Design, synthesis, and biological evaluation of substituted-N-(thieno[2,3-b]pyridin-3-yl)-guanidines, N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidines, and N-(1H-indol-3-yl)-guanidines

Bioorganic & Medicinal Chemistry 15 (2007) 3248–3265

Design, synthesis, and biological evaluation of

substituted-N-(thieno[2,3-b]pyridin-3-yl)-guanidines,

N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidines,

and N-(1H-indol-3-yl)-guanidines^q

Rajesh H. Bahekar, Mukul R. Jain,^*Ashish Goel, Dipam N. Patel, Vijay M. Prajapati,

Arun A. Gupta, Pradip A. Jadav and Pankaj R. Patel

Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavala N.H. 8A, Moraiya, Ahmedabad 382210, India

Received 28 December 2006; revised 13 February 2007; accepted 14 February 2007

Available online 16 February 2007

Abstract—Sulfonylureas stimulate insulin secretion independent of the blood glucose concentration and therefore cause hypoglyce-

mia in type 2 diabetic patients. Over the last years, a number of aryl-imidazoline derivatives have been identiﬁed that stimulate

insulin secretion in a glucose-dependent manner. In the present study, we have developed three series of substituted N-(thie-

no[2,3-b]pyridin-3-yl)-guanidine (2a–l), N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3a–l), and N-(1H-indol-3-yl)-guanidine (4a–l)

as new class of antidiabetic agents. In vitro glucose-dependent insulinotropic activity of test compounds 2a–l, 3a–l, and 4a–l was

evaluated using RIN5F (Rat Insulinoma cell) based assay. All the test compounds showed concentration-dependent insulin secre-

tion, only in presence of glucose load (16.7 mmol). Some of the test compounds (2c, 3c, and 4c) from each series were found to be

equipotent to BL 11282 (standard aryl-imidazoline), which indicated that the guanidine group acts as a bioisostere of imidazoline

ring system.

1. Introduction

therapeutic option for the safe and eﬀective treatment

of the type 2 diabetes.

The incidence of type 2 diabetes is increasing worldwide

due to changing lifestyle and prevalence of obesity and

the metabolic syndrome.¹Clinically type 2 diabetes is

characterized by elevated blood glucose level, caused

by decreased insulin secretion from the pancreas, insulin

resistance or both.²In diabetic patients it is important to

control the elevated blood glucose level, both for the

prevention and mitigation of diabetic complications.^3,4

Today many therapeutic options are available to treat

hyperglycemia.⁵However, most of the insulin secreta-

gogues which are commonly in practice exhibit serious

side-eﬀects such as hypoglycemia.⁶Therefore, agents

that do not stimulate basal insulin secretion but aug-

ment glucose-induced insulin secretion hold a better

In this regard, endogenous incretin hormone such as

glucagon-like peptide (GLP-1) and its synthetic analog

Exendin-4 appears to be very promising for the treat-

ment and management of type 2 diabetes.⁷However,

the GLP-1 agonists, which are available in the market

or under clinical development, are peptide-based drugs

and therefore mainly administered by the parenteral

route of administration. Thus, the patient incompliance

is going to be the major problem with such GLP-1

mimetics, until an oral drug or a non-invasive delivery

system is made available.

In the last two decades, several aryl-imidazolines are

reported to be potent stimulators of insulin secretion.^8,9

Aryl-imidazolines are known to bind with a putative I₃

receptor (a 3rd imidazoline binding site distinct from

two imidazoline receptors I₁and I₂) in pancreatic b-cells

and thereby regulate insulin secretion.^10–12Such aryl-

imidazolines do not bind to a-adrenoceptors or K_ATP

channels and exhibit only glucose-dependent insulin

Keywords: Guanidine; Pyrrolo[2,3-b]pyridine; Thieno[2,3-b]pyridine;

Indole; Type 2 diabetes; Insulinotropic; Antidiabetic.

q

ZRC communication No. 189.

Corresponding author. Tel.: +91 2717 250801; fax: +91 2717

250606; e-mail: mukul.jain@zyduscadila.com

*

doi:10.1016/j.bmc.2007.02.029

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

3249

NH₂

HN

N

HN

S

NH

R₂

NH

R₂

NH

R₂

R₁

Cl

R₁

N

H

N

H

N

H

2a-l

BL11282 (1)

3a-l

4a-l

2,3&4a: R₁=H & R₂=H;

2,3&4c: R₁=Cl & R₂=CH₃;

2,3&4e: R₁=H & R₂=C₆H₅;

2,3&4b: R₁=Cl & R₂=H;

2,3&4d: R₁=H & R₂=CH₃;

2,3&4f: R₁=Cl & R₂=C₆H₅;

2,3&4g: R₁=H & R₂=Cyclohex;

2,3&4i: R₁=H & R₂=C₂H₅;

2,3&4h: R₁=Cl & R₂=Cyclohex;

2,3&4j: R₁=Cl & R₂=C₂H₅;

2,3&4k: R₁=H & R₂=CH₂-C₆H₅;

2,3&4l: R₁=Cl & R₂=CH₂-C₆H₅;

Figure 1. General structures of arylimidazoline (BL 11282) and hetero-aryl guanidine derivatives.

secretion.¹³Thus, aryl-imidazolines have developed sub-

stantial interest and have potential to become therapeu-

tic agents for the treatment of type 2 diabetes.^14,15

In this reaction, metal salt HgCl₂was used to increase

the reactivity of bis-Boc-thiourea, via its complex for-

mation with the sulfur atom. When the same reaction

was attempted without using a metal salt, instead of

guanylated product, it led to the formation of unsym-

metrical thiourea, indicating that the addition of metal

salt is crucial for the facile reaction.³⁰The bis-Boc-thio-

urea was used as a guanylating agent because the strong

electron-withdrawing Boc-groups, present on bis-Boc-

thiourea, increase the reactivity of thiourea and thereby

facilitate the guanylation reaction, under the mild reac-

tion condition.³¹The bis-Boc-thiourea was prepared

from thiourea and di-tert-butyl-dicarbonate, in tetrahy-

drofuran (THF), using the literature procedure.³¹Final-

ly, the bis-Boc-protected hetero-aryl guanidines (6, 10,

and 14) upon deprotection with triﬂuoroacetic acid

(TFA) cleavage mixture lead to the formation of title

compounds 2–4.

One such novel imidazoline compound is BL 11282 (1;

Fig. 1).¹⁶Interestingly, BL 11282 does not block K_ATP

channel and has shown glucose-dependent insulin secre-

tion (in vitro), a pharmacological proﬁle similar to GLP-1

agonist.^17,18Knowing the in vitro glucose-dependent

insulin secretion potential of BL 11282, in the present

investigation, three series of hetero-aryl guanidine

derivatives, mainly substituted N-(thieno[2,3-b]pyridin-

3-yl)-guanidines (2a–l), N-(1H-pyrrolo[2,3-b]pyridin-3-

yl)-guanidines (3a–l), and N-(1H-indol-3-yl)-guanidines

(4a–l), were designed as analog of BL 11282 and their

in vitro glucose-dependent insulinotropic activity was

evaluated using RIN5F (Rat insulinoma) cell-based

assay.

The starting material 2,5-disubstituted-thieno[2,3-b]pyri-

din-3-ylamine (5) was prepared from 2-mercapto-5-

substituted-nicotinonitrile and diﬀerent alkyl halides.³²

Intermediate compound 2,5-disubstituted-3-amino-7-

azaindole (9) was prepared starting from 2,5-disubsti-

tuted-7-azaindole (7). In this reaction, nitrosation of

the compound 7 was carried out by treatment with

sodium nitrite (NaNO₂) and 2,5-disubstituted-3-nitro-

so-7-azaindole (8) was obtained, which was subsequently

reduced to compound 9, by treatment with sodium dithi-

onite (Na₂S₂O₄) in sodium hydroxide (NaOH) and etha-

nol.³³Furthermore, compound 7 was prepared starting

from 5-substituted-3-methyl-pyridin-2-ylamine, by the

directed ortho-lithiation reaction.³⁴The 2,5-disubsti-

tuted-3-amino-indole (13) was prepared starting from

2,5-disubstituted-indole (11). In this reaction, nitration

2. Chemistry

Synthesis of hetero-aryl guanidines (2–4) was carried

out, using appropriate synthetic routes (Schemes 1–3).

Initially, attempts were made to prepare hetero-aryl

guanidines using commercially available guanylating re-

agents such as cyanamide,¹⁹O-methylisourea hydrogen

sulfate,²⁰2-ethyl-2-thiopseudo hydrobromide,²¹3,5-

dimethylpyrazole-1-carboxamidine nitrate,²²and 1H-

pyrazole-1-carboxamidine hydrochloride.^23,24However,

none of the guanylating agents showed suﬃcient reactiv-

ity toward heteroaryl amines (compounds 5, 9, and 13).

Therefore, synthesis of compounds 2–4 was carried out

by condensation of respective heteroaryl amines with

bis-Boc-thiourea, using mercuric chloride (HgCl₂).^25–29

NBoc

NH

NH₂

HN

S

HN

S

R₁

NHBoc

R₂

NH₂

R₂

R₁

a

b

R₂

S

N

6a-l

2a-l

5a-l

Scheme 1. Reagents and conditions: (a) bis-Boc-thiourea, DMF, HgCl₂, TEA, 48 h stirring; (b) TFA:DCM (1:1, v/v), 1 h stirring at rt.

3250

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

NO

NH₂

R₁

a

R₂

b

N

R₂

N

H

N

H

7a-l

8a-l

9a-l

c

NH₂

NH-Boc

N-Boc

HN

NH

R₁

d

R₂

N

H

N

H

3a-l

10a-l

Scheme 2. Reagents and conditions: (a) NaNO₂, acetic acid, 30 min stirring at rt; (b) Na₂S₂O₄, NaOH, ethanol, 30 min reﬂux; (c) bis-Boc-thiourea,

HgCl₂, TEA, DMF, 3 days stirring; (d) DCM:TFA (1:1, v/v), 1 h stirring at rt.

NO₂

NH₂

R₁

a

R₂

b

N

R₂

H

N

H

11a-l

12a-l

13a-l

c

NH₂

NH

NH-Boc

HN

N-Boc

R₁

d

R₂

N

H

4a-l

14a-l

Scheme 3. Reagents and conditions: (a) AgNO₃, benzoyl chloride, ACN, 0 ꢁC stirring for 45 min; (b) Pd/C (10%), H₂(g); 50 psi, ethanol, 3 h; (c) bis-

Boc-thiourea, HgCl₂, TEA, DMF, 3 day stirring; (d) DCM:TFA (1:1, v/v), 1 h stirring at rt.

of the compound 11 was carried out by treatment with

benzoyl nitrate and 2,5-disubstituted-3-nitro-indole (12)

was obtained, which was subsequently reduced to com-

pound 13, by treatment with Palladium charcoal.³⁵The

starting material 2,5-disubstituted-indoles (11) was pre-

pared from aniline or p-chloro aniline, according to the

Fischer indole synthesis.^36–38

The ¹H NMR spectra of compounds 6, 10, and 14

showed chemical shift (d ppm) in the range of ꢀ1.3 (s,

9H) and 1.54 (s, 9H), due to bis-Boc groups. Com-

pounds 2–4 showed disappearance of signals due to

bis-Boc group and appearance of additional signals in

the range of ꢀ6.6 (br s, 2H) and 6.9 (s, 1H), due to

–NH₂and NH groups of free guanidine. Compounds

5, 9, and 13 showed chemical shift in the range of

ꢀ8.78 (br s, 2H), due to free amino group. The

In general, compounds 2a–l, 3a–l, and 4a–l were pre-

pared in good yield, under the mild reaction condition,

and the overall percentage yield was found to be in the

range of 60–70%. The Infrared (IR) spectra of com-

pounds 2–4 showed peaks in the region of ꢀ3400 (N–

H stretching) and 1600 (C–N bending), due to free

NH₂groups of guanidine. Compounds 6, 10, and 14

showed absorption peaks in the region of ꢀ2850 (C–H

stretching, aromatic), 1710 (C@O stretching), 1375

(CAH stretching, CH₃), and 1050 (CAO stretching),

mainly due to bis-Boc groups. Compounds 5, 9, and

13 showed peaks in the region of ꢀ3400 (NAH stretch-

ing) and 1610 (NAH bending), due to free amino group,

and compounds 8 and 12 showed peak in the region of

ꢀ1540 (N@O stretching), due to nitroso group.

1

corresponding IR, H NMR, ESI-MS, and CHN data

are presented in Section 5.2. Synthesis of BL 11282

was carried out by literature procedure³⁷. The Exen-

din-4 used in the in vitro assay was prepared in-house

by Fmoc-based solid-phase peptide synthesis approach

(peptide content 94%).

3. Results and discussion

3.1. In vitro insulin secretion assay results

In vitro glucose-dependent or -independent insulin

secretion properties of test compounds 2a–l, 3a–l, and

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

3251

4a–l were determined using a RIN5F cell assay.^39,40

Insulin secretion, both in presence and absence of

16.7 mM glucose was measured for Exendin-4, at 0.1,

1, and 10 nM and compounds 1, 2a–l, 3a–l, and 4a–l,

at 0.1, 1, and 10 lM concentrations. At 0 mM glucose

load, incubation of test and standard compounds with

RIN5F cells, showed only basal insulin secretion.

However, in presence of 16.7 mM glucose load, signiﬁ-

cant concentration-dependent insulin secretions were

observed, both for standard and test compounds. Fur-

ther to validate the in vitro assay, RIN5F cells were

incubated with Tolbutamide (sulfonylurea), both in

presence or absence of glucose load (0 and 16.7 mM),

at 0.1 and 1 lM concentrations. Tolbutamide showed

signiﬁcant insulin secretion both in presence or absence

of glucose load (Tables 1–3).

compounds 2c, 3c, and 4c were found to be most potent

compounds and among these three most potent com-

pounds, compound N-(2-methyl, 5-chloro-1H-indol-

3-yl)-guanidine (4c) was found to be equipotent to

BL 11282.

Overall, substitution of R₁with hydrogen atom drasti-

cally reduces potency of the test compound, in all the

three series and as a result, compounds 2a, 2g, 2i, 2k,

3a, 3g, 3i, 3k, 4a, 4g, 4i, and 4k were found to be least

potent compounds, among the representative com-

pounds from each series. Substitution of R₂with hydro-

gen (2b, 3b, and 4b), cyclohexyl (2h, 3h, and 4h) or

benzyl group (2l, 3l, and 4l) signiﬁcantly reduces activ-

ity. Among all the three series, compounds 2a, 2b,

2g–i, 2k, 2l, 3a, 3b, 3g–i, 3k, 3l, 4a, 4b, 4g–i, 4k, and

4l were found to be the least potent compounds. Com-

pounds with chloro-substitution at R₁position and

CH₃group at R₂position were found to be the most

potent compounds among all the three series, indicating

that small hydrophobic (alkyl group) substitution at R₂

position is favorable. Substitution of R₁with H and R₂

with methyl or phenyl groups (2d, 2e, 3d, 3e, 4d, and 4e)

showed moderate insulin secretion.

In thieno[2,3-b]pyridin-3-yl-guanidine series (2a–l), com-

pounds 2c, 2f, and 2j showed highest insulin secretion,

compounds 2a, 2b, 2g–i, 2k and 2l showed minimal insu-

lin secretion, while compounds 2d and 2e showed mod-

erate insulin secretion (Table 1). Among compounds 2c,

2f, and 2j, compound 2c showed highest insulin secre-

tion. In 1H-pyrrolo[2,3-b]pyridin-3-yl-guanidine series

(3a–l), compounds 3c, 3f, and 3j showed highest insulin

secretion, compounds 3a, 3b, 3g, 3i, 3k, and 3l showed

minimal insulin secretion, while compounds 3d and 3e

showed moderate insulin secretion (Table 2). In 1H-in-

dol-3-yl-guanidine series (4a–l), compounds 4c, 4f, and

4j showed highest insulin secretion, compound 4a, 4b,

4g, 4i, 4k, and 4l showed minimal insulin secretion,

while compounds 4d and 4e showed moderate insulin

secretion (Table 3). Among the compounds 4c, 4f, and

4j, compound 4c showed highest insulin secretion. In

general, insulin secretion proﬁle of compounds 2c, 2f,

2j, 3c, 3f, and 3j was found to be comparable with that

of BL 11282, while compounds 4c, 4f, and 4j showed BL

11282 like insulin secretion, in vitro. Furthermore,

among these nine compounds from three diﬀerent series,

4. Conclusions

Most of the clinically available sulfonylurea class of

insulin secretagogues showed hypoglycemia because

they cause glucose-independent insulin secretion.

Therefore, for a safe and eﬀective treatment of type 2

diabetes, it is essential to develop insulin-secreting

agents, which show glucose-dependent insulin secretion

only. In the recent years, many essential features of the

aryl-imidazolines have been reviewed and as a result,

imidazolines have emerged as promising therapeutic

agent for the treatment of type

Aryl-imidazoline derivative, BL 11282 (1), showed

2

diabetes.^41,42

Table 1. In vitro glucose-dependent insulin secretion activity of compounds 2a–l

Compound

R₁

R₂

Concn (lM)

Insulin secretion (pg/lg/h)^a

0.66

10 0.62

Control 1 (0 mM glucose)

6

Control 2 (16.7 mM glucose)

Tolbutamide (0 mM glucose)

Tolbutamide (16.7 mM glucose)

BL 11282 (1)

0.1/1

19.6 0.61 / 26.0 0.52

19.9 0.56 / 27.1 0.59

0.1/1/10

16.4 0.61 / 20.6 0.52 / 36.4 0.36

19.2 0.56 / 22.5 0.59 / 40.5 0.61

10.1 0.52 / 12.1 0.16 / 14.1 0.36

10.2 0.26 / 12.2 0.33 / 14.2 0.51

15.1 0.16 / 18.1 0.26 / 32.1 0.22

11.1 0.23 / 15.1 0.34 / 29.1 0.27

11.1 0.15 / 15.1 0.55 / 27.9 0.44

14.9 0.19 / 17.8 0.46 / 31.6 0.56

10.1 0.31 / 12.1 0.54 / 14.1 0.26

10.5 0.26 / 12.5 0.46 / 14.5 0.28

10.6 0.25 / 12.6 0.22 / 14.6 0.28

14.8 0.52 / 17.8 0.51 / 31.5 0.59

10.5 0.46 / 12.5 0.26 / 14.5 0.16

10.6 0.26 / 12.6 0.46 / 14.5 0.18

EX-4 peptide (nM)

2a

2b

2c

2d

2e

2f

H

Cl

H

CH₃

C₆H₅

H

Cl

H

2g

2h

2i

Cyclohex

C₂H₅

Cl

H

2j

Cl

H

C₂H₅

CH₂–C₆H₅

2k

2l

Cl

^aIn vitro glucose-dependent (16.7-mM glucose load) insulin secretion with various concentrations of test and standard compounds was measured

using rat insulinoma (RIN5F) cells. The total insulin content (pg) was divided with total protein (lg) to normalize diﬀerence in cell density between

wells. n = 3, values represent means SD.

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R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

Table 2. In vitro glucose-dependent insulin secretion activity of compounds 3a–l

Compound

R₁

R₂

Concn (lM)

Insulin secretion (pg/lg/h)^a

0.66

10 0.62

Control 1 (0 mM glucose)

6

Control 2 (16.7 mM glucose)

Tolbutamide (0 mM glucose)

Tolbutamide (16.7 mM glucose)

BL 11282 (1)

0.1/1

19.6 0.61 / 26.0 0.52

19.9 0.56 / 27.1 0.59

0.1/1/10

16.4 0.61 / 20.6 0.52 / 36.4 0.36

19.2 0.56 / 22.5 0.59 / 40.5 0.61

10.5 0.16 / 12.5 0.26 / 14.5 0.22

10.5 0.42 / 12.5 0.39 / 14.6 0.60

15.5 0.15 / 19.1 0.19 / 35.1 0.20

11.5 0.42 / 15.5 0.39 / 29.5 0.60

11.5 0.31 / 15.5 0.36 / 28.5 0.22

15.2 0.61 / 18.1 0.33 / 33.1 0.12

10.2 0.17 / 12.5 0.45 / 14.5 0.19

10.8 0.60 / 13.1 0.41 / 15.1 0.19

10.8 0.61 / 13.0 0.16 / 15.0 0.32

15.1 0.60 / 18.1 0.36 / 33.1 0.39

10.9 0.66 / 12.6 0.36 / 14.9 0.14

10.9 0.16 / 12.9 0.26 / 15.0 0.46

EX-4 peptide (nM)

3a

3b

3c

3d

3e

3f

H

Cl

H

CH₃

C₆H₅

H

Cl

H

3g

3h

3i

Cyclohex

C₂H₅

Cl

H

3j

Cl

H

C₂H₅

CH₂–C₆H₅

3k

3l

Cl

^aIn vitro glucose-dependent (16.7-mM glucose load) insulin secretion with various concentrations of test and standard compounds was measured

using rat insulinoma (RIN5F) cells. The total insulin content (pg) was divided with total protein (lg) to normalize diﬀerence in cell density between

wells. n = 3, values represent means SD.

Table 3. In vitro glucose-dependent insulin secretion activity of compounds 4a–l

Compound

R₁

R₂

Concn (lM)

Insulin secretion (pg/lg/h)^a

0.66

10 0.62

Control 1 (0 mM glucose)

6

Control 2 (16.7 mM glucose)

Tolbutamide (0 mM glucose)

Tolbutamide (16.7 mM glucose)

BL 11282 (1)

0.1/1

19.6 0.61 / 26.0 0.52

19.9 0.56 / 27.1 0.59

0.1/1/10

16.4 0.61 / 20.6 0.52 / 36.4 0.36

19.2 0.56 / 22.5 0.59 / 40.5 0.61

10.9 0.36 / 13.0 0.39 / 15.0 0.30

11.1 0.26 / 13.2 0.22 / 15.5 0.29

16.1 0.43 / 20.1 0.45 / 36.0 0.31

12.1 0.36 / 16.1 0.35 / 30.1 0.46

12.1 0.26 / 16.1 0.22 / 29.1 0.21

15.9 0.19 / 19.5 0.44 / 35.5 0.45

10.9 0.27 / 13.1 0.38 / 15.1 0.43

11.2 0.33 / 13.2 0.31 / 15.9 0.34

11.1 0.44 / 13.4 0.49 / 16.1 0.56

15.8 0.36 / 19.5 0.26 / 35.2 0.46

11.1 0.38 / 13.1 0.22 / 15.1 0.29

11.2 0.16 / 13.2 0.19 / 15.4 0.55

EX-4 peptide (nM)

4a

4b

4c

4d

4e

4f

H

Cl

H

CH₃

C₆H₅

H

Cl

H

4g

4h

4i

Cyclohex

C₂H₅

Cl

H

4j

Cl

H

C₂H₅

CH₂–C₆H₅

4k

4l

Cl

^aIn vitro glucose-dependent (16.7-mM glucose load) insulin secretion with various concentrations of test and standard compounds was measured

using rat insulinoma (RIN5F) cells. The total insulin content (pg) was divided with total protein (lg) to normalize diﬀerence in cell density between

wells. n = 3, values represent means SD.

glucose-dependent insulin secretion from the pancreatic

b-cells, without modulating the K_ATPchannels.¹⁶Re-

sults of the present study indicated that all the three

series of hetero-aryl guanidines, which were designed

as analog of BL 11282, showed glucose- and concentra-

tion-dependent insulin secretion. Among all the 36 new

compounds tested, compound N-(2-methyl, 5-chloro-

1H-indol-3-yl)-guanidine (4c; R₁= Cl and R₂= CH₃)

was found to be equipotent to BL11282. Overall, the

in vitro proﬁle of the test compounds appears like

the BL11282, indicated that guanidine group acts as

a bioisostere of imidazoline ring system. Combined

evaluation of our in vitro results suggests that this

new class of compounds could be useful for the preven-

tion and mitigation of type2 diabetes. The in vivo

pharmacological and detailed mechanistic studies to

investigate the exact mode of action of our test com-

pounds are in progress and will be published elsewhere.

5. Experimental

5.1. Chemistry

Melting points were determined in open glass capillaries,

using a scientiﬁc melting point apparatus and are uncor-

rected. IR spectra were recorded on a Shimadzu FT

IR8300 spectrophotometer (V_maxin cm^À1, using KBr

pellets). The ¹H NMR spectra were recorded on a Bruc-

ker Avanc-300 spectrometer (300 MHz). The chemical

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

3253

shifts (d) are reported in parts per million (ppm) relative

to TMS, either in CDCl₃or DMSO-d₆solution. Signal

multiplicities are represented by s (singlet), d (doublet),

t (triplet), q (quartet), br s (broad singlet), and m (mul-

tiplet). Mass spectra (ESI MS) were obtained on Shima-

dzu LCMS 2010-A spectrometer. Elemental analyses

were carried out, using a Perkin-Elmer 2400 CHN ana-

lyzer, and values within limit of 0.4% of the theoretical

values were taken into consideration. Purity of synthe-

sized compounds was checked by precoated TLC plates

(E. Merck Kieselgel 60 F₂₅₄) and the spots were visual-

ized by iodine vapors. The chromatographic puriﬁcation

was carried out on silica gel (100–200 mesh size). All the

chemicals used for the synthesis were purchased from

Aldrich Company Limited, Dorset (UK).

5.2.1.4. Bis-Boc-N-(2-methyl-thieno[2,3-b]pyridin-3-

yl)-guanidine (6d). Yield: 63%; white solid; mp 147–

149 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1375

1

1050 cm^À1. H NMR (300 MHz, CDCl₃): d 1.43 (s, 9H,

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

COANHA), 2.41 (s, 3H, –CH₃), 7.21–7.22 (d, 1H, pyri-

dine ring), 7.31–7.32 (dd, 1H, pyridine ring), 8.51–8.52

(d, 1H, pyridine ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H,

–NH). MS (ESI) m/z 407 [M+1]+; analysis for

C₁₉H₂₆N₄O₄S (406), calcd: C, 56.14; H, 6.45; N, 11.96.

Found: C, 56.11; H, 6.43; N 11.93.

5.2.1.5. Bis-Boc-N-(2-phenyl-thieno[2,3-b]pyridin-3-yl)-

guanidine (6e). Yield: 63%; white solid; mp 143–145 ꢁC; IR

(KBr): 3400, 2850, 1710, 1610, 1050 cm^À^{1. 1}H NMR

(300 MHz, CDCl₃): d 1.43 (s, 9H, (CH₃)₃CAOACOA

N@), 1.56 (s, 9H, (CH₃)₃CAOACOANHA), 7.21–7.22

(d, 1H, pyridine ring), 7.30–7.31 (dd, 1H, pyridine ring),

7.33–7.42(m, 5H, benzenering), 8.51–8.52(d,1H, pyridine

ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H, –NH). MS (ESI) m/z

187.2 [M+1]⁺; analysis for C₂₄H₂₈N₄O₄S (186), calcd: C,

61.52; H, 6.02; N, 11.96. Found: C, 61.50; H, 6.00; N,

11.98.

5.2. Experimental details

5.2.1. General method for the synthesis of N-(2,5-disubsti-

tuted-thieno[2,3-b]pyridin-3-yl)-guanidine (2a–l; Scheme 1).

5.2.1.1. Synthesis of bis-Boc-N-(thieno[2,3-b]pyridin-3-

yl)-guanidine (6a). A mixture ofthieno[2,3-b]pyridin-3-yla-

mine (5a; 0.1 g, 0.666 mmol), bis-Boc-thiourea (0.184 g,

0.666 mmol), HgCl₂(0.179 g, 0.666 mmol) and triethyl-

amine (TEA; 0.25 mL, 1.8 mmol), in dry dimethylform-

amide (DMF; 6 mL) was stirred for 48 h, under nitrogen

atmosphere. The reaction mixture was poured onto

crushed ice and solid product was ﬁltered. The crude

product was puriﬁed by column chromatography,

using a mixture of petroleum ether and ether (8:2) as

an eluent system, fractions were evaporated, and white so-

lid product was isolated. Yield: 61%; white solid; mp

125–127 ꢁC; IR (KBr): 3400, 2850, 1710, 1610,

5.2.1.6. Bis-Boc-N-(5-chloro-2-phenyl-thieno[2,3-b]pyri-

din-3-yl)-guanidine (6f). Yield: 64%; white solid; mp 127–

129 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1050,

1

775 cm^À1. H NMR (300 MHz, CDCl₃): d 1.43 (s, 9H,

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

COANHA), 7.21–7.22 (d, 1H, pyridine ring), 7.31– 7.41

(m, 5H, benzene ring), 8.51–8.52 (d, 1H, pyridine ring),

9.97 (s, 1H, –NH), 11.65 (s, 1H, –NH). MS (ESI) m/z

469 [M+1]⁺, 470 [M+2]⁺; analysis for C₂₄H₂₇ClN₄O₄S

(468), calcd: C, 57.31; H, 5.41; N, 11.14. Found: C,

57.29; H, 5.39; N, 11.12.

1

1050 cm^À1. H NMR (300 MHz, CDCl₃): d 1.43 (s, 9H,

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

COANHA), 6.10 (s, 1H, thiophene ring), 7.21–7.22 (d,

1H, pyridine ring), 7.31–7.32 (dd, 1H, pyridine ring),

8.51–8.52 (d, 1H, pyridine ring), 9.97 (s, 1H, –NH), 11.65

(s, 1H, –NH). MS (ESI) m/z 393.2 [M+1]⁺; analysis for

C₁₈H₂₄N₄O₄S (392), calcd: C, 55.08; H, 6.16; N 14.28.

Found: C, 55.05; H, 6.13; N 14.25.

5.2.1.7. Bis-Boc-N-(2-cyclohexyl-thieno[2,3-b]pyridin-

3-yl)-guanidine (6g). Yield: 66%; white solid; mp 107–

105 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1050,

720 cm^À^{1 1}H NMR (300 MHz, CDCl₃): d 1.29–1.30

.

(m, 6H, –cyclohex), 1.43 (s, 9H, (CH₃)₃CAOA

COAN@), 1.56 (s, 9H, (CH₃)₃CAOACOANHA),

1.58–1.59 (m, 4H, –cyclohex), 2.76–2.77 (m, 1H, –cyclo-

hex), 7.21–7.22 (d, 1H, pyridine ring), 7.31–7.32 (dd, 1H,

pyridine ring), 8.50–8.51 (d, 1H, pyridine ring), 9.97 (s,

1H, –NH), 11.65 (s, 1H, –NH). MS (ESI) m/z 475.2

[M+1]+; analysis for C₂₄H₃₄N₄O₄S (474), calcd: C,

60.73; H, 7.22; N, 11.80. Found: C, 60.70; H, 7.20; N,

11.77.

5.2.1.2. Bis-Boc-N-(5-chloro-thieno[2,3-b]pyridin-3-yl)-

guanidine (6b). Yield: 60%; white solid; mp 129–

131 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1050,

1

775 cm^À1. H NMR (300 MHz, CDCl₃): d 1.43 (s, 9H,

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

COANHA), 7.21–7.22 (d, 1H, pyridine ring), 8.51–8.52

(d, 1H, pyridine ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H,

–NH). MS (ESI) m/z 427.2 [M+1]⁺, 428.2 [M+2]⁺; analy-

sis for C₁₈H₂₃ClN₄O₄S (426), calcd: C, 50.64; H, 5.43; N

13.12. Found: C, 50.63; H, 5.41; N, 13.10.

5.2.1.8. Bis-Boc-N-(5-chloro-2-cyclohexyl-thieno[2,3-

b]pyridin-3-yl)-guanidine (6h). Yield: 61%; white solid;

mp 114–116 ꢁC; IR (KBr): 3400, 2850, 1710, 1610,

1

5.2.1.3. Bis-Boc-N-(5-chloro-2-methyl-thieno[2,3-b]pyri-

din-3-yl)-guanidine (6c). Yield: 65%; white solid; mp

135–137 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1375

1050, 775, 720 cm^À1. H NMR (300 MHz, CDCl₃): d

1.29-1.30 (m, 6H, –cyclohex), 1.43 (s, 9H, (CH₃)₃CA

OACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA COANHA),

1.58–1.59 (m, 4H, –cyclohex), 2.76–2.77 (m, 1H,

–cyclohex), 7.21–7.22 (d, 1H, Pyridine ring), 8.52–

8.53 (d, 1H, pyridine ring), 9.97 (s, 1H, –NH), 11.65

(s, 1H, –NH). MS (ESI) m/z 510.2 [M+1]⁺, 511.2

[M+2]⁺; analysis for C₂₄H₃₃ClN₄O₄S (509), calcd: C,

56.63; H, 6.53; N, 11.01. Found: C, 56.60; H, 6.50;

N, 11.00.

1050, 775 cm^À^{1 1}H NMR (300 MHz, CDCl₃): d 1.43

.

(s, 9H, (CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CA

OACOANHA), 2.41 (s, 3H, –CH₃), 7.2 (d, 1H, pyridine

ring), 8.51–8.52 (d, 1H, pyridine ring), 9.97 (s, 1H, –NH),

11.65 (s, 1H, –NH). MS (ESI) m/z 441 [M+1]⁺, 442

[M+2]⁺; analysis for C₁₉H₂₅ClN₄O₄S (440), calcd: C,

51.75; H, 5.71; N 12.71. Found: C, 51.73; H, 5.70; N, 12.68.

3254

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

5.2.1.9. Bis-Boc-N-(2-ethyl-thieno[2,3-b]pyridin-3-yl)-

guanidine (6i). Yield: 63%; white solid; mp 119–121 ꢁC;

mp 121 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1375

dried. Yield: 60%; white solid; mp 137–139 ꢁC; IR

(KBr): 3430, 2854, 1610 cm^À^{1 1}H NMR (300 MHz,

.

CDCl₃): d 6.10 (s, 1H, thiophene ring), 7.22–7.23 (d,

1H, pyridine ring), 7.33–7.34 (dd, 1H, pyridine ring),

8.55–8.56 (d, 1H, pyridine ring), 9.97 (s, 1H, –NH),

11.65 (s, 1H, –NH). MS (ESI) m/z 193.2 [M+1]⁺; analy-

sis for C₈H₈N₄S (192.2), calcd: C, 58.07; H, 5.65; N,

10.84. Found: C, 58.03; H, 5.61; N, 10.82.

1050 cm^À^{1 1}H NMR (300 MHz, CDCl₃): d 1.24 (t,

.

3H, –CH₂CH₃), 1.43 (s, 9H, (CH₃)₃CAOACOAN@),

1.56 (s, 9H, (CH₃)₃CAOACOANHA), 2.59–2.60 (m,

2H, –CH₂CH₃), 7.20–7.21 (d, 1H, pyridine ring), 7.31–

7.32 (dd, 1H, pyridine ring), 8.53–8.54 (d, 1H, pyridine

ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H, –NH). MS

(ESI) m/z 421 [M+1]⁺; analysis for C₂₀H₂₈N₄O₄S

(420.1), calcd: C, 57.12; H, 6.71; N, 13.32. Found: C,

57.09 H, 6.69; N, 13.29.

5.2.1.14. N-(5-Chloro-thieno[2,3-b]pyridin-3-yl)-guani-

dine (2b). Yield: 63%; white solid; mp 140–142 ꢁC; IR

(KBr): 3430, 2854, 1610, 774 cm^À1

.

¹H NMR

(300 MHz, CDCl₃): d 7.20–7.21 (d, 1H, pyridine ring),

8.50–8.51 (d, 1H, pyridine ring), 9.97 (s, 1H, –NH),

11.65 (s, 1H, –NH). MS (ESI) m/z 227.4 [M+1]⁺, 228.4

[M+2]⁺; analysis for C₈H₇ClN₄S (226.2), calcd: C,

42.39; H, 3.11; N, 24.72. Found: C, 42.36; H, 3.08; N,

24.69.

5.2.1.10. Bis-Boc-N-(5-chloro-2-ethyl-thieno[2,3-b]pyri-

din-3-yl)-guanidine (6j). Yield: 66%; white solid; mp 113–

115 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1375 1050,

1

775 cm^À1. H NMR (300 MHz, CDCl₃): d 1.24–1.25 (t,

3H, –CH₂CH₃), 1.43 (s, 9H, (CH₃)₃CAOACOAN@),

1.56 (s, 9H, (CH₃)₃CAOACOANHA), 2.59–2.60 (m,

2H, –CH₂CH₃), 7.21–7.22 (d, 1H, pyridine ring), 8.51–

8.53 (d, 1H, pyridine ring), 9.97 (s, 1H, –NH), 11.65 (s,

1H, –NH). MS (ESI) m/z 455 [M+1]⁺, 456 [M+2]⁺; analy-

sis for C₂₀H₂₇ClN₄O₄S (454.2), calcd: C, 52.80; H, 5.98; N,

12.31. Found: C, 52.78; H, 5.96; N, 12.29.

5.2.1.15. N-(5-Chloro-2-methyl-thieno[2,3-b]pyridin-3-

yl)-guanidine (2c). Yield: 60%; white solid; mp 150–151

ꢁC; IR (KBr): 3400, 2854, 1610, 1375, 775 cm^À1

.

¹H

NMR (300 MHz, CDCl₃): d 2.41 (s, 3H, –CH₃), 7.23–

7.24 (d, 1H, pyridine ring), 8.54–8.55 (d, 1H, pyridine

ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H, –NH). MS

(ESI) m/z 241.2 [M+1]⁺, 242.2 [M+2]⁺; analysis for

C₉H₉ClN₄S (240.1), calcd: C, 44.91; H, 3.77; N, 23.28.

Found: C, 44.88; H, 3.74; N, 23.25.

5.2.1.11. Bis-Boc-N-(2-benzyl-thieno[2,3-b]pyridin-3-

yl)-guanidine (6k). Yield: 67%; white solid; mp 113–

115 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1050 cm^À1. ¹H

NMR (300 MHz, CDCl₃): d 1.43 (s, 9H, (CH₃)₃CAOA

COAN@), 1.56 (s, 9H, (CH₃)₃CAOACOANHA), 3.81

(s, 2H, –CH₂–Ph), 7.21–7.23 (dd, 1H, pyridine ring),

7.30–7.31 (d, 1H, pyridine ring), 7.33–7.40 (m, 5H, ben-

zene ring), 8.51–8.52 (d, 1H, pyridine ring), 9.97 (s, 1H,

–NH), 11.65 (s, 1H, –NH). MS (ESI) m/z 483.2 [M+1]⁺;

analysis for C₂₅H₃₀N₄O₄S (482.2), calcd: C, 62.22; H,

6.27; N, 11.61. Found: C, 62.20; H, 6.24; N, 11.58.

5.2.1.16. N-(2-Methyl-thieno[2,3-b]pyridin-3-yl)-gua-

nidine (2d). Yield: 61%; white solid; mp 126–127 ꢁC;

IR (KBr): 3400, 2854, 1610, 1375 cm^À^{1 1}H NMR

.

(300 MHz, CDCl₃): d 2.41 (s, 3H, –CH₃), 7.21–7.22 (d,

1H, pyridine ring), 7.31–7.32 (dd, 1H, pyridine ring),

8.51–8.52 (d, 1H, pyridine ring), 9.97 (s, 1H, –NH),

11.65 (s, 1H, –NH). MS (ESI) m/z 207.5 [M+1]⁺; analy-

sis for C₉H₁₀N₄S (206.2), calcd: C, 52.41; H, 4.89; N,

27.16. Found: C, 52.38; H, 4.86; N, 27.13.

5.2.1.12. Bis-Boc-N-(2-benzyl-5-chloro-thieno[2,3-b]pyri-

din-3-yl)-guanidine (6l). Yield: 67%; white solid; mp 134–

136 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1050, 775 cm^À1

.

5.2.1.17. N-(2-Phenyl-thieno[2,3-b]pyridin-3-yl)-guani-

dine (2e). Yield: 63%; white solid; mp 158–159 ꢁC; IR

¹H NMR (300 MHz, CDCl₃):d 1.43 (s, 9H,

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOACOA

NHA), 3.81 (s, 2H, –CH₂–Ph), 7.21–7.22 (d, 1H, pyridine

ring), 7.32–7.44 (m, 5H, benzene ring), 8.53–8.54 (d, 1H,

pyridine ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H, –NH). MS

(ESI) m/z 518.2 [M+1]⁺, 519.2 [M+2]⁺; analysis for

C₂₅H₂₉ClN₄O₄S (517), calcd: C, 58.07; H, 5.65; N, 10.84.

Found: C, 58.03; H, 5.61; N, 10.82.

(KBr): 3430, 2854,1610 cm^{À1 1}H NMR (300 MHz,

.

CDCl₃): d 7.21–7.22 (d, 1H, pyridine ring), 7.29–7.30

(dd, 1H, pyridine ring), 7.31–7.41 (m, 5H, benzene ring),

8.51–8.52 (d, 1H, pyridine ring), 9.97 (s, 1H, –NH),

11.65 (s, 1H, –NH). MS (ESI) m/z 269.3 [M+1]⁺; analy-

sis for C₁₄H₁₂N₄S (268.1), calcd: C, 62.66; H, 4.51; N,

20.88. Found: C, 62.63; H, 4.48; N, 20.84.

5.2.1.13. Synthesis of N-(thieno[2,3-b]pyridin-3-yl)-

guanidine (2a). A cleavage mixture of TFA: DCM

(1: 1 v/v; 10 mL) was added to Bis-Boc-N-(thieno[2,3-

b]pyridin-3-yl)-guanidine (6a; 0.1 g, 0.255 mmol) and

stirred for 1 h at room temperature. The reaction mix-

ture was evaporated to dryness and traces of TFA were

removed by azeotroping with ether. The residue ob-

tained was dissolved in water, basiﬁed with NaHCO₃,

upto pH 8. The aqueous layer was extracted with

DCM and the organic layer was washed with water

and brine solution. The DCM layer was dried over

Na₂SO₄and evaporated to obtain the solid residue.

The residue was dissolved in methanol, precipitated with

diisopropylether, and the solid product was ﬁltered and

5.2.1.18. N-(5-Chloro-2-phenyl-thieno[2,3-b]pyridin-3-

yl)-guanidine (2f). Yield: 66%; white solid; mp 125–

126 ꢁC; IR (KBr): 3400, 2854, 1610, 775 cm^À1

.

¹H

NMR (300 MHz, CDCl₃): d 7.31–7.42 (m, 5H, benzene

ring), 7.21–7.22 (d, 1H, pyridine ring), 8.51–8.52 (d, 1H,

pyridine ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H, –NH).

MS (ESI) m/z 303.2 [M+1]⁺, 304.2 [M+2]⁺; analysis

for C₁₄H₁₁ClN₄S (302), calcd: C, 55.53; H, 3.66; N,

18.50. Found: C, 55.50; H, 3.63; N, 18.47.

5.2.1.19. N-(2-Cyclohexyl-thieno[2,3-b]pyridin-3-yl)-

guanidine (2g). Yield: 67%; white solid; mp 128–131 ꢁC;

1

IR (KBr): 3400, 2854, 1610, 1410.,720 cm^À1. H NMR

(300 MHz, CDCl₃): d 1.29–1.31 (m, 6H, –cyclohex),

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

3255

1.58–1.59 (m, 4H, –cyclohex), 2.76–2.77 (m, 1H, –cyclo-

hex), 7.21–7.22 (d, 1H, pyridine ring), 7.30–7.31 (dd,

1H, pyridine ring), 8.50–8.51 (d, 1H, pyridine ring),

9.97 (s, 1H, –NH), 11.65 (s, 1H, –NH). MS (ESI) m/z

275.2 [M+1]⁺; analysis for C₁₄H₁₈N₄S (274), calcd:

C, 61.28; H, 6.61; N, 20.42. Found: C, 61.25; H, 6.58;

N, 20.39.

5.2.2. General method for the synthesis of N-(2,5-disub-

stituted-1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3a–l;

Scheme 2).

5.2.2.1. Synthesis of 3-nitroso-1H-pyrrolo[2,3-b]pyri-

dine (8a). To a solution of pyrrolo[2,3-b]pyridine (7a,

0.2 g, 1.69 mmol), dissolved in acetic acid (5 mL), a solu-

tion of NaNO₂(0.1 g) in water (5 mL) was added and

the reaction mixture was stirred at room temperature

for 30 min. The mixture was diluted with water, the solid

obtained was ﬁltered, dried, and recrystallized from

chloroform. Yield: 66%; yellow solid; mp 216–218 ꢁC;

5.2.1.20. N-(5-Chloro-2-cyclohexyl-thieno[2,3-b]pyri-

din-3-yl)-guanidine (2h). Yield: 71%; white solid; mp

133–135 ꢁC; IR (KBr): 3400, 2854, 1610, 1410, 775,

1

720 cm^À1. H NMR (300 MHz, CDCl₃): d 1.29–1.31

IR (KBr): 3400, 2845, 1610, 1540 cm^À^{1 1}H NMR

.

(m, 6H, –cyclohex), 1.58–159 (m, 4H, –cyclohex),

2.76–2.77 (m, 1H, –cyclohex), 7.22–7.23 (d, 1H, pyridine

ring), 8.51–8.50 (d, 1H, pyridine ring), 9.97 (s, 1H,

–NH), 11.65 (s, 1H, –NH). MS (ESI) m/z 309.2

[M+1]⁺, 310.2 [M+2]⁺; analysis for C₁₄H₁₇ClN₄S

(308.1), calcd: C, 54.45; H, 5.55; N, 18.14. Found: C,

54.42; H, 5.51; N, 18.11.

(300 MHz, CDCl₃) d 6.61 (s, 1H, pyrrole ring), 7.38–

7.39 (m, 1H, pyridine ring), 7.65–7.66 (d, 1H, pyridine

ring), 8.51–8.52 (d, 1H, pyridine ring), 11.65 (s, 1H,

–NH). MS (ESI) m/z 147.8 [M+1]⁺; analysis for

C₇H₅N₃O (147.2), calcd: C, 57.14; H, 3.43; N, 28.56;

Found: C, 57.12; H, 3.45; N, 28.52.

5.2.2.2. 5-Chloro-3-nitroso-1H-pyrrolo[2,3-b]pyridine

(8b). Yield: 60%; yellow solid; mp 224–226 ꢁC; IR

5.2.1.21. N-(2-Ethyl-thieno[2,3-b]pyridin-3-yl)-guani-

dine (2i). Yield: 63%; white solid; mp 127–129 ꢁC; IR

(KBr): 3400, 2845, 1610, 1545, 775 cm^À^{1 1}H NMR

.

(KBr): 3400, 2854, 1610, 1400, 1375 cm^À1

.

¹H NMR

(300 MHz, CDCl₃) d 6.60 (s, 1H, pyrrole ring), 7.65–

7.66 (d, 1H, pyridine ring), 8.48–8.49 (d, 1H, pyridine

ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 181.9 [M+1]⁺,

182.9 [M+2]⁺; analysis for C₇H₄ClN₃O (181.5), calcd:

C, 46.30; H, 2.22; N, 23.14. Found: C, 46.26; H, 2.24;

N, 23.12.

(300 MHz, CDCl₃): d 1.24–1.26 (t, 3H, –CH₂CH₃),

2.59–2.60 (m, 2H, –CH₂CH₃), 7.21–7.22 (d, 1H, pyridine

ring), 7.33–7.34 (dd, 1H, pyridine ring), 8.54–8.55 (d,

1H, pyridine ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H,

–NH). MS (ESI) m/z 221.3 [M+1]⁺; analysis for

C₁₀H₁₂N₄S (220.1), calcd: C, 54.52; H, 5.49; N, 25.43.

Found: C, 54.49; H, 5.45; N, 25.40.

5.2.2.3. 5-Chloro-2-methyl-3-nitroso-1H-pyrrolo[2,3-b]

pyridine (8c). Yield: 63%; yellow solid; mp 230–232 ꢁC; IR

(KBr): 3400, 2845, 1610, 1545, 1375 775 cm^À1. ¹H NMR

(300 MHz, CDCl₃) d 2.14 (s, 3H, Methyl), 7.65–7.66 (d,

1H, pyridine ring), 8.50–8.51 (d, 1H, pyridine ring), 11.7

(s, 1H, –NH). MS (ESI) m/z 196.3 [M+1]⁺, 197.3

[M+2]⁺; analysis for C₈H₆ClN₃O (195.6), calcd: C,

49.12; H, 3.09; N, 21.48; Found: C, 49.15; H, 3.12; N,

21.43.

5.2.1.22. N-(5-Chloro-2-ethyl-thieno[2,3-b]pyridin-3-

yl)-guanidine (2j). Yield: 65%; white solid; mp 134–

136 ꢁC; IR (KBr): 3400, 2854, 1610, 1400, 1375,

1

775 cm^À1. H NMR (300 MHz, CDCl₃): d 1.24–1.25 (t,

3H, –CH₂CH₃), 2.59–2.60 (m, 2H, –CH₂CH₃), 7.21–

7.22 (d, 1H, pyridine ring), 8.50–8.51 (d, 1H, pyridine

ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H, –NH). MS

(ESI) m/z 255.5 [M+1]⁺, 256.5 [M+2]⁺; analysis for

C₁₀H₁₁ClN₄S (254), calcd: C, 47.15; H, 4.35; N, 21.99.

Found: C, 47.11; H, 4.31; N, 21.96.

5.2.2.4. 2-Methyl-3-nitroso-1H-pyrrolo[2,3-b]pyridine

(8d). Yield: 67%; yellow solid; mp 206–208 ꢁC; IR

(KBr): 3400, 2845, 1610, 1545, 1375 cm^À^{1 1}H NMR

.

5.2.1.23. N-(2-Benzyl-thieno[2,3-b]pyridin-3-yl)-guani-

dine (2k). Yield: 63%; white solid; mp 117–119 ꢁC; IR

(300 MHz, CDCl₃) d 2.14 (s, 3H, Methyl), 7.32–7.33

(m, 1H, pyridine ring), 7.65–7.66 (d, 1H, pyridine ring),

8.51–8.52 (d, 1H, pyridine ring), 11.7 (s, 1H, –NH). MS

(ESI) m/z 162.8 [M+1]⁺; analysis for C₈H₇N₃O (161.2),

calcd: C, 59.62; H, 4.38; N, 26.07; Found: C, 59.58; H,

4.35; N, 26.11.

(KBr): 3400, 2854, 1610, 1400 cm^À1

.

¹H NMR

(300 MHz, CDCl₃): d 3.81 (s, 2H, –CH₂–Ph), 7.30–

7.40 (m, 5H, benzene ring), 7.30–7.31 (d, 1H, pyridine

ring), 7.21–7.22 (dd, 1H, pyridine ring), 8.50–8.51 (d,

1H, pyridine ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H,

–NH). MS (ESI) m/z 283.6 [M+1]⁺; analysis for

C₁₅H₁₄N₄S (282.1), calcd: C, 63.80; H, 5.00; N, 19.84.

Found: C, 63.76; H, 4.98; N, 19.81.

5.2.2.5. 3-Nitroso-2-phenyl-1H-pyrrolo[2,3-b]pyridine

(8e). Yield: 68%; yellow solid; mp 234–236 ꢁC; IR

(KBr): 3400, 2845, 1610, 1545 1435 cm^À^{1 1}H NMR

.

(300 MHz, CDCl₃) d 7.31–7.40 (m, 5H, benzene ring),

7.21–7.22 (m, 1H, pyridine ring), 7.60–7.61 (d, 1H, pyr-

idine ring), 8.50–8.51 (d, 1H, pyridine ring), 11.65 (s,

1H, –NH). MS (ESI) m/z 223.8 [M+1]⁺; analysis for

C₁₃H₉N₃O (223.2), calcd: C, 69.95; H, 4.06; N, 18.82;

Found: C, 69.93; H, 4.10; N, 18.80.

5.2.1.24. N-(2-Benzyl-5-chloro-thieno[2,3-b]pyridin-3-

yl)-guanidine (2l). Yield: 66%; white solid; mp 130–

131 ꢁC; IR (KBr): 3400, 2854, 1610, 1400, 775,

720 cm^À^{1 1}H NMR (300 MHz, CDCl₃): d 3.81 (s,

.

2H, –CH₂–Ph), 7.31–7.39 (m, 5H, benzene ring), 7.19–

7.20 (d, 1H, pyridine ring), 8.49–8.50 (d, 1H, pyridine

ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H, –NH). MS

(ESI) m/z 317.3 [M+1]⁺, 318.3 [M+2]⁺; analysis for

C₁₅H₁₃ClN₄S (316), calcd: C, 56.87; H, 4.14; N, 17.68.

Found: C, 56.84; H, 4.11; N, 17.65.

5.2.2.6. 5-Chloro-3-nitroso-2-phenyl-1H-pyrrolo[2,3-

b]pyridine (8f). Yield: 63%; yellow solid; mp 256–

258 ꢁC; IR (KBr): 3400, 2845, 1610, 1545 1435,

770 cm^À^{1 1}H NMR (300 MHz, CDCl₃) d 7.18–7.19

.

3256

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

(d, 1H, pyridine ring), 7.29–7.38 (m, 5H, benzene ring),

8.48–8.49 (d, 1H, pyridine ring), 11.65 (s, 1H, –NH). MS

(ESI) m/z 258 [M+1]⁺, 259 [M+2]⁺; analysis for

C₁₃H₈ClN₃O (257.2), calcd: C, 60.60; H, 3.13; N,

16.31. Found: C, 60.56; H, 3.12; N, 16.28.

(KBr): 3400, 2845, 1610, 1545 1440, 775 cm^À1. ¹H NMR

(300 MHz, CDCl₃) d 3.81 (s, 2H, –CH₂–Ph), 7.22–7.23

(m, 5H, benzene ring), 7.77–7.78 (d, 1H, pyridine ring),

8.54–8.55 (d, 1H, pyridine ring), 11.65 (s, 1H, –NH). MS

(ESI) m/z 272.5 [M+1]⁺, 273.5 [M+2]⁺; analysis for

C₁₄H₁₀ClN₃O (271.6), calcd: C, 61.89; H, 3.71; N, 15.47.

Found: C, 61.85; H, 3.73; N, 15.43.

5.2.2.7. 2-Cyclohexyl-3-nitroso-1H-pyrrolo[2,3-b]pyri-

dine (8g). Yield: 66%; yellow solid; mp 222–224 ꢁC; IR

(KBr): 3400, 2845, 1610, 1545 1440, 1375, 720 cm^À1

.

5.2.2.13. Synthesis of 3-amino-1H-pyrrolo[2,3-b]pyri-

dine (9a). A mixture of 3-nitroso-1H-pyrrolo[2,3-b]pyri-

dine (8a; 0.1 g, 0.680 mmol), Na₂S₂O₄(0.34 g,

1.97 mmol), and NaOH (1.1 mL; 2 N) in ethanol

(10 mL) was heated under reﬂux for 30 min. The

yellow solid obtained was ﬁltered, washed with water,

and dried to get the pure compound 9a.Yield: 74%;

yellow solid; mp 194–196 ꢁC; IR (KBr): 3400, 2845,

¹H NMR (300 MHz, CDCl₃) d 1.29–1.30 (m, 6H,

–cyclohex), 1.58–1.59 (m, 4H, –cyclohex), 7.21–7.22

(m, 1H, pyridine ring), 7.60–7.61 (d, 1H, pyridine ring),

2.76–2.77 (m, 1H, –cyclohex), 8.51–8.52 (d, 1H, pyridine

ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 229.7 [M+1]⁺;

analysis for C₁₃H₁₅N₃O (229.2), calcd: C, 68.10; H,

6.59; N, 18.33. Found: C, 68.13; H, 6.62; N, 18.31.

1

1610 cm^À1. H NMR (300 MHz, CDCl₃) d 6.61 (s, 1H,

5.2.2.8. 5-Chloro-2-cyclohexyl-3-nitroso-1H-pyrrolo-

[2,3-b]pyridine (8h). Yield: 69%; yellow solid; mp 228–

230 ꢁC; IR (KBr): 3400, 2845, 1610, 1545 1440, 1375,

pyrrole ring), 7.38–7.39 (m, 1H, pyridine ring),

7.65–7.66 (d, 1H, pyridine ring), 8.51–8.52 (d, 1H,

pyridine ring), 11.65 (s, 1H, –NH). MS (ESI) m/z

133.8 [M+1]⁺; analysis for C₇H₇N₃(133.2), calcd: C,

63.14; H, 5.30; N, 31.56. Found: C, 63.16; H, 5.32; N,

31.53.

775, 720 cm^À^{1 1}H NMR (300 MHz, CDCl₃) d 1.28–

.

1.29 (m, 6H, –cyclohex), 1.57–1.58 (m, 4H, –cyclohex),

7.59–2.60 (d, 1H, pyridine ring), 2.77–2.78 (m, 1H,

–cyclohex), 8.49–8.50 (d, 1H, pyridine ring), 11.65 (s,

1H, –NH). MS (ESI) m/z 264.7 [M+1]⁺, 265.7 [M+2]⁺;

analysis for C₁₃H₁₄ClN₃O (263.7), calcd: C, 59.21; H,

5.35; N, 15.93. Found: C, 59.17; H, 5.30; N, 15.90.

5.2.2.14. 5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylamine

(9b). Yield: 62%; yellow solid; mp 202–204 ꢁC; IR

(KBr): 3400, 2845, 1610, 775 cm^À1

.

¹H NMR

(300 MHz, CDCl₃) d 6.69 (s, 1H, pyrrole ring), 7.66–

7.67 (d, 1H, pyridine ring), 8.52–8.53 (d, 1H, pyridine

ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 168.3 [M+1]⁺,

169.3 [M+2]⁺; analysis for C₇H₆ClN₃(167.5), calcd: C,

15.17; H, 3.61; N, 21.15. Found: C, 15.15; H, 3.63; N,

21.12.

5.2.2.9. 2-Ethyl-3-nitroso-1H-pyrrolo[2,3-b]pyridine

(8i). Yield: 62%; yellow solid; mp 213–215 ꢁC; IR

(KBr): 3400, 2845, 1610, 1545 1440, 1375 cm^À^{1 1}H

.

NMR (300 MHz, CDCl₃)

d

1.24–1.25 (t, 3H,

–CH₂CH₃), 2.59–2.60 (m, 2H, –CH₂CH₃), 7.00–7.13

(m, 1H, pyridine ring), 7.53–7.54 (d, 1H, pyridine ring),

8.52–8.53 (d, 1H, Pyridine ring), 11.65 (s, 1H, –NH). MS

(ESI) m/z 175.9 [M+1]⁺; analysis for C₉H₉N₃O (175.2),

calcd: C, 61.70; H, 5.18; N, 23.99. Found: C, 61.68; H,

5.21; N, 23.97.

5.2.2.15. 5-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-

3-ylamine (9c). Yield: 67%; yellow solid; mp 197–199 ꢁC;

1

IR (KBr): 3400, 2845, 1610, 1375, 775 cm^À1. H NMR

(300 MHz, CDCl₃) d 2.14 (s, 3H, methyl), 7.65–7.66

(d, 1H, pyridine ring), 8.50–8.51 (d, 1H, pyridine ring),

11.70 (s, 1H, –NH). MS (ESI) m/z 182.3 [M+1]⁺, 183.3

[M+2]⁺; analysis for C₈H₈ClN₃(181.6), calcd: C,

52.90; H, 4.44; N, 23.14. Found: C, 52.92; H, 4.47; N,

23.10.

5.2.2.10. 5-Chloro-2-ethyl-3-nitroso-1H-pyrrolo[2,3-b]

pyridine (8j). Yield: 65%; yellow solid; mp 218–220 ꢁC;

IR (KBr): 3400, 2845, 1610, 1545 1440, 1375,

1

745 cm^À1. H NMR (300 MHz, CDCl₃) d 1.22–1.23 (t,

3H, –CH₂CH₃), 2.59–2.60 (m, 2H, –CH₂CH₃), 7.48–

7.49 (d, 1H, pyridine ring), 8.51–8.52 (d, 1H, pyridine

ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 210.3 [M+1]⁺,

211.3 [M+2]⁺; analysis for C₉H₈ClN₃O (209.6), calcd:

C, 51.56; H, 3.85; N, 20.04. Found: C, 51.52; H, 3.82;

N, 20.06.

5.2.2.16. 2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine

(9d). Yield: 62%; yellow solid; mp 200–202 ꢁC; IR

(KBr): 3400, 2845, 1600, 1375 cm^À1

.

¹H NMR

(300 MHz, CDCl₃) d 2.14 (s, 3H, methyl), 7.32–7.33

(m, 1H, pyridine ring), 7.65–7.66 (d, 1H, pyridine ring),

8.50–8.51 (d, 1H, pyridine ring), 11.70 (s, 1H, –NH). MS

(ESI) m/z 148 [M+1]⁺; analysis for C₈H₉N₃(147.2),

calcd: C, 65.29; H, 6.16; N, 28.55. Found: C, 65.26; H,

6.18; N, 28.58.

5.2.2.11. 2-Benzyl-3-nitroso-1H-pyrrolo[2,3-b]pyridine

(8k). Yield: 64%; yellow solid; mp 230–232 ꢁC; IR

(KBr): 3400, 2845, 1610, 1545 1440 cm^À^{1 1}H NMR

.

(300 MHz, CDCl₃) d 3.81 (s, 2H, –CH₂–Ph), 7.28–7.29

(m, 1H, pyridine ring), 7.31–7.40 (m, 5H, benzene ring),

7.70–7.71 (d, 1H, pyridine ring), 8.48–8.49 (d, 1H, pyri-

dine ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 237.8

[M+1]⁺; analysis for C₁₄H₁₁N₃O (237.2.6), calcd: C,

70.87; H, 4.67; N, 17.71. Found: C, 70.84; H, 4.65; N,

17.74.

5.2.2.17. 2-Phenyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine

(9e). Yield: 68%; yellow solid; mp 207–209 ꢁC; IR (KBr):

3400, 2845, 1600, 1375 cm^À^{1 1}H NMR (300 MHz,

.

CDCl₃) d 7.20–7.21 (m, 1H, pyridine ring), 7.30 –7.40

(m, 5H, benzene ring), 7.60–7.61 (d, 1H, pyridine ring),

8.50–8.51 (d, 1H, pyridine ring), 11.65 (s, 1H, –NH). MS

(ESI) m/z 209.8 [M+1]⁺; analysis for C₁₃H₁₁N₃(209.2),

calcd: C, 74.62; H, 5.30; N, 20.08. Found: C, 74.60; H,

5.33; N, 20.11.

5.2.2.12. 2-Benzyl-5-chloro-3-nitroso-1H-pyrrolo[2,3-b]

pyridine (8l). Yield: 66%; yellow solid; mp 236–238 ꢁC; IR

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

3257

5.2.2.18. 5-Chloro-2-phenyl-1H-pyrrolo[2,3-b]pyridin-

3-ylamine (9f). Yield: 67%; yellow solid; mp 213–215 ꢁC;

5.2.2.24. 2-Benzyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-

3-ylamine (9l). Yield: 63%; yellow solid; mp 222–

IR (KBr): 3400, 2845, 1600, 776 cm^À1

.

¹H NMR

224 ꢁC; IR (KBr): 3400, 2845, 1600, 1400, 776 cm^À1

.

(300 MHz, CDCl₃) d 7.30–7.40 (m, 5H, benzene ring),

7.20–7.21 (m, 1H, pyridine ring), 7.60–7.61 (d, 1H, pyr-

idine ring), 8.50–8.51 (d, 1H, pyridine ring), 11.65 (s,

1H, –NH). MS (ESI) m/z 244.3 [M+1]⁺, 245.3 [M+2]⁺;

analysis for C₁₃H₁₀ClN₃(243.6), calcd: C, 64.07; H,

4.14; N, 17.24. Found: C, 64.09; H, 4.11; N, 17.20.

¹H NMR (300 MHz, CDCl₃) d 3.81 (s, 2H, –CH₂–Ph),

7.29–7.31 (m, 5H, benzene ring), 7.70–7.71 (d, 1H, pyr-

idine ring), 8.49–8.50 (d, 1H, pyridine ring), 11.65 (s,

1H, –NH). MS (ESI) m/z 223.8 [M+1]⁺, 224.8 [M+2]⁺;

analysis for C₁₄H₁₃N₃(223.2), calcd: C, 65.25; H, 4.69;

N, 16.30. Found: C, 65.22; H, 4.66; N, 16.27.

5.2.2.19. 2-Cyclohexyl-1H-pyrrolo[2,3-b]pyridin-3-yl-

amine (9g). Yield: 66%; yellow solid; mp 215–217 ꢁC;

5.2.2.25. Synthesis of bis-Boc-(1H-pyrrolo[2,3-b]pyri-

din-3-yl)-guanidine (10a). Synthesis of compound 10a

was carried out starting from 3-amino-1H-pyrrolo[2,3-

b]pyridine (9a), using a general procedure described

for the synthesis of compound 6a. Yield: 72%; white

solid; mp 292–294 ꢁC; IR (KBr): 3400, 2850, 1710,

1

IR (KBr): 3400, 2845, 1600, 1400, 720 cm^À1. H NMR

(300 MHz, CDCl₃) d 1.29–1.30 (m, 6H, –cyclohex),

1.58–1.59 (m, 4H, –cyclohex), 2.76–2.77 (m, 1H, –cyclo-

hex), 7.20–7.21 (m, 1H, pyridine ring), 7.60–7.61 (d, 1H,

pyridine ring), 8.50–8.51 (d, 1H, pyridine ring), 11.65 (s,

1H, –NH). MS (ESI) m/z 215.8 [M+1]⁺; analysis for

C₁₃H₁₇N₃(215.2), calcd: C, 72.52; H, 7.96; N, 19.52.

Found: C, 72.55; H, 7.99; N, 19.50.

1

1610, 1050 cm^À1. H NMR (300 MHz, CDCl₃) d 1.43

(s, 9H, (CH₃)₃CAOACOAN@), 1.56 (s, 9H,

(CH₃)₃CAOACOANHA), 6.60 (s, 1H, Pyrrole ring),

7.20–7.21 (d, 1H, pyridine ring), 7.68–7.69 (dd, 1H, Pyr-

idine ring), 8.50–8.51 (d, 1H, pyridine ring), 11.65 (s,

1H, –NH). MS (ESI) m/z 375.8 [M+1]⁺; analysis for

C₁₈H₂₅N₅O₄(375.3), calcd: C, 57.59; H, 6.71; N,

18.65. Found: C, 57.56; H, 6.75; N, 18.68.

5.2.2.20. 5-Chloro-2-cyclohexyl-1H-pyrrolo[2,3-b]pyri-

din-3-ylamine (9h). Yield: 60%; yellow solid; mp 209–

211 ꢁC; IR (KBr): 3400, 2845, 1600, 1400, 775 cm^À1. ¹H

NMR (300 MHz, CDCl₃) d 1.29–1.30 (m, 6H, –cyclohex),

1.57–1.58 (m, 4H, –cyclohex), 2.76–2.77 (m, 1H, –cyclo-

hex), 7.50–7.51 (d, 1H, pyridine ring), 8.50–8.51 (d, 1H,

pyridine ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 250.8

[M+1]⁺, 251.8 [M+2]⁺; analysis for C₁₃H₁₆ClN₃(250),

calcd C, 62.52; H, 6.46; N, 16.83. Found: C, 62.48; H,

6.43; N, 16.79.

5.2.2.26. Bis-Boc-N-(5-chloro-1H-pyrrolo[2,3-b]pyri-

din-3-yl)-guanidine (10b). Yield: 61%; white solid; mp

297–299 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1050,

1

775 cm^À1. H NMR (300 MHz, CDCl₃) d 1.43 (s, 9H,

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

COANHA), 6.60 (s, 1H, pyrrole ring), 7.68–7.69 (dd,

1H, pyridine ring), 8.50–8.51 (d, 1H, pyridine ring),

11.65 (s, 1H, –NH). MS (ESI) m/z 410.2 [M+1]⁺, 411.2

[M+2]⁺; analysis for C₁₈H₂₄ClN₅O₄(409.5), calcd: C,

52.75; H, 5.90; N, 17.09. Found: C, 52.72; H, 5.93; N,

17.05.

5.2.2.21. 2-Ethyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine

(9i). Yield: 72%; yellow solid; mp 202–204 ꢁC; IR

(KBr): 3400, 2845, 1600, 1400, 1375 cm^À^{1 1}H NMR

.

(300 MHz, CDCl₃) d 1.24–1.25 (t, 3H, –CH₂CH₃),

2.59–2.60 (m, 2H, –CH₂CH₃), 7.20–7.21 (m, 1H, pyri-

dine ring), 7.50–7.51 (d, 1H, pyridine ring), 8.50–8.51

(d, 1H, pyridine ring), 11.65 (s, 1H, –NH). MS (ESI)

m/z 161.9 [M+1]⁺; analysis for C₉H₁₁N₃(161.2), calcd:

C, 67.06; H, 6.88; N, 26.07. Found: C, 67.01; H, 6.80;

N, 26.00.

5.2.2.27. Bis-Boc-N-(5-chloro-2-methyl-1H-pyrrolo-

[2,3-b]pyridin-3-yl)-guanidine (10c). Yield: 64%; white so-

lid; mp 296–298 ꢁC; IR (KBr): 3400, 2850, 1710, 1610,

1

1375, 1050, 775 cm^À1. H NMR (300 MHz, CDCl₃) d

1.43 (s, 9H, (CH₃)₃CAOACOAN@), 1.56 (s, 9H,

(CH₃)₃CAOACOANHA), 2.10 (s, 1H, –CH₃proton),

7.68–7.69 (dd, 1H, pyridine ring), 8.50–8.51 (d, 1H, pyr-

idine ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 424

[M+1]⁺, 425 [M+2]⁺; analysis for C₁₉H₂₆ClN₅O₄

(423.5), calcd: C, 53.84; H, 6.18; N, 16.52. Found: C,

53.82; H, 6.19; N, 16.55.

5.2.2.22. 5-Chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-

ylamine (9j). Yield: 71%; yellow solid; mp 212–214 ꢁC;

1

IR (KBr): 3400, 2845, 1600, 1400, 1375, 770 cm^À1. H

NMR (300 MHz, CDCl₃) d 1.24–1.25 (t, 3H, –CH₂CH₃),

2.59–2.60 (m, 2H, –CH₂CH₃), 7.48–7.49 (d, 1H, pyridine

ring), 8.50–8.51 (d, 1H, pyridine ring), 11.65 (s, 1H, –NH).

MS (ESI) m/z 196 [M+1]⁺, 197 [M+2]⁺; analysis for

C₉H₁₀ClN₃(195.5), calcd: C, 55.25; H, 5.15; N, 21.48.

Found: C, 55.23; H, 5.12; N, 21.51.

5.2.2.28. Bis-Boc-N-(2-methyl-1H-pyrrolo[2,3-b]pyri-

din-3-yl)-guanidine (10d). Yield: 72%; white solid; mp

286–288 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1375,

1

1050 cm^À1. H NMR (300 MHz, CDCl₃) d 1.43 (s, 9H,

5.2.2.23. 2-Benzyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine

(9k). Yield: 67%; yellow solid; mp 218–220 ꢁC; IR

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

COANHA), 2.10 (s, 1H, –CH₃proton), 7.20–7.21 (d,

1H, pyridine ring), 7.68–7.69 (dd, 1H, pyridine ring),

8.50–8.51 (d, 1H, pyridine ring), 11.65 (s, 1H, –NH).

MS (ESI) m/z 389.8 [M+1]⁺; analysis for C₁₉H₂₇N₅O₄

(389.2), calcd: C, 58.60; H, 6.99; N, 17.98. Found: C,

58.58; H, 6.96; N, 17.97.

(KBr): 3400, 2845, 1600, 1400 cm^À1

.

¹H NMR

(300 MHz, CDCl₃) d 3.81 (s, 2H, –CH₂–Ph), 7.30 –

7.40 (m, 5H, benzene ring), 7.30–7.31 (m, 1H, pyridine

ring), 7.71–7.72 (d, 1H, pyridine ring), 8.50–8.51 (d,

1H, pyridine ring), 11.65 (s, 1H, –NH). MS(ESI) m/z

223.8 [M+1]⁺; analysis for C₁₄H₁₃N₃(223.2), calcd: C,

75.31; H, 5.87; N, 18.82. Found: C, 75.28; H, 5.89; N,

18.85.

5.2.2.29. Bis-Boc-N-(2-phenyl-1H-pyrrolo[2,3-b]pyri-

din-3-yl)-guanidine (10e). Yield: 68%; white solid; mp

3258

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

1

>300 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1050 cm^À1

.

1.43 (s, 9H,

1375 1050 cm^À1. H NMR (300 MHz, CDCl₃) d 1.22–

1.23 (t, 3H, –CH₂CH₃), 1.40 (s, 9H, (CH₃)₃CA

OACOAN@), 1.56 (s, 9H, (CH₃)₃CAOACOANHA),

2.59–2.60 (m, 2H, –CH₂CH₃), 7.67–7.68 (dd, 1H, pyri-

dine ring), 8.50–8.51 (d, 1H, pyridine ring), 11.65 (s,

1H, –NH). MS (ESI) m/z 437.8 [M+1]⁺, 438.8 [M+2]⁺;

analysis for C₂₀H₂₈ClN₅O₄(437), calcd: C, 54.85; H,

6.44; N, 15.99. Found: C, 54.82; H, 6.47; N, 15.96.

¹H NMR (300 MHz, CDCl₃)

d

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

COANHA), 7.30–7.40 (m, 5H, benzene ring), 7.20–

7.21 (m, 1H, pyridine ring), 7.61–7.62 (d, 1H, pyridine

ring), 8.50–8.51 (d, 1H, pyridine ring), 11.65 (s, 1H,

–NH). MS (ESI) m/z 452.1 [M+1]⁺; analysis for

C₂₄H₂₉N₅O₄(451), calcd: C, 63.84; H, 6.47; N, 15.51.

Found: C, 63.82; H, 6.49; N, 15.47.

5.2.2.35. Bis-Boc-N-(2-benzyl-1H-pyrrolo[2,3-b]pyri-

din-3-yl)-guanidine (10k). Yield: 68%; white solid;

mp >300 ꢁC; IR (KBr): 3400, 2850, 1710, 1610,

5.2.2.30. Bis-Boc-N-(5-chloro-2-Phenyl-1H-pyrrolo-

[2,3-b]pyridin-3-yl)-guanidine (10f). Yield: 63%; white so-

lid; mp >300 ꢁC; IR (KBr): 3400, 2850, 1710, 1610,

1050 cm^À^{1 1}H NMR (300 MHz, CDCl₃) d 1.43 (s,

.

1050, 775 cm^À1

.

¹H NMR (300 MHz, CDCl₃) d 1.43

9H, (CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CA

OACOANHA), 3.81 (s, 2H, –CH₂–Ph), 7.28–7.29 (m,

1H, pyridine ring), 7.30–7.40 (m, 5H, benzene ring),

7.66–7.67 (dd, 1H, pyridine ring), 8.47–8.48 (d, 1H, pyr-

idine ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 467

[M+1]⁺; analysis for C₂₅H₃₁N₅O₄(465.5), calcd: C,

64.50; H, 6.71; N, 15.04. Found: C, 64.47; H, 6.74; N,

15.07.

(s, 9H, (CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CA

OACOANHA), 7.31–7.41 (m, 5H, benzene ring), 7.61–

7.62 (d, 1H, pyridine ring), 8.48–8.49 (d, 1H, pyridine

ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 485.8 [M+1]⁺,

486.8 [M+2]⁺; analysis for C₂₄H₂₈ClN₅O₄(485), calcd:

C, 59.32; H, 5.81; N, 14.41. Found: C, 59.29; H, 5.78;

N, 14.45.

5.2.2.31. Bis-Boc-N–(2-cyclohexyl-1H-pyrrolo[2,3-b]-

pyridin-3-yl)-guanidine (10g). Yield: 64%; white solid;

mp 295–297 ꢁC; IR (KBr): 3400, 2850, 1710, 1610,

5.2.2.36. Bis-Boc-N-(2-benzyl-5-chloro-1H-pyrrolo[2,3-

b]pyridin-3-yl)-guanidine (10l). Yield: 66%; white solid;

mp >300 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1050,

1

1050, 720 cm^À1. H NMR (300 MHz, CDCl₃) d 1.29–

775 cm^À1. H NMR (300 MHz, CDCl₃) d 1.43 (s, 9H,

1.30 (m, 6H, –cyclohex), 1.43 (s, 9H, (CH₃)₃CA

OACOAN@), 1.56 (s, 9H, (CH₃)₃CAOACOANHA),

1.57–1.58 (m, 4H, –cyclohex), 2.76–2.77 (m, 1H, –cyclo-

hex), 7.21–7.22 (m, 1H, pyridine ring), 7.61–7.62 (d, 1H,

pyridine ring), 8.50–8.51 (d, 1H, pyridine ring), 11.65 (s,

1H, –NH). MS (ESI) m/z 457.8 [M+1]⁺; analysis for

C₂₄H₃₅N₅O₄(457.2), calcd: C, 63.00; H, 7.71; N,

15.31. Found: C, 63.03; H, 7.75; N, 15.28.

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

COANHA), 3.81 (s, 2H, –CH₂–Ph), 7.33 – 7.43 (m,

5H, benzene ring), 7.56–7.57 (dd, 1H, pyridine ring),

8.51–8.52 (d, 1H, pyridine ring), 11.65 (s, 1H, –NH.

MS (ESI) m/z 500.2 [M+1]⁺, 501.2 [M+2]⁺; analysis

for C₂₅H₃₀ClN₅O₄(499.5), calcd: C, 60.05; H, 6.05; N,

14.01. Found: C, 60.09; H, 6.08; N, 14.03.

5.2.2.37. Synthesis of N-(1H-pyrrolo[2,3-b]pyridin-3-

yl)-guanidine (3a). Synthesis of compound 3a was car-

ried out starting from bis-Boc-N-(1H-pyrrolo[2,3-b]pyri-

din-3-yl)-guanidine (10a), using a general procedure

described for the synthesis of compound 2a. Yield:

58%; white solid; mp 218–220 ꢁC; IR (KBr): 3430,

5.2.2.32. Bis-Boc-N-(5-chloro-2-cyclohexyl-1H-pyrro-

lo[2,3-b]pyridin-3-yl)-guanidine (10h). Yield: 62%; white

solid; mp >300 ꢁC; IR (KBr): 3400, 2850, 1710, 1610,

1

1050, 775, 720 cm^À1. H NMR (300 MHz, CDCl₃) d

1.29–1.30 (m, 6H, –cyclohex), 1.43 (s, 9H, (CH₃)₃CA

OACOAN@), 1.56 (s, 9H, (CH₃)₃CAOACOANHA),

1.58–1.59 (m, 4H, –cyclohex), 2.76–2.77 (m, 1H,–cyclo-

hex), 7.59–7.60 (d, 1H, pyridine ring), 8.52–8.53 (d,

1H, pyridine ring), 11.65 (s, 1H, –NH). MS (ESI) m/z

492.6 [M+1]⁺, 493.6 [M+2]⁺; analysis for C₂₄H₃₄ClN₅O₄

(492), calcd: C, 58.59; H, 6.97; N, 14.23. Found: C,

58.56; H, 6.94; N, 14.26.

1

2854, 1610 cm^À1. H NMR (300 MHz, CDCl₃) d 6.70

(s, 1H, Pyrrole ring), 7.10–7.11 (m, 1H, pyridine ring),

7.67–7.68 (d, 1H, pyridine ring), 8.20–8.21 (d, 1H, pyri-

dine ring), 11.77 (s, 1H, –NH). MS (ESI) m/z 175.8

[M+1]⁺; analysis for C₈H₉N₅(175.2), calcd: C, 54.85;

H, 5.18; N, 39.98. Found: C, 54.82; H, 5.19; N, 39.95.

5.2.2.38. N-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-

guanidine (3b). Yield: 63%; white solid; mp 224–

5.2.2.33. Bis-Boc-N-(2-ethyl-1H-pyrrolo[2,3-b]pyridin-

3-yl)-guanidine (10i). Yield: 60%; white solid; mp 286–

288 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1375

226 ꢁC; IR (KBr): 3430, 2854,, 1610, 774 cm^À1

.

¹H

NMR (300 MHz, CDCl₃) d 6.69 (s, 1H, pyrrole ring),

7.64–7.65 (d, 1H, pyridine ring), 8.22–8.23 (d, 1H, pyri-

dine ring), 11.77 (s, 1H, –NH). MS (ESI) m/z 210

[M+1]⁺, 211 [M+2]⁺; analysis for C₈H₈ClN₅(209.5),

calcd: C, 45.83; H, 3.85; N, 33.41. Found: C, 45.80; H,

3.88; N, 33.44.

1050 cm^À^{1 1}H NMR (300 MHz, CDCl₃) d 1.24–1.25

.

(t, 3H, –CH₂CH₃), 1.43 (s, 9H, (CH₃)₃CAOACOAN@),

1.56 (s, 9H, (CH₃)₃CAOACOANHA), 2.59–2.60 (m,

2H, –CH₂CH₃), 7.20–7.21 (d, 1H, pyridine ring), 7.67–

7.68 (dd, 1H, pyridine ring), 8.50–8.51 (d, 1H, pyridine

ring), 11.65 (s, 1H, –NH). MS(ESI) m/z 404.3 [M+1]⁺;

analysis for C₂₀H₂₉N₅O₄(403.5), calcd: C, 59.54; H,

7.24; N, 17.36. Found: C, 59.52; H, 7.23; N, 17.39.

5.2.2.39. N-(5-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyri-

din-3-yl)-guanidine (3c). Yield: 69%; white solid; mp

227–229 ꢁC; IR (KBr): 3400, 2854, 1610, 1375,

1

5.2.2.34. Bis-Boc-N-(5-chloro-2-ethyl-1H-pyrrolo[2,3-

b]pyridin-3-yl)-guanidine (10j). Yield: 71%; white solid;

mp 294–296 ꢁC; IR (KBr): 3400, 2850, 1710, 1610,

775 cm^À1. H NMR (300 MHz, CDCl₃) d 2.16 (s, 3H,

Methyl), 7.80 (s, 1H, pyridine ring), 8.48 (s, 1H, pyridine

ring), 11.70 (s, 1H, –NH). MS (ESI) m/z 224.2 [M+1]⁺,

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

3259

225.2 [M+2]⁺; analysis for C₉H₁₀ClN₅(223.5), calcd: C,

48.33; H, 4.51; N, 31.31. Found: C, 48.30; H, 4.55; N,

31.28.

(m, 1H, pyridine ring), 7.74–7.75 (d, 1H, pyridine ring),

8.49–8.50 (d, 1H, pyridine ring), 11.65 (s, 1H, –NH). MS

(ESI) m/z 203.7 [M+1]⁺; analysis for C₁₀H₁₃N₅(203.2),

calcd: C, 59.10; H, 6.45; N, 34.46. Found: C, 59.13; H,

6.48; N, 34.42.

5.2.2.40. N-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-

guanidine (3d). Yield: 65%; white solid; mp 214–216 ꢁC;

IR (KBr): 3400, 2854, 1610, 1375 cm^À1

.

¹H NMR

5.2.2.46. N-(5-Chloro-2-ethyl-1H-pyrrolo[2,3-b]pyri-

din-3-yl)-guanidine (3j). Yield: 67%; white solid; mp

224–226 ꢁC; IR (KBr): 3400, 2854, 1610, 1400, 1375,

(300 MHz, CDCl₃) d 2.16 (s, 3H, methyl), 7.10–7.11

(m, 1H, pyridine ring), 7.67 (s, 1H, pyridine ring), 8.50

(s, 1H, pyridine ring), 11.70 (s, 1H, –NH). MS (ESI)

m/z 189.8 [M+1]⁺; analysis for C₉H₁₁N₅(189.2), calcd:

C, 57.13; H, 5.86; N, 37.01. Found: C, 57.10; H, 5.89;

N, 37.05.

1

775 cm^À1. H NMR (300 MHz, CDCl₃) d 1.22–1.23 (t,

3H, –CH₂CH₃), 2.58–2.59 (m, 2H, –CH₂CH₃), 7.44–

7.45 (d, 1H, pyridine ring), 8.48–8.49 (d, 1H, pyridine

ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 238.4 [M+1]⁺,

239.4 [M+2]⁺; analysis for C₁₀H₁₂ClN₅(237.6), calcd:

C, 50.53; H, 5.09; N, 29.46. Found: C, 50.50; H, 5.11;

N, 29.49.

5.2.2.41. N-(2-Phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-

guanidine (3e). Yield: 68%; white solid; mp 236–238

ꢁC; IR (KBr): 3430, 2854, 1610 cm^À1

.

¹H NMR

(300 MHz, CDCl₃) d 7.03–7.04 (m, 1H, benzene ring),

7.12–7.13 (m, 1H, pyridine ring), 7.39–7.48 (m, 2H, ben-

zene ring), 7.67–7.68 (d, 1H, pyridine ring), 7.97–7.98 (d,

2H, benzene ring), 8.20–8.21 (d, 1H, pyridine ring),

11.77 (s, 1H, –NH). MS (ESI) m/z 251.8 [M+1]⁺; analy-

sis for C₁₄H₁₃N₅(251.2), calcd: C, 66.92; H, 5.21; N,

27.87. Found: C, 66.89; H, 5.22; N, 27.85.

5.2.2.47. N-(2-Benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-

guanidine (3k). Yield: 66%; white solid; mp 232–

234 ꢁC; IR (KBr): 3400, 2854, 1610, 1400 cm^À1

.

¹H

NMR (300 MHz, CDCl₃) d 3.81 (s, 2H, –CH₂–Ph),

7.12–7.13 (m, 1H, pyridine ring), 7.28–7.29 (d, 1H, pyr-

idine ring), 7.30 – 7.41 (m, 5H, benzene ring), 8.55–8.56

(d, 1H, pyridine ring). MS (ESI) m/z 265.7 [M+1]⁺; anal-

ysis for C₁₅H₁₅N₅(265.1), calcd: C, 67.90; H, 5.70; N,

26.40. Found: C, 67.88; H, 5.73; N, 26.44.

5.2.2.42. N-(5-Chloro-2-phenyl-1H-pyrrolo[2,3-b]pyri-

din-3-yl)-guanidine (3f). Yield: 63%; white solid; mp 243–

245 ꢁC; IR (KBr): 3400, 2854, 1610, 775 cm^À1. ¹H NMR

(300 MHz, CDCl₃) d 7.10–7.11 (m, 1H, benzene ring),

7.39–7.48 (m, 2H, benzene ring), 7.80 (s, 1H, pyridine

ring), 7.96–7.97 (d, 2H, benzene ring), 8.48 (s, 1H, pyr-

idine ring), 11.71 (s, 1H, –NH). MS (ESI) m/z 285.8

[M+1]⁺, 286.8 [M+2]⁺; analysis for C₁₄H₁₂ClN₅(285),

calcd: C, 58.85; H, 4.23; N, 24.51. Found: C, 58.82; H,

4.26; N, 24.48.

5.2.2.48. N-(2-Benzyl-5-chloro-1H-pyrrolo[2,3-b]pyri-

din-3-yl)-guanidine (3l). Yield: 68%; white solid; mp 240–

242 ꢁC; IR (KBr): 3400, 2854, 1610, 1400, 775,

1

720 cm^À1. H NMR (300 MHz, CDCl₃) d 3.81 (s, 2H,

–CH₂–Ph), 7.23–7.24 (m, 5H, benzene ring), 7.31–7.32

(d, 1H, pyridine ring), 8.52–8.53 (d, 1H, pyridine ring).

MS (ESI) m/z 300.3 [M+1]⁺, 301.3 [M+2]⁺; analysis

for C₁₅H₁₄ClN₅(299.6.1), calcd: C, 60.10; H, 4.71; N,

23.36. Found: C, 60.13; H, 4.75; N, 23.38.

5.2.2.43. N-(2-Cyclohexyl-1H-pyrrolo[2,3-b]pyridin-3-

yl)-guanidine (3g). Yield: 65%; white solid; mp 228–

5.2.3. General method for the synthesis of N-(2,5-disub-

stituted-1H-indol-3-yl)-guanidine (4a–l; Scheme 3).

230 ꢁC; IR (KBr): 3400, 2854, 1610, 1410, 720 cm^À1

.

¹H NMR (300 MHz, CDCl₃) d 1.29–1.30 (m, 6H,

–cyclohex), 1.58–1.59 (m, 4H, –cyclohex), 2.76–2.77

(m, 1H, –cyclohex), 7.20–7.21 (m, 1H, pyridine ring),

7.65–7.66 (d, 1H, pyridine ring), 8.51–8.52 (d, 1H, pyri-

dine ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 257.8

[M+1]⁺; analysis for C₁₄H₉N₅(257), calcd: C, 65.34;

H, 7.44; N, 27.22. Found: C, 65.32; H, 7.47; N, 27.18.

5.2.3.1. Synthesis of 3-nitro-1H-indole (12a). To a mix-

ture of indole (11a; 1 g, 8.55 mmol) and silver nitrate

(AgNO₃; 1.55 g, 9.1 mmol), dissolved in acetonitrile

(8 mL), a solution of benzoyl chloride (1.25 g, 9.1 mmol)

was added dropwise, at 0 ꢁC. The reaction mixture was

stirred at 0 ꢁC for 45 min. The mixture was diluted with

water (200 mL), extracted with benzene (3 · 30 mL),

and the extract was washed with Na₂CO₃solution

(2 N). The organic layer was dried over Na₂SO₄and evap-

orated under reduced pressure to obtain the amorphous

material. Residue obtained was acidiﬁed with HCl (2 N)

solution. The white precipitate obtained was ﬁltered,

dried and recrystallized from Benzene to get the pure com-

pound 12a. Yield: 61%; yellow solid; mp 212–213 ꢁC; IR

5.2.2.44.

N-(5-Chloro-2-cyclohexyl-1H-pyrrolo[2,3-

b]pyridin-3-yl)-guanidine (3h). Yield: 61%; white solid;

mp 234–236 ꢁC; IR (KBr): 3400, 2854, 1610, 1410,

1

775, 720 cm^À1. H NMR (300 MHz, CDCl₃) d 1.29–

1.30 (m, 6H, –cyclohex), 1.58–1.59 (m, 4H, –cyclohex),

2.76–2.77 (m, 1H, –cyclohex), 7.66–7.67 (d, 1H, pyridine

ring), 8.50–8.51 (d, 1H, pyridine ring), 11.65 (s, 1H,

–NH). MS (ESI) m/z 292.3 [M+1]⁺, 293.3 [M+2]⁺; anal-

ysis for C₁₄H₁₈ClN₅(291.5), calcd: C, 57.63; H, 6.22; N,

24.00. Found: C, 57.60; H, 6.18; N, 24.04.

(KBr): 3400, 2845, 1610, 1540 cm^À1

.

¹H NMR

(300 MHz, CDCl₃): d 6.60 (s, 1H, pyrrole ring), 7.38–

7.39 (m, 1H, benzene ring), 7.55–7.56 (d, 1H, benzene

ring), 7.65–7.66 (d, 1H, benzene ring), 8.55–8.56 (d, 1H,

benzene ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 163.2

[M+1]⁺; analysis for C₈H₆N₂O₂(162), calcd: C, 59.26;

H, 3.73; N, 17.28. Found: C, 59.22; H, 3.70; N, 17.25.

5.2.2.45. N-(2-Ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-

guanidine (3i). Yield: 63%; white solid; mp 218–220 ꢁC;

IR (KBr): 3400, 2854, 1610, 1400, 1375 cm^À^{1 1}H

.

NMR (300 MHz, CDCl₃)

–CH₂CH₃), 2.59–2.60 (m, 2H, –CH₂CH₃), 7.22–7.23

d

1.24–1.25 (t, 3H,

5.2.3.2. 5-Chloro-3-nitro-1H-indole (12b). Yield: 60%;

yellow solid; mp 218–220 ꢁC; IR (KBr): 3400, 2845,

3260

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

1

1610, 1545, 775 cm^À1. H NMR (300 MHz, CDCl₃): d

6.61 (s, 1H, pyrrole ring), 7.55–7.56 (d, 1H, benzene

ring), 7.65–7.66 (d, 1H, benzene ring), 8.44–8.45 (d,

1H, benzene ring), 11.65 (s, 1H, –NH). MS (ESI) m/z

197.3 [M+1]⁺, 198.3 [M+2]⁺; analysis for C₈H₅ClN₂O₂

(196), calcd: C, 48.88; H, 2.56; N, 14.25. Found: C,

48.84; H, 2.52; N, 14.21.

NMR (300 MHz, CDCl₃): d 1.29–1.30 (m, 6H, –cyclo-

hex), 1.58–1.59 (m, 4H, –cyclohex), 2.75–2.76 (m, 1H,

–cyclohex), 7.53–7.54 (d, 1H, benzene ring), 7.68–7.69

(d, 1H, benzene ring), 8.48–8.49 (d, 1H, benzene ring),

11.65 (s, 1H, –NH). MS (ESI) m/z 279.5 [M+1]⁺, 280.5

[M+2]⁺; analysis for C₁₄H₁₅ClN₂O₂(278.1), calcd: C,

58.99; H, 4.95; N 10.58. Found: C, 58.96; H, 4.91; N,

10.54.

5.2.3.3. 5-Chloro-2-methyl-3-nitro-1H-indole (12c).

Yield: 63%; yellow solid; mp 203–205 ꢁC; IR (KBr):

5.2.3.9. 2-Ethyl-3-nitro-1H-indole (12i). Yield: 62%;

yellow solid; mp 213–215 ꢁC; IR (KBr): 3400, 2845,

1

3400, 2845, 1610, 1545, 1375 775 cm^À1. H NMR (300

MHz, CDCl₃): d 2.14 (s, 3H, Methyl), 7.55–7.56 (d,

1H, benzene ring), 7.65–7.66 (d, 1H, benzene ring),

8.55–8.56 (d, 1H, benzene ring), 11.70 (s, 1H, –NH).

MS (ESI) m/z 211.3 [M+1]⁺, 212.3 [M+2]⁺; analysis

for C₉H₇ClN₂O₂(210), calcd: C, 51.32; H, 3.35; N,

13.30. Found: C, 51.30; H, 3.31; N, 13.27.

1610, 1545 1440, 1375 cm^À^{1 1}H NMR (300 MHz,

.

CDCl₃): d 1.23–1.24 (t, 3H, –CH₂CH₃), 2.59–2.60 (m,

2H, –CH₂CH₃), 7.22–7.23 (m, 1H, benzene ring), 7.54–

7.55 (d, 1H, benzene ring), 7.57–7.58 (d, 1H, benzene

ring), 8.53–8.54 (d, 1H, benzene ring), 11.65 (s, 1H,

–NH). MS (ESI) m/z 191.2 [M+1]⁺; analysis for

C₁₀H₁₀N₂O₂(190), calcd: C, 63.15; H, 5.30; N, 14.73.

Found: C, 63.11; H, 5.27; N, 14.70.

5.2.3.4. 2-Methyl-3-nitro-1H-indole (12d). Yield: 67%;

yellow solid; mp 246–248 ꢁC; IR (KBr): 3400, 2845,

1

1610, 1545, 1375 cm^À1. H NMR (300 MHz, CDCl₃):

5.2.3.10. 5-Chloro-2-ethyl-3-nitro-1H-indole (12j).

Yield: 65%; yellow solid; mp 223–224 ꢁC; IR (KBr):

d 2.14 (s, 3H, methyl), 7.32–7.33 (m, 1H, benzene ring),

7.54–7.55 (d, 1H, benzene ring), 7.65–7.66 (d, 1H, ben-

zene ring), 8.50–8.51 (d, 1H, benzene ring), 11.69 (s,

1H, –NH). MS (ESI) m/z 177.2 [M+1]⁺; analysis for

C₉H₈N₂O₂(176), calcd: C, 61.36; H, 4.58; N, 15.90.

Found: C, 61.32; H, 4.55; N, 15.86.

3400, 2845, 1610, 1545 1440, 1375, 745 cm^À1

.

¹H

1.26–1.27 (t, 3H,

NMR (300 MHz, CDCl₃):

d

–CH₂CH₃), 2.61–2.62 (m, 2H, –CH₂CH₃), 7.48–7.49

(d, 1H, Benzene ring), 7.55–7.56 (d, 1H, benzene ring),

8.51–8.52 (d, 1H, benzene ring), 11.65 (s, 1H, –NH).

MS (ESI) m/z 225.3 [M+1]⁺, 226.3 [M+2]⁺; analysis

for C₁₀H₉ClN₂O₂(224.1), calcd: C, 54.47; H, 4.04; N,

12.47. Found: C, 54.43; H, 4.00; N, 12.43.

5.2.3.5. 3-Nitro-2-phenyl-1H-indole (12e). Yield: 68%;

yellow solid; mp 237–239 ꢁC; IR (KBr): 3400, 2845,

1

1610, 1545 1435 cm^À1. H NMR (300 MHz, CDCl₃): d

7.39–7.40 (m, 5H, benzene ring), 7.21–7.22 (m, 1H, ben-

zene ring), 7.55–7.56 (d, 1H, benzene ring), 7.66–7.67 (d,

1H, benzene ring), 8.52–8.53 (d, 1H, benzene ring),

11.65 (s, 1H, –NH). MS (ESI) m/z 239.5 [M+1]⁺; analy-

sis for C₁₄H₁₀N₂O₂(238.2), calcd: C, 70.58; H, 4.23; N,

11.76. Found: C, 70.55; H, 4.22; N, 11.73.

5.2.3.11. 2-Benzyl-3-nitro-1H-indole (12k). Yield:

64%; yellow solid; mp 237–239 ꢁC; IR (KBr): 3400,

2845, 1610, 1545 1440 cm^À^{1 1}H NMR (300 MHz,

.

CDCl₃): d 3.81 (s, 2H, –CH₂–Ph), 7.30–7.40 (m, 5H,

benzene ring), 7.43–7.44 (m, 1H, benzene ring), 7.55–

7.56 (d, 1H, benzene ring), 7.77–7.78 (d, 1H, benzene

ring), 8.53–8.54 (d, 1H, benzene ring), 11.65 (s, 1H,

–NH). MS (ESI) m/z 253.2 [M+1]⁺; analysis for

C₁₅H₁₂N₂O₂(252), calcd: C, 71.42; H, 4.79; N, 11.10.

Found: C, 71.40; H, 4.76; N, 11.07.

5.2.3.6. 5-Chloro-3-nitro-2-phenyl-1H-indole (12f).

Yield: 63%; yellow solid; mp 223–225 ꢁC; IR (KBr):

1

3400, 2845, 1610, 1545 1435, 770 cm^À1. H NMR (300

MHz, CDCl₃): d 7.30 –7.39 (m, 5H, benzene ring),

7.41–7.42 (d, 1H, benzene ring), 7.55–7.56 (d, 1H, ben-

zene ring), 8.50–8.51 (d, 1H, benzene ring), 11.65 (s,

1H, –NH). MS (ESI) m/z 273.3 [M+1]⁺, 274.3 [M+2]⁺;

analysis for C₁₄H₉ClN₂O₂(272), calcd: C, 61.66; H,

3.33; N, 10.27. Found: C, 61.63; H, 3.30; N, 10.24.

5.2.3.12. 2-Benzyl-5-chloro-3-nitro-1H–indole (12l).

Yield: 66%; yellow solid; mp 225–226 ꢁC; IR (KBr):

1

3400, 2845, 1610, 1545 1440, 775 cm^À1. H NMR (300

MHz, CDCl₃): d 3.81 (s, 2H, –CH₂–Ph), 7.29–7.30 (m,

5H, benzene ring), 7.55–7.56 (d, 1H, benzene ring),

7.71–7.72 (d, 1H, benzene ring), 8.56–8.57 (d, 1H, ben-

zene ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 287.2

[M+1]⁺, 288.2 [M+2]⁺; analysis for C₁₅H₁₁ClN₂O₂

(286), calcd: C, 62.84; H, 3.87; N, 9.77. Found: C,

62.80; H, 3.83; N, 9.75.

5.2.3.7. 2-Cyclohexyl-3-nitro-1H-indole (12g). Yield:

66%; yellow solid; mp 207–209 ꢁC; IR (KBr): 3400,

2845, 1610, 1545 1440, 1375, 720 cm^À^{1 1}H NMR

.

(300 MHz, CDCl₃): d 1.29–1.30 (m, 6H, –cyclohex),

1.58–1.59 (m, 4H, –cyclohex), 2.76–2.77 (m, 1H, –cyclo-

hex), 7.21–7.22 (m, 1H, benzene ring), 7.55–7.56 (d, 1H,

benzene ring), 7.66–7.67 (d, 1H, benzene ring), 8.52–8.53

(d, 1H, benzene ring), 11.65 (s, 1H, –NH). MS (ESI) m/z

245.3 [M+1]⁺; analysis for C₁₄H₁₆N₂O₂(244), calcd: C,

68.83; H, 6.60; N, 11.47. Found: C, 68.80; H, 6.56; N,

11.43.

5.2.3.13. Synthesis of 3-amino-1H-indole (13a). A mix-

ture of 3-nitro-1H-indole (12a; 0.2 g, 1.234 mmol) and

Pd/C (10%; 100 mg), dissolved in ethanol (10 mL), was

hydrogenated for 3 h, at 50 psi. The reaction mixture

was ﬁltered and the excess of ethanol was evaporated

under reduced pressure. Solid product was recrystallized

from petroleum ether to obtain the pure compound 13a.

Yield: 61%; yellow solid; mp 115–117 ꢁC; IR (KBr):

5.2.3.8. 5-Chloro-2-cyclohexyl-3-nitro-1H-indole (12h).

Yield: 69%; yellow solid; mp 224–225 ꢁC; IR (KBr):

1

3400, 2845, 1610 cm^À1. H NMR (300 MHz, CDCl₃):

1

3400, 2845, 1610, 1545 1440, 1375, 775, 720 cm^À1. H

d 6.60 (s, 1H, pyrrole ring), 7.38–7.39 (m, 1H, benzene

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

3261

ring), 7.55–7.56 (d, 1H, benzene ring), 7.65–7.66 (d, 1H,

benzene ring), 8.52–8.53 (d, 1H, benzene ring), 11.65 (s,

2H, –NH₂). MS (ESI) m/z 133.3 [M+1]⁺; analysis for

C₈H₈N₂(132), calcd: C, 72.70; H, 6.10; N, 21.20. Found:

C, 72.68; H, 6.07; N, 21.17.

(d, 1H, benzene ring), 11.65 (s, 2H, –NH₂). MS (ESI) m/

z 216.2 [M+1]⁺; analysis for C₁₄H₁₈N₂(215), calcd: C,

78.46; H, 8.47; N, 13.07. Found: C, 78.42; H, 8.43; N,

13.05.

5.2.3.20. 5-Chloro-2-cyclohexyl-1H-indol-3-ylamine

(13h). Yield: 71%; yellow solid; mp 127–129 ꢁC; IR

5.2.3.14. 5-Chloro-1H-indol-3-ylamine (13b). Yield:

64%; yellow solid; mp 104–105 ꢁC; IR (KBr): 3400,

(KBr): 3400, 2845, 1600, 1400, 775 cm^À^{1 1}H NMR

.

1

2845, 1610, 775 cm^À1. H NMR (300 MHz, CDCl₃): d

(300 MHz, CDCl₃): d 1.29–1.30 (m, 6H, –cyclohex),

1.58–1.59 (m, 4H, –cyclohex), 2.75–2.76 (m, 1H, –cyclo-

hex), 7.54–2.55 (d, 1H, benzene ring), 7.61–7.62 (d, 1H,

benzene ring), 8.49–8.50 (d, 1H, benzene ring), 11.65 (s,

2H, –NH₂). MS (ESI) m/z 250.2 [M+1]⁺, 251.2 [M+2]⁺;

analysis for C₁₄H₁₇ClN₂(249), calcd: C, 67.60; H, 6.89;

N, 11.26. Found: C, 67.57; H, 6.86; N, 11.23.

6.59 (s, 1H, pyrrole ring), 7.45–7.46 (d, 1H, benzene

ring), 7.61–7.62 (d, 1H, benzene ring), 8.48–8.49 (d,

1H, benzene ring), 11.65 (s, 2H, –NH₂). MS (ESI) m/z

168.3 [M+1]⁺, 169.3 [M+2]⁺; analysis for C₈H₇ClN₂

(167), calcd: C, 57.67; H, 4.23; N, 16.81. Found: C,

57.64; H, 4.20; N, 16.79.

5.2.3.15. 5-Chloro-2-methyl-1H-indol-3-ylamine (13c).

Yield: 67%; yellow solid; mp 137–139 ꢁC; IR (KBr):

5.2.3.21. 2-Ethyl-1H-indol-3-ylamine (13i). Yield:

67%; yellow solid; mp 129–131 ꢁC; IR (KBr): 3400,

3400, 2845, 1610, 1375, 775 cm^À1

.

¹H NMR

2845, 1600, 1400, 1375 cm^À^{1 1}H NMR (300 MHz,

.

(300 MHz, CDCl₃): d 2.14 (s, 3H, methyl), 7.55–7.56

(d, 1H, benzene ring), 7.69–7.70 (d, 1H, benzene ring),

8.55–8.56 (d, 1H, benzene ring), 11.70 (s, 2H, –NH₂).

MS (ESI) m/z 181.1 [M+1]⁺, 182.1 [M+2]⁺; analysis

for C₉H₉ClN₂(180), calcd: C, 59.84; H, 5.02; N, 15.51.

Found: C, 59.81; H, 5.00; N, 15.49.

CDCl₃): d 1.22–1.23 (t, 3H, –CH₂CH₃), 2.59–2.60 (m,

2H, –CH₂CH₃), 7.55–7.56 (d, 1H, benzene ring), 7.61–

7.62 (m, 1H, benzene ring), 7.65–7.66 (d, 1H, benzene

ring), 8.45–8.46 (d, 1H, benzene ring), 11.65 (s, 2H,

–NH₂). MS (ESI) m/z 161.2 [M+1]⁺; analysis for

C₁₀H₁₂N₂(160), calcd: C, 74.97; H, 7.55; N, 17.48.

Found: C, 74.94; H, 7.52; N, 17.44.

5.2.3.16. 2-Methyl-1H-indol-3-ylamine (13d). Yield:

62%; yellow solid; mp 115–116 ꢁC; IR (KBr): 3400,

5.2.3.22. 5-Chloro-2-ethyl-1H-indol-3-ylamine (13j).

Yield: 67%; yellow solid; mp 124–136 ꢁC; IR (KBr):

1

2845, 1600, 1375 cm^À1. H NMR (300 MHz, CDCl₃):

d 2.14 (s, 3H, methyl), 7.32–7.33 (m, 1H, benzene ring),

7.51–7.52 (d, 1H, benzene ring), 7.58–7.59 (d, 1H, ben-

zene ring), 8.49–8.50 (d, 1H, benzene ring), 11.66 (s,

2H, –NH₂). MS (ESI) m/z 148.2 [M+1]⁺; analysis for

C₉H₁₀N₂(147), calcd: C, 73.94; H, 6.89; N, 19.16.

Found: C, 73.91; H, 6.87; N, 19.13.

3400, 2845, 1600, 1400, 1375, 770 cm^À^{1 1}H NMR

.

(300 MHz, CDCl₃): d 1.24–1.25 (t, 3H, –CH₂CH₃),

2.59–2.60 (m, 2H, –CH₂CH₃), 7.48–7.49 (d, 1H, benzene

ring), 7.55–7.56 (d, 1H, benzene ring), 8.51–8.52 (d, 1H,

benzene ring), 11.65 (s, 2H, –NH₂). MS (ESI) m/z 195.2

[M+1]⁺, 196.2 [M+2]⁺; analysis for C₁₀H₁₁ClN₂(194),

calcd: C, 61.70; H, 5.70; N, 14.39. Found: C, 61.67; H,

5.67; N, 14.36.

5.2.3.17. 2-Phenyl-1H-indol-3-ylamine (13e). Yield:

68%; yellow solid; mp 108–110 ꢁC; IR (KBr): 3400,

1

2845, 1600, 1375 cm^À1. H NMR (300 MHz, CDCl₃):

5.2.3.23. 2-Benzyl-1H-indol-3-ylamine (13k). Yield:

62%; yellow solid; mp 143–145 ꢁC; IR (KBr): 3400,

d 7.13–7.18 (m, 5H, benzene ring), 7.20–7.21 (m, 1H,

benzene ring), 7.55–7.56 (d, 1H, benzene ring), 7.63–

7.64 (d, 1H, benzene ring), 8.52–8.53 (d, 1H, benzene

ring), 11.65 (s, 2H, –NH₂). MS (ESI) m/z 210.2

[M+1]⁺; analysis for C₁₄H₁₂N₂(209), calcd: C, 80.74;

H, 5.81; N, 13.45. Found: C, 80.72; H, 5.79; N, 13.42.

1

2845, 1600, 1400 cm^À1. H NMR (300 MHz, CDCl₃):

d 3.81 (s, 2H, –CH₂–Ph), 7.29 – 7.39 (m, 5H, benzene

ring), 7.42–7.43 (m, 1H, benzene ring), 7.55–7.56 (d,

1H, benzene ring), 7.76–7.77 (d, 1H, benzene ring),

8.51–8.52 (d, 1H, benzene ring), 11.65 (s, 2H, –NH₂).

MS (ESI) m/z 224.3 [M+1]⁺; analysis for C₁₅H₁₄N₂

(223), calcd: C, 81.05; H, 6.35; N, 12.60. Found: C,

81.03; H, 6.31; N, 12.56.

5.2.3.18. 5-Chloro-2-phenyl-1H-indol-3-ylamine (13f).

Yield: 66%; yellow solid; mp 125–127 ꢁC; IR (KBr):

3400, 2845, 1600, 776 cm^À1

.

¹H NMR (300 MHz,

CDCl₃): d 7.30 – 7.40 (m, 5H, benzene ring), 7.42–7.43

(d, 1H, benzene ring), 7.45–7.46 (d, 1H, benzene ring),

8.51–8.52 (d, 1H, benzene ring), 11.65 (s, 2H, –NH₂).

MS (ESI) m/z 243.2 [M+1]⁺, 244.2 [M+2]⁺; analysis

for C₁₄H₁₁ClN₂(242), calcd: C, 69.28; H, 4.57; N

11.54. Found: C, 69.25; H, 4.54; N 11.51.

5.2.3.24. 2-Benzyl-5-chloro-1H-indol-3-ylamine (13l).

Yield: 61%; yellow solid; mp 124–126 ꢁC; IR (KBr):

3400, 2845, 1600, 1400, 776 cm^À1

.

¹H NMR

(300 MHz, CDCl₃): d 3.81 (s, 2H, –CH₂–Ph), 7.34–

7.42 (m, 5H, benzene ring), 7.70–7.71 (d, 1H, benzene

ring), 8.55–8.56 (d, 1H, benzene ring), 11.65 (s, 2H,

–NH₂). MS (ESI) m/z 257.4 [M+1]⁺, 258.4 [M+2]⁺; anal-

ysis for C₁₅H₁₃ClN₂(256), calcd: C, 70.18; H, 5.10; N,

10.91. Found: C, 70.14; H, 5.06; N, 10.87.

5.2.3.19. 2-Cyclohexyl-1H-indol-3-ylamine (13g).

Yield: 69%; yellow solid; mp 109–111 ꢁC; IR (KBr):

3400, 2845, 1600, 1400, 720 cm^À1

.

¹H NMR

(300 MHz, CDCl₃): d 1.29–1.30 (m, 6H, –cyclohex),

1.58–1.59 (m, 4H, –cyclohex), 2.76–2.77 (m, 1H, –cyclo-

hex), 7.21–7.22 (m, 1H, benzene ring), 7.55–7.56 (d, 1H,

benzene ring), 7.61–7.62 (d, 1H, benzene ring), 8.50–7.51

5.2.3.25. Synthesis of bis-Boc-N-(1H-indol-3-yl)-gua-

nidine (14a). Synthesis of compound 14a was carried out

starting from 3-amino-1H-indole (13a), using a general

procedure described for the synthesis of compound 6a.

3262

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

Yield: 62%; white solid; mp 188–189 ꢁC; IR (KBr): 3400,

2850, 1710, 1610, 1050 cm^À^{1 1}H NMR (300 MHz,

COANHA), 7.30 –7.40 (m, 5H, benzene ring), 7.55–

7.56 (d, 1H, benzene ring), 7.60–7.61 (d, 1H, benzene

ring), 8.50–8.51 (d, 1H, benzene ring), 11.65 (s, 1H,

–NH). MS (ESI) m/z 485.3 [M+1]⁺, 486.3 [M+2]⁺; anal-

ysis for C₂₅H₂₉ClN₄O₄(484), calcd: C, 61.91; H, 6.03; N,

11.55. Found: C, 61.88; H, 6.00; N, 11.53.

.

CDCl₃): d 1.43 (s, 9H, (CH₃)₃CAOACOAN@), 1.56

(s, 9H, (CH₃)₃CAOACOANHA), 6.60 (s, 1H, pyrrole

ring), 7.20–7.21 (d, 1H, benzene ring), 7.55–7.56 (d,

1H, benzene ring), 7.68–7.69 (dd, 1H, benzene ring),

8.49–8.50 (d, 1H, benzene ring), 11.65 (s, 1H, –NH).

MS (ESI) m/z 375.3 [M+1]⁺; analysis for C₁₉H₂₆N₄O₄

(374), calcd: C, 60.95; H, 7.00; N, 14.96. Found: C,

60.91; H, 6.98; N, 14.93.

5.2.3.31. Bis-Boc-N-(2-cyclohexyl-1H-indol-3-yl)-gua-

nidine (14g). Yield: 68%; white solid; mp 142–143 ꢁC; IR

(KBr): 3400, 2850, 1710, 1610, 1050, 720 cm^{À1 1}H

.

NMR (300 MHz, CDCl₃): d 1.27–1.28 (m, 6H, –cyclo-

hexyl), 1.43 (s, 9H, (CH₃)₃CAOACOAN@), 1.56 (s,

9H, (CH₃)₃CAOACOANHA), 1.58–1.59 (m, 4H,

–cyclohexyl), 2.76–2.77 (m, 1H, –cyclohexyl), 7.20–2.21

(m, 1H, benzene ring), 7.55–7.56 (d, 1H, benzene ring),

7.60–7.61 (d, 1H, benzene ring), 8.50–8.51 (d, 1H, ben-

zene ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 457.3

[M+1]⁺; analysis for C₂₅H₃₆N₄O₄(456), calcd: C,

65.76; H, 7.95; N, 12.27. Found: C, 65.73; H, 7.93; N,

12.24.

5.2.3.26. Bis-Boc-N-(5-chloro-1H-indol-3-yl)-guani-

dine (14b). Yield: 63%; white solid; mp 168–169 ꢁC; IR

(KBr): 3400, 2850, 1710, 1610, 1050, 775 cm^À^{1 1}H

.

NMR (300 MHz, CDCl₃):

d

1.43 (s, 9H,

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

COANHA), 6.60 (s, 1H, pyrrole ring), 7.55–7.56 (d,

1H, benzene ring), 7.68–7.69 (dd, 1H, benzene ring),

8.50–8.51 (d, 1H, benzene ring), 11.65 (s, 1H, –NH).

MS (ESI) m/z 409.3 [M+1]⁺, 410.3 [M+2]⁺; analysis

for C₁₉H₂₅ClN₄O₄(408), calcd: C, 55.81; H, 6.16; N,

13.70. Found: C, 55.78; H, 6.14; N, 13.68.

5.2.3.32. Bis-Boc-N-(5-chloro-2-cyclohexyl-1H-indol-

3-yl)-guanidine (14h). Yield: 61%; white solid; mp 158–

159 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1050, 775,

5.2.3.27.

Bis-Boc-N-(5-chloro-2-methyl-1H-indol-3-

yl)-guanidine (14c). Yield: 58%; white solid; mp 168–

169 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1375, 1050,

720 cm^À^{1 1}H NMR (300 MHz, CDCl₃): d 1.29–1.30

.

(m, 6H, –cyclohex), 1.43 (s, 9H, (CH₃)₃CAOA

COAN@), 1.56 (s, 9H, (CH₃)₃CAOACOAN), 1.58–

1.59 (m, 4H, –cyclohex), 2.76–2.77 (m, 1H, –cyclohex),

7.55–7.56 (d, 1H, benzene ring), 7.60–7.61 (d, 1H, ben-

zene ring), 8.49–8.50 (d, 1H, benzene ring), 11.65 (s,

1H, –NH). MS (ESI) m/z 491.2 [M+1]⁺, 492.2 [M+2]⁺;

analysis for C₂₅H₃₅ClN₄O₄(490), calcd: C, 61.15; H,

7.18; N, 11.41. Found: C, 61.11; H, 7.15; N, 11.38.

1

775 cm^À1. H NMR (300 MHz, CDCl₃): d 1.43 (s, 9H,

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

COANHA), 2.16 (s, 3H, methyl), 7.80 (s, 1H, benzene

ring), 8.48 (s, 1H, benzene ring), 11.70 (s, 1H, –NH).

MS (ESI) m/z 423.2 [M+1]⁺, 424.2 [M+2]⁺; analysis

for C₂₀H₂₇ClN₄O₄(422), calcd: C, 56.80; H, 6.44; N,

13.25. Found: C, 56.77; H, 6.42; N, 13.23.

5.2.3.28. Bis-Boc-N-(2-methyl-1H-indol-3-yl)-guani-

dine (14d). Yield: 70%; white solid; mp 155–157 ꢁC; IR

5.2.3.33. Bis-Boc-N-(2-ethyl-1H-indol-3-yl)-guanidine

(14i). Yield: 63%; white solid; mp 168–169 ꢁC; IR (KBr):

(KBr): 3400, 2850, 1710, 1610, 1375, 1050 cm^À1

.

¹H

1.43 (s, 9H,

3400, 2850, 1710, 1610, 1375 1050 cm^À^{1 1}H NMR

.

NMR (300 MHz, CDCl₃):

d

(300 MHz, CDCl₃): d 1.23–1.24 (t, 3H, –CH₂CH₃),

1.43 (s, 9H, (CH₃)₃CAOACOAN@), 1.56 (s, 9H,

(CH₃)₃CAOACOANA), 2.58–2.59 (m, 2H, –CH₂CH₃),

7.23–7.24 (d, 1H, benzene ring), 7.55–7.56 (d, 1H, ben-

zene ring), 7.67–7.68 (dd, 1H, benzene ring), 8.54–8.55

(d, 1H, benzene ring), 11.65 (s, 1H, –NH). MS (ESI)

m/z 403.2 [M+1]⁺; analysis for C₂₁H₃₀N₄O₄(402), calcd:

C, 62.67; H, 7.51; N, 13.92. Found: C, 62.64; H, 7.49; N,

13.88.

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

COANHA), 2.16(s, 3H, methyl), 7.11–7.12 (m, 1H, ben-

zene ring), 7.55–7.56 (d, 1H, benzene ring), 7.67 (s, 1H,

benzene ring), 8.53 (s, 1H, benzene ring), 11.72 (s, 1H,

–NH). MS (ESI) m/z 389.2 [M+1]⁺; analysis for

C₂₀H₂₈N₄O₄(388), calcd: C, 61.84; H, 7.27; N, 14.42.

Found: C, 61.81; H, 7.25; N, 14.40.

5.2.3.29. Bis-Boc-N-(2-phenyl-1H-indol-3-yl)-guani-

dine (14e). Yield: 65%; white solid; mp 152–153 ꢁC; IR

5.2.3.34. Bis-Boc-N-(5-chloro-2-ethyl-1H-indol-3-yl)-

guanidine (14j). Yield: 66%; white solid; mp 170–

171 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1375

(KBr): 3400, 2850, 1710, 1610, 1050 cm^{À1 1}H NMR

.

(300 MHz, CDCl₃):

d 1.43 (s, 9H, (CH₃)₃CA

1

OACOAN@), 1.56 (s, 9H, (CH₃)₃CAOACOANHA),

7.44–7.45 (m, 5H, benzene ring), 7.23–7.24 (m, 1H, ben-

zene ring), 7.56–7.57 (d, 1H, benzene ring), 7.67–7.68 (d,

1H, benzene ring), 8.58–8.59 (d, 1H, benzene ring),

11.65 (s, 1H, –NH). MS (ESI) m/z 451.1 [M+1]⁺

C₂₅H₃₀N₄O₄(450), calcd: C, 66.65; H, 6.71; N, 12.44.

Found: C, 66.63; H, 6.68; N, 12.41.

1050 cm^À1. H NMR (300 MHz, CDCl₃): d 1.24–1.25

(t, 3H, –CH₂CH₃), 1.43 (s, 9H, (CH₃)₃CAOACOAN@),

1.56 (s, 9H, (CH₃)₃CAOACOANHA), 2.59–2.60 (m,

2H, –CH₂CH₃), 7.55–7.56 (d, 1H, benzene ring), 7.67–

7.68 (dd, 1H, benzene ring), 8.50–8.51 (d, 1H, benzene

ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 437.2 [M+1]⁺,

438.2 [M+2]⁺; analysis for C₂₁H₂₉ClN₄O₄9436), calcd:

C, 57.73; H, 6.69; N, 12.82. Found: C, 57.70; H, 6.66;

N, 12.80.

5.2.3.30. Bis-Boc-N-(5-chloro-2-Methyl-1H-indol-3-

yl)-guanidine (14f). Yield: 67%; white solid; mp 172–

174 ꢁC; IR (KBr): 3400, 2850, 1710, 1610, 1050,

5.2.3.35. Bis-Boc-N-(2-benzyl-1H-indol-3-yl)-guani-

dine (14k). Yield: 69%; white solid; mp 185–186 ꢁC; IR

1

775 cm^À1. H NMR (300 MHz, CDCl₃): d 1.43 (s, 9H,

(CH₃)₃CAOACOAN@), 1.56 (s, 9H, (CH₃)₃CAOA

(KBr): 3400, 2850, 1710, 1610, 1050 cm^À^{1 1}H NMR

.

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

3263

(300 MHz, CDCl₃): d 1.43 (s, 9H, (CH₃)₃CAOA

COAN@), 1.56 (s, 9H, (CH₃)₃CAOACOANHA), 3.81

(s, 2H, –CH₂–Ph), 7.30–7.40 (m, 5H, benzene ring),

7.42–7.43 (m, 1H, benzene ring), 7.55–7.56 (d, 1H, ben-

zene ring), 7.61–7.62 (dd, 1H, benzene ring), 8.50–8.51

(d, 1H, benzene ring), 11.65 (s, 1H, –NH). MS (ESI)

m/z 465.3 [M+1]⁺; analysis for C₂₆H₃₂N₄O₄(464), calcd:

C, 67.22; H, 6.94; N, 12.06. Found: C, 67.19; H, 6.91; N,

12.03.

5.2.3.41. N-(2-Phenyl-1H-indol-3-yl)-guanidine (4e).

Yield: 63%; white solid; mp 118–119 ꢁC; IR (KBr):

1

3430, 2854, 1610 cm^À1. H NMR (300 MHz, CDCl₃): d

7.03–7.04 (m, 1H, benzene ring), 7.12–7.13 (m, 1H, ben-

zene ring), 7.39–7.48 (m, 2H, benzene ring), 7.55–7.56

(d, 1H, benzene ring), 7.67–7.68 (d, 1H, benzene ring),

7.96–7.97 (d, 2H, benzene ring), 8.20–8.21 (d, 1H, benzene

ring), 11.77 (s, 1H, –NH). MS (ESI) m/z 251.2 [M+1]⁺;

analysis for C₁₅H₁₄N₄(250), calcd: C, 71.98; H, 5.64; N,

22.38. Found: C, 71.95; H, 5.60; N, 22.34.

5.2.3.36. Bis-Boc-N-(5-chloro-2-benzyl-1H-indol-3-yl)-

guanidine (14l). Yield: 60%; white solid; mp 153–154 ꢁC;

5.2.3.42. N-(5-Chloro-2-phenyl-1H-indol-3-yl)-guani-

dine (4f). Yield: 67%; white solid; mp 145–147 ꢁC; IR

1

IR (KBr): 3400, 2850, 1710, 1610, 1050, 775 cm^À1. H

NMR (300 MHz, CDCl₃): d 1.43 (s, 9H, (CH₃)₃CA

OACOAN@), 1.56 (s, 9H, (CH₃)₃CAOACOANHA),

3.81 (s, 2H, –CH₂–Ph), 7.22–7.23 (m, 5H, benzene;

7.55–7.56 (d, 1H, benzene ring), 7.66–7.67 (dd, 1H, ben-

zene ring), 8.52–8.53 (d, 1H, benzene ring), 11.65 (s, 1H,

–NH). MS (ESI) m/z 499.2 [M+1]⁺, 500.2 [M+2]⁺; Anal.

Calcd for C₂₆H₃₁ClN₄O₄(498), calcd: C, 62.58; H, 6.26;

N, 11.23. Found: C, 62.55; H, 6.22; N, 11.20.

(KBr) 3400, 2854, 1610, 775 cm^À1

.

¹H NMR

(300 MHz, CDCl₃): d 7.11–7.12 (m, 1H, benzene ring),

7.39–7.48(m, 2H, benzene ring), 7.55–7.56 (d, 1H, ben-

zene ring), 7.8 (s, 1H, benzene ring), 7.97–7.98 (d, 2H,

benzene ring), 8.48 (s, 1H, benzene ring), 11.7 (s, 1H,

–NH). MS (ESI) m/z 285.2 [M+1]⁺, 286.2 [M+2]⁺; anal-

ysis for C₁₅H₁₃ClN₄(284), calcd: C, 63.27; H, 4.60; N,

19.68. Found: C, 63.23; H, 4.56; N, 19.64.

5.2.3.37. Synthesis of N-(1H-Indol-3-yl)-guanidine

(4a). Synthesis of compound 4a was carried out starting

from bis-Boc-N-(1H-indol-3-yl)-guanidine (14a), using a

general procedure described for the synthesis of com-

pound 2a. Yield: 61%; white solid; mp 122–123 ꢁC; IR

5.2.3.43.

N-(2-Cyclohexyl-1H-indol-3-yl)-guanidine

(4g). Yield: 61%; white solid; mp 115–116 ꢁC; IR (KBr):

3400, 2854, 1610, 1410, 720 cm^À1. H NMR (300 MHz,

1

CDCl₃): d 1.29–1.30 (m, 6H, –cyclohex), 1.58–1.59 (m,

4H, –cyclohex), 2.76–2.77 (m, 1H, –cyclohex), 7.20–7.21

(m, 1H, benzene ring), 7.55–7.56 (d, 1H, benzene ring),

7.62–7.63 (d, 1H, benzene ring), 8.52–8.53 (d, 1H, benzene

ring), 11.65 (s, 1H, –NH). MS (ESI) m/z 257.2 [M+1]⁺;

analysis for C₁₅H₂₀N₄(256), calcd: C, 70.28; H, 7.86; N,

21.86. Found: C, 70.25; H, 7.82; N, 21.83.

(KBr): 3430, 2854, 1610 cm^À^{1 1}H NMR (300 MHz,

.

CDCl₃): d 6.70 (s, 1H, pyrrole ring), 7.13–7.14 (m, 1H,

benzene ring), 7.56–7.57 (d, 1H, benzene ring), 7.68–

7.69 (d, 1H, benzene ring), 8.22–8.23 (d, 1H, benzene

ring), 11.77 (s, 1H, –NH). MS (ESI) m/z 175 [M+1]⁺;

analysis for C₉H₁₀N₄(174), calcd: C, 62.05; H, 5.79;

N, 32.16. Found: C, 62.01; H, 5.75; N, 32.13.

5.2.3.44. N-(5-Chloro-2-cyclohexyl-1H-indoyl-3-yl)-

guanidine (4h). Yield: 65%; white solid; mp 138–139 ꢁC;

1

5.2.3.38. N-(5-Chloro-1H-indol-3-yl)-guanidine (4b).

Yield: 66%; white solid; mp 99–101 ꢁC; IR (KBr):

IR (KBr): 3400, 2854, 1610, 1410, 775, 720 cm^À1. H

NMR (300 MHz, CDCl₃): d 1.29–1.31 (m, 6H, –cyclo-

hex), 1.58–1.59 (m, 4H, –cyclohex), 2.76–2.77 (m, 1H,

–cyclohex), 7.55–7.56 (d, 1H, benzene ring), 7.66–7.77

(d, 1H, benzene ring), 8.50–8.51 (d, 1H, benzene ring),

11.65 (s, 1H, –NH). MS (ESI) m/z 292.2 [M+1]⁺, 293.2

[M+2]⁺; analysis for C₁₅H₁₉ClN₄(291), calcd: C, 61.96;

H, 6.59; N, 19.27. Found: C, 61.92; H, 6.56; N, 19.24.

3430, 2854, 1610, 774 cm^À1

.

¹H NMR (300 MHz,

CDCl₃): d 6.70 (s, 1H, pyrrole ring), 7.55–7.56 (d, 1H,

benzene ring), 7.67–7.68 (d, 1H, benzene ring), 8.20–

8.21 (d, 1H, benzene ring), 11.77 (s, 1H, –NH); MS

(ESI) m/z 209.3 [M+1]⁺, 210.3 [M+2]⁺; analysis for

C₉H₉ClN₄(208), calcd: C, 51.81; H, 4.35; N, 26.85.

Found: C, 51.78; H, 4.31; N, 26.82.

5.2.3.45. N-(2-Ethyl-1H-indol-3-yl)-guanidine (4i).

Yield: 67%; white solid; mp 133–134 ꢁC; IR (KBr):

5.2.3.39. N-(5-Chloro-2-methyl-1H-indol-3-yl)-guani-

dine (4c). Yield: 60%; white solid; mp 138–139 ꢁC; IR

3400, 2854, 1610, 1400, 1375.cm^À^{1 1}H NMR (300

.

(KBr): 3400, 2854, 1610, 1375, 775 cm^À1

.

¹H NMR

MHz, CDCl₃): d 1.22–1.23 (t, 3H, –CH₂CH₃), 2.59–

2.60 (m, 2H, –CH₂CH₃), 7.22–7.23 (m, 1H, benzene

ring), 7.55–7.56 (d, 1H, benzene ring), 7.70–7.71 (d,

1H, benzene ring), 8.53–8.54 (d, 1H, benzene ring),

11.65 (s, 1H, –NH). MS (ESI) m/z 203.2 [M+1]⁺; analysis

for C₁₁H₁₄N₄(202), calcd: C, 65.32; H, 6.98; N, 27.70.

Found: C, 65.28; H, 6.96; N, 27.66.

(300 MHz, CDCl₃): d 2.16 (s, 3H, methyl), 7.80 (s, 1H,

benzene ring), 8.48 (s, 1H, benzene ring), 11.70 (s, 1H,

–NH). MS (ESI) m/z 223.1 [M+1]⁺, 224.1 [M+2]⁺; anal-

ysis for C₁₀H₁₁ClN₄(222), calcd: C, 53.94; H, 4.98; N,

25.16. Found: C, 53.92; H, 4.95; N, 25.12.

5.2.3.40. N-(2-Methyl-1H-indol-3-yl)-guanidine (4d).

Yield: 66%; white solid; mp 125–126 ꢁC; IR (KBr): 3400,

5.2.3.46.

dine (4j). Yield: 60%; white solid; mp 148–149 ꢁC; IR

(KBr): 3400, 2854, 1610, 1400, 1375, 775 cm^À^{1 1}H

NMR (300 MHz, CDCl₃): 1.24–1.25 (t, 3H,

–CH₂CH₃), 2.59–2.60 (m, 2H, –CH₂CH₃), 7.55–7.56

(d, 1H, benzene ring), 7.70–7.71 (d, 1H, benzene ring),

8.53–8.54 (d, 1H, benzene ring), 11.65 (s, 1H, –NH).

MS (ESI) m/z 237.2 [M+1]⁺, 238.2 [M+2]⁺; analysis

N-(5-Chloro-2-ethyl-1H-indol-3-yl)-guani-

1

2854,1610, 1375 cm^À1. H NMR (300 MHz, CDCl₃): d

2.16 (s, 3H, methyl), 7.13–7.14 (m, 1H, benzene ring),

7.54–7.55 (d, 1H, benzene ring), 7.67 (s, 1H, Benzene

ring), 8.5 (s, 1H, benzene ring), 11.7 (s, 1H, –NH). MS

(ESI) m/z 189.2 [M+1]⁺; analysis for C₁₀H₁₂N₄(188),

calcd: C, 63.81; H, 6.43; N, 29.77. Found: C, 63.77; H,

6.40; N, 29.73.

.

d

3264

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 3248–3265

for C₁₁H₁₃ClN₄(236), calcd: C, 55.82; H, 5.54; N, 23.67.

Found: C, 55.79; H, 5.51; N, 23.64.

References and notes

1. Wagman, A. S.; Nuss, J. M. Curr. Pharm. Des. 2001, 7,

417.

2. Cavaghan, M. K.; Ehrmann, D. A.; Polonsky, K. S.

J. Clin. Invest. 2000, 106, 329.

3. Chen, K. W.; Boyko, E. J.; Bergstrom, R. W.; Leonetti, D.

L.; Morris, L. N.; Wahl, P. W.; Fujimoto, F. W. Diabetes

Care 1995, 18, 747.

4. Haﬀner, S. M.; Miettinin, H.; Gaskill, S. P.; Stern, M.

Diabetes Care 1995, 18, 1201.

5. Chehade, J. M.; Mooradian, A. D. Drugs 2000, 60, 95.

6. Burge, M. R.; Sood, V.; Sobhy, T. A.; Rassam, A. G.;

Schade, D. S. Diabetes Obes. Metab. 1999, 1, 199.

7. Perry, T. A.; Greig, N. H. Trends Pharmacol. Sci. 2003, 24,

377.

5.2.3.47. N-(2-Benzyl-1H-indol-3-yl)-guanidine (4k).

Yield: 63%; white solid; mp 103–105 ꢁC; IR (KBr):

3400, 2854, 1610, 1400 cm^À^{1 1}H NMR (300 MHz,

.

CDCl₃): d 3.81 (s, 2H, –CH₂–Ph), 7.21–7.29 (m, 1H,

benzene ring), 7.32 – 7.43 (m, 5H, benzene ring), 7.55–

7.56 (d, 1H, benzene ring), 7.63–7.64 (dd, 1H, benzene

ring), 8.53–8.54 (d, 1H, benzene ring), 9.97 (s, 1H,

–NH), 11.65 (s, 1H, –NH). MS (ESI) m/z 265.2

[M+1]⁺; analysis for C₁₆H₁₆N₄(264), calcd: C, 72.70;

H, 6.10; N, 21.20. Found: C, 72.68; H, 6.06; N, 21.17.

5.2.3.48. N-(2-Benzyl-5-chloro-1H-indol-3-yl)-guani-

dine (4l). Yield: 69%; white solid; mp 124–126 ꢁC; IR

8. Schulz, A.; Hasselblatt, A. Naunyn Schmiedeberg’s Arch.

Pharmacol. 1989, 340, 321.

(KBr): 3400, 2854, 1610, 1400, 775, 720 cm^{À1 1}H

.

9. Le Brigand, L.; Virsolvy, A.; Manechez, D.; Godfroid, J.

J.; Guardiola-Lemaitre, B.; Gribble, M.; Ashcroft, F. M.;

Bataille, D. Br. J. Pharmacol. 1999, 128, 1021.

10. Eglen, R. M.; Hudson, A. L.; Kendall, D. A.; Nutt, D. J.;

Morgan, N. G.; Wilson, V. G.; Dilon, M. P. Trends

Pharmacol. Sci. 1998, 19, 381.

11. Brown, C. A.; Loweth, A. C.; Smith, S. A.; Morgan, N. G.

Br. J. Pharmacol. 1993, 108, 312.

12. Chan, S. F.; Brown, C. A.; Scarpello, K. E.; Morgan, N.

G. Br. J. Pharmacol. 1994, 112, 1065.

13. Hoy, M.; Olsen, H. L.; Andersen, H. S.; Okvist, K.;

Buschard, K.; Hansen, J.; Jacobsen, P.; Petersen, J. S.;

Rorsman, P.; Gromada, J. Eur. J. Pharmacol. 2003, 466,

213.

14. Mest, H. J.; Raap, A.; Schloss, J.; Treinies, I.; Paal, M.;

Giese, U.; Koivisto, V. Naunyn Schmiedeberg’s Arch.

Pharmacol. 2001, 364, 47.

15. Morgan, N. G.; Chan, S. L. F.; Mourtada, M.; Monks, L.

K.; Ramsden, C. A. Ann. N.Y. Acad. Sci. 1999, 381, 217.

16. Efendic, S.; Efanov, A. M.; Berggen, P.; Zaitsev, S. V.

Diabetes 2002, 51, S448.

17. Brenner, M. B.; Gromada, J.; Efanov, A. M.; Bokvist, K.;

Mest, H. J. Ann. N.Y. Acad. Sci. 2003, 1009, 332.

18. Efanov, A. M.; Zaitse, S. V.; Mest, H. J.; Raap, A.;

Appelskog, I. B.; Larsson, O.; Berggren, P. O.; Efendic, S.

Diabetes 2001, 50, 797.

19. Davis, T. L. Org. Synth. 1927, 7, 46.

20. Cosand, W. L.; Merriﬁeld, R. B. Proc. Natl. Acad. Sci.

U.S.A. 1977, 74, 2771.

21. Braun, C. E. J. Am. Chem. Soc. 1933, 55, 1280.

22. Bannard, R. A. B.; Casselman, A. A.; Cockburn, W. F.;

Brown, G. M. Can. J. Chem. 1958, 36, 1541.

23. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. Tetrahedron

Lett. 1993, 34, 3389.

24. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J. Org.

Chem. 1992, 57, 2497.

25. Cunha, S.; Costa, M. B.; Napolitano, H. B.; Lariucci, C.;

Vencato, I. Tetrahedron 2001, 57, 1671.

26. Levallet, C.; Lerpiniere, J.; Ko, S. Y. Tetrahedron 1997,

53, 5291.

27. Jeong, J. H.; Murray, B. W.; Takayama, S.; Wong, C. H.

J. Am. Chem. Soc. 1996, 118, 4227.

28. Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677.

29. Ishikawa, T.; Kumamoto, T. Synthesis 2006, 5, 737.

30. Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z.

Tetrahedron Lett. 1992, 33, 5933.

31. Iwanowicz, E.; Poss, M. A.; Lin, J. Syn. Comm. 1993, 23,

1443.

NMR (300 MHz, CDCl₃): d 3.81 (s, 2H, –CH₂–Ph),

7.31 – 7.40 (m, 5H, benzene ring), 7.55–7.56 (d, 1H, ben-

zene ring), 7.63–7.64 (dd, 1H, benzene ring), 8.55–8.56

(d, 1H, benzene ring), 9.97 (s, 1H, –NH), 11.65 (s, 1H,

–NH). MS (ESI) m/z 299.2 [M+1]⁺, 300.2 [M+2]⁺; anal-

ysis for C₁₆H₁₅ClN₄(298), calcd: C, 64.32; H, 5.06; N,

18.75. Found: C, 64.28; H, 5.02; N, 18.73.

5.3. In vitro glucose-dependent insulin secretion (RIN5F

cell assay screening protocol)

RIN5F (rat insulinoma) cells were cultured in RPMI

1640 medium supplemented with sodium pyruvate

(1 mM) Hepes and glucose (4.5 g/L) in a humidiﬁed

incubator (5% CO₂), at 37 ꢁC. After trypsinization,

RIN5F cells were seeded at

a concentration of

0.2 · 10⁶cells per well, in 12-well plates. The cells were

grown overnight to 80% conﬂuence and insulin secretion

experiments were performed as follows.^39,40

Cells were washed once with phosphate-buﬀered saline

(PBS) solution, followed by 40 min incubation in fresh

Krebs–Ringer balanced buﬀer containing NaCl

(115 mmol/L);KCl (4.7 mmol/L), CaCl₂(1.28 mmol/L),

MgSO₄Æ7H₂O (1.2 mmol/L), KH₂PO₄(1.2 mmol/L),

NaHCO₃(10 mmol/L), and Hepes (25 mmol/L), contain-

ing glucose (1.1 mM) and BSA (0.5%), pH 7.4. The buﬀer

was replaced after 40 min and the cells were incubated

(37 ꢁC) with the test and the standard compounds, at dif-

ferent concentrations, for 30 min, both in the presence

(16.7 mM) and absence (0 mM) of glucose load. The

supernatant was collected and the insulin amount was

measured by ultra sensitive Rat insulin ELISA kit (Crys-

tal Chem, IL). The protein was estimated in the superna-

tant using Bicinchoninic Acid kit, according to the

manufacturer’s protocol (Sigma–Aldrich, MO). The total

insulin content obtained in picogram (pg) was divided

with the total protein (lg) in order to normalize for diﬀer-

ences in cell density between wells.

Acknowledgment

We are grateful to the management of Zydus Group for

encouragement and thankful to analytical department

for analytical support.

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Article Doi

Design, synthesis, and biological evaluation of substituted-N-(thieno[2,3-b]pyridin-3-yl)-guanidines, N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidines, and N-(1H-indol-3-yl)-guanidines

DOI: 10.1016/j.bmc.2007.02.029

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Article abstract of DOI:10.1016/j.bmc.2007.02.029

Full text of DOI:10.1016/j.bmc.2007.02.029

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