 3938

100

0

20

40

60

80

100

120

140









5 Conclusion





NAr

NH2

CNPh

Ph Ph

X

Anti AntiH H

Ar = CH2PhX = Ph

(Cl)2Ph (Cl)2Ph

Ia Ib Ic Id Ie

(a)

N

N

N

Ph

Ph

Cl

CH3

Anti

IVg

(b)

NN

NPh

PhCH3

HS

CH2PhVIf

(c)

N

Ar

CN

CN CNCN

Ph

Ph


NHN=CHRR998400

COOEt

VIIa VIIb VIIf

R998400= CN

(d)

N NN

NH2

CNPh

Ph NHN=

Y

Y = NH2 OH

CH2Ph

VIIIa VIIIf

(e)





References


























































6 300MHz) 120575 (ppm) 521


13C NMR (DMSO-1198896) 120575 11433 11824 11937 1258 12618


2) 2220


23H15Cl2N3(40306) C

6833 H 374 Cl 1754 N 1039 Found C 6855 H 392Cl 1723 N 1072



6 300MHz) 120575 (ppm) 243

(s 3H CH3) 312 (s 3H N-CH

3) 613 (brs 2H NH

2 D2O




Found C 7155 H 526 N 1870 O 305



6 300MHz) 120575 (ppm) 130 (t 3H J = 71Hz

CH3) 42 (q 2H J = 71Hz OCH



O 348 Found C 6803 H 411 Cl 1563 N 891 O 369


6


CH3) 31 (s 3H N-CH

3) 401 (q 2H J = 71Hz OCH

2)



Found C 7021 H 517 N 1612 O 718



6 300MHz) 120575 (ppm) 223 (s 3H CO-CH

3)



25H17Cl2N3O (44507) C 6728 H




Ph Ph

PhPh

Ph

Ph

Ph

PhPh

O

O

O

O

O

O

1NH

2

CN

Ar

Ar

Ar

Ar

XX

NH2

5 6Y

NHX998400

Br 3 4

Ar =CH2C6H5

CH3

CH3

X = H Ph

Y = CN

HN

+ ArNH2

+ ArNH2

N

NN

N

Iandashe Ifndasho

34-(Cl)2C6H3


3EtOH (4)


2O

PhPh

Ph

Ph

Ph Ph

Ph

Ph

XX

X

X X

X

XNN

N

N N

N N

N

NN N

N

N

N

N

N

NN

N

N

NH2

ArAr

Ar

Ar Ar

Ar

Ar

1 (Y = H)2 (Y = CH3)


5

ΙVandashi

CI

Y Y Y

Y

6 6

Vandashi

NHNH2

NNH2 Ιfndashj


S

VIandashf

3 (Y998400= H)

H2N

Y998400

IIIandashj

Ar =

CH2C6H5

CH3

CH3

X = H Ph

Y = H CH3

CNO

O

HHN

4 (Y998400= SH)

(X998400=

CHOEt)

Cl

7

(Y = H CH3)

34-(Cl)2C6H3Y998400

= HSH


2 (4) NH

2CSNH

2

(5) POCl3 (6) N


2CSNH

2


120575 (ppm) 223 (s 3H CO-CH3) 243 (s 3H CH

3) 312 (s


6-H) 94 (s 1H



24H21N5O2(41117) C

7006 H 514 N 1702 O 778 Found C 7037 H 545 N1734 O 795



Ph Ph Ph

Ph

Ph

CN CN CN

CN

X X X

X

N N N

N

NN

N

N

NH2

Ar Ar Ar

Ar

1 2

3

Ιandashc

N2Cl NHN = C(Y)CN

VIIandashf

Ar =

CH2C6H5

CH3

CH3

X = H Ph

Y = CN CO2Et

H2N

NHN

Y998400998400

VIIIandashfO

minus+

34-(Cl)2C6H3Y998400998400

= NH2OH


NCCH2YCH


2H4sdotH2O




84 (s 1H C2-H) 1240 (s 1H NH D

2O exchangeable)

13C NMR (DMSO-1198896) 12057511824 11937 1258 12618 12780



972 O 370 Found C 6632 H 318 Cl 1621 N 950 O346


6 300MHz) 120575

(ppm) 241 (s 3H CH3) 321 (s 3H N-CH

3) 69ndash78 (m


2-H) 1232 (s 1H NH


2)


23H19N5O2(37943) C 6951 H 482 N

1762 O 805 Found C 6989 H 516 N 1797 O 841




6 300MHz) 120575 (ppm) 235 (s 3H


2O



O 358 Found C 6745 H 411 Cl 1622 N 974 O 382


6


3)


6-H) 1236 (s


(NH2) 1730 1700 (C=O) 1560 (C=N) MS (EI) mz 487


(41146) C 7006 H 514 N 1702 O 778 Found C 7024H 532 N 1731 O 796



6 300MHz) 120575 (ppm) 54 (brs 2H NH

2 D2O





24H16Cl2N4(43008) C 6683

H 374 Cl 1644 N 1299 Found C 6707 H 511 Cl1681 N 1336


6 300MHz) 120575 (ppm)

241 (s 3H CH3) 314 (s 3H N-CH

3) 58 (brs 2H NH

2


6-H) 83


2)


23H20N6O

(39644) C 6968 H 508 N 2120 O 404 Found C6942 H 492 N 2089 O 432



6 300MHz) 120575 (ppm) 662 (s 2H NH

2





S 692 Found C 6245 H 362 Cl 1549 N 1241 S 721


6 300MHz)

120575 (ppm) 234 (s 3H CH3) 311 (s 3H N-CH

3) 651 (brs 2H


6-H)

83 (s 1H C2-H) 892 (s 1H NH D

2O exchangeable) IR



23H20N6OS (42851) C 6447 H

470 N 1961 O 373 S 748 Found C 6478 H 497 N1992 O 391 S 762




(s 1H C2-H) 13C NMR (DMSO-119889

6) 1205751175 1188 12618


24H14Cl3N3(44903) C

6395 H 313 Cl 2360 N 932 Found C 6423 H 342Cl 2391 N 949


6 300MHz) 120575 (ppm)

243 (s 3H CH3) 312 (s 3H N-CH



2-H) IR (KBr) 120592 (cmminus1) 3080 2840


23H18ClN5O



6 300MHz) 120575 (ppm) 232 (s 3H CH

3) 512 (s


6-H) IR (KBr)


Found C 7647 H 523 Cl 896 N 1059


6 300MHz)


3)


30H24ClN5O



6 300MHz) 120575 (ppm) 236 (s 3H CH

3)


25H16Cl3N3(46477) C 6461 H 347

Cl 2288 N 904 Found C 6499 H 373 Cl 2308 N929


6 300MHz) 120575


3)




C24H20ClN5O (42990) C 6705 H 469 Cl 825 N 1629

O 372 Found C 6742 H 508 Cl 857 N 1665 O402





6 300MHz) 120575 (ppm) 49ndash52



2-H) 13C NMR

(DMSO-1198896) 12057511745 11869 12621 12747 1284 12974


2) 3210 (NH)


Found C 6495 H 420 Cl 1623 N 1604


6


3)


H C6-H and NH D


2-H) IR



23H21N7O (41146) C 6714

H 514 N 2383 O 389 Found C 6752 H 548 N 2415O 452


6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 49ndash52


2)




26H23N5(40549) C 7701 H 572

N 1727 Found C 7738 H 605 N 1762


6





(cmminus1) 3420 3350 (NH2) 3240 (NH) 1700 (C=O) 1605


30H27N7O (50158) C 7184 H

543 N 1955 O 319 Found C 7220 H 581 N 1992 O355


6 300MHz) 120575 (ppm) 225 (s 3H




3440 3360 (NH2) 3250 (NH) 1610 (C=C) 1560 (C=N) MS


25H19Cl2N5(46036) C 6522 H

416 Cl 1540 N 1521 Found C 6557 H 452 Cl 1578N 1556


6






120592 (cmminus1) 3430 3360 (NH2) 3250 (NH) 1705 (C=O) 1600


24H23N7O (42549) C 6775 H

545 N 2304 O 376 Found C 6812 H 576 N 2337O 411




H) 902 (s 1H C2-H) 1171 (s 1H NH D

2O exchangeable)


24H15Cl2N3S (44704) C 6429 H



6 300MHz) 120575

(ppm) 244 (s 3H CH3) 313 (s 3H N-CH

3) 72ndash78 (m


2-H) 1210 (s 1H NH



23H19N5OS




6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 578


2O


26H21N3S

(40753) C 7663 H 519 N 1031 S 787 Found C 7656H 511 N 1026 S 780


2O to give VII


6 300MHz) 120575 (ppm) 671 (s 1H



26H14Cl2N6(48133)



3) 311 (s 3H N-CH

3)




25H18N8O

(44646) C 6725 H 406 N 2510 O 358 Found C6754 H 412 N 2523 O 369


6 300MHz) 120575 (ppm) 131 (t 3H


2) 562 (s 2H


2O exchangeable)



C29H23N5O2(47353) C 7356 H 490 N 1479 O 676

Found C 7348 H 464 N 1463 O 670


2O



6





1906 O 311 Found C 6098 H 341 Cl 1395 N 1943O 327


6 300MHz) 120575 (ppm) 242

(s 3H CH3) 311 (s 3H N-CH


2


2O




25H22N10O (47851) C 6275

H 463 N 2927 O 334 Found C 6264 H 447 N2902 O 309


6 300MHz)


2


2O


2) 2310 (CequivN) 1690 (C=O)


27H21N7O (45950) C 7057 H

461 N 2134 O 348 Found C 7065 H 469 N 2107O 341
























to controlSLM STZ


[Ia] 174a 333a

[Ib] 109a NA[Ic] 18a 353a


[IVg] 13a 112a







1094311617

9699

3619 3938

100

0

20

40

60

80

100

120

140









5 Conclusion





NAr

NH2

CNPh

Ph Ph

X

Anti AntiH H

Ar = CH2PhX = Ph

(Cl)2Ph (Cl)2Ph

Ia Ib Ic Id Ie

(a)

N

N

N

Ph

Ph

Cl

CH3

Anti

IVg

(b)

NN

NPh

PhCH3

HS

CH2PhVIf

(c)

N

Ar

CN

CN CNCN

Ph

Ph


NHN=CHRR998400

COOEt

VIIa VIIb VIIf

R998400= CN

(d)

N NN

NH2

CNPh

Ph NHN=

Y

Y = NH2 OH

CH2Ph

VIIIa VIIIf

(e)





References






















































Ph Ph

PhPh

Ph

Ph

Ph

PhPh

O

O

O

O

O

O

1NH

2

CN

Ar

Ar

Ar

Ar

XX

NH2

5 6Y

NHX998400

Br 3 4

Ar =CH2C6H5

CH3

CH3

X = H Ph

Y = CN

HN

+ ArNH2

+ ArNH2

N

NN

N

Iandashe Ifndasho

34-(Cl)2C6H3


3EtOH (4)


2O

PhPh

Ph

Ph

Ph Ph

Ph

Ph

XX

X

X X

X

XNN

N

N N

N N

N

NN N

N

N

N

N

N

NN

N

N

NH2

ArAr

Ar

Ar Ar

Ar

Ar

1 (Y = H)2 (Y = CH3)


5

ΙVandashi

CI

Y Y Y

Y

6 6

Vandashi

NHNH2

NNH2 Ιfndashj


S

VIandashf

3 (Y998400= H)

H2N

Y998400

IIIandashj

Ar =

CH2C6H5

CH3

CH3

X = H Ph

Y = H CH3

CNO

O

HHN

4 (Y998400= SH)

(X998400=

CHOEt)

Cl

7

(Y = H CH3)

34-(Cl)2C6H3Y998400

= HSH


2 (4) NH

2CSNH

2

(5) POCl3 (6) N


2CSNH

2


120575 (ppm) 223 (s 3H CO-CH3) 243 (s 3H CH

3) 312 (s


6-H) 94 (s 1H



24H21N5O2(41117) C

7006 H 514 N 1702 O 778 Found C 7037 H 545 N1734 O 795



Ph Ph Ph

Ph

Ph

CN CN CN

CN

X X X

X

N N N

N

NN

N

N

NH2

Ar Ar Ar

Ar

1 2

3

Ιandashc

N2Cl NHN = C(Y)CN

VIIandashf

Ar =

CH2C6H5

CH3

CH3

X = H Ph

Y = CN CO2Et

H2N

NHN

Y998400998400

VIIIandashfO

minus+

34-(Cl)2C6H3Y998400998400

= NH2OH


NCCH2YCH


2H4sdotH2O




84 (s 1H C2-H) 1240 (s 1H NH D

2O exchangeable)

13C NMR (DMSO-1198896) 12057511824 11937 1258 12618 12780



972 O 370 Found C 6632 H 318 Cl 1621 N 950 O346


6 300MHz) 120575

(ppm) 241 (s 3H CH3) 321 (s 3H N-CH

3) 69ndash78 (m


2-H) 1232 (s 1H NH


2)


23H19N5O2(37943) C 6951 H 482 N

1762 O 805 Found C 6989 H 516 N 1797 O 841




6 300MHz) 120575 (ppm) 235 (s 3H


2O



O 358 Found C 6745 H 411 Cl 1622 N 974 O 382


6


3)


6-H) 1236 (s


(NH2) 1730 1700 (C=O) 1560 (C=N) MS (EI) mz 487


(41146) C 7006 H 514 N 1702 O 778 Found C 7024H 532 N 1731 O 796



6 300MHz) 120575 (ppm) 54 (brs 2H NH

2 D2O





24H16Cl2N4(43008) C 6683

H 374 Cl 1644 N 1299 Found C 6707 H 511 Cl1681 N 1336


6 300MHz) 120575 (ppm)

241 (s 3H CH3) 314 (s 3H N-CH

3) 58 (brs 2H NH

2


6-H) 83


2)


23H20N6O

(39644) C 6968 H 508 N 2120 O 404 Found C6942 H 492 N 2089 O 432



6 300MHz) 120575 (ppm) 662 (s 2H NH

2





S 692 Found C 6245 H 362 Cl 1549 N 1241 S 721


6 300MHz)

120575 (ppm) 234 (s 3H CH3) 311 (s 3H N-CH

3) 651 (brs 2H


6-H)

83 (s 1H C2-H) 892 (s 1H NH D

2O exchangeable) IR



23H20N6OS (42851) C 6447 H

470 N 1961 O 373 S 748 Found C 6478 H 497 N1992 O 391 S 762




(s 1H C2-H) 13C NMR (DMSO-119889

6) 1205751175 1188 12618


24H14Cl3N3(44903) C

6395 H 313 Cl 2360 N 932 Found C 6423 H 342Cl 2391 N 949


6 300MHz) 120575 (ppm)

243 (s 3H CH3) 312 (s 3H N-CH



2-H) IR (KBr) 120592 (cmminus1) 3080 2840


23H18ClN5O



6 300MHz) 120575 (ppm) 232 (s 3H CH

3) 512 (s


6-H) IR (KBr)


Found C 7647 H 523 Cl 896 N 1059


6 300MHz)


3)


30H24ClN5O



6 300MHz) 120575 (ppm) 236 (s 3H CH

3)


25H16Cl3N3(46477) C 6461 H 347

Cl 2288 N 904 Found C 6499 H 373 Cl 2308 N929


6 300MHz) 120575


3)




C24H20ClN5O (42990) C 6705 H 469 Cl 825 N 1629

O 372 Found C 6742 H 508 Cl 857 N 1665 O402





6 300MHz) 120575 (ppm) 49ndash52



2-H) 13C NMR

(DMSO-1198896) 12057511745 11869 12621 12747 1284 12974


2) 3210 (NH)


Found C 6495 H 420 Cl 1623 N 1604


6


3)


H C6-H and NH D


2-H) IR



23H21N7O (41146) C 6714

H 514 N 2383 O 389 Found C 6752 H 548 N 2415O 452


6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 49ndash52


2)




26H23N5(40549) C 7701 H 572

N 1727 Found C 7738 H 605 N 1762


6





(cmminus1) 3420 3350 (NH2) 3240 (NH) 1700 (C=O) 1605


30H27N7O (50158) C 7184 H

543 N 1955 O 319 Found C 7220 H 581 N 1992 O355


6 300MHz) 120575 (ppm) 225 (s 3H




3440 3360 (NH2) 3250 (NH) 1610 (C=C) 1560 (C=N) MS


25H19Cl2N5(46036) C 6522 H

416 Cl 1540 N 1521 Found C 6557 H 452 Cl 1578N 1556


6






120592 (cmminus1) 3430 3360 (NH2) 3250 (NH) 1705 (C=O) 1600


24H23N7O (42549) C 6775 H

545 N 2304 O 376 Found C 6812 H 576 N 2337O 411




H) 902 (s 1H C2-H) 1171 (s 1H NH D

2O exchangeable)


24H15Cl2N3S (44704) C 6429 H



6 300MHz) 120575

(ppm) 244 (s 3H CH3) 313 (s 3H N-CH

3) 72ndash78 (m


2-H) 1210 (s 1H NH



23H19N5OS




6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 578


2O


26H21N3S

(40753) C 7663 H 519 N 1031 S 787 Found C 7656H 511 N 1026 S 780


2O to give VII


6 300MHz) 120575 (ppm) 671 (s 1H



26H14Cl2N6(48133)



3) 311 (s 3H N-CH

3)




25H18N8O

(44646) C 6725 H 406 N 2510 O 358 Found C6754 H 412 N 2523 O 369


6 300MHz) 120575 (ppm) 131 (t 3H


2) 562 (s 2H


2O exchangeable)



C29H23N5O2(47353) C 7356 H 490 N 1479 O 676

Found C 7348 H 464 N 1463 O 670


2O



6





1906 O 311 Found C 6098 H 341 Cl 1395 N 1943O 327


6 300MHz) 120575 (ppm) 242

(s 3H CH3) 311 (s 3H N-CH


2


2O




25H22N10O (47851) C 6275

H 463 N 2927 O 334 Found C 6264 H 447 N2902 O 309


6 300MHz)


2


2O


2) 2310 (CequivN) 1690 (C=O)


27H21N7O (45950) C 7057 H

461 N 2134 O 348 Found C 7065 H 469 N 2107O 341
























to controlSLM STZ


[Ia] 174a 333a

[Ib] 109a NA[Ic] 18a 353a


[IVg] 13a 112a







1094311617

9699

3619 3938

100

0

20

40

60

80

100

120

140









5 Conclusion





NAr

NH2

CNPh

Ph Ph

X

Anti AntiH H

Ar = CH2PhX = Ph

(Cl)2Ph (Cl)2Ph

Ia Ib Ic Id Ie

(a)

N

N

N

Ph

Ph

Cl

CH3

Anti

IVg

(b)

NN

NPh

PhCH3

HS

CH2PhVIf

(c)

N

Ar

CN

CN CNCN

Ph

Ph


NHN=CHRR998400

COOEt

VIIa VIIb VIIf

R998400= CN

(d)

N NN

NH2

CNPh

Ph NHN=

Y

Y = NH2 OH

CH2Ph

VIIIa VIIIf

(e)





References






















































Ph Ph Ph

Ph

Ph

CN CN CN

CN

X X X

X

N N N

N

NN

N

N

NH2

Ar Ar Ar

Ar

1 2

3

Ιandashc

N2Cl NHN = C(Y)CN

VIIandashf

Ar =

CH2C6H5

CH3

CH3

X = H Ph

Y = CN CO2Et

H2N

NHN

Y998400998400

VIIIandashfO

minus+

34-(Cl)2C6H3Y998400998400

= NH2OH


NCCH2YCH


2H4sdotH2O




84 (s 1H C2-H) 1240 (s 1H NH D

2O exchangeable)

13C NMR (DMSO-1198896) 12057511824 11937 1258 12618 12780



972 O 370 Found C 6632 H 318 Cl 1621 N 950 O346


6 300MHz) 120575

(ppm) 241 (s 3H CH3) 321 (s 3H N-CH

3) 69ndash78 (m


2-H) 1232 (s 1H NH


2)


23H19N5O2(37943) C 6951 H 482 N

1762 O 805 Found C 6989 H 516 N 1797 O 841




6 300MHz) 120575 (ppm) 235 (s 3H


2O



O 358 Found C 6745 H 411 Cl 1622 N 974 O 382


6


3)


6-H) 1236 (s


(NH2) 1730 1700 (C=O) 1560 (C=N) MS (EI) mz 487


(41146) C 7006 H 514 N 1702 O 778 Found C 7024H 532 N 1731 O 796



6 300MHz) 120575 (ppm) 54 (brs 2H NH

2 D2O





24H16Cl2N4(43008) C 6683

H 374 Cl 1644 N 1299 Found C 6707 H 511 Cl1681 N 1336


6 300MHz) 120575 (ppm)

241 (s 3H CH3) 314 (s 3H N-CH

3) 58 (brs 2H NH

2


6-H) 83


2)


23H20N6O

(39644) C 6968 H 508 N 2120 O 404 Found C6942 H 492 N 2089 O 432



6 300MHz) 120575 (ppm) 662 (s 2H NH

2





S 692 Found C 6245 H 362 Cl 1549 N 1241 S 721


6 300MHz)

120575 (ppm) 234 (s 3H CH3) 311 (s 3H N-CH

3) 651 (brs 2H


6-H)

83 (s 1H C2-H) 892 (s 1H NH D

2O exchangeable) IR



23H20N6OS (42851) C 6447 H

470 N 1961 O 373 S 748 Found C 6478 H 497 N1992 O 391 S 762




(s 1H C2-H) 13C NMR (DMSO-119889

6) 1205751175 1188 12618


24H14Cl3N3(44903) C

6395 H 313 Cl 2360 N 932 Found C 6423 H 342Cl 2391 N 949


6 300MHz) 120575 (ppm)

243 (s 3H CH3) 312 (s 3H N-CH



2-H) IR (KBr) 120592 (cmminus1) 3080 2840


23H18ClN5O



6 300MHz) 120575 (ppm) 232 (s 3H CH

3) 512 (s


6-H) IR (KBr)


Found C 7647 H 523 Cl 896 N 1059


6 300MHz)


3)


30H24ClN5O



6 300MHz) 120575 (ppm) 236 (s 3H CH

3)


25H16Cl3N3(46477) C 6461 H 347

Cl 2288 N 904 Found C 6499 H 373 Cl 2308 N929


6 300MHz) 120575


3)




C24H20ClN5O (42990) C 6705 H 469 Cl 825 N 1629

O 372 Found C 6742 H 508 Cl 857 N 1665 O402





6 300MHz) 120575 (ppm) 49ndash52



2-H) 13C NMR

(DMSO-1198896) 12057511745 11869 12621 12747 1284 12974


2) 3210 (NH)


Found C 6495 H 420 Cl 1623 N 1604


6


3)


H C6-H and NH D


2-H) IR



23H21N7O (41146) C 6714

H 514 N 2383 O 389 Found C 6752 H 548 N 2415O 452


6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 49ndash52


2)




26H23N5(40549) C 7701 H 572

N 1727 Found C 7738 H 605 N 1762


6





(cmminus1) 3420 3350 (NH2) 3240 (NH) 1700 (C=O) 1605


30H27N7O (50158) C 7184 H

543 N 1955 O 319 Found C 7220 H 581 N 1992 O355


6 300MHz) 120575 (ppm) 225 (s 3H




3440 3360 (NH2) 3250 (NH) 1610 (C=C) 1560 (C=N) MS


25H19Cl2N5(46036) C 6522 H

416 Cl 1540 N 1521 Found C 6557 H 452 Cl 1578N 1556


6






120592 (cmminus1) 3430 3360 (NH2) 3250 (NH) 1705 (C=O) 1600


24H23N7O (42549) C 6775 H

545 N 2304 O 376 Found C 6812 H 576 N 2337O 411




H) 902 (s 1H C2-H) 1171 (s 1H NH D

2O exchangeable)


24H15Cl2N3S (44704) C 6429 H



6 300MHz) 120575

(ppm) 244 (s 3H CH3) 313 (s 3H N-CH

3) 72ndash78 (m


2-H) 1210 (s 1H NH



23H19N5OS




6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 578


2O


26H21N3S

(40753) C 7663 H 519 N 1031 S 787 Found C 7656H 511 N 1026 S 780


2O to give VII


6 300MHz) 120575 (ppm) 671 (s 1H



26H14Cl2N6(48133)



3) 311 (s 3H N-CH

3)




25H18N8O

(44646) C 6725 H 406 N 2510 O 358 Found C6754 H 412 N 2523 O 369


6 300MHz) 120575 (ppm) 131 (t 3H


2) 562 (s 2H


2O exchangeable)



C29H23N5O2(47353) C 7356 H 490 N 1479 O 676

Found C 7348 H 464 N 1463 O 670


2O



6





1906 O 311 Found C 6098 H 341 Cl 1395 N 1943O 327


6 300MHz) 120575 (ppm) 242

(s 3H CH3) 311 (s 3H N-CH


2


2O




25H22N10O (47851) C 6275

H 463 N 2927 O 334 Found C 6264 H 447 N2902 O 309


6 300MHz)


2


2O


2) 2310 (CequivN) 1690 (C=O)


27H21N7O (45950) C 7057 H

461 N 2134 O 348 Found C 7065 H 469 N 2107O 341
























to controlSLM STZ


[Ia] 174a 333a

[Ib] 109a NA[Ic] 18a 353a


[IVg] 13a 112a







1094311617

9699

3619 3938

100

0

20

40

60

80

100

120

140









5 Conclusion





NAr

NH2

CNPh

Ph Ph

X

Anti AntiH H

Ar = CH2PhX = Ph

(Cl)2Ph (Cl)2Ph

Ia Ib Ic Id Ie

(a)

N

N

N

Ph

Ph

Cl

CH3

Anti

IVg

(b)

NN

NPh

PhCH3

HS

CH2PhVIf

(c)

N

Ar

CN

CN CNCN

Ph

Ph


NHN=CHRR998400

COOEt

VIIa VIIb VIIf

R998400= CN

(d)

N NN

NH2

CNPh

Ph NHN=

Y

Y = NH2 OH

CH2Ph

VIIIa VIIIf

(e)





References

























































24H16Cl2N4(43008) C 6683

H 374 Cl 1644 N 1299 Found C 6707 H 511 Cl1681 N 1336


6 300MHz) 120575 (ppm)

241 (s 3H CH3) 314 (s 3H N-CH

3) 58 (brs 2H NH

2


6-H) 83


2)


23H20N6O

(39644) C 6968 H 508 N 2120 O 404 Found C6942 H 492 N 2089 O 432



6 300MHz) 120575 (ppm) 662 (s 2H NH

2





S 692 Found C 6245 H 362 Cl 1549 N 1241 S 721


6 300MHz)

120575 (ppm) 234 (s 3H CH3) 311 (s 3H N-CH

3) 651 (brs 2H


6-H)

83 (s 1H C2-H) 892 (s 1H NH D

2O exchangeable) IR



23H20N6OS (42851) C 6447 H

470 N 1961 O 373 S 748 Found C 6478 H 497 N1992 O 391 S 762




(s 1H C2-H) 13C NMR (DMSO-119889

6) 1205751175 1188 12618


24H14Cl3N3(44903) C

6395 H 313 Cl 2360 N 932 Found C 6423 H 342Cl 2391 N 949


6 300MHz) 120575 (ppm)

243 (s 3H CH3) 312 (s 3H N-CH



2-H) IR (KBr) 120592 (cmminus1) 3080 2840


23H18ClN5O



6 300MHz) 120575 (ppm) 232 (s 3H CH

3) 512 (s


6-H) IR (KBr)


Found C 7647 H 523 Cl 896 N 1059


6 300MHz)


3)


30H24ClN5O



6 300MHz) 120575 (ppm) 236 (s 3H CH

3)


25H16Cl3N3(46477) C 6461 H 347

Cl 2288 N 904 Found C 6499 H 373 Cl 2308 N929


6 300MHz) 120575


3)




C24H20ClN5O (42990) C 6705 H 469 Cl 825 N 1629

O 372 Found C 6742 H 508 Cl 857 N 1665 O402





6 300MHz) 120575 (ppm) 49ndash52



2-H) 13C NMR

(DMSO-1198896) 12057511745 11869 12621 12747 1284 12974


2) 3210 (NH)


Found C 6495 H 420 Cl 1623 N 1604


6


3)


H C6-H and NH D


2-H) IR



23H21N7O (41146) C 6714

H 514 N 2383 O 389 Found C 6752 H 548 N 2415O 452


6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 49ndash52


2)




26H23N5(40549) C 7701 H 572

N 1727 Found C 7738 H 605 N 1762


6





(cmminus1) 3420 3350 (NH2) 3240 (NH) 1700 (C=O) 1605


30H27N7O (50158) C 7184 H

543 N 1955 O 319 Found C 7220 H 581 N 1992 O355


6 300MHz) 120575 (ppm) 225 (s 3H




3440 3360 (NH2) 3250 (NH) 1610 (C=C) 1560 (C=N) MS


25H19Cl2N5(46036) C 6522 H

416 Cl 1540 N 1521 Found C 6557 H 452 Cl 1578N 1556


6






120592 (cmminus1) 3430 3360 (NH2) 3250 (NH) 1705 (C=O) 1600


24H23N7O (42549) C 6775 H

545 N 2304 O 376 Found C 6812 H 576 N 2337O 411




H) 902 (s 1H C2-H) 1171 (s 1H NH D

2O exchangeable)


24H15Cl2N3S (44704) C 6429 H



6 300MHz) 120575

(ppm) 244 (s 3H CH3) 313 (s 3H N-CH

3) 72ndash78 (m


2-H) 1210 (s 1H NH



23H19N5OS




6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 578


2O


26H21N3S

(40753) C 7663 H 519 N 1031 S 787 Found C 7656H 511 N 1026 S 780


2O to give VII


6 300MHz) 120575 (ppm) 671 (s 1H



26H14Cl2N6(48133)



3) 311 (s 3H N-CH

3)




25H18N8O

(44646) C 6725 H 406 N 2510 O 358 Found C6754 H 412 N 2523 O 369


6 300MHz) 120575 (ppm) 131 (t 3H


2) 562 (s 2H


2O exchangeable)



C29H23N5O2(47353) C 7356 H 490 N 1479 O 676

Found C 7348 H 464 N 1463 O 670


2O



6





1906 O 311 Found C 6098 H 341 Cl 1395 N 1943O 327


6 300MHz) 120575 (ppm) 242

(s 3H CH3) 311 (s 3H N-CH


2


2O




25H22N10O (47851) C 6275

H 463 N 2927 O 334 Found C 6264 H 447 N2902 O 309


6 300MHz)


2


2O


2) 2310 (CequivN) 1690 (C=O)


27H21N7O (45950) C 7057 H

461 N 2134 O 348 Found C 7065 H 469 N 2107O 341
























to controlSLM STZ


[Ia] 174a 333a

[Ib] 109a NA[Ic] 18a 353a


[IVg] 13a 112a







1094311617

9699

3619 3938

100

0

20

40

60

80

100

120

140









5 Conclusion





NAr

NH2

CNPh

Ph Ph

X

Anti AntiH H

Ar = CH2PhX = Ph

(Cl)2Ph (Cl)2Ph

Ia Ib Ic Id Ie

(a)

N

N

N

Ph

Ph

Cl

CH3

Anti

IVg

(b)

NN

NPh

PhCH3

HS

CH2PhVIf

(c)

N

Ar

CN

CN CNCN

Ph

Ph


NHN=CHRR998400

COOEt

VIIa VIIb VIIf

R998400= CN

(d)

N NN

NH2

CNPh

Ph NHN=

Y

Y = NH2 OH

CH2Ph

VIIIa VIIIf

(e)





References






















































C24H20ClN5O (42990) C 6705 H 469 Cl 825 N 1629

O 372 Found C 6742 H 508 Cl 857 N 1665 O402





6 300MHz) 120575 (ppm) 49ndash52



2-H) 13C NMR

(DMSO-1198896) 12057511745 11869 12621 12747 1284 12974


2) 3210 (NH)


Found C 6495 H 420 Cl 1623 N 1604


6


3)


H C6-H and NH D


2-H) IR



23H21N7O (41146) C 6714

H 514 N 2383 O 389 Found C 6752 H 548 N 2415O 452


6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 49ndash52


2)




26H23N5(40549) C 7701 H 572

N 1727 Found C 7738 H 605 N 1762


6





(cmminus1) 3420 3350 (NH2) 3240 (NH) 1700 (C=O) 1605


30H27N7O (50158) C 7184 H

543 N 1955 O 319 Found C 7220 H 581 N 1992 O355


6 300MHz) 120575 (ppm) 225 (s 3H




3440 3360 (NH2) 3250 (NH) 1610 (C=C) 1560 (C=N) MS


25H19Cl2N5(46036) C 6522 H

416 Cl 1540 N 1521 Found C 6557 H 452 Cl 1578N 1556


6






120592 (cmminus1) 3430 3360 (NH2) 3250 (NH) 1705 (C=O) 1600


24H23N7O (42549) C 6775 H

545 N 2304 O 376 Found C 6812 H 576 N 2337O 411




H) 902 (s 1H C2-H) 1171 (s 1H NH D

2O exchangeable)


24H15Cl2N3S (44704) C 6429 H



6 300MHz) 120575

(ppm) 244 (s 3H CH3) 313 (s 3H N-CH

3) 72ndash78 (m


2-H) 1210 (s 1H NH



23H19N5OS




6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 578


2O


26H21N3S

(40753) C 7663 H 519 N 1031 S 787 Found C 7656H 511 N 1026 S 780


2O to give VII


6 300MHz) 120575 (ppm) 671 (s 1H



26H14Cl2N6(48133)



3) 311 (s 3H N-CH

3)




25H18N8O

(44646) C 6725 H 406 N 2510 O 358 Found C6754 H 412 N 2523 O 369


6 300MHz) 120575 (ppm) 131 (t 3H


2) 562 (s 2H


2O exchangeable)



C29H23N5O2(47353) C 7356 H 490 N 1479 O 676

Found C 7348 H 464 N 1463 O 670


2O



6





1906 O 311 Found C 6098 H 341 Cl 1395 N 1943O 327


6 300MHz) 120575 (ppm) 242

(s 3H CH3) 311 (s 3H N-CH


2


2O




25H22N10O (47851) C 6275

H 463 N 2927 O 334 Found C 6264 H 447 N2902 O 309


6 300MHz)


2


2O


2) 2310 (CequivN) 1690 (C=O)


27H21N7O (45950) C 7057 H

461 N 2134 O 348 Found C 7065 H 469 N 2107O 341
























to controlSLM STZ


[Ia] 174a 333a

[Ib] 109a NA[Ic] 18a 353a


[IVg] 13a 112a







1094311617

9699

3619 3938

100

0

20

40

60

80

100

120

140









5 Conclusion





NAr

NH2

CNPh

Ph Ph

X

Anti AntiH H

Ar = CH2PhX = Ph

(Cl)2Ph (Cl)2Ph

Ia Ib Ic Id Ie

(a)

N

N

N

Ph

Ph

Cl

CH3

Anti

IVg

(b)

NN

NPh

PhCH3

HS

CH2PhVIf

(c)

N

Ar

CN

CN CNCN

Ph

Ph


NHN=CHRR998400

COOEt

VIIa VIIb VIIf

R998400= CN

(d)

N NN

NH2

CNPh

Ph NHN=

Y

Y = NH2 OH

CH2Ph

VIIIa VIIIf

(e)





References
























































6 300MHz) 120575 (ppm) 229 (s 3H CH

3) 578


2O


26H21N3S

(40753) C 7663 H 519 N 1031 S 787 Found C 7656H 511 N 1026 S 780


2O to give VII


6 300MHz) 120575 (ppm) 671 (s 1H



26H14Cl2N6(48133)



3) 311 (s 3H N-CH

3)




25H18N8O

(44646) C 6725 H 406 N 2510 O 358 Found C6754 H 412 N 2523 O 369


6 300MHz) 120575 (ppm) 131 (t 3H


2) 562 (s 2H


2O exchangeable)



C29H23N5O2(47353) C 7356 H 490 N 1479 O 676

Found C 7348 H 464 N 1463 O 670


2O



6





1906 O 311 Found C 6098 H 341 Cl 1395 N 1943O 327


6 300MHz) 120575 (ppm) 242

(s 3H CH3) 311 (s 3H N-CH


2


2O




25H22N10O (47851) C 6275

H 463 N 2927 O 334 Found C 6264 H 447 N2902 O 309


6 300MHz)


2


2O


2) 2310 (CequivN) 1690 (C=O)


27H21N7O (45950) C 7057 H

461 N 2134 O 348 Found C 7065 H 469 N 2107O 341
























to controlSLM STZ


[Ia] 174a 333a

[Ib] 109a NA[Ic] 18a 353a


[IVg] 13a 112a







1094311617

9699

3619 3938

100

0

20

40

60

80

100

120

140









5 Conclusion





NAr

NH2

CNPh

Ph Ph

X

Anti AntiH H

Ar = CH2PhX = Ph

(Cl)2Ph (Cl)2Ph

Ia Ib Ic Id Ie

(a)

N

N

N

Ph

Ph

Cl

CH3

Anti

IVg

(b)

NN

NPh

PhCH3

HS

CH2PhVIf

(c)

N

Ar

CN

CN CNCN

Ph

Ph


NHN=CHRR998400

COOEt

VIIa VIIb VIIf

R998400= CN

(d)

N NN

NH2

CNPh

Ph NHN=

Y

Y = NH2 OH

CH2Ph

VIIIa VIIIf

(e)





References










































































to controlSLM STZ


[Ia] 174a 333a

[Ib] 109a NA[Ic] 18a 353a


[IVg] 13a 112a







1094311617

9699

3619 3938

100

0

20

40

60

80

100

120

140









5 Conclusion





NAr

NH2

CNPh

Ph Ph

X

Anti AntiH H

Ar = CH2PhX = Ph

(Cl)2Ph (Cl)2Ph

Ia Ib Ic Id Ie

(a)

N

N

N

Ph

Ph

Cl

CH3

Anti

IVg

(b)

NN

NPh

PhCH3

HS

CH2PhVIf

(c)

N

Ar

CN

CN CNCN

Ph

Ph


NHN=CHRR998400

COOEt

VIIa VIIb VIIf

R998400= CN

(d)

N NN

NH2

CNPh

Ph NHN=

Y

Y = NH2 OH

CH2Ph

VIIIa VIIIf

(e)





References
























































NAr

NH2

CNPh

Ph Ph

X

Anti AntiH H

Ar = CH2PhX = Ph

(Cl)2Ph (Cl)2Ph

Ia Ib Ic Id Ie

(a)

N

N

N

Ph

Ph

Cl

CH3

Anti

IVg

(b)

NN

NPh

PhCH3

HS

CH2PhVIf

(c)

N

Ar

CN

CN CNCN

Ph

Ph


NHN=CHRR998400

COOEt

VIIa VIIb VIIf

R998400= CN

(d)

N NN

NH2

CNPh

Ph NHN=

Y

Y = NH2 OH

CH2Ph

VIIIa VIIIf

(e)





References





















































Synthesis and Evaluation of Novel Pyrroles and ......Synthesis and Evaluation of Novel Pyrroles and...

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Transcript of Synthesis and Evaluation of Novel Pyrroles and ......Synthesis and Evaluation of Novel Pyrroles and...