Structure-activity relationships and CoMFA of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues as NOP receptor agonists with analgesic properties

Available online at www.sciencedirect.com

Bioorganic & Medicinal Chemistry 16 (2008) 2829–2851

Structure–activity relationships and CoMFA of N-3

substituted phenoxypropyl piperidine benzimidazol-2-one

analogues as NOP receptor agonists with analgesic properties

Ronald Palin,^a,*John K. Clark,^aLouise Evans,^bAndrea K. Houghton,^bPhilip S. Jones,^a

Alan Prosser,^aGrant Wishart^aand Kazuya Yoshiizumi^a,ꢀ

^aDepartment of Chemistry, Organon Laboratories Ltd, Newhouse, Lanarkshire ML1 5SH, UK

^bDepartment of Pharmacology, Organon Laboratories Ltd, Newhouse, Lanarkshire ML1 5SH, UK

Received 11 October 2007; revised 20 December 2007; accepted 4 January 2008

Available online 10 January 2008

Abstract—The N-3 position of a series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues was optimised using the

predictive power of a CoMFA model. The model was used to prioritise compounds for synthesis culminating in the triazole

(+)-24. (+)-24 was found to be a high aﬃnity, potent NOP agonist and demonstrated both antinociceptive and antiallodynic eﬀects

when administered iv to rodents.

1. Introduction

opioids such as dynorphin A do not show appreciable

aﬃnity for the NOP receptor.²

The discovery in 1994 of the fourth member of the opi-

oid receptor family, opioid receptor-like receptor

(ORL1, NOP), has led to extensive research into its bio-

logical signiﬁcance.¹Its endogenous ligand, nociceptin

(or Orphanin FQ), is a 17-amino acid neuropeptide ﬁrst

isolated from the brain in 1995.²The peptide binds the

receptor with a very high aﬃnity although activation

of NOP is functionally complex.³Given the nociceptin

receptor is widely distributed throughout the central

nervous system it participates in a variety of roles. Sup-

raspinally NOP appears to have potent anti-analgesic

actions^2,4whereas spinally analgesic properties are ob-

served.⁵Other accounts also demonstrate the NOP sys-

tem plays a signiﬁcant role in pathways of anxiety,

learning, memory, reward, tolerance, cardiovascular

and respiratory function. Despite signiﬁcant sequence

homology of NOP with the classical opioid receptors,

Opioids such as morphine are the most eﬀective treat-

ments for postoperative pain.⁶However, drugs that act

via the mu opioid (MOP) receptor also suﬀer from opi-

oid related side-eﬀects such as constipation, nausea and

vomiting, thus leading to non-compliance with pa-

tients.⁷It is believed that the development of new li-

gands with a high degree of selectivity and potency for

NOP would provide a novel treatment for the manage-

ment of pain without the unfavourable side-eﬀects ob-

served with MOP agonists.

Several small-molecule NOP ligands have now been re-

ported in the literature.⁸Some of these ligands have high

selectivity and potency for the NOP receptor versus the

other opioid receptors.⁹Although many diﬀerent classes

of NOP ligands have been reported limited pharmaco-

phore models have been deﬁned for NOP binding and

selectivity compared with opioid receptors.

Keywords: NOP/ORL1 agonist; Antinociception; Antiallodynia; Pain;

CoMFA model.

In earlier work we had identiﬁed a series of 3-phenoxy-

propyl piperidine benzimidazol-2-ones¹⁰that led to the

optimised compounds (+)-1 and (+)-2 (Fig. 1). These

agonists have high aﬃnity for NOP (pK_i= 9.30 and

8.70, respectively) with excellent selectivity over the

other opioid receptors, in particular MOP (pK_i= 7.27,

*

Corresponding author. Tel.: +44 1698 736128; fax: +44 1698

736187; e-mail addresses: r.palin@organon.co.uk; k.yoshiizumi@

nippon-soda.co.jp

ꢀ

Chemistry Department, Odawara Research Center, Nippon Soda

Co., Ltd, 345, Takada, Odawara, Kanagawa 250-0280, Japan.

doi:10.1016/j.bmc.2008.01.005

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R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

H

N

O

OMe

O

N

OMe

O

N

O

N

O

N

(+)-1

(+)-2

Figure 1. Structure of ORL1 agonist lead compounds.

NOP/MOP = 108 for (+)-1). We attributed the higher

aﬃnity and selectivity of 1 to both the H-bond donating

and accepting capacity of the terminal amide appended

from the N-3 position of the benzimidazol-2-one. In or-

der to explore structure–activity relationships (SAR)

and further optimise this series we focussed on replacing

the amide with suitable heterocyclic (bio)isosteres.

Given the diverse nature of heterocycles we were able to

employ a CoMFA model based on the analysis of the

SAR observed in our own series of NOP ligands. This

technique allowed chemists to ultimately design and pre-

dict activities of molecules to help prioritise the chemis-

try eﬀorts. Herein we report the culmination of this

series, with the synthesis and antinociceptive eﬀects

in vivo.

Figure 2. CoMFA steric ﬁeld standard deviation · coeﬃcient contour

map surrounding (+)-1. Green contours (80% contribution) indicate

regions where steric bulk is favourable. Yellow contours (20%) indicate

regions where steric bulk is not favourable.

contour plot (Fig. 3) is more diﬃcult to interpret. The

red contours favouring negative charge at the 5-position

of the phenoxy moiety are consistent with the preference

for a methoxy substituent. The region surrounding the

benzimidazol-2-one N-3 substituent shows favourable

regions for both positive and negative charge whereas

favourable positive charge at the benzimidazol-2-one

5-position is likely to reﬂect the preference for the

unsubstituted analogue.

2. Results and discussion

2.1. CoMFA modelling

To aid the prioritisation of synthesis a CoMFA 3D

QSAR model was developed. The full model encom-

passed a dataset of 113 3-phenoxypropyl piperidine ben-

zimdazol-2-one compounds all with NOP aﬃnity data

(see Supplementary data). The majority of these com-

pounds have been disclosed in previous publications

around this series.¹⁰The 113 compounds were superim-

posed onto an X-ray structure of (+)-2¹¹by electrostatic

and steric similarity. Initial eﬀorts using a smaller data-

set indicated that a predictive model could be obtained.

The full model was generated using default CoMFA ste-

ric and electrostatic ﬁelds and default CoMFA parame-

The CoMFA model was used to provide predictions

prior to synthesis at the idea generation stage. Com-

pounds maintaining the 3-phenoxypropyl piperidine

benzimdazol-2-one scaﬀold but with variations of the

phenoxy substituents or benzimidazol-2-one N-3 substi-

tuent were predicted using the model. Subsequent prior-

˚

ters except for 1 A grid spacing. Models were generated

using partial least squares with default CoMFA scaling

and a 2 kcal minimum r cut-oﬀ. The statistics of the best

model were as follows: Q²(10 groups) = 0.75, cross vali-

dated s.e. = 0.48, R²= 0.95, s.e. = 0.22, F_6,106= 305.15

(p ꢀ 0.05), n = 113, 6 components, steric contribu-

tion = 0.55, electrostatic contribution = 0.45.

The CoMFA steric ﬁeld contour plot (Fig. 2) indicates

that 2,5-disubstitution of the phenoxy moiety is most

favourable (green) but substitution is not tolerated at

the 5-position of the benzimidazol-2-one ring system

(yellow). The region in the vicinity of the ben-

zimidazol-2-one N-3 position is of great interest. The

steric contours suggest that some steric bulk in this re-

gion is favourable however the nearby yellow contours

indicate that larger groups in this region are likely to

have reduced aﬃnity. The CoMFA electrostatic ﬁeld

Figure 3. CoMFA electrostatic ﬁeld standard deviation · coeﬃcient

contour map surrounding (+)-1. Blue contours (80% contribution)

indicate regions where positive charge is favourable. Red contours

(20%) indicate regions where negative charge is favourable.

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

2831

itisation, synthesis and NOP aﬃnity evaluation yielded a

dataset of more than 30 compounds ranging in NOP pK_i

from 6.74 to 8.92 and a standard error of prediction of

0.82 log units highlighting the predictive tendency of the

model. Among the compounds predicted and prioritised

for synthesis were a number of heterocycle replacements

for the N-methyl acetamide of 1, only the predictions

and experimental data for these compounds are shown

in Table 1 (all other prediction data are not shown).

The model was only used in a truly predictive manner

to aid the prioritisation process prior to synthesis. Some

compounds in Table 1 were not predicted prior to syn-

thesis and therefore have no predicted pK_idata.

the nitrile intermediate 17. Treatment with hydroxyl-

amine under reﬂux conditions gave the amidoxime 18

which when reacted with sodium hydride and ethyl ace-

tate cyclises to the 1,2,4-oxadiazole 19.²²Again this is

readily converted to the desired ﬁnal compound 20 via

de-protection with acid and coupling to the phenoxypro-

pyl chloride intermediate 6 in a similar manner to that

outlined in Scheme 1. The unsubstituted triazole 24 was

prepared following the methods of Ladduwahetty and

co-workers.²³The benzimidazol-2-one 3 was alkylated

with the appropriate (chloromethyl)amidrazone and sub-

sequently heated to 130 ꢁC to eﬀect cyclisation to the de-

sired compound 21. Treatment of the triazole 21 with

methyl iodide under basic conditions aﬀords both the 1-

methyl-1,2,4-trazole²⁴22 and 2-methyl-1,2,4-trazole²⁴

23 following chromatographic separation of the two

regioisomers. These intermediates can then be coupled

to phenoxypropyl chloride 6 in the usual manner to give

triazoles 24–26.

2.2. Chemistry

Compounds were initially prioritised for synthesis on

the basis of the CoMFA model and further compounds

synthesised to explore SAR within the series. The syn-

thesis of benzimidazol-2-ones substituted at N-3 with

heterocycles are shown in Schemes 1–4. These Schemes

can be divided into two categories. The ﬁrst includes dis-

placement of an activated heterocycle by benzimidazol-

2-one 3. The second involves manipulation of functional

groups already present on the benzimidazol-2-one to de-

rive the heterocycle.

Both tetrazole²⁵28 and oxadiazole²⁶29 can be accessed

from the readily available intermediate 27. Treatment of

27 with tributyltinazide (Scheme 5) converts the nitrile

to the tetrazole 28. Reﬂuxing 27 in hydroxylamine re-

sults in the amidoxime 30 which readily cyclises to the

unsubstituted oxadiazole 29 on heating with triethylor-

thoformate in the presence of a Lewis acid. Alkylation

of 8 with propargyl bromide gives the terminal alkyne

32 which upon treatment with tributyltinazide following

the methods of Dillard et al.²⁷resulted in the 1,2,3-tria-

zole 31. Triazolone 33 is accessed from the alkylation of

8 with N-carbomethoxy-2-chloroactamidrazone²³de-

rived from chloroacetonitrile and methyl hydrazino-

carboxylate to give the intermediate amidrazone which

without isolation was heated neat to eﬀect cyclisation

to the ﬁnal compound triazolone 33. The thiadiazole

34 was accessed from the chloro precursor 35 using

hydrogenation conditions to extrude the halogen. All

compounds were prepared as either the hydrochloride

or methanesulfonate salt to increase solubility in water.

In Scheme 1 N-Boc benzimidazol-2-one 3¹⁰is deproto-

nated with sodium hydride and treated with a series of

heteroaromatic halomethyls. Many of the halomethyls

were commercially available, however those that could

not be purchased were prepared according to literature

protocols.^12–17In some instances the more stable mesy-

late was prepared. The Boc group of 4 was then removed

with acid and the free amine 5 coupled to intermediate

phenoxypropyl chloride 6¹⁰aﬀording the ﬁnal com-

pounds 7a–f. In some instances the activated aromatic

was attached directly to the coupled benzimidazolone

8¹⁰(Scheme 2) to aﬀord the target compounds 7l–o.

N-linked heterocycles were introduced from the methy-

lene mesylate intermediate (Scheme 3). Following the

methods of Davoll et al.,¹⁸treatment of the benzimi-

dazolone 3 with formalin under reﬂux yielded the meth-

ylene alcohol 9 in moderate yield. This could be

converted to the mesylate followed by treatment with

the nucleophilic heterocycle to give imidazoles 4p and

4r, pyrazole 4q and triazole 4s. In a similar manner to

that outlined in Scheme 1, these intermediates were de-

protected and coupled to the phenoxypropyl chloride 6

to give ﬁnal compounds 7p–s.

2.3. Aﬃnity and functional data

Table 1 shows the receptor binding aﬃnities and NOP

agonist potency data resulting from the replacement of

the N-methylacetamide of 1¹⁰with a variety of heterocy-

cles. The oxazol-2-yl analogue 7h shows both a reduc-

tion in NOP aﬃnity and an increase in MOP aﬃnity

in comparison to 1, resulting in almost an 8-fold de-

crease in selectivity. A decrease in NOP aﬃnity and

selectivity is also observed for the oxazol-4-yl derivative

7g. Replacement of the oxygen of 7g to give thiazole 7a

yielded an approximate 2-fold increase in aﬃnity for

both NOP and MOP over the oxazole. 2-Methyl substi-

tution of the thiazol-4-yl (7d) however resulted in a 14-

fold decrease in NOP aﬃnity and unchanged MOP

aﬃnity in comparison to the parent heterocycle suggest-

ing steric intolerance in this region. Thiadiazole 34

shows similar NOP aﬃnity to the thiazole 7k but a slight

decrease in MOP aﬃnity leads to a 58-fold selectivity

window between NOP and MOP. Interestingly oxadiaz-

ole 29 shows similar NOP aﬃnity and no decrease

in MOP aﬃnity relative to the oxazole 7g. Methyl

Modiﬁcation of the ester 11 derived from alkylation of 3

with chloro-ethyl acetate allowed access to both 1,2,4-

triazole¹⁹14 and 1,2,4-oxadiazole²⁰16 (Scheme 4).

Treatment of the ester 11 with hydrazine aﬀords the

hydrazide 12, which was condensed with acetamidine¹⁹

using sodium hydride to give the cyclised 1,2,4-triazole

13. Treating the ester 11 with N-hydroxyacetamidine²¹

under similar conditions yielded the 1,2,4-oxadiazole 15.

Both intermediates were then coupled to 6 as outlined in

Scheme 1 to give 14 and 16, respectively. Alkylation of

the benzimidazol-2-one 3 with chloroacetonitrile gives

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R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

Table 1. Opioid receptor binding aﬃnity of N-3 heterocycle substituted benzimidazol-2-one analogues

R1

O

OMe

N

O

Compound

R1

ORL1 pK_i

CoMFA pK_i

MOP pK_i

MOP/ORL1

cAMP IC₅₀(nM)

(% NC resp.)

1^*

2^*

CONHMe

CH₂OMe

9.00

8.39

ND

6.78

6.73

164

46

10 (113)

60 (109)

N

*

7a

7b

7c

7d

7e

8.92

8.82

8.31

7.76

7.54

8.69

ND

8.30

ND

7.37

7.41

7.28

7.41

7.37

35.5

25.7

10.7

2.2

31.1 (105)

192.8(103)

95.4 (105)

ND

S

*

S

N

S

*

1.5

815.5(98)

N

O

N

7f

N

5.93

ND

6.28

0.4

ND

N

*

7g

7h

7i

8.60

8.41

7.66

8.45

8.62

8.87

ND

6.98

7.08

6.84

7.25

41.7

21.4

6.6

22.3 (116)

29.1 (114)

1301.67(90)

186.69(102)

O

N

*

O

N

O

*

7j

15.8

N

O

7k

7l

8.85

8.02

8.23

ND

7.35

7.32

7.12

32.6

5.0

150.3 (96)

329.6(102.7)

467.6(106)

S

N

*

7m

12.9

N

7o

7p

8.43

8.38

8.72

8.85

6.67

6.92

57.5

28.8

133.73 (105)

296.6 (110)

N

H

*

N

7q

8.48

8.79

6.65

67.6

102.7 (106)

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

2833

Table 1 (continued)

Compound

R1

ORL1 pK_i

8.31

CoMFA pK_i

ND

MOP pK_i

6.91

7.41

6.92

7.02

6.69

6.86

7.44

7.32

7.00

5.99

7.11

6.74

7.60

7.00

MOP/ORL1

25.1

20.9

2.9

cAMP IC₅₀(nM)

(% NC resp.)

*

7r

361.3(105)

N

*

N

7s

8.73

ND

39.5(108)

506.4 (97)

394(91)

ND

N

O

N

O

14

7.38

ND

N

H

*

16

7.53

8.17

8.68

9.22

ND

3.2

N

20

7.43

5.8

N

24

8.76

79.4

40.7

4.1

10.8 (109)

11.5 (109)

77.9 (108)

ND

N

H

N

(+)-24

25

9.05

N

H

N

*

7.93

ND

N

26

7.02

ND

1.0

28

6.04

ND

1.1

ND

N

H

N

*

29

8.62

8.93

8.92

ND

32.4

22.9

4.3

32.8 (107)

253.7 (100)

60.4(106)

ND

O

N

31

8.10

N

H

N

*

NH

O

33

8.23

N

H

N

*

34

8.77

ND

58.9

N

S

ND, not determined.

^*Data for racemate.

R

O

N

O

Boc

N

Boc

iii

i

ii

N

HN

N

NH

N

R

O

N

O

Cl

3

4a-k

5a-k

7a-k

6

Scheme 1. Reagents and conditions: (i) 60% NaH, DMF, 1 h, then RCH₂Cl or RCH₂OMs, rt, 16 h; (ii) TFA, DCM, 16 h, rt; (iii) 6, DiPEA, NaI,

CH₃CN, 80 ꢁC, 20 h.

2834

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

R

H

O

N

Ts

N

H

N

R =

i

ii

N

O

N

O

N

n

o

8

7l-o

Scheme 2. Reagents and conditions: (i) 60% NaH, DMF, 1 h, then RCH₂Cl or RCH₂OMs, rt, 16 h; (ii) HCl, DCM, rt, 1 h.

R

O

N

O

Boc

N

ii

i

iv

v

N

NH

N

OH

R

iii

O

N

O

3

9

4p-s

7p-s

O

Cl

6

Scheme 3. Reagents and conditions: (i) 35% formalin, 1,4-dioxane, reﬂux, 20 h; (ii) MsCl, DCM, 1.5 h, 0 ꢁC; (iii) HNHet, DCM, rt, 3 days; (iv) TFA,

DCM, 16 h, rt; (v) 6, DiPEA, NaI, CH₃CN, 80 ꢁC, 20 h.

O

Boc

O

N

Boc

N

O

iv

v

N

14

HN

NH

iii

O

N

NH₂

Boc

N

vi

12

N

CO₂Et

13

O

ii

Boc

N

v

11

N

O

N

16

N

vi

i

15

O

Boc

N

v

viii

vii

ix

N

NH

N

20

CN

O

OH

N

vi

NH₂

3

17

18

19

x, xi

O

Boc

O

N

Boc

N

xii

N

NH

N

+

N

21

22

23

v, vi

26

24

25

˚

Scheme 4. Reagents and conditions: (i) 60% NaH, DMF, 15 min, then ClCH₂CO₂Et, rt, 16 h; (ii) 4 A MS, N-hydroxyacetamidine, NaH, THF,

reﬂux, 2 h; (iii) NH₂NH₂ÆH₂O, EtOH; (iv) acetamidineÆHCl, NaOMe, then MeOCH₂CH₂OH, heat; (v) TFA, DCM, 16 h rt; (vi) 6, DiPEA, NaI,

˚

CH₃CN, 80 ꢁC, 20 h; (vii) 60% NaH, DMF, 15 min, then CNCH₂Cl, rt, 16 h; (viii) NH₂OHÆHCl, i-Pr₂EtN, EtOH, reﬂux, 16 h; (ix) 4 A MS, 60%

NaH, THF, 50 ꢁC, 2 h then EtOAc, reﬂux, 2 h; (x) 60% NaH, DMF, 15 min, then N-formyl-2-chloroacetamidrazone, rt, 16 h; (xi) 130 ꢁC neat; (xii)

MeI, K₂CO₃, acetone, reﬂux, 15 min.

substituted oxadiazoles 16 and 20 both show reduced

NOP aﬃnities which is consistent with the thiazole

SAR. Further increasing the bulk in this region exempli-

ﬁed by the tert-butyl analogue 7f gives a dramatic 490-

fold decrease in NOP aﬃnity and a modest 6.7-fold de-

crease in MOP aﬃnity relative to the unsubstituted oxa-

diazole 29. This clearly highlights that further steric bulk

in this region is highly unfavourable for NOP receptor

binding, although the MOP receptor appears to be

somewhat more tolerant. This seems to be consistent

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

2835

H

N

O

N

O

N

ii

CN

O

28

N

O

OH

N

O

N

O

NH₂

N

O

N

iv

N

iii

O

N

O

N

27

29

30

i

H

N

O

H

O

N

O

N

O

N

v

N

vi

O

N

O

N

O

N

32

8

31

ix

N

vii

S

N

S

O

N

viii

N

O

H

O

N

Cl

N

x

N

O

N

O

N

O

N

H

O

N

O

N

34

35

33

Scheme 5. Reagents and conditions: (i) 60% NaH, DMF, 15 min, then CNCH₂Cl, rt, 16 h; (ii) Bu₃SnN₃, xylene, 140 ꢁC, 24 h; (iii) NH₂OHÆHCl,

DiPEA, EtOH, reﬂux, 16 h; (iv) BF₃OEt, triethylorthoformate, 115 ꢁC, 30 min; (v) 60% NaH, DMF, 50 ꢁC, 1 h, then propargyl bromide, rt, 16 h; (vi)

Bu₃SnN₃, xylene, 150 ꢁC, 16 h; (vii) 60% NaH, DMF, 15 min, then N-carboxymethyl-2-chloroacetamidrazone; (viii) 130 ꢁC neat; (ix) 60% NaH,

DMF, 50 ꢁC, 15 min, then HetCH₂Cl, rt, 18 h; (x) 10% Pd-C, AcOH, H₂, 28 h.

with the steric contours of the CoMFA model which

indicate that some steric bulk is favourable but exten-

sion beyond this favourable region is likely to be detri-

mental to NOP aﬃnity. The 5-methyl isoxazol-3-yl

compound 7i unsurprisingly exhibits a similar aﬃnity

proﬁle to the oxadiazole analogue 20. However, methyl

substitution at the positions adjacent to the ring attach-

ment point as in compound 7j shows good NOP aﬃnity

but a modest 16-fold selectivity.

zol-1-yl analogue 7s resulted in a 2.2-fold increase in

NOP aﬃnity over the imidazole 7p and a restoration

of functional potency but selectivity over MOP dropped

to 21-fold. 1,2,3-Triazol-4-yl 31 showed decreased NOP

aﬃnity, however the 1,2,4-triazol-3-yl 24 yielded high

NOP aﬃnity, good selectivity over MOP and a func-

tional potency equivalent to the N-methylacetamide 1.

It is noted that the 1,2,4-triazol-3-yl heterocycle was pre-

dicted prior to synthesis to exhibit the highest NOP

aﬃnity of all the analogues that were predicted by the

CoMFA model therefore highlighting this particular

heterocycle as a priority compound for synthesis.

Removal of the hydrogen bond capability of the hetero-

cycle to aﬀord the thiophenes 7k and 7b resulted in high

NOP aﬃnity similar to the N-methylacetamide 1 but re-

duced selectivity over MOP and reduced NOP func-

tional potency in a cAMP assay. Pyrazole 7q and

imidazole 7o show similar proﬁles with high NOP recep-

tor aﬃnity and selectivity over MOP, however func-

tional potency decreases by an order of magnitude

relative to 1. N-linked imidazole 7p shows similar

NOP aﬃnity to the C-linked imidazole 7o but an in-

crease in MOP aﬃnity leads to a decreased selectivity

of 29-fold, functional potency is also further decreased.

2-Methyl substituted imidazole 7r fails to show any

improvement in selectivity or potency. Insertion of a fur-

ther nitrogen into the ring system to aﬀord the 1,2,4-tria-

Methyl substituted triazole analogues 14, 25 and 26 all

show decreased NOP aﬃnities compared to 24 with

the most pronounced decreases for 14 and 26 exhibiting

24- and 55-fold reduced NOP aﬃnities, respectively. The

decreased NOP aﬃnities coupled with similar or in-

creased MOP aﬃnities relative to 24 eﬀectively abolish

selectivity for all 3 methyl triazoles. Insertion of a

carbonyl into the triazole ring system of 24 to give 33

resulted in a small decrease in NOP aﬃnity but a 5.5-

fold increase in MOP aﬃnity leading to a signiﬁcantly

reduced 4-fold selectivity ratio. Tetrazole 28 unsurpris-

ingly showed a loss of NOP and MOP binding aﬃnities

2836

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

to give a similar proﬁle to the carboxylic acid analogue

described previously.¹⁰A limited number of 6 membered

heterocyclic systems were explored without further

improvement of the in vitro proﬁle. The 2-pyridyl com-

pound 7c exhibited good NOP aﬃnity, a modest 10-fold

selectivity over MOP and a functional potency of

95.4 nM in the cAMP assay. However the 3-pyridyl, 4-

pyridyl and pyrazine analogues (7l, 7e and 7m) all

showed similar or reduced NOP aﬃnity relative to 7c

but signiﬁcant decreases in functional potency. Compar-

ing the CoMFA predicted aﬃnities with the experimen-

tal aﬃnities it can be seen that generally the model

showed good predictivity. Of the 12 heterocycles shown

in Table 1 that were predicted in the CoMFA model

prior to synthesis 10 were found to be well predicted

with an absolute error less than 0.7 log units, only oxa-

diazole 20 and triazole 31 showed poorer predictions.

ous, noxious stimulation generated by injection of a di-

lute solution of formalin into one hindpaw, and in a

model of post-surgical pain, the Brennan model. In the

FPT test, (+)-24 administered iv (0.03–3.0 lmol/kg)

5 min prior to injection of formalin dose-dependently re-

duced the amount of time spent licking the formalin-in-

jected paw, during both phases of licking (Fig. 4). This

eﬀect was signiﬁcant after administration of the

3 lmol/kg dose for both phases of licking (Dunn’s vehi-

cle versus 3 lmol/kg, p < 0.01 and p < 0.05 for phases 1

and 2, respectively). The calculated ED₅₀value for the

inhibition of licking during the ﬁrst phase it was

2.62 lmol/kg (95% CI 0.63–4.40 lmol/kg) and the sec-

ond phase was 0.65 lmol/kg (95% CI 0.31–1.61 lmol/

kg). Previously, we have demonstrated within this series

that this eﬀect is mediated by NOP by blocking the inhi-

bition of licking by pre-treatment with

antagonist.¹⁰

a NOP

Results, taken together, suggest that hydrogen bond

acceptor and donor capabilities adjacent to the hetero-

cyclic ring attachment point appear to yield an optimal

combination of NOP aﬃnity, selectivity over MOP and

NOP agonist potency. This is consistent with previous

SAR ﬁndings indicating that the donor and acceptor

functionality of the N-methylacetamide was required

to yield a similar optimal combination of aﬃnity, selec-

tivity and potency.¹⁰In general the heterocycles im-

proved solubility over the parent N-methylacetamide

(e.g., 7o had solubility of 200 mg/L). Given the activity

of 24, this was separated into its component enantio-

mers using chiral HPLC. It was shown that the (+)

enantiomer [(+)-24] was the eutomer as previously ob-

served with NOP ligands within this series.¹⁰However,

triazole (+)-24 exhibited a solubility of 4 mg/L as the

hydrochloride salt.

In the Brennan model, mechanical allodynia was in-

duced by making a 1.5 cm incision, under isoﬂurane

anaesthesia, through the skin and fascia of the plantar

surface of a rat’s hindpaw, elevating the underlying

muscle and using 2 sutures to close the wound. With-

drawal thresholds using von Frey ﬁlaments were mea-

sured prior to the surgery, 2 h after surgery at which

time the compound was administered and at regular

intervals after compound administration. Compound

(+)-24 reversed the mechanical allodynia that develops

in this model (Fig. 5). After intravenous administra-

tion the calculated ED₅₀value was 12.1 lmol/kg. In

this assay it should be noted that although it appeared

that 100% reversal of mechanical allodynia was ob-

served after administration of the top dose 30 lmol/

kg this was due to the fact that the animals lost their

righting reﬂex at this dose and could not respond to

the stimulus. However, after administration of the

10 lmol/kg dose a signiﬁcant reversal of allodynia

(Dunn’s vehicle versus 10 lmol/kg, p < 0.05) was ob-

served without any loss of righting reﬂex at the time

points assessed.

2.4. Behavioural eﬀects of compound (+)-24

The antinociceptive properties of compound (+)-24 were

evaluated in the mouse formalin paw test²⁸(FPT), a

model that assesses behavioural responses to continu-

160

140

120

100

80

*

60

**

40

20

0

0-5

2

0-30

Time after formalin injection (min)

vehicle

0.3 µmol/kg (+)-24

0.03 µmol/kg (+)-24 0.1 µmol/kg (+)-24

1 µmol/kg (+)-24 3 µmol/kg (+)-24

Figure 4. Eﬀect of vehicle or increasing doses of (+)-24 administered intravenously, 5 min prior to the injection of formalin, on the time spent licking (s).

^*,**p < 0.05 and 0.01 when compound (+)-24 treated mice were compared to vehicle treated mice (Kruskal–Wallis test followed by Dunn’s post hoc test).

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

2837

16

14

12

10

8

**

Paw

incision

Compound *

Injection

6

4

2

0

120

150

180

210

240

Time (min)

10 µmol/kg (+)-24

vehicle

3 µmol/kg (+)-24

30 µmol/kg (+)-24

Figure 5. Eﬀect of vehicle or increasing doses of (+)-24, administered intravenously 2 h after paw incision, on mechanical allodynia. ^*,**p < 0.05 and

0.01, respectively (Kruskal–Wallis test followed by Dunn’s post hoc test). N.B., statistical comparisons were only carried out at the time of maximum

eﬀect (150 min).

3. Conclusion

receptors (NOP pK_i= 9.05, MOP pK_i= 7.44, DOP

pK_i= 5.89, KOP pK_i= 6.06).

The main drive within this investigation was to ﬁnd a

follow-up compound to the N-methyl acetamide 1. A

CoMFA model was developed focussing on the N-3

substitution of 3-phenoxypropyl piperidine ben-

zimidazol-2-one analogues. The model allowed the

chemist to predict activities of the heterocyclic replace-

ments prior to synthesis, thus allowing the prioritisation

of key compounds and ultimately accessing triazole

derivative (+)-24. (+)-24 was shown to be a potent ago-

nist at NOP and selective over the other classical opioid

The SAR indicates that the presence of both hydrogen

bond acceptor and donor functions adjacent to the het-

erocyclic ring attachment point provides optimal aﬃnity

and selectivity for NOP. Furthermore, when (+)-24 is gi-

ven iv the compound produces antinociceptive eﬀects

comparable to morphine (Fig. 6) in the FPT and in

the Brennan model was shown to reverse mechanical

allodynia indicating that this compound could have a

potential utility in treating postoperative pain.

300

250

200

150

100

**

50

**

0

0-5

20-30

Time after formalin injection (min)

1umol/kg morphine 3umol/kg morphine

vehicle

0.3umol/kg morphine

10umol/kg morphine

Figure 6. Eﬀect of vehicle or increasing doses of morphine administered intravenously, 5 min prior to the injection of formalin, on the time spent

licking (s). ^**p < 0.01 when morphine treated mice were compared to vehicle treated mice (Kruskal–Wallis test followed by Dunn’s post hoc test).

2838

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

4. Experimental

alkylating reagent the residue was puriﬁed by ﬂash col-

umn chromatography on silica gel (heptane/ethyl ace-

tate; 50:50; as eluant) to give the title compound as a

pale yellow solid in 36% yield. ESI-MS m/z = 414.3

4.1. Chemistry

1

4.1.1. General information. NMR spectra were recorded

using a Bruker DPX 400 or DRX 400 instrument with

tetramethylsilane used as internal standard. The chemical

shifts are reported in d values (ppm). The following nota-

tions are used for ¹H NMR signal patterns: s, singlet; d,

doublet; t, triplet; q, quartet; m, multiplet; br, broad.

Optical rotations were recorded on an Optical Activity

AA-1000 polarimeter. Mass spectrometry was carried

out on either a PE SCIEX API 150EX or ESCi microm-

assZQ machine. High resolution mass spectra (HRMS)

were recorded on an Applied Biosystems Inc Mariner

(TOF) instrument, error limit <5 ppm. HPLC analyses

were recorded on a Perkin-Elmer Integral 4000 Quater-

nary HPLC system with UV detection or a Perkin-Elmer

Series 200 HPLC system with 200 Diode Array detectors.

Max RP C12 (Phenomenex) columns (150 · 4.6 mm,

4 lm) or Xterra RP C18 (Waters) columns (100 ·

4.6 mm, 5 lm) for purity determinations. Thin layer

chromatography (TLC) was carried out using Kieselgel

60 F₂₅₄aluminium backed plates (Merck). Matrix silica

gel, particle size 0.040–0.063 mm, was used for column

chromatography. Solvents used were commercial grades

from either Aldrich or BDH and used without further

puriﬁcation. All chemicals and reagents were obtained

from commercial suppliers and used without further

puriﬁcation. All compounds passed in-house purity anal-

ysis of >90% as determined by NMR and LC.

[M+H]⁺. H NMR (400 MHz, CDCl₃): d 1.50 (s, 9H),

1.78–1.88 (m, 2H), 2.26–2.41 (m, 2H), 2.78–2.97 (m,

2H), 4.20–4.44 (br s, 2H), 4.45–4.58 (m, 1H), 5.06 (s,

2H), 6.94–6.98 (m, 1H), 7.01–7.08 (m, 3H), 7.10–7.15

(m, 1H), 7.17–7.21 (m, 1H), 7.25–7.29 (m, 1H).

4.1.4.

4-(2-Oxo-3-pyridin-2-ylmethyl-2,3-dihydro-ben-

zimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl

ester (4c). Using 2-chloromethylpyridine as the alkylat-

ing reagent the residue was puriﬁed by precipitating

from diethyl ether to give the title compound as a white

solid in 66% yield. ESI-MS m/z = 409 [M+H]⁺, 432

[M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): d 1.50 (s,

9H), 1.84–1.87 (m, 2H), 2.34 (dd, J = 12.8 and 4.4 Hz,

2H), 2.85–2.91 (m, 2H), 4.33 (br s, 2H), 4.53 (tt,

J = 12.4 and 4.4 Hz, 1H), 5.19 (s, 2H), 6.99–7.07 (m,

3H), 7.11–7.20 (m, 3H), 7.61 (dt, J = 7.6 and 1.6 Hz,

1H), 8.56–8.58 (m, 1H).

4.1.5. 4-[3-(2-Methylthiazol-4-ylmethyl)-2-oxo-2,3-dihy-

dro-benzimidazol-1-yl]-piperidine-1-carboxylic acid tert-

butyl ester (4d). Using 4-chloromethyl-2-methylthiazole

hydrochloride as alkylating agent, the crude product

was puriﬁed by chromatography on silica gel (dichloro-

methane/ethanol; 98:2; as eluant) to give the title com-

pound as a yellow oil in quantitative yield. ESI

1

m/z = 429.4 [M+H]⁺. H NMR (400 MHz, CDCl₃): d

1.50 (s, 9H), 1.84 (br d, J = 12.8 Hz, 2H), 2.34 (dq,

J = 12.5 and 4.5 Hz, 2H), 2.68 (s, 3H), 2.86 (br t,

J = 12.8 Hz, 2H), 4.26–4.37 (m, 2H), 4.51 (tt, J = 12.5

and 4.2 Hz, 1H), 5.15 (s, 2H), 6.87 (s, 1H), 7.02–7.07

(m 2H), 7.08–7.15 (m, 2H).

4.1.2.

4-(2-Oxo-3-thiazol-4-ylmethyl-2,3-dihydro-ben-

zimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl

ester (4a). Sodium hydride (60% suspension in mineral

oil, 180 mg, 4.50 mmol) was added in portions to a solu-

tion of 4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-piperi-

dine-1-carboxylic acid tert-butyl ester 3¹⁰(1.30 g,

4.10 mmol) in N,N-dimethylformamide (13 mL) under

ice-water bath cooling and stirred at 50 ꢁC for 15 min.

The reaction mixture was then cooled to 5 ꢁC, and a

solution of 4-chloromethylthiazole (657 mg, 4.92 mmol)

in tetrahydrofuran (2 mL) added dropwise. The result-

ing mixture was stirred at room temperature for 16 h be-

fore diluting with brine (300 mL) and extracted with

ethyl acetate (4· 100 mL). The organic layers were com-

bined, washed with brine, dried (MgSO₄), ﬁltered and

concentrated in vacuo. The residue was puriﬁed by ﬂash

column chromatography on silica gel (dichloromethane/

methanol; 99.4:0.6; as eluant) to give the title compound

as a colourless solid (1.30 g, 76%). ESI-MS m/z = 415.0

4.1.6.

4-(2-Oxo-3-pyridin-4-ylmethyl-2,3-dihydro-ben-

zimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl

ester (4e). Using 4-chloromethylpyridine as the alkylat-

ing reagent the residue was puriﬁed by precipitating

from diethyl ether to give the title compound as a yellow

solid in 89% yield. ESI-MS m/z = 409 [M+H]⁺, 432

[M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): d 1.50 (s,

9H), 1.84–1.87 (m, 2H), 2.35 (dd, J = 12.4 and 4.4 Hz,

2H), 2.84–2.90 (m, 2H), 4.33 (br s, 2H), 4.51 (tt,

J = 12.5 and 4.4 Hz, 1H), 5.06 (s, 2H), 6.81 (d,

J = 8.0 Hz, 1H), 7.00–7.09 (m, 2H), 7.16–7.18 (m, 3H),

8.55 (dd, J = 4.4 and 1.6 Hz, 2H).

4.1.7. 4-[3-(5-tert-Butyl-1,2,4-oxadiazol-3-ylmethyl)-2-

oxo-2,3-dihydro-benzimidazol-1-yl]-piperidine-1-carboxylic

acid tert-butyl ester (4f). Using 5-tert-butyl-3-chloro-

methyl-1,2,4-oxadiazole as alkylating agent, the crude

product was puriﬁed by chromatography on silica gel

(heptane/ethyl acetate; 1:1; as eluant) to give the title

compound as a clear oil in quantitative yield. ESI

[M+H]⁺. H NMR (400 MHz, CDCl₃): d 1.50 (s, 9H),

1

1.78–1.90 (m, 2H), 2.24–2.42 (m, 2H), 2.76–2.98 (m,

2H), 4.20–4.42 (br s, 2H), 4.45–4.57 (m, 1H), 5.25 (s,

2H), 7.03–7.09 (m, 2H), 7.10–7.17 (m, 2H), 7.19–7.22

(m, 1H), 7.25–7.28 (m, 1H), 8.76–8.80 (m, 1H).

1

The following compounds were prepared in the same

manner as 4a, using the appropriate alkylating reagent.

m/z = 456.4 [M+H]⁺. H NMR (400 MHz, CDCl₃): d

1.34 (s, 9H), 1.50 (s, 9H), 1.85 (br d, J = 12.6 Hz, 2H),

2.34 (dq, J = 12.6 and 4.5 Hz, 2H), 2.87 (br t,

J = 12.5 Hz, 2H), 4.23–4.39 (m, 2H), 4.51 (tt, J = 12.8

and 4.0 Hz, 1H), 5.16 (s, 2H), 7.04–7.12 (m, 3H), 7.12–

7.18 (m, 1H).

4.1.3. 4-(2-Oxo-3-thiophen-3-ylmethyl-2,3-dihydro-ben-

zimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl

ester (4b). Using 3-bromomethylthiophene¹³as the

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

2839

4.1.8.

4-(3-Oxazol-4-ylmethyl-2-oxo-2,3-dihydro-ben-

4.1.13. 4-(3-Hydroxymethyl-2-oxo-2,3-dihydro-benzi-

midazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester

(9). A mixture of 3 (10.0 g, 31.5 mmol), 35% formalin

(30 mL), and 1,4-dioxane (100 mL) was stirred at reﬂux

temperature for 20 h. The reaction mixture was concen-

trated in vacuo, and the resultant residue was dissolved

in water (200 mL) and extracted with dichloromethane

(4· 250 mL). The organic layers were combined, washed

with brine, dried (MgSO₄), ﬁltered and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chro-

matography on silica gel (n-heptane/ethyl acetate;

75:25; as eluant) to give a colourless solid. The solid

zimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl

ester (4g). Using methanesulfonic acid oxazol-4-yl-

methyl ester¹⁴as alkylating agent, the crude product

was chromatographed on silica gel (dichloromethane/

ethanol; 99:1 then 98:2; gradient as eluant) to give the

title compound as a pale gum in 44% yield. ESI

m/z = 399.3 [M+H]⁺. H NMR (400 MHz, CDCl₃): d

1

1.50 (s, 9H), 1.80 (d, J = 12.2 Hz, 2H), 2.24–2.39 (m,

2H), 2.83–2.93 (m, 2H), 4.30–4.39 (m, 2H), 4.41–4.51

(m, 1H), 5.01 (s, 2H), 7.07–7.15 (m, 3H), 7.18–7.26 (m,

1H), 7.62 (s, 1H), 7.82 (s, 1H).

was

then

washed

with

a

mixture

of

4.1.9.

4-(3-Oxazol-2-ylmethyl-2-oxo-2,3-dihydro-ben-

n-heptane/ethyl acetate 1:1 to give the title compound

as a colourless solid (6.39 g, 59%). ESI-MS m/z = 348.3

zimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl

ester (4h). Using methanesulfonic acid oxazol-2-yl-

methyl ester¹⁵as the alkylating reagent, the residue

was puriﬁed by ﬂash column chromatography on silica

gel (dichloromethane/methanol; 98:2; as eluant) to give

the title compound as a yellow solid in 16% yield. ESI-

1

[M+H]⁺. H NMR (400 MHz, CDCl₃): d 1.50 (s, 9H),

1.72–1.82 (m, 2H), 2.22–2.38 (m, 2H), 2.74–2.94 (m,

2H), 3.17 (t, J = 7.7 Hz, 1H), 4.20–4.38 (br s, 2H),

4.38–4.49 (m, 1H), 5.43 (d, J = 7.7 Hz, 2H), 7.06–7.16

(m, 3H), 7.17–7.22 (m, 1H).

MS m/z = 399.5 [M+H]⁺. H NMR (400 MHz, CDCl₃):

1

d 1.50 (s, 9H), 1.82–1.85 (m, 2H), 2.28–2.37 (m, 2H),

2.83–2.88 (m, 2H), 4.31 (br s, 1H), 4.47–4.53 (m, 1H),

5.19 (s, 2H), 5.29 (s, 1H), 7.01–7.09 (m, 4H), 7.12–7.18

(m, 1H), 7.59–7.62 (m, 1H).

4.1.14. 4-(3-Imidazol-1-ylmethyl-2-oxo-2,3-dihydro-ben-

zimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl

ester (4p). Methanesulfonyl chloride (317 mg,

2.76 mmol) was added dropwise to a solution of 9

(800 mg, 2.30 mmol) in dichloromethane (8 mL) with

ice-water bath cooling and stirred for 1.5 h. The reaction

mixture was then diluted with dichloromethane (40 mL)

and washed with cold water. The combined organics

were dried (MgSO₄), ﬁltered and concentrated in vacuo

to give the intermediate mesylate as an oil which was

4.1.10.

4-[3-(5-Methyl-isoxazol-3-ylmethyl)-2-oxo-2,3-

dihydro-benzimidazol-1-yl]-piperidine-1-carboxylic acid

tert-butyl ester (4i). Using 3-chloromethyl-5-methyl-

isoxazole as alkylating agent, the crude compound was

obtained in quantitative yield and used without further

puriﬁcation. ESI m/z = 413.1 [M+H]⁺. ¹H NMR

1

used without further puriﬁcation. H NMR (400 MHz,

(400 MHz, CDCl₃):

d

1.50 (s, 9H), 1.85 (d,

CDCl₃): d 1.50 (s, 9H), 1.75–1.90 (m, 2H), 2.20–2.40

(m, 2H), 2.75–2.95 (m, 2H), 4.20–4.50 (m, 3H), 5.76 (s,

2H), 7.05–7.25 (m, 4H).

J = 12.3 Hz, 2H), 2.32 (dq, J = 12.3 and 4.3 Hz, 2H),

2.35 (s, 3H), 2.87 (br t,J = 12.3 Hz, 2H), 4.31 (br s,

2H), 4.47–4.53 (m, 1H), 5.07 (s, 2H), 5.96 (s, 1H),

7.06–7.18 (m, 4H).

The mesylate from the previous step was dissolved in

dichloromethane (8 mL), and imidazole (783 mg,

11.5 mmol) added to the solution under ice-water bath

cooling. The resulting mixture was stirred at room tem-

perature for 3 days. The reaction mixture was diluted

with dichloromethane (40 mL), and the resulting mix-

ture was washed with 5% aqueous solution of sodium

carbonate. The organic layer was separated and ex-

tracted further with dichloromethane (4· 100 mL). The

organic layers were combined, washed with brine, dried

(MgSO₄), ﬁltered and concentrated in vacuo. The resi-

due was then puriﬁed by ﬂash column chromatography

on silica gel (dichloromethane/methanol; 96:4; as eluant)

to give the title compound as a yellow solid (740 mg,

81%). ESI-MS m/z = 398.1 [M+H]⁺. ¹H NMR

(400 MHz, CDCl₃): d 1.50 (s, 9H), 1.77–1.88 (m, 2H),

2.24–2.38 (m, 2H), 2.76–2.94 (m, 2H), 4.20–4.39 (br s,

2H), 4.39–4.50 (m, 1H), 5.95 (s, 2H), 7.02–7.22 (m,

6H), 7.78 (s, 1H).

4.1.11.

4-[3-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-oxo-

2,3-dihydro-benzimidazol-1-yl]-piperidine-1-carboxylic acid

tert-butyl ester (4j). Using 4-(chloromethyl)-3,5-di-

methyl-isoxazole as the alkylating reagent, the residue

was puriﬁed by ﬂash column chromatography on silica

gel (ethyl acetate; as eluant) to give the title compound

as a yellow solid in 45% yield. ESI-MS m/z = 427

[M+H]⁺, 327 [M-Boc]⁺. H NMR (400 MHz, CDCl₃):

1

d 1.50 (s, 9H), 1.78–1.81 (m, 2H), 2.19 (s, 3H), 2.27–

2.41 (m, 2H), 2.44 (s, 3H), 2.82–2.88 (m, 2H), 4.32 (br

s, 2H), 4.37–4.50 (m, 1H), 4.80 (s, 2H), 6.81–6.84 (m,

1H), 7.00–7.08 (m, 2H), 7.12–7.15 (m, 1H).

4.1.12. 4-(2-Oxo-3-thiophen-2-ylmethyl-2,3-dihydro-ben-

zimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl

ester (4k). Using 2-chloromethylthiophene¹²as the

alkylating reagent the residue was puriﬁed by ﬂash col-

umn chromatography on silica gel (dichloromethane/

methanol; 99.7:0.3; as eluant) to give the title compound

as a pale yellow solid in 69% yield. ESI-MS m/z = 414.1

The following compounds were prepared in the same

manner as 4p, using the appropriate N-heterocycle.

[M+H]⁺. H NMR (400 MHz, CDCl₃): d 1.50 (s, 9H),

1

1.76–1.88 (m, 2H), 2.24–2.40 (m, 2H), 2.76–2.96 (m,

2H), 4.12–4.44 (br s, 2H), 4.44–4.56 (m, 1H), 5.21 (s,

2H), 6.91–6.96 (m, 1H), 7.02–7.15 (m, 5H), 7.18–7.22

(m, 1H).

4.1.15. 4-(2-Oxo-3-pyrazol-1-ylmethyl-2,3-dihydro-ben-

zimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl

ester (4q). Using pyrazole as the amine heterocycle the

resultant residue was puriﬁed by ﬂash column chroma-

2840

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

tography on silica gel (dichloromethane/methanol; 98:2;

as eluant) to give the title compound as a colourless so-

lid in 74% yield. ESI-MS m/z = 398.1 [M+H]⁺. ¹H NMR

(400 MHz, CDCl₃): d 1.50 (s, 9H), 1.74–1.86 (m, 2H),

2.23–2.38 (m, 2H), 2.76–2.93 (m, 2H), 4.22–4.39 (br s,

2H), 4.39–4.50 (m, 1H), 6.13 (s, 2H), 6.24–5.29 (m,

1H), 7.06–7.14 (m, 3H), 7.44–7.49 (m, 1H), 7.49–7.53

(m, 1H), 7.69–7.82 (m, 1H).

umn chromatography on silica gel (dichloromethane/

methanol; 98:2; as eluant). The obtained free base of

the title compound was dissolved in diethyl ether, and

1 M solution of hydrochloric acid in diethyl ether added

dropwise. The resulting solution was concentrated in va-

cuo to give the title compound as a colourless solid

(320 mg, 39%). ESI-MS m/z = 535.3 [M+H]⁺. ¹H

NMR (400 MHz, CD₃OD): d 1.01 (d, J = 6.8 Hz, 3H),

1.05 (d, J = 6.8 Hz, 3H), 1.98–2.24 (m, 8H), 2.80–2.96

(m, 2H), 3.18–3.38 (m, 4H), 3.70–3.83 (m, 5H), 4.32–

4.40 (m, 1H), 4.56–4.70 (m, 1H), 5.26 (s, 2H), 6.43

(dd, J = 2.5, 8.3 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 7.03

(d, J = 8.3 Hz, 1H), 7.04–7.17 (m, 3H), 7.36–7.43 (m,

1H), 7.53 (d, J = 2.0 Hz, 1H), 9.07 (d, J = 2.0 Hz, 1H).

4.1.16. 4-[3-(2-Methyl-imidazol-1-ylmethyl)-2-oxo-2,3-

dihydro-benzimidazol-1-yl]-piperidine-1-carboxylic acid

tert-butyl ester (4r). Using 2-methyl-imidazole as the

amine heterocycle the resultant residue was puriﬁed by

ﬂash column chromatography on silica gel (dichloro-

methane/methanol; 97:3; as eluant) to give the title com-

pound as a white solid in 79% yield. ESI-MS m/z = 412.3

The following compounds were prepared in the same

manner as 7a.

1

[M+H]⁺. H NMR (400 MHz, CDCl₃): d 1.50 (s, 9H),

1.78–1.88 (m, 2H), 2.26–2.44 (m, 2H), 2.59 (s, 3H),

2.78–2.96 (m, 2H), 4.20–4.38 (br s, 2H), 4.38–4.50 (m,

1H), 5.88 (s, 2H), 6.89–6.93 (m, 1H), 7.05–7.19 (m, 5H).

4.1.19. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-thiophen-3-ylmethyl-1,3-dihydro-

benzimidazol-2-one hydrochloride (7b). Starting with 4b

the title compound was puriﬁed by ﬂash column chro-

matography on silica gel (dichloromethane/methanol;

99.4:0.6; as eluant). The obtained free base was dis-

solved in diethyl ether, and 1 M solution of hydrochloric

acid in diethyl ether added dropwise. The resulting solu-

tion was concentrated in vacuo to give the title com-

pound as a pale yellow solid in 34% yield. ESI-MS

4.1.17. 4-(2-Oxo-3-1,2,4-triazol-1-ylmethyl-2,3-dihydro-

benzimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl

ester (4s). Using 1,2,4-triazole as the amine heterocycle

the resultant residue was puriﬁed by ﬂash column chro-

matography on silica gel (dichloromethane/methanol;

98:2; as eluant) to give the title compound as colourless

oil in 26% yield. ESI-MS m/z = 399.3 [M+H]⁺. ¹H NMR

(400 MHz, CDCl₃): d 1.50 (s, 9H), 1.76–1.88 (m, 2H),

2.24–2.40 (m, 2H), 2.76–2.94 (m, 2H), 4.24–4.38 (br s,

2H), 4.38–4.50 (m, 1H), 6.17 (s, 2H), 7.10–7.19 (m,

3H), 7.41–7.47 (m, 1H), 7.93 (s, 1H), 8.40 (s, 1H).

1

m/z = 534.3 [M+H]⁺. H NMR (400 MHz, CD₃OD): d

1.01 (d, J = 7.2 Hz, 3H), 1.05 (d, J = 7.2 Hz, 3H),

2.00–2.24 (m, 8H), 2.78–2.94 (m, 2H), 3.14–3.44 (m,

4H), 3.68–3.84 (m, 5H), 4.32–4.41 (m, 1H), 4.54–4.66

(m, 1H), 5.08 (s, 2H), 6.43 (dd, J = 8.2 and 2.3 Hz,

1H), 6.52 (d, J = 2.3 Hz, 1H), 7.00–7.18 (m, 5H), 7.26–

7.40 (m, 3H).

4.1.18. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-thiazol-4-ylmethyl-1,3-dihydro-

benzimidazol-2-one hydrochloride (7a). Triﬂuoroacetic

acid (3.0 mL) was added dropwise to a solution of 4a

(600 mg, 1.45 mmol) in dichloromethane (30 mL) under

ice-water cooling and stirred at room temperature for

16 h. Aqueous solution (1 M) of sodium hydroxide

(30 mL) was then added carefully to the reaction mix-

ture, and the resulting organic layer was separated.

The aqueous layer was extracted with dichloromethane

(4· 100 mL). The combined organics were washed with

brine, dried (MgSO₄), ﬁltered and concentrated in vacuo

to give the free amine 5a as a colourless solid (420 mg,

92%). ESI-MS m/z = 315.1 [M+H]⁺. ¹H NMR

(400 MHz, CDCl₃): d 1.62 (br s, 1H), 1.78–1.92 (m,

2H), 2.28–2.44 (m, 2H), 2.74–2.88 (m, 2H), 3.20–3.34

(m, 2H), 4.42–4.56 (m, 1H), 5.25 (s, 2H), 7.03–7.14 (m,

3H), 7.17–7.20 (m, 1H), 7.26–7.31 (m, 1H), 8.77 (s, 1H).

4.1.20. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-pyridin-2-ylmethyl-1,3-dihydro-

benzimidazol-2-one hydrochloride (7c). Starting with 4c

the title compound was puriﬁed by ﬂash column chro-

matography on silica gel (dichloromethane/ethanol;

98:2; as eluant). The obtained free base was dissolved

in diethyl ether, and 1 M solution of hydrochloric acid

in diethyl ether added dropwise. The resulting solution

was concentrated in vacuo to give the title compound

as a white solid in 41% yield. ESI-MS m/z = 409.6

[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): d 0.97 (d,

J = 6.8 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H), 1.98–2.16

(m, 6H), 2.25–2.44 (m, 2H), 2.85–2.95 (m, 2H), 3.11–

3.16 (m, 2H), 3.31–3.48 (m, 2H), 3.64–3.66 (m, 1H),

3.78 (s, 3H), 3.77–3.80 (m, 1H), 4.24–4.28 (m, 1H),

4.75–4.81 (m, 1H), 5.58 (s, 2H), 6.39–6.44 (m, 2H),

7.01–7.11 (m, 2H), 7.18–7.24 (m, 2H), 7.60–7.65 (m,

2H), 7.93 (d, J = 8.0 Hz, 1H), 8.08 (t, J = 7.6 Hz, 1H),

8.69 (d, J = 4.8 Hz, 1H).

A mixture of 2-[1-(2-chloro-ethyl)-2-methyl-propoxy]-4-

methoxy-1-methyl-benzene 6¹⁰(624 mg, 2.00 mmol), 5a

(420 mg, 1.34 mmol), diisopropylethylamine (259 mg,

2.00 mmol), sodium iodide (30 mg) and acetonitrile

(15 mL) was stirred at gentle reﬂux temperature for

20 h. The reaction mixture was diluted with 1 M aque-

ous solution of sodium hydroxide (20 mL), then the

resulting mixture was extracted with dichloromethane

(4· 100 mL). The organic layers were combined, washed

with brine, dried (MgSO₄), ﬁltered and concentrated in

vacuo. The resultant residue was puriﬁed by ﬂash col-

4.1.21. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-(2-methylthiazol-4-ylmethyl)-

1,3-dihydro-benzimidazol-2-one hydrochloride (7d). Start-

ing with 4d the title compound was puriﬁed by ﬂash col-

umn chromatography on silica gel (dichloromethane/

ethanol; 98:2 then 96:4 gradient; as eluant). The free

base of the title compound (64% yield) was dissolved

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

2841

1

in dichloromethane, and 1 M solution of hydrochloric

acid in diethyl ether added. The hydrochloride salt was

then precipitated twice from acetone/ether to give an

oﬀ-white solid in 73% yield from free base. ESI-MS

m/z = 519.0 [M+H]⁺. H NMR (400 MHz, CD₃OD): d

1.01 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H),

2.03–2.19 (m, 5H), 2.16 (s, 3H), 2.71 (s, 3H), 2.84 (dq,

J = 12.8 and 2.5 Hz, 2H), 3.24 (br t, J = 12.6 Hz, 2H),

3.73–3.76 (m, 2H), 3.76 (s, 3H), 4.37 (q, J = 5.0 Hz,

1H), 4.58 (tt, J = 12.2 and 4.0 Hz, 1H), 5.03 (s, 2H),

6.44 (dd, J = 2.3 and 8.3 Hz, 1H), 6.52 (d, J = 2.3 Hz,

1H), 7.04 (d, J = 8.3 Hz, 1H), 7.08–7.15 (m, 2H), 7.21

(d, J = 7.5 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.93 (s,

1H), 8.11 (s, 1H).

1

m/z = 549.3 [M+H]⁺. H NMR (400 MHz, CD₃OD): d

1.02 (d, J = 7.0 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H),

2.03–2.23 (m, 5H), 2.16 (s, 3H), 2.65 (s, 3H), 2.81–2.94

(m, 2H), 3.20–3.29 (m, 2H), 3.76 (s, 3H), 4.36 (q,

J = 5.5 Hz, 1H), 4.63 (tt, J = 12.2 and 3.9 Hz, 1H),

5.13 (s, 2H), 6.42 (dd, J = 12.2 and 3.9 Hz, 1H), 6.52

(br s, 1H), 7.02 (d, J = 8.3 Hz, 1H), 7.06–7.15 (m, 3H),

7.21 (s, 1H), 7.39 (d, J = 7.3 Hz, 1H).

4.1.25. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-oxazol-2-ylmethyl-1,3-dihydro-

benzimidazol-2-one methanesulfonate (7h). Starting with

4h the title compound was puriﬁed by ﬂash column

chromatography on silica gel (dichloromethane/ethanol;

97:3; as eluant). The obtained free base was converted to

the methanesulfonate salt by addition of one equivalent

of methanesulfonic acid. The salt was crystallised twice

from acetone/diethyl ether to give a white solid in 47%

yield. ESI-MS m/z = 519.6 [M+H]⁺. ¹H NMR

(400 MHz, CDCl₃): d 0.96–0.99 (m, 6H), 1.70–1.83 (m,

4H), 1.99–2.15 (m, 6H), 2.38–2.51 (m, 4H), 2.96–2.98

(m, 1H), 3.07–3.10 (m, 1H), 3.75 (s, 3H), 4.23–4.24 (m,

1H), 4.38–4.44 (m, 1H), 5.19 (s, 2H), 6.36 (d,

J = 8.0 Hz, 1H), 6.62 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H),

7.05–7.07 (m, 4H), 7.32 (d, J = 6.8 Hz, 1H), 7.58 (s, 1H).

4.1.22. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-pyridin-4-ylmethyl-1,3-dihydro-

benzimidazol-2-one hydrochloride (7e). Starting with 4e

the title compound was puriﬁed by ﬂash column chro-

matography on silica gel (dichloromethane/methanol;

98:2; as eluant). The obtained free base was dissolved

in diethyl ether, and 1 M solution of hydrochloric acid

in diethyl ether added dropwise. The resulting solution

was concentrated in vacuo to give the title compound

as a white solid in 12% yield. ESI-MS m/z = 409.5

[M+H]. ¹H NMR (400 MHz, CD₃OD): d 1.01 (d,

J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 2.03–2.23

(m, 8H), 2.87–2.97 (m, 2H), 3.25–3.34 (m, 4H), 3.75–

3.80 (m, 5H), 4.36–4.39 (m, 1H), 4.67–4.73 (m, 1H),

4.77–4.81 (m, 2H), 5.43 (s, 2H), 6.42 (dd, J = 8.0 and

2.0 Hz, 1H), 6.53 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H),

7.07–7.14 (m, 2H), 7.19 (t, J = 7.6 Hz, 1H), 7.53 (d,

J = 8.0 Hz, 1H), 7.92 (d, J = 5.6 Hz, 2H), 8.79 (s, 2H).

4.1.26. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-(5-methyl-isoxazol-3-ylmethyl)-

1,3-dihydro-benzimidazol-2-one methanesulfonate (7i).

Starting with 4i the title compound was puriﬁed by ﬂash

column chromatography on silica gel (dichloromethane/

ethanol; 98.5:1.5; as eluant). The obtained free base of

(46% yield) was dissolved in dichloromethane and 1

equivalent of methanesulfonic acid was added. The

methanesulfonate salt was precipitated three times from

acetone by adding copious amounts of diethyl ether to

give a white solid in 64% yield from free base. ESI-MS

4.1.23. 1-(5-tert-Butyl-1,2,4-oxadiazol-3-ylmethyl)-3-{1-

[3-(5-methoxy-2-methyl-phenoxy)-4-methyl-pentyl]-pip-

eridin-4-yl}-1,3-dihydro-benzimidazol-2-one methansulfo-

nate (7f). Starting with 4f the title compound was

puriﬁed by ﬂash column chromatography on silica gel

(dichloromethane/ethanol; 98:2 then 96:4 gradient; as

eluant). The obtained free base of the title compound

(18% yield) was dissolved in dichloromethane, and 1

equivalent of methanesulfonic acid was added. The

methanesulfonate salt was crystallised from acetone to

give a white solid in 74% yield from free base. ESI-MS

1

m/z = 533.3 [M+H]⁺. H NMR (400 MHz, CDCl₃): d

0.98 (d, J = 7.0 Hz, 3H), 1.03 (d, J = 7.0 Hz, 3H),

1.96–2.18 (m, 4H), 2.15 (s, 3H), 2.19–2.40 (m, 4H),

2.35 (s, 3H), 2.80–2.95 (m, 2H), 3.03–3.28 (m, 4H),

3.74 (d, J = 10.0 Hz, 1H), 3.77 (s, 3H), 3.87 (d,

J = 10.0 Hz, 1H), 4.26 (m, 1H), 4.73 (m, 1H), 5.06 (s,

2H), 5.92 (s, 1H), 6.41 (br s, 2H), 7.04 (d, J = 8.2 Hz,

1H), 7.06–7.11 (m, 2H), 7.13–7.18 (m, 1H), 7.68 (d,

J = 8.0 Hz, 1H).

1

m/z = 576.3 [M+H]⁺. H NMR (400 MHz, CD₃OD): d

1.02 (d, J = 7.0 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 1.39

(s, 3H), 2.05–2.20 (m, 5H), 2.16 (s, 3H), 2.70 (s, 3H),

2.76–2.88 (m, 2H), 3.16–3.32 (m, 4H), 3.75 (s, 3H),

4.35 (q, J = 5.5 Hz, 1H), 4.58 (tt, J = 12.2 and 4.0 Hz,

1H), 5.20 (s, 2H), 6.44 (dd, J = 8.2 and 2.2 Hz, 1H),

6.52 (br s, 1H), 7.02 (d, J = 8.8 Hz, 1H), 7.07–7.19 (m,

3H), 7.33 (d, J = 7.8 Hz, 1H).

4.1.27. 1-(3,5-Dimethyl-isoxazol-4-ylmethyl)-3-{1-[3-(5-

methoxy-2-methyl-phenoxy)-4-methyl-pentyl]-piperidin-

4-yl}-1,3-dihydro-benzimidazol-2-one hydrochloride (7j).

Starting with 4j the title compound was puriﬁed by ﬂash

column chromatography on silica gel (dichloromethane/

ethanol; 99:1; as eluant). The obtained free base was dis-

solved in diethyl ether, and 1 M solution of hydrochloric

acid in diethyl ether added dropwise. The resulting solu-

tion was concentrated in vacuo to give the title com-

pound as a pale yellow solid in 5% yield. ESI-MS

4.1.24. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-oxazol-4-ylmethyl-1,3-dihydro-

benzimidazol-2-one methanesulfonate (7g). Starting with

4g the title compound was puriﬁed by ﬂash column

chromatography on silica gel (dichloromethane/ethanol;

98:2 then 96:4 gradient; as eluant). The obtained free

base (25% yield) was dissolved in dichloromethane,

and converted to the methanesulfonate salt by addition

of one equivalent of methanesulfonic acid. The salt was

crystallised twice from acetone/diethyl ether to give a

white solid (68% yield from free base). ESI-MS

1

m/z = 547.6 [M+H]. H NMR (400 MHz, CD₃OD): d

0.96 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H),

1.72–1.85 (m, 4H), 1.97–2.14 (m, 3H), 3.15 (s, 3H),

2.19 (s, 3H), 2.38–2.49 (m, 7H), 2.96–2.98 (m, 1H),

2842

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

3.07–3.10 (m, 1H), 3.75 (s, 3H), 4.22–4.26 (m, 1H), 4.34–

4.40 (m, 1H), 4.79 (s, 2H), 6.36 (dd, J = 8.0 and 2.4 Hz,

1H), 6.61 (d, J = 2.4 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H),

7.00–7.08 (m, 3H), 7.31 (d, J = 7.6 Hz, 1H).

brown solid in a yield of 36%. ESI-MS m/z = 530.3

[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): d 1.01 (d,

J = 6.6 Hz, 3H), 1.05 (d, J = 6.6 Hz, 3H), 1.98–2.24

(m, 8H), 2.78–2.94 (m, 2H), 3.18–3.38 (m, 4H), 3.70–

3.83 (m, 5H), 4.32–4.41 (m, 1H), 4.57–4.68 (m, 1H),

5.27 (s, 2H), 6.43 (dd, J = 8.2 and 2.0 Hz, 1H), 6.52 (d,

J = 2.0 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 7.04–7.19

(m, 3H), 7.39 (d, J = 7.2 Hz, 1H), 8.47–8.55 (m, 2H),

8.61 (s, 1H).

4.1.28. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-thiophen-2-ylmethyl-1,3-dihydro-

benzimidazol-2-one hydrochloride (7k). Starting with 4k

the title compound was puriﬁed by ﬂash column chro-

matography on silica gel (dichloromethane/methanol;

99.2:0.8; as eluant). The obtained free base was dis-

solved in diethyl ether, and 1 M solution of hydrochloric

acid in diethyl ether added dropwise. The resulting solu-

tion was concentrated in vacuo to give the title com-

pound as a pale yellow solid in 45% yield. ESI-MS

4.1.31. 1-(1H-Imidazol-4-ylmethyl)-3-{1-[3-(5-methoxy-

2-methyl-phenoxy)-4-methyl-pentyl]-piperidin-4-yl}-1,3-

dihydro-benzimidazol-2-one hydrochloride (7o). Using 1-

(4-methylphenylsulfonyl)-4-methanesulfonyloxymethyl

imidazole¹⁷as the alkylating agent for substrate 8,¹⁰

and following the methods outlined for 4a, the inter-

mediate 7n was puriﬁed by column chromatography

on silica gel (dichloromethane/ethanol; 98.5:1.5; as elu-

ant) to give the free base in 23% yield. ESI-MS m/

z = 672.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): d

0.96 (d, J = 7.2 Hz, 3H), 0.98 (d, J = 7.2 Hz, 3H),

1.75–1.90 (m, 4H), 1.95–2.12 (m, 2H), 2.15 (s, 3H),

2.35–2.50 (m, 5H), 2.92–2.98 (m, 1H), 3.05–3.10

(m, 1H), 3.76 (s, 3H), 4.20–4.23 (m, 1H), 4.33–4.40

(m, 1H), 4.95 (s, 2H), 6.36 (d, J = 8.2 Hz, 1H), 6.62

(s, 1H), 7.00–7.13 (m, 3H), 7.17 (s, 1H), 7.32–7.34

(m, 3H), 7.77 (d, J = 8.0 Hz, 2H), 7.92 (s, 1H). This

material was dissolved in dichloromethane and treated

with excess 1 M solution of hydrochloric acid in

diethyl ether and stirred for 1 h. The solution was

evaporated to dryness and dissolved in dichlorometh-

ane, diethyl ether was added slowly to eﬀect precipita-

tion and the solid collected by ﬁltration. The white

solid was crystallised from dichloromethane and ace-

tone to give the detosylated compound 7o (100%

yield). ESI-MS m/z = 518.3 [M+H]⁺. ¹H NMR

(400 MHz, D₂O): d 0.90 (d, J = 8.0 Hz, 3H), 0.93 (d,

J = 8.0 Hz, 3H), 1.96–2.01 (m, 1H), 2.11 (s, 3H),

2.13–2.11 (m, 4H), 2.60–2.71 (m, 2H), 3.12–3.20 (m,

2H), 3.23–3.29 (m, 2H), 3.68–3.70 (m, 2H), 3.75 (s,

3H), 4.30–4.33 (m, 1H), 4.55–4.61 (m, 1H), 5.20 (s,

2H), 6.50 (d, J = 8.0 Hz, 1H), 6.58 (s, 1H), 7.10 (d,

J = 8.3 Hz, 1H), 7.12–7.23 (m, 3H), 7.33 (d,

J = 8.3Hz, 1H), 7.40 (s, 1H), 8.6 (s, 1H).

1

m/z = 534.3 [M+H]⁺. H NMR (400 MHz, CD₃OD): d

1.01 (d, J = 7.0 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H),

2.00–2.23 (m, 8H), 2.77–2.94 (m, 2H), 3.16–3.40 (m,

4H), 3.66–3.82 (m, 5H), 4.32–4.41 (m, 1H), 4.54–4.65

(m, 1H), 5.25 (s, 2H), 6.43 (dd, J = 2.2 and 8.2 Hz,

1H), 6.52 (d, J = 2.2 Hz, 1H), 6.94 (dd, J = 5.2 and

3.2 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 7.06–7.23 (m,

4H), 7.26–7.39 (m, 2H).

4.1.29. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-pyridin-3-ylmethyl-1,3-dihydro-

benzimidazol-2-one hydrochloride (7l). Using 3-chlorom-

ethylpyridine as the alkylating reagent 4l was prepared

in a similar manner to 4a. The residue was puriﬁed by

precipitating the solid from diethyl ether to give the

intermediate compound as a yellow solid in 77% yield.

ESI-MS m/z = 409.5 [M+H]⁺. The material was used

without further puriﬁcation. Starting with 4l the title

compound was prepared in a similar manner to 7a.

The residue was puriﬁed by ﬂash column chromatogra-

phy on silica gel (dichloromethane/ethanol; 97:3; as elu-

ant). The obtained free base of the title compound was

dissolved in diethyl ether, and 1 M solution of hydro-

chloric acid in diethyl ether added dropwise. The result-

ing solution was concentrated in vacuo to give the title

compound as a white solid in 19% yield. ESI-MS

1

m/z = 409.4 [M+H]⁺. H NMR (400 MHz, CD₃OD): d

1.01 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H),

2.03–2.12 (m, 8H), 2.85–2.96 (m, 2H), 3.23–3.33 (m,

2H), 3.74–3.80 (m, 5H), 4.35–4.39 (m, 1H), 4.62–4.70

(m, 1H), 4.77–4.81 (m, 2H), 5.35 (s, 2H), 6.42 (dd,

J = 8.0 and 2.4 Hz, 2H), 6.53 (d, J = 2.4 Hz, 1H), 7.02

(d, J = 8.4 Hz, 1H), 7.08–7.21 (m, 3H), 7.49 (d,

J = 8.0 Hz, 1H), 8.06 (dd, J = 8.0 and 5.6 Hz, 1H),

8.55 (d, J = 8.4 Hz, 1H), 8.80 (d, J = 5.6 Hz, 1H), 8.90

(s, 1H).

4.1.32. 1-Imidazol-1-ylmethyl-3-{1-[3-(5-methoxy-2-methyl-

phenoxy)-4-methyl-pentyl]-piperidin-4-yl}-1,3-dihydro-

benzimidazol-2-one hydrochloride (7p). Starting with 4p

the title compound was puriﬁed by ﬂash column chro-

matography on silica gel (dichloromethane/methanol;

98:2; as eluant). The obtained free base was dissolved

in diethyl ether, and 1 M solution of hydrochloric acid

in diethyl ether added dropwise. The resulting solution

was concentrated in vacuo to give the title compound

as a colourless solid in 15% yield. ESI-MS m/z = 518.3

[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): d 1.01 (d,

J = 6.6 Hz, 3H), 1.05 (d, J = 6.6 Hz, 3H), 1.98–2.28

(m, 8H), 2.78–2.98 (m, 2H), 3.16–3.40 (m, 4H), 3.68–

3.86 (m, 5H), 4.32–4.44 (m, 1H), 4.56–4.70 (m, 1H),

6.37 (s, 2H), 6.43 (dd, J = 8.3 and 2.4 Hz, 1H), 6.50–

6.56 (m, 1H), 7.03 (d, J = 8.3 Hz, 1H), 7.16–7.28 (m,

2H), 7.42–7.54 (m, 2H), 7.58 (s, 1H), 7.76 (s, 1H), 9.22

(s, 1H).

4.1.30. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-pyrazin-2-ylmethyl-1,3-dihydro-

benzimidazol-2-one hydrochloride (7m). Using 2-chlo-

romethylpyrazine¹⁶was used as the alkylating agent

for substrate 8¹⁰and following the methods for 4a.

The ﬁnal compound was puriﬁed by column chromatog-

raphy on silica gel (dichloromethane/methanol; 98.5:1.5;

as eluant) to give the free base. This was then dissolved

in diethyl ether, and mixed with 1 M solution of hydro-

chloric acid in diethyl ether. The resulting mixture was

concentrated in vacuo to give the title compound as a

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

2843

4.1.33. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-pyrazol-1-ylmethyl-1,3-dihydro-

benzimidazol-2-one hydrochloride (7q). Starting with 4q

the title compound was puriﬁed by ﬂash column chro-

matography on silica gel (dichloromethane/methanol;

98:2; as eluant). The obtained free base was dissolved

in diethyl ether, and 1 M solution of hydrochloric acid

in diethyl ether added dropwise. The resulting solution

was concentrated in vacuo to give the title compound

as a yellow solid in 23% yield. ESI-MS m/z = 518.3

[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): d 1.01 (d,

J = 6.6 Hz, 3H), 1.05 (d, J = 6.6 Hz, 3H), 1.96–2.23

(m, 8H), 2.75–2.91 (m, 2H), 3.15–3.38 (m, 4H), 3.70–

3.82 (m, 5H), 4.30–4.40 (m, 1H), 4.51–4.63 (m, 1H),

6.18 (s, 2H), 6.32 (s, 1H), 6.43 (dd, J = 8.6 and 2.2 Hz,

1H), 6.52 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H),

7.09–7.20 (m, 2H), 7.27–7.34 (m, 1H), 7.38–7.46 (m,

1H), 7.46–7.53 (m, 1H), 7.85 (s, 1H).

solid in 84% yield. ESI-MS m/z = 404.3 [M+H]⁺. ¹H

NMR (400 MHz, CDCl₃): d 1.27 (t, J = 7.0 Hz, 3H),

1.50 (s, 9H), 1.78–1.89 (m, 2H), 2.24–2.39 (m, 2H),

2.77–2.94 (m, 2H), 4.22–4.38 (m, 3H), 4.41–4.53 (m,

1H), 4.61 (s, 2H), 6.85–6.92 (m, 1H), 7.02–7.16 (m, 3H).

4.1.37.

4-(3-Hydrazinocarbonylmethyl-2-oxo-2,3-dihy-

dro-benzimidazol-1-yl)-piperidine-1-carboxylic acid tert-

butyl ester (12). Compound 11 (2.4 g, 5.96 mmol) was

treated with a large excess of hydrazine hydrate (55%,

4.0 mL) in ethanol (25 mL) for 45 min at reﬂux. The

reaction mixture was cooled and poured into water

and the resulting solid ﬁltered oﬀ and washed well with

water. The solid was dissolved in dichloromethane,

washed with water then brine and the organics dried

(Na₂SO₄). The dichloromethane was removed under

vacuum and replaced with diethyl ether. The resultant

solid was ﬁltered oﬀ and dried to give the title com-

pound as a dense white solid (2.0 g, 86% yield). ESI

1

4.1.34. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-(2-methyl-imidazol-1-ylmethyl)-

1,3-dihydro-benzimidazol-2-one hydrochloride (7r). Start-

ing with 4r the title compound was puriﬁed by ﬂash col-

umn chromatography on silica gel (dichloromethane/

methanol; 98:2; as eluant). The obtained free base was

dissolved in diethyl ether, and 1 M solution of hydro-

chloric acid in diethyl ether added dropwise. The result-

ing solution was concentrated in vacuo to give the title

compound as a pale brown solid in 11% yield. ESI-MS

m/z = 390.1 [M+H]⁺. H NMR (400 MHz, CDCl₃): d

1.50 (s, 9H), 1.82 (br d, J = 12.6 Hz, 2H), 2.30 (dq,

J = 12.3 and 4.5 Hz, 2H), 2.87 (br t, J = 12.5 Hz, 2H),

3.72–3.97 (br m, 2H), 4.24–4.37 (m, 2H), 4.43 (tt,

J = 12.5 and 4.2 Hz, 1H), 4.52 (s, 2H), 7.04–7.18 (m,

4H), 7.46 (br s, 1H).

4.1.38.

4-[3-(5-Methyl-2H-1,2,4-triazol-3-ylmethyl)-2-

oxo-2,3-dihydro-benzimidazol-1-yl]-piperidine-1-carboxylic

acid tert-butyl ester (13). Acetamidine hydrochloride

(486 mg, 5.14 mmol) was dissolved in ethanol (6.0 mL)

and treated with sodium methoxide (280 mg, 5.18 mmol)

in ethanol (3.0 mL) and stirred for 20 min. The precipi-

tated white solid was ﬁltered oﬀ and 12 (1.0 g,

2.57 mmol) was added to the ﬁltrate and the mixture

stirred for 2 h. The intermediate acyl amidrazone was

then ﬁltered oﬀ and heated in methoxyethanol at

1

m/z = 532.3 [M+H]⁺. H NMR (400 MHz, CD₃OD): d

1.01 (d, J = 7.0 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H), 1.98-

2.26 (m, 8H), 2.76–2.98 (m, 5H), 2.87 (s, 3H), 3.15–

3.40 (m, 4H), 3.66–3.85 (m, 5H), 4.30–4.42 (m, 1H),

4.54–4.71 (m, 1H), 6.28 (s, 2H), 6.42 (dd, J = 8.4 and

2.8 Hz, 1H), 6.47–6.58 (m, 1H), 7.03 (d, J = 8.4 Hz,

1H), 7.16–7.28 (m, 2H), 7.39–7.54 (m, 3H), 7.62–7.70

(m, 1H).

˚

140 ꢁC for 1 h in the presence of 4 A molecular sieves.

Removal of solvent under high vacuum gave the title

4.1.35. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-(1,2,4-triazol-1-ylmethyl)-1,3-

dihydro-benzimidazol-2-one hydrochloride (7s). Starting

with 4s the title compound was puriﬁed by ﬂash column

chromatography on silica gel (dichloromethane/metha-

nol; 99:1; as eluant). The obtained free base was dis-

solved in diethyl ether, and 1 M solution of

hydrochloric acid in diethyl ether added dropwise. The

resulting solution was concentrated in vacuo to give

the title compound as a pale yellow solid in 19% yield.

ESI-MS m/z = 519.3 [M+H]⁺. ¹H NMR (400 MHz,

compound as a gum (620 mg, 58% yield). ESI

m/z = 413.0 [M+H]⁺. H NMR (400 MHz, CDCl₃): d

1.50 (s, 9H), 1.81 (br d, J = 12.5 Hz, 2H), 2.29 (dq,

J = 12.5 and 4.5 Hz, 2H), 2.39 (s, 3H), 2.83 (br t,

J = 12.5 Hz, 2H), 4.23–4.37 (br m, 2H), 4.48 (tt,

J = 12.5 and 4.0 Hz, 1H), 5.13 (s, 2H), 7.02–7.08 (m,

2H), 7.08–7.13 (m, 1H), 7.13–7.18 (m, 1H).

1

4.1.39. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-(5-methyl-1H-1,2,4-triazol-3-

ylmethyl)-1,3-dihydro-benzimidazol-2-one hydrochloride

(14). Prepared according to the method outlined for 7k

using 13, the title compound was puriﬁed by ﬂash col-

umn chromatography on silica gel (dichloromethane/

ethanol; 98:2 then 92:8 gradient; as eluant). The ob-

tained free base of the title compound (58% yield) was

dissolved in dichloromethane plus a few drops of etha-

nol and 1 M solution of hydrochloric acid in diethyl

ether added. The hydrochloride salt was crystallised

twice from acetone to give a creamy white solid in quan-

titative yield from the free amine. ESI-MS m/z = 533.3

[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): d 1.02 (d,

J = 7.0 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 2.03–2.21

(m, 5H), 2.16 (s, 3H), 2.62 (s, 3H), 2.85–2.97 (m, 2H),

3.21–3.34 (m, 4H), 3.73–3.81 (m, 2H), 3.76 (s, 3H),

CD₃OD):

d 1.01 (d, J = 6.6 Hz, 3H), 1.05 (d,

J = 6.6 Hz, 3H), 1.96–2.30 (m, 8H), 2.72–2.96 (m, 2H),

3.10–3.43 (m, 4H), 3.66–3.86 (m, 5H), 4.28–4.44 (m,

1H), 4.50–4.67 (m, 1H), 6.35 (s, 2H), 6.39–6.60 (m,

2H), 7.03 (d, J = 8.0 Hz, 1H), 7.11–7.28 (m, 2H), 7.31–

7.55 (m, 2H), 8.13 (br s, 1H), 8.98 (br s, 1H).

4.1.36.

4-(3-Ethoxycarbonylmethyl-2-oxo-2,3-dihydro-

benzimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl

ester (11). Prepared according to the method outlined

for 4a using ethyl chloroacetate as the alkylating re-

agent. The residue was puriﬁed by ﬂash column chroma-

tography on silica gel (dichloromethane/methanol; 98:2;

as eluant) to give the title compound as a colourless

2844

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

4.36 (q, J = 5.5 Hz, 1H), 4.66 (tt, J = 12.5 and 4.2 Hz,

1H), 5.33 (s, 2H), 6.42 (dd, J = 8.3 and 2.2 Hz, 1H),

6.52 (d, J = 2.2 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H),

7.10–7.21 (m, 3H), 7.47 (d, J = 7.5 Hz, 1H).

4.1.43.

4-[3-(N-Hydroxycarbamimidoylmethyl)-2-oxo-

2,3-dihydro-benzimidazol-1-yl]-piperidine-1-carboxylic

acid tert-butyl ester (18). Hydroxylamine hydrochloride

(351 mg, 5.05 mmol) was added to a solution of 17

(900 mg, 2.53 mmol), diisopropylethylamine (653 mg,

5.05 mmol), and ethanol (23 mL), and the resulting mix-

ture stirred at reﬂux for 16 h. The reaction mixture was

concentrated in vacuo, and the resultant residue dis-

solved in dichloromethane. The resulting mixture was

washed with brine, dried (MgSO₄), ﬁltered and concen-

trated in vacuo. The residue was then puriﬁed by ﬂash

column chromatography on silica gel (dichlorometh-

ane/methanol; 97:3; as eluant) to give the title com-

pound as a pale yellow solid (715 mg, 73%). ESI-MS

4.1.40. 4-[3-(3-Methyl-1,2,4-oxadiazol-5-ylmethyl)-2-oxo-

2,3-dihydro-benzimidazol-1-yl]-piperidine-1-carboxylic

˚

acid tert-butyl ester (15). Molecular sieves (4 A

powdered, 200 mg) were added to a suspension of N-

hydroxyacetamidine²¹(222 mg, 3.00 mmol) in tetrahy-

drofuran (10 mL), and the resulting mixture stirred at

room temperature for 30 min. Sodium hydride (60% sus-

pension in mineral oil, 120 mg, 3.00 mmol) was added to

the mixture and stirred at 50 ꢁC for 20 min. After the

reaction mixture had been cooled to room temperature,

11 (403 mg, 1.00 mmol) was added to the reaction mix-

ture and stirred at reﬂux temperature for 2 h. The reac-

tion mixture was concentrated in vacuo, and the

resultant residue poured into water (200 mL) and ex-

tracted with dichloromethane (4· 100 mL). The organic

layers were combined, washed with brine, dried

(MgSO₄), ﬁltered and concentrated in vacuo. The resi-

due was puriﬁed by ﬂash column chromatography on

silica gel (dichloromethane/methanol; 99:1; as eluant)

to give the title compound as a colourless solid

(110 mg, 27%). ESI-MS m/z = 414.1 [M+H]⁺, 437.1

[M+Na]⁺. ¹H NMR (400 MHz, CDCl₃): d 1.50 (s,

9H), 1.78–1.90 (m, 2H), 2.24–2.46 (m, 5H), 2.72–2.98

(m, 2H), 4.16–4.42 (br s, 2H), 4.42–4.56 (m, 1H), 5.27

(s, 2H), 6.94–7.20 (m, 4H).

m/z = 390.3 [M+H]⁺. H NMR (400 MHz, DMSO-d₆):

1

d 1.44 (s, 9H), 1.66–1.76 (m, 2H), 2.12–2.28 (m, 2H),

2.72–3.04 (br s, 2H), 4.00–4.20 (m, 2H), 4.32–4.46 (m,

3H), 5.43 (s, 2H), 6.98–7.14 (m, 3H), 7.20–7.29 (m,

1H), 9.20 (s, 1H).

4.1.44. 4-[3-(5-Methyl-1,2,4-oxadiazol-3-ylmethyl)-2-

oxo-2,3-dihydro-benzimidazol-1-yl]-piperidine-1-carboxylic

˚

acid tert-butyl ester (19). Molecular sieves (4 A pow-

dered, 200 mg) were added to a suspension of 18

(500 mg, 1.28 mmol) in tetrahydrofuran (10 mL), and

the resulting mixture stirred at room temperature for

30 min. Sodium hydride (60% suspension in mineral

oil, 77 mg, 1.93 mmol) was added to the mixture and

stirred at 50 ꢁC for 20 min. After the reaction mixture

had been cooled to room temperature, ethyl acetate

(452 mg, 5.13 mmol) was added to the mixture and stir-

red at reﬂux for 2 h. The reaction mixture was poured

into water (200 mL) and extracted with dichlorometh-

ane (4· 100 mL). The organic layers were combined,

washed with brine, dried (MgSO₄), ﬁltered and concen-

trated in vacuo. The resultant oil was puriﬁed by ﬂash

column chromatography on silica gel (dichlorometh-

ane/methanol; 99:1; as eluant) to give the title com-

pound as a colourless oil (432 mg, 81%). ESI-MS

m/z = 414.2 [M+H]⁺, 437.2 [M+Na]⁺. ¹H NMR

(400 MHz, CDCl₃): d 1.50 (s, 9H), 1.79–1.90 (m, 2H),

2.25–2.39 (m, 2H), 2.55 (s, 3H), 2.76–2.96 (m, 2H),

4.16–4.44 (br s, 2H), 4.46–4.57 (m, 1H), 5.16 (s, 2H),

7.02–7.18 (m, 4H).

4.1.41. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]piperidin-4yl}-3-[(3-methyl[1,2,4]oxadiazol-5-yl)-

methyl]-1,3-dihydro-benzimidazol-2-one

hydrochloride

(16). Prepared according to the method outlined for 7a

using 15, the title compound was puriﬁed by ﬂash col-

umn chromatography on silica gel (dichloromethane/

methanol; 99:1; as eluant). The obtained free base was

dissolved in isopropanol and diethyl ether, and 1 M

solution of hydrochloric acid in diethyl ether added

dropwise. The resulting solution was concentrated in va-

cuo to give the title compound as a pale yellow solid in

38% yield. ESI-MS m/z = 534.2 [M+H]⁺. ¹H NMR

(400 MHz, CD₃OD): d 1.01 (d, J = 6.4 Hz, 3H), 1.05

(d, J = 6.4 Hz, 3H), 2.00–2.23 (m, 8H), 2.31 (s, 3H),

2.78–2.94 (m, 2H), 3.16–3.38 (m, 4H), 3.69–3.83 (m,

5H), 4.33–4.41 (m, 1H), 4.56–4.67 (m, 1H), 5.38 (s,

2H), 6.43 (dd, J = 8.4 and 2.0 Hz, 1H), 6.52 (d,

J = 2.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.10–7.22

(m, 3H), 7.36–7.45 (m, 1H).

4.1.45. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]piperidin-4yl}-3-[(5-methyl[1,2,4]oxadiazol-3-yl)-

methyl]-1,3-dihydro-benzimidazol-2-one

hydrochloride

(20). Prepared according to the method outlined for 7a

using 19, the title compound was puriﬁed by ﬂash col-

umn chromatography on silica gel (dichloromethane/

methanol; 99:1; as eluant). The obtained free base was

dissolved in isopropanol and diethyl ether, and 1 M

solution of hydrochloric acid in diethyl ether added

dropwise. The resulting solution was concentrated in va-

cuo to give the title compound as a pale yellow solid in

46% yield. ESI-MS m/z = 534.2 [M+H]⁺. ¹H NMR

(400 MHz, CD₃OD): d 1.01 (d, J = 6.8 Hz, 3H), 1.05

(d, J = 6.8 Hz, 3H), 1.98–2.28 (m, 8H), 2.53 (s, 3H),

2.77–2.95 (m, 2H), 3.15–3.39 (m, 4H), 3.70–3.84 (m,

5H), 4.32–4.42 (m, 1H), 4.54–4.68 (m, 1H), 5.19 (s,

2H), 6.38–6.46 (m, 1H), 6.47–6.56 (m, 1H), 7.03 (d,

J = 8.4 Hz, 1H), 7.06–7.20 (m, 3H), 7.32–7.44 (m, 1H).

4.1.42. 4-(3-Cyanomethyl-2-oxo-2,3-dihydro-benzimidazol-

1-yl)-piperidine-1-carboxylic acid tert-butyl ester (17).

Prepared according to the method outlined for 4a using

chloroacetonitrile as the alkylating reagent. The residue

was puriﬁed by ﬂash column chromatography on silica

gel (n-heptane/ethyl acetate; 60:40; as eluant) to give

the title compound as a yellow oil in 83% yield. ESI-

MS m/z = 357.1 [M+H]⁺, 380.1 [M+Na]⁺. ¹H NMR

(400 MHz, CDCl₃): d 1.50 (s, 9H), 1.78–1.88 (m, 2H),

2.25–2.40 (m, 2H), 2.78–2.94 (m, 2H), 4.24–4.38

(br s, 2H), 4.38–4.50 (m, 1H), 4.81 (s, 2H), 7.11–7.22

(m, 4H).

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

2845

4.1.46. 4-[2-Oxo-3-(2H-1,2,4-triazol-3-ylmethyl)-2,3-

dihydro-benzimidazol-1-yl]-piperidine-1-carboxylic acid

tert-butyl ester (21). Prepared according to the method

outlined for 4a using N-formyl-2-chloroacetamidraz-

one²³as alkylating agent, the intermediate product

was not isolated, but ring closure was eﬀected by heating

the reaction mixture in N,N-dimethylformamide at

140 ꢁC for 1 h. The resulting mixture was chromato-

graphed on silica gel (dichloromethane/ethanol; 98:2

then 94:6; gradient as eluant) to give the title compound

as a yellow gum in 27% yield. ESI m/z = 399.3 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃): d 1.50 (s, 9H), 1.78 (d,

J = 12.5 Hz, 2H), 2.31 (dq, J = 12.5 and 4.2 Hz, 2H),

2.84 (t, J = 12.2 Hz, 2H), 4.29 (m, 2H), 4.47 (tt,

J = 12.3 and 4.1 Hz, 1H), 5.21 (s, 2H), 7.05–7.14 (m,

3H), 7.19–7.24 (m, 1H), 8.06 (br s, 1H).

1H), 5.34 (s, 2H), 6.42 (dd, J = 8.5 and 2.5 Hz, 1H),

6.53 (br s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 7.07–7.18 (m,

3H), 7.44 (d, J = 7.6 Hz, 1H), 9.02 (s, 1H).

Racemic 24 was subjected to chiral chromatography on

a Chiralpak^ꢂAD column (2 cm · 25 cm), eluting with

isohexane/isopropanol/diethylamine (85:15:0.1; v/v) at

15 mL/min. The puriﬁed enantiomers were converted

to the methanesulfonate salts with 1 equivalent of

methanesulfonic acid in dichloromethane and then pre-

cipitated twice from a concentrated acetone solution by

ﬂooding with diethyl ether to give (+)-24. Purity by

HPLC 98.68%, enantiomeric ratio 100:0. [a]_D+26.7ꢁ

1

in methanol. H NMR (CD₃OD): d 8.92 (1H, s), 7.44

(1H, d, J = 7.5 Hz), 7.13–7.18 (1H, m), 7.08–7.13 (2H,

m), 7.02 (1H, d, J = 9.0 Hz), 6.53 (1H, d, J = 2.0 Hz),

6.42 (1H, dd, J = 2.5 and 8.0 Hz), 5.32 (2H, s), 4.64

(1H, tt, J = 4.0 and 12.5 Hz), 4.37 (1H, q, J = 5.5 Hz),

3.76 (3H, s), 3.72–3.81 (2H, m), 3.26–3.34 (2H, m),

3.25 (2H, t, br, J = 13.0 Hz), 2.89 (2H, dq, J = 3.5 and

13.0 Hz), 2.16 (3H, s), 2.02–2.24 (5H, m), 1.05 (3H, d,

J = 6.5 Hz), 1.02 (3H, d, J = 6.5 Hz). HRMS (TOF)

(M+H)⁺calculated for C₂₉H₃₉N₆O₃519.3078, found

519.3061.

4.1.47.

4-[3-(2-Methyl-2H-1,2,4-triazol-3-ylmethyl)-2-

oxo-2,3-dihydro-benzimidazol-1-yl]-piperidine-1-carboxylic

acid tert-butyl ester (22) and 4-[3-(1-Methyl-1H-1,2,4-

triazol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-

piperidine-1-carboxylic acid tert-butyl ester (23). Com-

pound 21 (500 mg, 1.25 mmol) was reﬂuxed in acetone

(20 mL) in the presence of potassium carbonate

(207 mg, 1.5 mmol) and methyliodide (0.177 mL,

2.8 mmol). After 15 min, the reaction mixture was

cooled and the inorganic material ﬁltered oﬀ. Acetone

was evaporated from the ﬁltrate and the component of

the residue soluble in dichloromethane was chromato-

graphed on silica gel (dichloromethane/ethanol; 98:2

then 96:4 gradient; as eluant). Pure samples of 22 (150

mg, 29%) and 23 (200 mg, 39%) were isolated. Isomer

assignment was based on HMBC NMR studies. 22:

ESI m/z = 413.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):

d 1.50 (s, 9H), 1.82 (br d, J = 12.5 Hz, 2H), 2.32 (dq,

J = 12.5 and 4.5 Hz, 2H), 2.86 (br t, J = 12.5 Hz, 2H),

3.97 (s, 3H), 4.25–4.38 (br m, 2H), 4.45 (tt, J = 12.5

and 4.0 Hz, 1H), 5.22 (s, 2H), 7.06–7.13 (m, 3H), 7.32–

7.35 (m, 1H), 7.83 (s, 1H). 23: ESI m/z = 413.1

4.1.49. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-(2-methyl-2H-1,2,4-triazol-3-yl-

methyl)-1,3-dihydro-benzimidazol-2-one

hydrochloride

(25). Starting with 22 the title compound was puriﬁed

by ﬂash column chromatography on silica gel (dichloro-

methane/ethanol; 98:2 then 95:5 gradient; as eluant).

The obtained free base of the title compound (46% yield)

was dissolved in dichloromethane plus a few drops of

ethanol and 1 M solution of hydrochloric acid in diethyl

ether added. The hydrochloride salt was precipitated

twice from acetone by adding copious amounts of

diethyl ether to give a ﬁlterable solid in 58% yield.

ESI-MS m/z = 533.3 [M+H]⁺. ¹H NMR (400 MHz,

CD₃OD):

d 1.02 (d, J = 7.0 Hz, 3H), 1.06 (d,

1

[M+H]⁺. H NMR (400 MHz, CDCl₃): d 1.50 (s, 9H),

J = 7.0 Hz, 3H), 2.03–2.22 (m, 5H), 2.16 (s, 3H), 2.79–

2.92 (m, 2H), 3.18–3.31 (m, 4H), 3.71–3.81 (m, 2H),

3.76 (s, 3H), 3.98 (s, 3H), 4.36 (q, J = 5.5 Hz, 1H),

4.60 (tt, J = 12.5 and 4.0 Hz, 1H), 5.29 (s, 2H), 6.44

(dd, J = 8.2 and 2.3 Hz, 1H), 6.52 (br s, 1H), 7.02 (d,

J = 8.0 Hz, 1H), 7.08–7.21 (m, 3H), 7.37 (d,

J = 7.5 Hz, 1H), 7.81 (s, 1H).

1.83 (br d, J = 12.5 Hz, 2H), 2.33 (dq, J = 12.5 and

4.6 Hz, 2H), 2.88 (br t, J = 12.5 Hz, 2H), 3.86 (s, 3H),

4.23–4.38 (br m, 2H), 4.52 (tt, J = 12.5 and 4.0 Hz,

1H), 5.14 (s, 2H), 7.01–7.06 (m, 2H), 7.07–7.14 (m,

2H), 7.93 (s, 1H).

4.1.48. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-(1H-1,2,4-triazol-3-ylmethyl)-

1,3-dihydro-benzimidazol-2-one hydrochloride (24). Start-

ing with 21 the title compound was puriﬁed by ﬂash col-

umn chromatography on silica gel (dichloromethane/

ethanol; 96:4 then 92:8; gradient, as eluant). The ob-

tained free base of the title compound (40% yield) was

dissolved in dichloromethane plus a few drops of etha-

nol and 1 M solution of hydrochloric acid in diethyl

ether added. The hydrochloride salt was precipitated

twice from ethanol plus acetone by adding copious

amounts of diethyl ether to give a yellow solid in 95%

yield. ESI-MS m/z = 519.3 [M+H]⁺. ¹H NMR

(400 MHz, CD₃OD): d 1.02 (d, J = 7.0 Hz, 3H), 1.06

(d, J = 7.0 Hz, 3H), 2.03–2.23 (m, 5H), 2.16 (s, 3H),

2.84–2.96 (m, 2H), 3.20–3.34 (m, 4H), 3.72–3.82 (m,

2H), 3.76 (s, 3H), 4.33–4.39 (m, 1H), 4.59–4.69 (m,

4.1.50. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-(1-methyl-1H-1,2,4-triazol-3-yl-

methyl)-1,3-dihydro-benzimidazol-2-one

hydrochloride

(26). Starting with 23 the title compound was puriﬁed

by ﬂash column chromatography on silica gel (dichloro-

methane/ethanol; 98:2 then 95:5 gradient; as eluant).

The obtained free base of the title compound (31% yield)

was dissolved in dichloromethane plus a few drops of

ethanol and 1 M solution of hydrochloric acid in diethyl

ether added. The hydrochloride salt was precipitated

twice from acetone by adding copious amounts of

diethyl ether to give a ﬁlterable solid in 35% yield.

ESI-MS m/z = 533.3 [M+H]⁺. ¹H NMR (400 MHz,

CD₃OD): d 1.01 (d, J = 7.0 Hz, 3H), 1.06 (d,

J = 7.0 Hz, 3H), 2.04–2.22 (m, 5H), 2.16 (s, 3H), 2.79–

2.93 (m, 2H), 3.18–3.35 (m, 4H), 3.71–3.81 (m, 2H),

2846

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

3.76 (s, 3H), 3.87 (s, 3H), 4.37 (q, J = 5.5 Hz, 1H), 4.61

(tt, J = 12.3 and 3.7 Hz, 1H), 5.14 (s, 2H), 6.44 (dd,

J = 8.3 and 2.2 Hz, 1H), 6.52 (d, J = 1.8 Hz, 1H),

7.01–7.14 (m, 4H), 7.35 (d, J = 7.5 Hz, 1H), 8.31 (s, 1H).

4.1.53. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-1,2,4-oxadiazol-3-ylmethyl-1,3-

dihydro-benzimidazol-2-one hydrochloride (29). Boron

triﬂuoride etherate (1 drop) was added to a suspension

of 30 (60 mg, 0.118 mmol) in triethyl orthoformate

(500 mg, 3.37 mmol), then the resulting mixture was stir-

red at 105–115 ꢁC for 30 min. The reaction mixture was

diluted with 5% aqueous solution of sodium carbonate

and resulting mixture extracted with dichloromethane

(4· 100 mL). The combined organic layers were washed

with brine, dried (MgSO₄), ﬁltered and concentrated in

vacuo. The residue was puriﬁed by ﬂash column chro-

matography on silica gel (dichloromethane/methanol;

98:2; as eluant) to give an oil. This oil was dissolved in

methanol and mixed with 1 M solution of hydrochloric

acid in diethyl ether. The resulting mixture was concen-

trated in vacuo to give the title compound as a colour-

less solid (32 mg, 49%). ESI-MS m/z = 520.2 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD): d 1.01 (d, J = 7.0 Hz,

3H), 1.05 (d, J = 7.0 Hz, 3H), 2.02–2.24 (m, 8H), 2.78–

2.94 (m, 2H), 3.15–3.40 (m, 4H), 3.68–3.82 (m, 5H),

4.32–4.41 (m, 1H), 4.55–4.66 (m, 1H), 5.30 (s, 2H),

6.40–6.46 (m, 1H), 6.50–6.55 (m, 1H), 7.03 (d,

J = 8.0 Hz, 1H), 7.08–7.20 (m, 3H), 7.33–7.42 (m, 1H),

9.19 (s, 1H).

4.1.51. (3-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-benzimidazol-1-

yl)-acetonitrile hydrochloride (27). Starting with 8¹⁰and

following the methods outlined for 17, the title com-

pound was puriﬁed by column chromatography on silica

gel (dichloromethane/methanol; 99.4:0.6; as eluant) to

give the free base of the title compound as an oil (5.60

g, 53%). ESI-MS m/z = 477.3 [M+H]⁺. ¹H NMR

(400 MHz, CD₃OD): d 1.00 (d, J = 6.8 Hz, 3H), 1.03

(d, J = 6.8 Hz, 3H), 1.70–2.08 (m, 5H), 2.11–2.23 (m,

5H), 2.44–2.60 (m, 4H), 3.00–3.08 (m, 1H), 3.09–3.18

(m, 1H), 3.74 (s, 3H), 4.26–4.39 (m, 2H), 4.99 (s, 2H),

6.38 (dd, J = 8.2 and 2.4 Hz, 1H), 6.59 (d, J = 2.4 Hz,

1H), 6.99 (d, J = 8.2 Hz, 1H), 7.11–7.28 (m, 3H), 7.38–

7.50 (m, 1H). A portion of this oil (255 mg) was dis-

solved in diethyl ether, then the resulting solution was

mixed with 1 M solution of hydrochloric acid in diethyl

ether. The resulting mixture was concentrated in vacuo

to give the title compound (195 mg). ESI-MS

1

m/z = 477.3 [M+H]⁺. H NMR (400 MHz, CD₃OD): d

1.01 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H),

2.02–2.22 (m, 8H), 2.75–2.91 (m, 2H), 3.14–3.38 (m,

4H), 3.68–3.82 (m, 5H), 4.31–4.40 (m, 1H), 4.52–4.64

(m, 1H), 5.00 (s, 2H), 6.43 (dd, J = 8.2 and 2.4 Hz,

1H), 6.52 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H),

7.18–7.33 (m, 3H), 7.34–7.41 (m, 1H).

4.1.54. N-Hydroxy-2-(3-{1-[3-(5-methoxy-2-methyl-phen-

oxy)-4-methyl-pentyl]-piperidin-4-yl}-2-oxo-2,3-dihydro-

benzimidazol-1-yl)-acetamidine hydrochloride (30).

A

mixture of 27 (170 mg, 0.357 mmol), hydroxylamine

hydrochloride (50 mg, 0.720 mmol) and diisopropyleth-

ylamine (93 mg, 0.720 mmol) in ethanol (4 mL) was

stirred at reﬂux temperature for 16 h. The reaction mix-

ture was concentrated in vacuo, and the residue was

mixed with 5% aqueous solution of sodium carbonate

and extracted with dichloromethane (4· 100 mL). The

combined organic layers were washed with brine, dried

(MgSO₄), ﬁltered and concentrated in vacuo. The resi-

due was puriﬁed by ﬂash column chromatography on

silica gel (dichloromethane/methanol; 97:3; as eluant)

to give the free base of the title compound as a colour-

less solid (135 mg, 74%). ESI-MS m/z = 510.5 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD): d 1.00 (d, J = 6.4 Hz,

3H), 1.03 (d, J = 6.4 Hz, 3H), 1.73–2.06 (m, 5H),

2.11–2.24 (m, 5H), 2.45–2.60 (m, 4H), 3.01–3.09 (m,

1H), 3.10–3.19 (m, 1H), 3.74 (s, 3H), 4.26–4.41 (m,

2H), 4.49 (s, 2H), 6.38 (dd, J = 8.2 and 2.7 Hz, 1H),

6.58 (d, J = 2.7 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H),

7.06–7.14 (m, 2H), 7.19–7.24 (m, 1H), 7.38–7.42 (m,

1H).

4.1.52. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-(1H-tetrazol-5-ylmethyl)-1,3-

dihydro-benzimidazol-2-one hydrochloride (28). Tribu-

tylstannylazide (700 mg, 2.11 mmol) was added to a

solution of 27 (200 mg, 0.420 mmol) in xylene

(10 mL), and the resulting mixture was stirred at

140 ꢁC for 24 h. The reaction mixture was then con-

centrated in vacuo, and the residue mixed with 2 M

aqueous hydrochloric acid (50 mL) and methanol

(50 mL). The mixture was stirred at room temperature

for 30 min then concentrated in vacuo. The residue

was mixed with 5% aqueous solution of sodium car-

bonate (50 mL) and the pH adjusted to 5 by addition

of 0.5 M hydrochloric acid. The resulting mixture was

extracted with dichloromethane (4· 100 mL) and the

combined organics washed with brine, dried (MgSO₄),

ﬁltered and concentrated in vacuo. The residue was

puriﬁed by ﬂash column chromatography on silica

gel (dichloromethane/methanol; 90:10; as eluant) to

give a pale brown oil. This oil was dissolved in meth-

anol and mixed with 1M solution of hydrochloric acid

in diethyl ether. The resulting mixture was concen-

trated in vacuo to give the title compound as a brown

oil (142 mg, 61%). ESI-MS m/z = 520.2 [M+H]⁺. ¹H

NMR (400 MHz, CD₃OD): d 1.01 (d, J = 7.0 Hz,

3H), 1.05 (d, J = 7.0 Hz, 3H), 2.01–2.25 (m, 8H),

2.80–2.95 (m, 2H), 3.17–3.39 (m, 4H), 3.69–3.82 (m,

5H), 4.33–4.41 (m, 1H), 4.56–4.69 (m, 1H), 5.43 (s,

2H), 6.42 (dd, J = 8.1 and 2.7 Hz, 1H), 6.52 (d,

J = 2.7 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 7.06–7.19

(m, 3H), 7.35–7.45 (m, 1H).

The free base was dissolved in methanol and the result-

ing solution was mixed with 1 M solution of hydrochlo-

ric acid in diethyl ether. The resulting mixture was

concentrated in vacuo to give the hydrochloric acid salt

1

as a colourless solid. ESI-MS m/z = 510.5 [M+H]⁺. H

NMR (400 MHz, CD₃OD): d 1.01 (d, J = 6.8 Hz, 3H),

1.05 (d, J = 6.8 Hz, 3H), 1.98–2.23 (m, 8H), 2.78–2.94

(m, 2H), 3.18–3.38 (m, 4H), 3.71–3.83 (m, 5H), 4.31–

4.39 (m, 1H), 4.55–4.67 (m, 1H), 4.89 (s, 2H), 6.43

(dd, J = 8.3 and 2.2 Hz, 1H), 6.49–6.54 (m, 1H), 7.03

(d, J = 8.3 Hz, 1H), 7.13–7.25 (m, 3H), 7.38–7.46 (m,

1H).

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

2847

1

4.1.55. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-(3H-1,2,3-triazol-4-ylmethyl)-1,3-

dihydro-benzimidazol-2-one hydrochloride (31). A mix-

ture of 32 (260 mg, 0.547 mmol), tributylstannylazide

(908 mg, 2.73 mmol) in xylene (5 mL) was stirred at

150 ꢁC for 16 h. The reaction mixture was evaporated

to dryness and subjected to ﬂash column chromatogra-

phy on silica gel (dichloromethane/methanol; 90:10; as

eluant). The oil obtained was dissolved in methanol

(10 mL), and then poured onto a 2 M solution of hydro-

chloric acid in water (10 mL). This was then stirred at

room temperature for 1 h. The mixture was concen-

trated in vacuo, and the oily residue taken up in 5%

aqueous solution of sodium carbonate (100 mL) and ex-

tracted with dichloromethane (4· 100 mL). The com-

bined organic layers were washed with brine, dried

(MgSO₄), ﬁltered and concentrated in vacuo. The oil ob-

tained was dissolved in methanol and 1 M solution of

hydrochloric acid in diethyl ether added and concen-

trated in vacuo to give the title compound as a brown

m/z = 476.3 [M+H]⁺. H NMR (400 MHz, CD₃OD): d

1.01 (d, J = 6.6 Hz, 3H), 1.05 (d, J = 6.6 Hz, 3H),

2.02–2.22 (m, 8H), 2.73 (t, J = 2.4 Hz, 1H), 2.75–2.91

(m, 2H), 3.15–3.38 (m, 4H), 3.68–3.81 (m, 5H), 4.32–

4.40 (m, 1H), 4.51–4.63 (m, 1H), 4.70 (d, J = 2.4 Hz,

2H), 6.43 (dd, J = 8.4 and 2.2 Hz, 1H), 6.52 (d,

J = 2.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.13–7.21

(m, 2H), 7.25–7.37 (m, 2H).

4.1.57. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-(5-oxo-4,5-dihydro-1H-1,2,4-

triazol-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one

hydrochloride (33). Compound 8 (3.31 g, 7.56 mmol) was

dissolved in N,N-dimethylformamide (40 mL) and trea-

ted with 60% dispersion of sodium hydride (333 mg,

8.34 mmol), stirring for 15 min at room temperature.

N-Carboxymethyl-2-chloroacetamidrazone²³was then

added and the mixture stirred overnight at room tem-

perature followed by 2 h at 50 ꢁC. The volume of N,N-

dimethylformamide was reduced under vacuum and

the residue then heated at 150–160 ꢁC for 1 h to eﬀect

ring closure. After partitioning between ethyl acetate

and water, the ethyl acetate was washed with water,

washed with brine and then dried (Na₂SO₄). The result-

ing complex mixture was chromatographed on silica

(dichloromethane/ethanol; 98:2 then 92:8 gradient; as

eluant). Approximately 100 mg of freebase was obtained

and converted to the hydrochloride salt with 1 M hydro-

chloric acid in diethyl ether and precipitated twice from

ethanol by adding copious amounts of diethyl ether to

give a brown solid (80 mg, 1.8%). ESI-MS m/z = 535.3

[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): d 1.02 (d,

J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 2.04–2.20

(m, 5H), 2.16 (s, 3H), 2.86 (dq, J = 12.8 and 3.0 Hz,

2H), 3.24 (br t, J = 12.5 Hz, 2H), 3.71–3.80 (m, 2H),

3.76 (s, 3H), 4.36 (q, J = 5.5 Hz, 1H), 4.60 (tt, J = 12.2

and 4.1 Hz, 1H), 4.97 (s, 2H), 6.44 (dd, J = 8.3 and

2.3 Hz, 1H), 6.52 (d, J = 2.3 Hz, 1H), 7.04 ( d,

J = 8.3 Hz, 1H), 7.10–7.18 (m, 3H), 7.36 (br d,

J = 7.3 Hz, 1H).

1

solid (72 mg, 22%). ESI-MS m/z = 519.3 [M+H]⁺. H

NMR (400 MHz, CD₃OD): d 1.01 (d, J = 7.0 Hz, 3H),

1.05 (d, J = 7.0 Hz, 3H), 2.02–2.22 (m, 8H), 2.78–2.92

(m, 2H), 3.22–3.38 (m, 4H), 3.69–3.83 (m, 5H), 4.32–

4.41 (m, 1H), 4.54–4.65 (m, 1H), 5.20 (s, 2H), 6.43

(dd, J = 8.6 and 2.2 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H),

7.03 (d, J = 8.6 Hz, 1H), 7.07–7.22 (m, 3H), 7.27–7.37

(m, 1H), 7.76 (br s, 1H).

4.1.56. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-prop-2-ynyl-1,3-dihydro-benzimid-

azol-2-one hydrochloride (32). Sodium hydride (60% sus-

pension in mineral oil, 44 mg, 1.10 mmol) was added in

portions to a solution of 8 (400 mg, 0.914 mmol) in N,N-

dimethylformamide (3 mL) at 0 ꢁC. The resulting solu-

tion was then heated to 50–60 ꢁC for 1 h. After the reac-

tion mixture had been cooled to 5 ꢁC, propargyl

bromide (141 mg, 1.19 mmol) was added dropwise to

the mixture and then allowed to warm to room temper-

ature for 16 h. The reaction mixture was concentrated in

vacuo, and the resultant residue combined with water

(150 mL) and extracted with ethyl acetate (4· 100 mL).

The organic layers were combined, washed with brine,

dried (MgSO₄), ﬁltered and concentrated in vacuo.

The oil obtained was puriﬁed by ﬂash column chroma-

tography on silica gel (dichloromethane/methanol;

99.3:0.7; as eluant) to give the free base of the title com-

4.1.58. 1-{1-[3-(5-Methoxy-2-methyl-phenoxy)-4-methyl-

pentyl]-piperidin-4-yl}-3-1,2,4-thiadiazol-3-ylmethyl-1,3-

dihydro-benzimidazol-2-one hydrochloride (34). A mix-

ture of 35 (1.20 g, 2.10 mmol), 10% Pd-C (1.50 g), and

acetic acid (30 mL) was stirred under a hydrogen atmo-

sphere at room temperature for 28 h. The resulting mix-

ture was diluted with methanol (200 mL), and Pd-C was

removed carefully by ﬁltration. The ﬁltrate was concen-

trated in vacuo and the residue puriﬁed by ﬂash column

chromatography on silica gel (dichloromethane/metha-

nol; 98.5:1.5; as eluant) to give an oil. This oil was dis-

solved in diethyl ether and treated with 1 M solution

of hydrochloric acid in diethyl ether. The resulting mix-

ture was concentrated in vacuo to give the title com-

pound as a colourless solid (69 mg, 5.8%). ESI-MS

pound as

a brown oil (325 mg, 75%). ESI-MS

m/z = 476.3 [M+H]⁺. H NMR (400 MHz, CD₃OD): d

1.00 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 7.2 Hz, 3H),

1.70–2.08 (m, 5H), 2.11–2.23 (m, 5H), 2.44–2.60 (m,

4H), 2.69–2.73 (m, 1H), 3.00–3.08 (m, 1H), 3.09–3.18

(m, 1H), 3.74 (s, 3H), 4.26–4.39 (m, 2H), 4.70 (d,

J = 2.4 Hz, 2H), 6.38 (dd, J = 2.4 and 8.2 Hz, 1H),

6.59 (d, J = 2.4 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H),

7.11–7.17 (m, 2H), 7.22–7.28 (m, 1H), 7.38–7.44 (m,

1H).

1

m/z = 536.3 [M+H]⁺. H NMR (400 MHz, CD₃OD): d

1.01 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H),

2.02–2.24 (m, 8H), 2.76–2.92 (m, 2H), 3.14–3.38 (m,

4H), 3.64–3.80 (m, 5H), 4.30–4.40 (m, 1H), 4.52–4.66

(m, 1H), 5.42 (s, 2H), 6.39–6.46 (m, 1H), 6.52 (d,

J = 2.4 Hz, 1H), 6.98–7.17 (m, 4H), 7.27–7.34 (m, 1H),

10.08 (s, 1H).

The free base (65 mg) was dissolved in diethyl ether

(10 mL), and the resulting solution poured onto 0.1 M

solution of hydrochloric acid in diethyl ether (2.5 mL).

The resulting mixture was concentrated in vacuo to give

the title compound as

a yellow solid. ESI-MS

2848

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

4.1.59. 1-(5-Chloro-1,2,4-thiadiazol-3-ylmethyl)-3-{1-[3-

(5-methoxy-2-methyl-phenoxy)-4-methyl-pentyl]-piperidin-

4-yl}-1,3-dihydro-benzimidazol-2-one hydrochloride (35).

Prepared according to the method outlined for 4k using

5-chloro-3-chloromethyl^1,2,4thiadiazole as the alkylat-

ing agent, the obtained residue was puriﬁed by ﬂash col-

umn chromatography on silica gel (dichloromethane/

methanol; 99.3:0.7; as eluant) to give the free base of

the title compound as a pale yellow oil in a yield of

61%. ESI-MS m/z = 570.3 [M+H]⁺. ¹H NMR

(400 MHz, CDCl₃): d 0.97 (d, J = 6.6 Hz, 3H), 0.99 (d,

J = 6.6 Hz, 3H), 1.74–1.90 (m, 4H), 1.94–2.20 (m, 6H),

2.34–2.56 (m, 4H), 2.91–3.14 (m, 2H), 3.76 (s, 3H),

4.18–4.28 (m, 1H), 4.34–4.50 (m, 1H), 5.29 (s, 2H),

6.36 (dd, J = 8.2 and 2.3 Hz, 1H), 6.62 (d, J = 2.3 Hz,

1H), 6.92–7.12 (m, 4H), 7.28–7.38 (m, 1H).

cross validated s.e. = 0.62, n = 61, components = 7.

The full partial least squares model was generated with-

out cross validation to yield: R²= 0.97, s.e. = 0.16,

n = 61, F_7,53= 288.3 (p ꢀ 0.05), components = 7. The

18 compound test set was then predicted by the model

showing a predictive R²= 0.84 and standard error of

prediction = 0.42. A further 34 compounds (see supple-

mentary data) with NOP pK_idata from the series were

added to the dataset. These 34 compounds were mod-

elled and superimposed identically to those described

previously to give a complete dataset of 113 compounds

with a pK_irange from 5.10 to 9.01. A ﬁnal CoMFA

model was generated for the 113 compounds using iden-

tical parameters to that of the initial model. Cross vali-

dated partial least squares was performed with 10

groups to determine the optimal number of components.

Partial least squares without cross validation was used

to generate the full CoMFA model. In both cases CoM-

FA standard scaling and a minimum r cut-oﬀ of 2 kcal

was applied. Potential new compounds were predicted

prior to synthesis using the full model by subjecting each

compound to an identical modelling and superposition

procedure to that described in the generation of the

model.

The free base was dissolved in diethyl ether and the

resulting solution treated with 1 M solution of hydro-

chloric acid in diethyl ether. The resulting mixture was

concentrated in vacuo to give the title compound as a

1

yellow solid. ESI-MS m/z = 570.3 [M+H]⁺. H NMR

(400 MHz, CD₃OD): d 1.01 (d, J = 6.6 Hz, 3H), 1.05

(d, J = 6.6 Hz, 3H), 2.02–2.23 (m, 8H), 2.78–2.93 (m,

2H), 3.16–3.40 (m, 4H), 3.69–3.82 (m, 5H), 4.31–4.40

(m, 1H), 4.54–4.66 (m, 1H), 5.32 (s, 2H), 6.43 (dd,

J = 8.2 and 2.2 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 7.03

(d, J = 8.2 Hz, 1H), 7.06–7.19 (m, 3H), 7.30–7.40 (m,

1H).

4.3. Receptor binding and functional assay

CHO cells expressing the human NOP receptor and dC6

cells expressing the human DOP receptor were grown

in-house and membrane preparations obtained using

standard methods. MOP receptor membranes were pur-

chased from Perkin-Elmer (RB-HOMM expressed in

CHO-K1 cells). Homogenates of guinea pig brain cortical

tissue were used as a source of KOP receptors. All binding

assays were conducted under equilibrium conditions and

optimised in 96-well formats to achieve the best signal to

noise ratio. The test compounds were examined at 6 con-

centrations (10^À6–10^À11M) and assays terminated by

vacuum ﬁltration through glass ﬁbre ﬁlters with adequate

washing steps to minimise non-speciﬁc binding. Filter-

plates were air dried before addition of scintillation ﬂuid

and counting in either a Packard TopCount or Wallac

Microbeta Trilux scintillation counter. Data were ana-

lysed using curve ﬁtting and a minimum sum of squares

method to produce IC₅₀values that were converted to

K_ivalues using the Cheng–Prusoﬀ equation.³¹

4.2. Molecular modelling

All computational studies were performed on Silicon

Graphics desktop workstations using Sybyl²⁹software

unless otherwise stated. Structures and data of all com-

pounds used in the QSAR modelling are given in the

supplementary data. Seventy-nine compounds all con-

taining the 3-phenoxypropyl piperidine benzimdazol-2-

one scaﬀold with NOP pK_idata measured in the de-

scribed NOP binding assay formed the initial training

and test sets. All data correspond to racemic mixtures

of the compounds with a pK_irange from 5.10 to 8.84.

All compounds were modelled within Sybyl as the ion-

ised form of the higher aﬃnity S enantiomer, converted

to 3D with Concord then energy minimised with the Tri-

pos forceﬁeld and Gasteiger-Huckel charges to a gradi-

¨

29

˚

ent less than 0.005 kcal/mol/A. Compounds were

subsequently superimposed onto an X-ray structure of

compound (+)-2 using a steric and electrostatic align-

ment algorithm similar to the published MIMIC.³⁰

CoMFA steric and electrostatic ﬁelds were calculated

using default box dimensions and parameters except a

4.3.1. [³H]Nociceptin competition assay. Binding to in-

house human NOP receptors was conducted in 2 mL

96-well plates (Beckmann) in 50 mM Tris–HCl, pH

7.4, in a total volume of 1.5 mL. Test drugs (150 lL), as-

say buﬀer (450 lL) and a ﬁnal concentration of 0.05 nM

[³H]nociceptin (300 lL, Amersham; 0.02 mCi/mL, spe-

ciﬁc activity 144–166 Ci/mmol) were incubated with pre-

pared hNOP cell homogenates (600 lL; ꢁ60 lg protein/

well) for 1 h. Non-speciﬁc binding was determined in the

presence of a ﬁnal concentration of 100 nM Noc(1-

13)NH₂. Binding was terminated using a Tomtec har-

vester followed by 3· 1.5 mL washes. K_ivalues were cal-

culated by the equation; K_i= IC₅₀/(1 + [L]/Kd).³¹

˚

1 A grid spacing was applied. The dataset (see supple-

mentary data) was separated into a training set

(n = 61) and a test set (n = 18) by hierarchical clustering

using the CoMFA ﬁelds and the complete linkage algo-

rithm as implemented in Sybyl. Cross validated partial

least squares was performed with 10 groups, CoMFA

standard scaling and a minimum r cut-oﬀ of 2 kcal.

The most appropriate model was selected on the basis

of minimum cross validated standard error, maximum

Q²and minimum number of components. The best cross

validated model was identiﬁed as follows: Q²= 0.62,

4.3.2. [³H]Diprenorphine competition assay. Membranes

from CHO cells stably expressing human MOP recep-

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

2849

tors were purchased from Perkin-Elmer (Product Code:

RBHOMM). Binding to human MOP receptors was

conducted in 200 lL 96-well plates (Beckmann) in

50 mM Tris–HCl/5 mM MgCl₂, pH 7.4, in a total vol-

ume of 100 lL. Test drugs (50 lL), assay buﬀer

(50 lL) and a ﬁnal concentration of 0.5 nM [³H]dipre-

norphine (50 lL, Perkin-Elmer; 1.0 mCi/mL, speciﬁc

activity 50 Ci/mmol) were incubated with MOP receptor

membranes for 150 min. Non-speciﬁc binding was deter-

mined in the presence of a ﬁnal concentration of 200 lM

naloxone. Binding was terminated using a Tomtec har-

vester followed by 3· 0.5 mL washes. K_ivalues were cal-

culated by the equation; K_i= IC₅₀/(1 + [L]/Kd).³¹

NOP receptor. The eﬃcacy of the test compounds is cal-

culated as a % of the NC response.

4.4. Formalin paw test

Experiments were performed in male ICR mice 21–29 g.

In the ﬁrst experiment, animals received increasing doses

of (+)-24 (0.03–3.0 lmol/kg) or vehicle (saline; 10 mL/

kg) administered intravenously 15 min. before injection

of formalin (20 lL; 3%) into the plantar surface of the

left hindpaw, (n = 8 animals per group). The time spent

licking the hindpaw after injection of formalin was then

measured. The total time spent licking was measured for

two epochs of time 0–5 min (ﬁrst phase) and 20–30 min

(second phase). The mean and s.e.m. values for each

treatment group were then calculated and compared be-

tween groups using the Kruskal–Wallis one-way analy-

sis of variance, a non-parametric statistical test. If

statistical signiﬁcance (p < 0.05) was observed with this

test, the vehicle group and each of the treatment groups

were compared using the non-parametric Dunn’s test.

To calculate the dose which inhibited licking by 50%

(ED₅₀), the data were normalised by expressing the time

spent licking for each animal as a percentage of the

mean time spent licking by the vehicle treated mice.

The percent inhibition data were calculated for both

epochs of time and used to calculate ED₅₀values for

both phases of licking using a non-linear regression ﬁt,

sigmoidal dose–response with constants of 0 and 100

for the bottom and top, respectively (XLFit software).

4.3.3. [³H]Naltrindole competition assay. Binding to in-

house human DOP receptors was conducted in 2 mL

96-well plates (Beckmann) in 50 mM Tris–HCl/5 mM

MgCl₂, pH 7.4, in a total volume of 1.5 mL. Test drugs

(150 lL), assay buﬀer (450 lL) and a ﬁnal concentration

of 0.5 nM [³H]naltrindole (50 lL, Tocris; 1 mCi/mL,

speciﬁc activity 60 Ci/mmol) were incubated with DOP

receptor membranes for 150 min. Non-speciﬁc binding

was determined in the presence of a ﬁnal concentration

of 200 lM naloxone. Binding was terminated using a

Tomtec harvester followed by 3· 0.5 mL washes. K_ival-

ues were calculated by the equation; K_i= IC₅₀/(1 + [L]/

Kd).³¹

4.3.4. [³H]U69593 competition assay. Binding to native

guinea pig KOP receptors was conducted in 2 mL 96-

well plates (Beckmann) in 50 mM Tris–HCl/5 mM

MgCl₂, pH 7.4, in a total volume of 1.0 mL. Test drugs

(100 lL), assay buﬀer (400 lL) and a ﬁnal concentration

of 0.5 nM [³H]U69593 (200 lL, Perkin-Elmer; 1 mCi/

mL, speciﬁc activity 41.4 Ci/mmol) were incubated with

cerebral cortex membrane homogenates from male gui-

nea pigs (250–300 g; Dunkin–Hartley strain; Bantin and

Kingman Ltd; UK) for 3 h. Non-speciﬁc binding was

determined in the presence of a ﬁnal concentration of

200 lM naloxone. Binding was terminated using a Bran-

dell harvester followed by 3· 1.5 mL washes. K_ivalues

were calculated by the equation; K_i= IC₅₀/(1 + [L]/

Kd).³¹

4.5. Brennan test

Experiments were performed in male Wistar rats weigh-

ing between 170 and 200 g; n = 6 animals per group. In

brief, the rats’ withdrawal threshold to a series of ﬁla-

ments was measured (baseline reading). Filaments of

increasing force (2.6–167.0 mN) were applied to the plan-

tar surface of the paw using an up and down method. The

paw was touched with 1 of a series of 8 von Frey hairs with

logarithmically incremental stiﬀness. The von Frey hair

was presented perpendicular to the plantar surface with

suﬃcient force to cause buckling against the paw and held

for approximately 1–3 s. A positive response was noted if

the paw was sharply withdrawn. A cut-oﬀ of 15 g was se-

lected as the upper limit for testing, since stiﬀer hairs tend

to raise the entire limb rather than buckling, substantially

changing the nature of the stimulus.

All functional assays were conducted using the Adenylyl

Cyclase Activation Flashplate^ꢂAssay purchased from

Perkin-Elmer (Cat. No.: SMP004A). This assay directly

measures levels of [¹²⁵I]cAMP that competes with

endogenous forskolin-induced cAMP. CHO cells

expressing the human NOP receptor were grown in-

house and assays conducted according to manufacturer

guidelines. The test compounds were examined at 6 con-

centrations (10^À6–10^À11M) and were added, together

with forskolin, to the cells to cause stimulation. A detec-

tion mix was added (containing [¹²⁵I]cAMP) after

30 min. The FlashPlates were read on a Packard Top-

Count scintillation counter, after a 2 h incubation. The

data are used to construct a standard curve from which

the cAMP values produced by the stimulated cells are

obtained by interpolation. Data were analysed using

curve ﬁtting and a minimum sum of squares method

to produce IC₅₀values. Test compounds were screened

in parallel with NC, the endogenous ligand for the

The animals were then anaesthetised with isoﬂurane and

an incision made in the plantar surface of the left hind-

paw (0.5 cm from the heel). The plantaris muscle was

then elevated using curved forceps before the wound

was sutured with 4–0 nylon and the animals allowed

to recover. Two hours after making the incision, paw

withdrawal thresholds were re-measured. Immediately

after this reading, the rats were injected intravenously

with vehicle (saline) or compound (+)-24 (3, 10 or

30 lmol/kg). Readings were then made at 30, 60, 90

and 120 min post-compound injection.

Data were expressed as means s.e.m. and compared

between groups using the Kruskal–Wallis one-way

2850

R. Palin et al. / Bioorg. Med. Chem. 16 (2008) 2829–2851

Toma, L.; Cignarella, G. Mini Rev. Med. Chem. 2001, 1,

363.

analysis of variance, a non-parametric statistical test.

Each of the treatment groups was then compared

against the vehicle group, using the non-parametric

Dunn’s test. The time of maximum eﬀect (T_max) was cal-

culated. The ED₅₀(dose at which allodynia is reversed

by approximately 50%) values were also calculated at

T_maxusing non-linear regression (sigmoidal dose–re-

sponse; variable slope) with constants of 0 and 15 g

(cut-oﬀ) for the bottom and top, respectively (XLFit).

9. (a) Ozaki, S.; Kawamoto, H.; Itoh, Y.; Miyaji, M.; Azuma,

T.; Ichikawa, D.; Nambu, H.; Iguchi, T.; Iwasawa, Y.;

Ohta, H. Eur. J. Pharmacol. 2000, 402, 45; (b) Ozaki, S.;

Kawamoto, H.; Itoh, Y.; Miyaji, M.; Iwasawa, Y.; Ohta, H.

Eur. J. Pharmacol. 2000, 387, R17–R18; (c) Kawamoto, H.;

Ozaki, S.; Itoh, Y.; Miyaji, M.; Arai, S.; Nakashima, H.;

Kato, T.; Ohta, H.; Iwasawa, Y. J. Med. Chem. 1999, 42,

5061; (d) Kawamoto, H.; Nakashima, H.; Kato, T.; Arai, S.;

Kamata, K.; Iwasawa, Y. Tetrahedron 2001, 57, 981; (e) De

Risi, C.; Pollini, G. P.; Trapella, C.; Peretto, I.; Ronzoni, S.;

Giardina, G. A. M. Bioorg. Med. Chem. 2001, 9, 1871; (f)

Wichmann, J.; Adam, G.; Rover, S.; Hennig, M.; Scalone,

M.; Cesura, A. M.; Dautzenburg, F. M.; Jenck, F. Eur. J.

Med. Chem. 2000, 53, 839; (g) Jenck, F.; Wichmann, J.;

Dautzenburg, F. M.; Moreau, J.-L.; Ouagazzal, A. M.;

Martin, J. R.; Lundstrom, K.; Cesura, A. M.; Poli, S. M.;

Rover, S.; Kolczewski, S.; Adam, G.; Kilpatrick, G. J. Proc.

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Hohlweg, R. Br. J. Pharmacol. 2000, 131, 903.

Acknowledgments

We thank our colleagues within the Analytical section

for structure and purity determinations of our ﬁnal

compounds.

Supplementary data

10. (a) Palin, R.; Barn, D. R.; Clark, J. K.; Cottney, J. E.;

Cowley, P. M.; Crockatt, M.; Evans, L.; Feilden, H.;

Goodwin, R. R.; Griekspoor, F.; Grove, S. J. A.; Hough-

ton, A. K.; Jones, P. S.; Morphy, R. J.; Smith, A. R. C.;

Sundaram, H.; Vrolijk, D.; Weston, M. A.; Wishart, G.;

Wren, P. Bioorg. Med. Chem. Lett. 2005, 15, 589; (b) Palin,

R.; Bom, A.; Clark, J. K.; Evans, L.; Feilden, H.; Houghton,

A. K.; Jones, P. S.; Montgomery, B.; Weston, M. A.;

Wishart, G. Bioorg. Med. Chem. 2007, 15, 1828; (c) Cowley,

P. M.; Cottney, J.; Barn, D. R.; Morphy, J. R.; Palin, R.;

Grove, S. J. A. PCT Int. Application, WO 2002100861,

2002. CAN 138:39189 AN 2002:964357.

11. Crystallographic data for 2 has been deposited with the

Cambridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 IEZ, UK as CCDC Reference No. 658439.

12. Caliendo, G.; Fiorino, F.; Perissutti, E.; Severino, B.;

Gessi, S.; Cattabriga, E.; Borea, P. A.; Santagada, V. Eur.

J. Med. Chem. 2001, 36, 873.

Supplementary data associated with this article can be

found, in the online version, at doi:10.1016/

j.bmc.2008.01.005.

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Article Doi

Structure-activity relationships and CoMFA of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues as NOP receptor agonists with analgesic properties

DOI: 10.1016/j.bmc.2008.01.005

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Article abstract of DOI:10.1016/j.bmc.2008.01.005

Full text of DOI:10.1016/j.bmc.2008.01.005

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