Design, synthesis, and evaluation of novel 2-substituted-4-aryl-6,7,8,9- tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-ones as NK1 antagonists

Bioorganic & Medicinal Chemistry 13 (2005) 5717–5732

Design, synthesis, and evaluation of novel

2-substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido-

[4,5-b][1,5]oxazocin-5-ones as NK₁antagonists

Shigeki Seto,^*Asao Tanioka, Makoto Ikeda and Shigeru Izawa

Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi, Nogi-machi, Shimotsuga-gun,

Tochigi 329-0114, Japan

Received 11 May 2005; revised 27 May 2005; accepted 1 June 2005

Available online 29 June 2005

Abstract—A series of novel bicyclic pyrimidine derivatives was prepared as part of a search for NK₁antagonist aimed at the treat-

ment of urinary incontinence. Among them, 3g, a pyrimido[4,5-b][1,5]oxazocine derivative, bearing a 4-acetylpiperazinyl group and

a 2-methylphenyl group, was shown to have potent NK₁antagonist activity with a K_Bvalue of 0.105 nM and markedly increased the

eﬀective bladder capacity of guinea pigs (59.4% at 0.3 mg/kg iv and 62.8% at 3 mg/kg id). Furthermore, the eﬀect of 3g on bladder

function appeared to diﬀer from that of tolterodine, another classical anti-pollakiuria agent, as determined by the distention-induced

rhythmic bladder contraction assay using a urethane-anesthetized guinea pig model. Compound 3g is expected to be a promising

agent for the treatment of urinary incontinence.

1. Introduction

intensive research in this ﬁeld. During the last few years,

several other structural classes of NK₁receptor antago-

nists have been reported, such as L-733060,⁶MK-869,⁷

and TAK-637.⁸(Fig. 1) The areas of neurokinin antag-

onist development have been extensively reviewed.^9–12

Tachykinin, a peptide neurotransmitter that was subse-

quently characterized as the undecapeptide Arg-Pro-

Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH₂,¹binds

to a series of three neurokinin receptors, NK₁, NK₂,

and NK₃, which have selective aﬃnity for substance P

(SP), neurokinin A, and neurokinin B, respectively.²

Among them, SP is known to exhibit a wide variety of

biological responses³both centrally and peripherally.

Through binding to the NK₁receptor, SP has been

implicated in the transmission of pain and stress signals,

inﬂammation, and the contraction of smooth muscle.

Therefore, NK₁antagonists may be eﬃcacious for the

clinical treatment of a wide range of diseases. Among

them, we were interested in the relationship between

tachykinin and the activation of micturition-related

reﬂexes,⁴with a view to possible application in the treat-

ment of pollakiuria and urinary incontinence. The

disclosure by Pﬁzer of the ﬁrst two non-peptide NK₁

antagonists, CP-96345 and CP-99994,⁵has spurred

Recently, we reported the design and synthesis of pyri-

do[4,3-b]-1,5-oxazocine 1a and pyrido[2,3-b]-1,5-oxazo-

cine 2a as potent NK₁antagonists,^13awhich were

derived from the arylpyridinecarboxamide derivative

made up by incorporating the 2-[3,5-bis(triﬂuorometh-

yl)benzyloxy]-1-phenylethylamine fragment¹⁴into the

pyridine ring. In these studies, we found that the com-

pounds 1a and 2a each similarly exhibited potent NK₁

antagonist activity (in vitro), although the in vivo activ-

ity of 2a is superior to that of 1a. These two compounds

diﬀer structurally in (1) the position of the nitrogen

atom in the pyridine ring and (2) the atropisomerism

about the biaryl bond due to the diﬀerence in nature

at the 8-position (1a, N; 2a, CH); the rotation about

the biaryl bond of 1a would be free, whereas that of

2a would be partially restricted on the NMR time sca-

le.^13b,15This property of 2a would aﬀect the stacking

conformation that is important for NK₁receptor recog-

nition.^8,16,17However, to avoid substantial analytical

complications during manufacture and drug develop-

ment, it is necessary to ensure either inseparable rapid

Keywords: NK₁antagonist; Pyrimido[4,5-b][1,5]oxazocine; Eﬀective

bladder capacity; KRP-103.

*

Corresponding author. Tel.: +81 280 56 2201; fax: +81 280 57

1293; e-mail: shigeki.seto@mb.kyorin-pharm.co.jp

doi:10.1016/j.bmc.2005.06.015

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S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

Figure 1. Chemical structures of the standard NK₁antagonists.

Figure 2.

interconversion of isomers or a completely separable

rigid conformation.

2. Chemistry

As shown in Scheme 1, we synthesized pyrimido[4,5-b]-

[1,5]oxazocine derivatives3 and pyrimido[5,4-f][1,4]oxaze-

pine derivatives 4 following the procedure for synthesizing

3a reported in our earlier paper.^13bCompound 7,¹⁸which

waspreparedfrom4,6-dichloro-2-(methylthio)pyrimidine,

was treated with SOCl₂, followed by condensation with

3-[[3,5-bis(triﬂuoromethyl)benzyl]amino]-1-propanol⁸and

cyclization using potassium carbonate to aﬀord the bicyclic

compound 8. Suzuki coupling reaction of 8 with various

substituted phenylboronic acids aﬀorded the correspond-

ing biaryl compounds 10 in good yield. Oxidation of sul-

ﬁde 10 with mCPBA aﬀorded sulfone 12. The synthesis

of compound 3 was achieved by nucleophilic amination

of 12 with the corresponding amine nucleophiles. When

N-protected diamine was used as a nucleophile, subse-

quentdeprotectionwithhydrogen chlorideandcondensa-

tion with acetic anhydride or methylsulfonyl chloride

were accomplished. The synthesis of 4, which contains

the oxazepine ring, was carried out in a manner similar

to that of 3.

On the basis of these results, pyrimido[4,5-b][1,5]oxazo-

cine 3a was synthesized as a hybrid compound of 1a and

2a.^13bCompound 3a was found to possess both features

of 1a and 2a; 3a showed potent in vivo activity similar to

2a, and free rotation about the biaryl bond similar to 1a

(Fig. 2).

To further examine the structural requirements for

activity, the compounds shown in Figure 3 were synthe-

sized and examined for their NK₁antagonist activity

and eﬀects on bladder function. Herein, we report the

synthesis and NK₁antagonist activity of novel pyrimi-

do[4,5-b][1,5]oxazocine derivatives and its analogue,

leading to the identiﬁcation of a candidate drug for

the treatment of urinary incontinence.

The synthesis of pyrimido[4,5-b][1,5]diazocine deriva-

tives 5 and pyrimido[4,5-e][1,4]diazepine derivatives 6

is shown in Scheme 2. The bicyclic compound 14 was

also synthesized from the acid chloride of 7 by reacting

with N-[[3,5-bis(triﬂuoromethyl)benzyl]amino]-N⁰-Boc-

1,3-propanediamine and subsequent deprotection with

hydrochloric acid and intramolecular cyclization with

potassium carbonate. Suzuki coupling reaction of 14

followed by oxidation of sulﬁde and substitution with

Figure 3. General formula of target compounds.

S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

5719

Scheme 1. Reagents: (a) SOCl₂, DMF; (b) 3-[[3,5-bis(triﬂuoromethyl)benzyl]amino]-l-propanol or 2-[[3,5-bis(triﬂuoromethyl)benzyl]amino]ethanol,

THF; (c) K₂CO₃, DMF; (d) 2-methylphenylboronic acid, 10 mol% Pd(PPh₃)₄, 2 M Na₂CO₃, toluene, dioxane; (e) mCPBA, THF; (f) R²H, 1,4-

dioxane, diisopropylethylamine; (g) (1) 4-(Boc-amino)piperidine or N-Boc-homopiperazine or N-Boc-piperazine, (2) 3 M HCl–AcOEt, (3) acetic

anhydride or methylsulfonyl chloride.

Scheme 2. Reagents: (a) SOCl₂, DMF; (b) N-[3,5-bis(triﬂuoromethyl)benzyl]-N⁰-Boc-l,3-diaminopropane or N-[3,5-bis(triﬂuoromethyl)benzyl]-N⁰-

Boc-l,2-diaminoethane; (c) 3 M HCl–AcOEt; (d) K₂CO₃, DMF; (e) 2-methylphenylboronic acid, 10 mol% Pd(PPh₃)₄, 2 M Na₂CO₃, toluene, dioxane;

(f) mCPBA, THF; (g) acethylpiperazine, 1,4-dioxane; (h) NaH, Mel; (i) acetic anhydride, pyridine.

1-acetylpiperazine provided 5a. Synthesis of 6, which

contains the diazepine ring, was carried out in a manner

similar to that of 5a. Synthesis of 5b and 5c was accom-

plished by alkylation with methyl iodide or acylation

with acetic anhydride, respectively.

iodopyridine-3-carboxylic acid 21 was prepared from 2-

chloro-3-iodopyridine 20²⁰by a known method²¹with

slight modiﬁcation. Treatment of 2-chloro-3-iodopyri-

dine 20 with LDA, followed by quenching with carbon

dioxide, and then hydrolysis with hydrochloric acid gave

2-chloro-4-iodopyridine-3-carboxylic acid 21 in a good

yield. Subsequent treatment with thionyl chloride, fol-

lowed by condensation with 3-[[3,5-bis(triﬂuorometh-

yl)benzyl]amino]-1-propanol aﬀorded the alcohol 22.

Conversion of the alcohol 22 to bicyclic compounds 23

As shown in Scheme 3, we synthesized pyrido[4,3-b]-1,5-

oxazocine derivative 1b and pyrido[2,3-b]-1,5-oxazocine

derivatives 2b,c following the procedure for synthesizing

1a and 2a reported in our earlier paper.^13a,192-Chloro-4-

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S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

Scheme 3. Reagents: (a) (1) LDA, THF, (2) CO₂, (3) HC1; (b) (1) SOC1₂, DMF, (2) 3-[[3,5-bis(triﬂuoromethyl)benzyl]amino]-l-propanol, THF;

(c) K₂CO₃, EtOH; (d) NaH, THF; (e) 2-methylphenylboronic acid, 10 mol% Pd(PPh₃)₄, 2 M Na₂CO₃, toluene, dioxane; (f) mCPBA, CH₂C1₂;

(g) POC1₃; (h) acethylpiperazine, 1,4-dioxane.

and 24 was accomplished in a regionselective manner.¹⁹

Suzuki coupling reaction of 23 and 24 with arylboronic

acids yielded 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-

and [4,3-b]-1,5-oxazocin-6-ones (25 and 26^8e) in good

yield. Formation of chlorides 29 and 30 via the Meisen-

heimer reaction²²was accomplished by treatment of 25

and 26 with mCPBA followed by rearrangement with

POCl₃. Coupling of intermediates 29 and 30 with 1-acet-

ylpiperazine under heat aﬀorded the desired compounds

1 and 2, respectively.

sults of the NK₁antagonist assay for pyrimido[4,5-

b][1,5]oxazocine 3a and the newly synthesized derivatives

3b–k are summarized in Table 1. The pyrimido[4,5-

b][1,5]oxazocine 3a bearing a 4-(pyrrolidinyl)piperidino

moiety exhibited potent NK₁antagonist activity. Com-

pounds 3b and 3e, carrying an aromatic amine moiety

or an ester moiety instead of the aliphatic amine moiety

of 3a, showed a 7- to 10-fold reduction of activity. The

NK₁antagonist activities of 3c, 3d, and 3f, which have

a substituted imidazolyl group, a morpholino group, or

a 4-carbamoylpiperidino group, were slightly less potent

than that of 3a. The 4-acetylpiperazinyl derivative 3g

showed excellent activity comparable to that of 3a. The

strong NK₁antagonist activity of 3g tended to decrease

slightly when the position of the acetamide group was

changed (3h, i). The NK₁antagonist activities of 3j and

3k, which have a substituted dioxothiomorpholino

group or a methylsulfonylpiperazinyl group, were com-

parable to that of 3a, with K_Bvalues within the range

of 0.0501–0.0794 nM. Among the compounds with cyclic

amino groups, which are substituted at the terminal

heteroatom or group at the 2-position on the pyrimido-

oxazocine ring, 4-(pyrrolidinyl)piperidine 3a, 4-acetyl-

3. Results and discussion

3.1. NK₁antagonist activity

The NK₁antagonist activities of the present series of

compounds are summarized in Tables 1–3. The NK₁

antagonist activity is displayed as the K_Bvalue measured

by the guinea pig ileum contraction assay.^23,24

To determine the eﬀects of substituents at the C-2 posi-

tion on the pyrimido[4,5-b][1,5]oxazocine ring, the re-

S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

5721

Table 1. NK₁antagonist activity of pyrimido[4,5-b][1,5]oxazocine

derivatives

Table 2. NK₁antagonist activity of pyrimido[4,5-b][1,5]oxazocine

derivatives

Compound

R²

NK₁antagonist

activity^aK_B(nM)

3a

3b

3c

3d

0.166

1.13

Compound

R¹

NK₁antagonist activity^a

K_B(nM)

3l

H

0.236

0.105

3g

3m

3n

Me

OMe

F

0.100

0.0584^b

0.459^b

0.354

^aData present the mean of K_Bvalue of guinea pig ileum contraction

assay (n = 3–5). The values of schild plot slope exhibited in 0.81–1.20.

3e

3f

1.82

enes (n = 1) caused a slight loss of activity; an 8-mem-

bered ring in the core scaﬀold was favorable for potent

NK₁antagonist activity in comparison with a 7-mem-

bered ring (3g vs 4, 5a vs 6). As for the position shown

as Z on the 8-membered ring, the NK₁antagonist activ-

ities of 3g and 5a, in which the C-10 position shown as Z

was substituted by an oxygen atom and a nitrogen atom,

respectively, were equal. In contrast to the case of 5b,

the additional methyl group on the nitrogen atom of

5a slightly debilitated the NK₁antagonist activity.

0.341

0.105

3g

3h

3i

0.308

0.440

3.2. Eﬀect on bladder function

Selected compounds with potent NK₁antagonist activi-

ty were examined for their eﬀect on eﬀective bladder

3j

0.0794

0.0501

Table 3. NK₁antagonist activity of bicyclic derivatives bearing

4-acetylpiperazinyl moiety

3k

^aData present the mean of K_Bvalue of guinea pig ileum contraction

assay (n = 3–5). The values of schild plot slope exhibited in 0.81–1.20.

^bThe value of schild plot slope exhibited in 0.44.

piperazine 3g, dioxothiomorpholine 3j, and methylsulfo-

nylpiperazine 3k possessed the most potent activity.

The eﬀects of substituents at the ortho position on the

phenyl ring, which might aﬀect the stacking conforma-

tion,^8,16,17are shown in Table 2. All compounds exhib-

ited potent activities, with K_Bvalues within the range

of 0.0584–0.236 nM. The observed eﬀects of introducing

substituents at the ortho position on the phenyl ring

were not signiﬁcant.

Compound

X

Y

Z

n

NK₁antagonist

activity^aK_B(nM)

3g

4

N

O

2

1

2

1

2

0.105

0.465

0.148

0.480

0.324

0.0794

0.275

0.0888

N

O

5a

6

N

NH

NMe

NAc

O

N

5b

5c

1b

2b

N

CH

N

The NK₁antagonist activities of the bicyclic pyrimidine

derivatives (3g, 4, 5a–c, and 6) together with the bicyclic

pyridine derivatives (1b and 2b) are shown in Table 3. In

general, shortening of the tether length to two methyl-

O

^aData present the mean of K_Bvalue of guinea pig ileum contraction

assay (n = 3–5). The values of schild plot slope exhibited in 0.81–1.20.

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S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

capacity in guinea pigs²⁵together with the results for

TAK-637,^8da representative NK₁antagonist aimed at

the treatment of bladder function disorders. The results

are shown in Table 4. The augmentative eﬀects on eﬀec-

tive bladder capacity approximately paralleled the corre-

sponding NK₁antagonist activity. Although the reason

is not clear, 3k, 3m, and 5c exhibited signiﬁcantly weaker

augmentative eﬀects in comparison with their corre-

sponding NK₁antagonist activities. Compounds 3g,

3j, and 5a showed potent increasing eﬀects. Preliminary

pharmacokinetic studies were conducted for compounds

3g, 3j, and 5a. The bioavailability (BA) of 3j in rats was

dramatically low (0%), probably due to its low water

solubility (0 lg/mL). Compounds 3g and 5a exhibited

good BA values (41% for 3g; 38% for 5a), and therefore

they were evaluated for their eﬃcacies in guinea pigs

after intraduodenal (id) administration. The augmenta-

tive eﬀect of 3g was more potent than that of 5a

(62.8% vs 29.0%), and the values were comparable to

those after iv administration. On the basis of these re-

sults, 3g was selected as a candidate for further

evaluation.

On the basis of the study described above, we selected

compound 3g and evaluated its eﬀect on bladder func-

tion in comparison with a representative anti-pollakiuria

agent, tolterodine (Figs. 4 and 5).

The eﬀect of iv-injected 3g on distention-induced rhyth-

mic bladder contraction in urethane-anesthetized guinea

pigs was examined. Figure 4 shows the percentage

contractile frequency and the contractile intravesical

Table 4. Water solubility, eﬀective bladder capacity, and bioavailability of selected compounds

Compound

NK₁antagonist activity^a

K_B(nM)

Water solubility^b(lg/mL)

Eﬀective bladder capacity^c

increasing ratio (%)

BA (%)^d

iv

id

2b

0.0888

43.3

2.21

0

32.3 13.5

16^e

26b

2c

0

11.9 10.8

33.4 11.0

21.3 3.47

59.4 12.3

36.8 11.6

25.6 3.73

40.4 6.65

24.3 12.4

25.3 11.6

43.0 15.4

34.3 5.46

24.2 9.41

12.0 5.86

3a

3d

0.166

0.354

0.105

0.308

0.440

0.0794

0.0501

0.100

0.148

0.324

0.0794

0.270

1453

0

3g

3h

6.42

8.70

28.3

0

62.8 12.0

41

0

3i

3j

3k

0

3m

5a

25.4

3.04

0

29.0 0.343

38

5b

5c

4.53

TAK-637

^aData present the mean of K_Bvalue of guinea pig ileum contraction assay (n = 3–5). Compounds were screened for antagonist activity on guinea pig

ileum as described in the text.

^bWater solubility value determined by a single experiment run in duplicate.

^cData present the mean of increasing ratio (%) of eﬀective bladder capacity measured as the volume of saline injected into spinalized guinea pigs at

0.3 mg/kg (iv) (n = 4–5) and 3 mg/kg (id) (n = 5–6).

^dBA = (AUC_0–8) po/(AUC_0–8) iv. AUC values were determined in rats following single intravenous (10 mg/kg, PET solution) or oral (10 mg/kg,

CMC Na suspension) administrations (n = 2–5) of the compounds.

^eThe value determined by a single experiment at 1 mg/kg (iv).

Figure 4. Reductions in contractile frequency and intravesical pressure on distention-induced rhythmic bladder contractions in urethane-anesthetized

guinea pigs with ascending concentrations. 3g (doses: 0.03, 0.1, and 0.3 mg/kg iv); tolterodine (doses: 0.1, 0.2, and 0.4 mg/kg iv).

S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

5723

the NMR spectrum; and a high-temperature NMR

study indicated that the atropisomer induced by oxazo-

cine ring inversion would not be separable at room tem-

perature.^13b,15,27From these results, it was expected that

the chemical properties related to the atropisomerism of

3g would not create an obstacle for further development.

4. Conclusion

As described previously, we have succeeded in synthesiz-

ing and evaluating a series of novel bicyclic pyrimidine

derivatives as a part of a search for NK₁antagonists

aimed at the treatment of urinary incontinence. Among

the diverse chemical modiﬁcations performed on the

bicyclic pyrimidines, 3g, a pyrimido[4,5-b][1,5]oxazocine

derivative bearing a 4-acetylpiperazinyl group and a 2-

methylphenyl group, showed potent NK₁antagonist

activity with a K_Bvalue of 0.105 nM, and also exhibited

the greatest augmentative eﬀect on eﬀective bladder

capacity in guinea pigs (59.4% at 0.3 mg/kg iv and

62.8% at 3 mg/kg id). Furthermore, the eﬀect of 3g on

bladder function appeared to diﬀer from that of toltero-

dine, another classical anti-pollakiuria agent; 3g de-

creased the frequency, but not the amplitude of

distention-induced rhythmic bladder contraction using

a urethane-anesthetized guinea pig model. Compound

3g, namely KRP-103, is expected to be a promising com-

pound for the treatment of urinary incontinence. Fur-

ther investigation of the pharmacological proﬁles of 3g

is currently in progress.

Figure 5. Increasing eﬀect of the eﬀective bladder capacity in spinal-

ized guinea pigs with ascending concentrations. 3g (doses: 0.03, 0.1,

and 0.3 mg/kg iv); tolterodine (doses: 0.1, 0.2, and 0.3 mg/kg iv).

pressure for 3g in contrast to the predrug value, together

with the corresponding data for tolterodine.

In this assay, 3g decreased the frequency of rhythmic

bladder contraction in a dose-dependent manner at dos-

es of 0.03, 0.1, and 0.3 mg/kg, without aﬀecting the con-

tractile intravesical pressure. On the other hand,

tolterodine decreased the contractile pressure dose-de-

pendently, without aﬀecting the frequency.

The eﬀect of 3g on eﬀective bladder capacity was mea-

sured as micturition volume in terms of the volume of

saline injected into spinalized guinea pigs. Figure 5

shows the ratio of the increase in eﬀective bladder capac-

ity induced by 3g compared with the predrug value,

together with the corresponding data for tolterodine.

Compound 3g increased the eﬀective bladder capacity

dose-dependently at 0.03, 0.1, and 0.3 mg/kg. On the

other hand, tolterodine was not eﬃcient at doses of

0.1, 0.2, and 0.4 mg/kg.

5. Experimental

5.1. Chemistry

Melting points were determined using a Yamato MP-

500 melting point apparatus and are uncorrected. H

1

NMR spectra were measured in CDCl₃or DMSO-d₆

with TMS and the solvent peak as internal standards,

on a JEOL ECA-400 (400 MHz) spectrometer. Mass

spectra (MS) were obtained on a Hitachi M-2000 mass

spectrometer. Column chromatography was carried

out on Merck silica gel 60. Analytical thin-layer chroma-

tography (TLC) was performed on Merck precoated sil-

ica gel 60F254 plates, and the compounds were

visualized by UV illumination (254 nm) or by heating

after spraying with phosphomolybdic acid in ethanol.

The data for elemental analysis are within 0.4% of the-

oretical values and were determined by a Yanaco CHN

corder MT-5.

These results suggested that compound 3g would not af-

fect the stage of urine storage, but rather the stage of

micturition, and would therefore have a low risk of

causing urinary retention, one of the side eﬀects of

anti-cholinergic agents.

Table 5 shows the binding aﬃnity for the three subtypes

of neurokinin receptor in human CHO cells.²⁶Com-

pound 3g showed potent NK₁antagonist activity, not

only in the guinea pig contraction assay, but also in

the hNK₁receptor binding assay (K_i= 0.0657 nM),

and exhibited high selectivity for the NK₁receptor.

5.1.1. 4,6-Dichloro-2-(methylthio)pyrimidine-5-carboxylic

acid (7). To a solution of LDA [prepared by reaction of

diisopropylamine (3.0 mL, 21.4 mmol) in THF (25 mL)

and n-butyllithium (13.6 mL, 1.52 M, 20.7 mmol) at

ꢀ20 °C for 30 min] was added a solution of 4,6-dichlo-

ro-2-(methylthio)pyrimidine (2.70 g, 13.8 mmol) in THF

(5 mL) at ꢀ78 °C. The mixture was stirred at the same

temperature for 3 h, and then CO₂gas was introduced

for 10 min. After the reaction had been quenched by addi-

tion of water (12 mL) and 2 N HCl (25 mL), the mixture

Compound 3g showed only a single peak on high-per-

formance liquid chromatography using a chiral column,

as far as we were able to ascertain. In addition, C-4

phenyl restricted rotation of 3g was not observed from

Table 5. Neurokinin receptor selectivity

Compound

Binding aﬃnity K_i(nm)

hNK₁

0.0657

hNK₂

>1000

hNK₃

>1000

3g

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S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

was extracted with ethyl acetate. The combined extracts

were dried over anhydrous Na₂SO₄, ﬁltered, and then

concentrated in vacuo. The residue was recrystallized

from toluene to aﬀord 7 as a pale yellow solid (1.93 g,

at 0 °C and then for 2 h at room temperature. The result-

ing mixture was diluted with ethyl acetate, then washed

with water and brine. The organic layer was dried over

anhydrous Na₂SO₄, ﬁltered, then concentrated in vacuo.

Flash chromatography (hexane:AcOEt = 3:1) of residue

was dissolved in 20% (w/w) HCl–EtOH (50 mL) and

stand for 2 h at room temperature. After concentration

in vacuo, to a solution of the residue in DMF (60 mL)

was added potassium carbonate (16.5 g, 0.119 mol) and

the mixture stirred for 1 h at 80 °C. The resulting mixture

was diluted with ethyl acetate, then washed with water

and brine. The organic layer was dried over anhydrous

Na₂SO₄, ﬁltered, then concentrated in vacuo. Flash chro-

matography (AcOEt:hexane = 1:1) of residue gave 14 as a

1

58%). mp: 160–163 °C. H NMR (400 MHz, CDCl₃): d

2.61 (1H, s). HRMS (EI) calcd for C₆H₄Cl₂N₂O₂S (M⁺)

237.9371; found, 237.9383. Anal. Calcd for

C₆H₄Cl₂N₂O₂S: C, 30.14; H, 1.69; N, 11.72. Found: C,

30.07; H, 1.57; N, 11.60.

5.1.2. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-chloro-2-meth-

ylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-

5-one (8). To a mixture of 7 (14.0 g, 58.6 mmol) and

thionyl chloride (40 mL) was added three drops of

DMF and the mixture was reﬂuxed for 2 h and then

concentrated. A solution of the residue in THF

(80 mL) was added dropwise to a solution of 3-[[3,5-

bis(triﬂuoromethyl)benzyl]amino]-1-propanol (18.5 g,

61.4 mmol) and triethylamine (40 mL) in THF

(100 mL) at 0 °C. The mixture was stirred for 1 h at

0 °C and then for 2 h at room temperature. After con-

centration in vacuo, to a solution of the residue in

DMF (60 mL) was added potassium carbonate (24.3 g,

0.176 mol) and the mixture was stirred for 1 h at

80 °C. The resulting mixture was diluted with ethyl ace-

tate, then washed with water and brine. The organic

layer was dried over anhydrous Na₂SO₄, ﬁltered, and

then concentrated in vacuo. Flash chromatography

(AcOEt:hexane = 1:1) of the residue gave 8 as a pale yel-

low solid (17.8 g, 63%). mp: 140–143 °C. ¹H NMR

(400 MHz, CDCl₃): d 2.00–2.12 (1H, m), 2.20–2.30

(1H, m), 2.60 (3H, s), 3.35 (1H, dd, J = 15.3 and

4.3 Hz), 3.63–3.74 (1H, m), 4.08 (1H, d, J = 15.3 Hz),

4.46–4.58 (2H, m), 5.63 (1H, d, J = 15.3 Hz), 7.88 (3H,

s). HRMS (EI) calcd for C₁₈H₁₄ClF₆N₃O₂S (M⁺)

485.0399; found, 485.0358. Anal. Calcd for

C₁₈H₁₄ClF₆N₃O₂S: C, 44.50; H, 2.90; N, 8.65. Found:

C, 44.44; H, 2.79; N, 8.54.

1

pale yellow foam (23.4 g, 81%). H NMR (400 MHz,

CDCl₃): d 1.80–2.02 (2H, m), 2.49 (3H, s), 3.23–3.36

(2H, m), 3.38–3.49 (1H, m), 3.67–3.78 (1H, m), 3.92

(1H, d, J = 15.3 Hz), 5.59 (1H, d, J = 15.3 Hz), 5.84

(1H, t, J = 7.3 Hz), 7.82 (1H, s), 7.84 (2H, s). HRMS

(EI) calcd for C₁₈H₁₅ClF₆N₄OS (M⁺) 484.0559; found,

484.0598. Anal. Calcd for C₁₈H₁₅ClF₆N₄OS: C, 44.59;

H, 3.12; N, 11.56. Found: C, 44.56; H, 3.04; N, 11.46.

5.1.5. triﬂuoromethyl)benzyl]-4-chloro-2-methylthio-6,7,8,9-

tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin-5-one (15). The

compound 15 (6.22 g, 68%) was prepared from 7

(5.00 g, 20.9 mmol) and 2-[[3,5-bis(triﬂuoromethyl)ben-

zyl]amino]-1-(Boc-amino)ethane (8.24 g, 21.3 mmol) in

a manner similar to that described for the preparation

1

of 14. Foam. H NMR (400 MHz, CDCl₃): d 2.54 (3H,

s), 3.59–3.68 (4H, m), 4.90 (2H, s), 5.66 (1H, br), 7.84

(2H, s), 7.88 (1H, s). HRMS (EI) calcd for C₁₇H₁₃ClF₆

N₄OS (M⁺) 470.0403; found, 470.0385. Anal. Calcd for

C₁₇H₁₃ClF₆N₄OS: C, 43.37; H, 2.78; N, 11.90. Found:

C, 43.29; H, 2.69; N, 11.84.

5.1.6.

6-[3,5-Bis(triﬂuoromethyl)benzyl]-2-methylthio-4-

phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-

5-one (10a). To a mixture of 8 (2.43 g, 5.00 mmol) and

phenylboronic acid (732 mg, 6.00 mmol) in toluene

(15 mL) and 1,4-dioxane (8 mL) were added 2 M

Na₂CO₃(15 mL) and Pd(PPh₃)₄(289 mg, 0.250 mmol),

and the mixture was stirred under reﬂux for 6 h. The

reaction mixture was cooled to room temperature, and

diluted with ethyl acetate, then washed with 2 M

Na₂CO₃and brine, and dried over Na₂SO₄, ﬁltered,

then concentrated in vacuo. Flash chromatography

(AcOEt:hexane = 1:1) of the residue gave 10a as a pale

5.1.3. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-chloro-2-meth-

ylthio-5,6,7,8-tetrahydro-pyrimido[5,4-f][1,4]oxazepin-5-

one (9). The compound 9 (5.15 g, 52%) was prepared

from 7 (5.00 g, 20.9 mmol) and 2-[[3,5-bis(triﬂuorometh-

yl)benzyl]amino]-1-ethanol (6.30 g, 21.9 mmol) in a

manner similar to that described for the preparation of

8. mp: 135–137 °C. ¹H NMR (400 MHz, CDCl₃): d

2.58 (3H, s), 3.64 (2H, t, J = 4.9 Hz), 4.50 (2H, t,

J = 4.9 Hz), 4.92 (2H, s), 7.81 (2H, s), 7.86 (1H, s).

HRMS (EI) calcd for C₁₇H₁₂ClF₆N₃O₂S (M⁺)

471.0243; found, 471.0236. Anal. Calcd for

C₁₇H₁₂ClF₆N₃O₂S: C, 43.28; H, 2.56; N, 8.91. Found:

C, 43.14; H, 2.48; N, 8.68.

1

yellow solid (2.28 g, 86%). mp: 143–146 °C. H NMR

(400 MHz, CDCl₃): d 2.02–2.22 (2H, m), 2.58 (3H, s),

3.43–3.52 (1H, m ), 3.84–3.94 (1H, m), 4.24 (1H, d,

J = 15.3 Hz), 4.39–4.46 (2H, m), 5.36 (1H, d, J =

15.3 Hz), 7.25–7.32 (2H, m), 7.37–7.46 (3H, m), 7.76

(2H, s), 7.87 (1H, s). HRMS (EI) calcd for C₂₄H₁₉F₆

N₃O₂S (M⁺) 527.1102; found, 527.1130. Anal. Calcd

for C₂₄H₁₉F₆N₃O₂S: C, 54.65; H, 3.63; N, 7.97. Found:

C, 54.64; H, 3.64; N, 7.70.

5.1.4. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-chloro-2-meth-

ylthio-5,6,7,8,9,10-hexahydropyrimido[4,5-b][1,5]diazocin-

5-one (14). To a mixture of 7 (15.0 g, 62.7 mmol) and

thionyl chloride (45 mL) was added DMF (0.50 mL)

andthemixturewasreﬂuxedfor2 h. Themixturewascon-

centrated. The solution of the residue in THF (100 mL)

was added dropwise to a solution of 3-[[3,5-bis(triﬂuo-

romethyl)benzyl]amino]-1-(Boc-amino)propane (25.6 g,

63.9 mmol) and triethylamine (40.0 mL, 0.287 mol) in

THF (100 mL) at 0 °C. The mixture was stirred for 1 h

5.1.7. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methylphenyl)-

2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxa-

zocin-5-one (10b). The compound 10b (5.12 g, 95%) was

prepared from 8 (4.86 g, 10.0 mmol) in a manner similar

to that described for the preparation of 10a. mp: 144–

S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

5725

1

145 °C. H NMR (400 MHz, CDCl₃): d 1.95–2.07 (1H,

CDCl₃): d 1.77–2.00 (2H, m), 2.15–2.36 (3H, m), 2.48

(3H, s), 3.23–3.42 (3H, m), 3.74 (1H, d, J = 15.3 Hz),

3.77–3.88 (1H, m), 5.34 (1H, d, J = 15.3 Hz), 5.77 (1H,

t, J = 7.3 Hz), 6.85–7.08 (2H, m), 7.15–7.24 (2H, m),

7.55 (2H, s), 7.80 (1H, s). HRMS (EI) Calcd for

C₂₅H₂₂F₆N₄OS (M⁺) 540.1419; found, 540.1390. Anal.

Calcd for C₂₅H₂₂F₆N₄OS: C, 55.55; H, 4.10; N, 10.37.

Found: C, 55.28; H, 4.06; N, 10.19.

m), 2.14–2.26 (1H, m), 2.23 (3H, s), 2.56 (3H, s), 3.33

(1H, dd, J = 15.3 and 4.9 Hz), 3.71–3.81 (1H, m), 3.87

(1H, d, J = 14.7 Hz), 4.37–4.48 (2H, m), 5.31 (1H, d,

J = 14.7 Hz), 6.92 (1H, d, J = 7.3 Hz), 7.04 (1H, dd,

J = 7.3 and 7.3 Hz), 7.20–7.25 (2H, m), 7.56 (2H, s),

7.82 (1H, s). HRMS (EI) calcd for C₂₅H₂₁F₆N₃O₂S

(M⁺) 541.1259; found, 541.1241. Anal. Calcd for

C₂₅H₂₁F₆N₃O₂S: C, 55.45; H, 3.91; N, 7.76. Found: C,

55.39; H, 3.78; N, 7.56.

5.1.12. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methylphe-

nyl)-2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]-

diazepin-5-one (17). The compound 17 (2.63 g, 99%) was

prepared from 15 (2.36 g, 5.01 mmol) in a manner simi-

lar to that described for the preparation of 10a. mp: 248–

250 °C. ¹H NMR (400 MHz, CDCl₃): d 2.34 (3H, s), 2.52

(3H, s), 3.64 (4H, br s), 4.69 (2H, br s), 5.59 (1H, br s), 7.11

(1H, dd, J = 7.3 and 1.2 Hz), 7.19 (1H, ddd, J = 7.3, 7.3,

and 1.2 Hz), 7.23–7.32 (2H, m), 7.63 (2H, s), 7.81 (1H,

s). HRMS (EI) calcd for C₂₄H₂₀F₆N₄OS (M⁺) 526.1262;

found, 526.1232. Anal. Calcd for C₂₄H₂₀F₆N₄OS: C,

54.75; H, 3.83; N, 10.64. Found: C, 54.57; H, 3.68; N,

10.46.

5.1.8.

6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methoxyl-

phenyl)-2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-

b][1,5]oxazocin-5-one (10c). The compound 10c (1.96 g,

88%) was prepared from 8 (1.95 g, 4.01 mmol) in a man-

ner similar to that described for the preparation of 10a.

1

mp: 164–165 °C. H NMR (400 MHz, CDCl₃): d 1.97–

2.14 (2H, m), 2.56 (3H, s), 3.32–3.43 (1H, m), 3.39 (3H,

s), 3.77–3.88 (1H, m), 4.05 (1H, d, J = 14.7 Hz), 4.34–

4.49 (2H, m), 5.19 (1H, d, J = 14.7 Hz), 6.74 (1H, d,

J = 7.9 Hz), 7.01 (1H, dd, J = 7.9 and 7.9 Hz), 7.34 (2H,

dd, J = 7.9 and 7.9 Hz), 7.69 (2H, s), 7.83 (1H, s). HRMS

(EI) calcd for C₂₅H₂₁F₆N₃O₃S (M⁺) 557.1208; found,

557.1216. Anal. Calcd for C₂₅H₂₁F₆N₃O₃S: C, 53.86; H,

3.80; N, 7.54. Found: C, 53.49; H, 3.63; N, 7.28.

5.1.13. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-2-methylsulfo-

nyl-4-phenyl-6,7,8,9- tetrahydro-5H-pyrimido[4,5-b][1,5]-

oxazocin-5-one (12a). To a solution of 10a (2.15 g,

4.08 mmol) in THF (8 mL) was added mCPBA (2.12 g,

12.3 mmol) portion-wise under ice cooling. The mixture

was stirred for 30 min at 0 °C and then for 3 h at room

temperature. The resulting mixture was diluted with ethyl

acetate, then washed with saturated sodium hydrogen

carbonate. The organic layer was dried over anhydrous

Na₂SO₄, ﬁltered, and then concentrated in vacuo. Flash

chromatography (AcOEt) of the residue gave 12a as a col-

5.1.9. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-ﬂuorophen-

yl)-2-methylthio-6,7,8,

b][1,5]oxazocin-5-one (10d). The compound 10d

(245 mg, 90%) was prepared from (243 mg,

9-tetrahydro-5H-pyrimido[4,5-

8

0.501 mmol) in a manner similar to that described for

the preparation of 10a. mp: 154–156 °C. ¹H NMR

(400 MHz, CDCl₃): d 2.01–2.17 (2H, m), 2.58 (3H, s),

3.33–3.43 (1H, m), 3.75–3.86 (1H, m), 4.02 (1H, d,

J = 15.3 Hz), 4.38–4.52 (2 H, m), 5.37 (1H, d,

J = 15.3 Hz), 6.90–6.97 (1H, m), 7.22 (1H, ddd,

J = 7.3, 7.3, and 1.2 Hz), 7.33–7.41 (1H, m), 7.51 (1H,

ddd, J = 7.3, 7.3, and 1.8 Hz), 7.74 (2H, s), 7.84 (1H,

s). HRMS (FAB⁺) calcd for C₂₄H₁₉F₇N₃O₂S (M⁺+1)

546.1086; found, 546.1108. Anal. Calcd for

C₂₄H₁₈F₇N₃O₂S: C, 52.85; H, 3.33; N, 7.70. Found: C,

52.87; H, 3.29; N, 7.39.

1

orless solid (17.8 g, 63%). mp: 239–241 °C. H NMR

(400 MHz, CDCl₃): d 2.10–2.32 (2H, m), 3.36 (3H, s),

3.52–3.61 (1H, m), 3.78–3.88 (1H, m), 4.10 (1H, d,

J = 15.3 Hz), 4.48–4.59 (2H, m), 5.36 (1H, d,

J = 15.3 Hz), 7.29 (2H, dd, J = 7.9 and 7.9 Hz), 7.42–

7.50 (3 H, m), 7.77 (2H, s), 7.90 (1H, s). HRMS (EI) calcd

for C₂₄H₁₉F₆N₃O₄S (M⁺) 559.1000; found, 559.0974.

Anal. Calcd for C₂₄H₁₉F₆N₃O₄S: C, 51.52; H, 3.42; N,

7.51. Found: C, 51.39; H, 3.32; N, 7.29.

5.1.10. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methylphen-

yl)-2-methylthio-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxa-

zepin-5-one (11). The compound 11 (2.13 g, 81%) was

prepared from 9 (2.36 g, 5.00 mmol) in a manner similar

to that described for the preparation of 10a. mp: 209–

5.1.14. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-2-methylsulfonyl-

4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]-

[1,5]oxazocin-5-one (12b). The compound 12b (4.98 g,

100%) was prepared from 10b (4.50 g, 8.31 mmol) in a

manner similar to that described for the preparation of

1

211 °C. H NMR (400 MHz, CDCl₃): d 2.30 (3H, s),

1

2.59 (3H, s), 3.69 (2H, t, J = 4.9 Hz), 4.60 (2H, t,

J = 4.9 Hz), 4.76 (2H, s), 7.08 (1H, dd, J = 7.3 and

1.2 Hz), 7.21 (1H, t, J = 7.3 Hz), 7.27–7.37 (2H, m),

7.66 (2H, s), 7.84 (1H, s). HRMS (EI) calcd for

C₂₄H₁₉F₆N₃O₂S (M⁺) 527.1102; found, 527.1130. Anal.

12a. mp: 211–212 °C. H NMR (400 MHz, CDCl₃): d

2.03–2.14 (1H, m), 2.23 (3H, s), 2.17–2.33 (1H, m), 3.34

(3H, s), 3.44 (1H, dd, J = 15.3 and 5.5 Hz), 3.66–3.77

(1H, m), 3.91 (1H, d, J = 14.7 Hz), 4.48–4.60 (2H, m),

5.29 (1H, d, J = 14.7 Hz), 6.88 (1H, d, J = 7.3 Hz), 7.02

(1H, dd, J = 7.3 and 7.3 Hz), 7.22–7.32 (2H, m), 7.57

(2H, s), 7.84 (1H, s). HRMS (EI) calcd for

C₂₅H₂₁F₆N₃O₄S (M⁺) 573.1157; found, 573.1144. Anal.

Calcd for C₂₅H₂₁F₆N₃O₄S: C, 52.36; H, 3.69; N, 7.33.

Found: C, 52.40; H, 3.52; N, 7.05.

1

Calcd for C₂₄H₁₉F₆N₃O₂S ꢁ H₂O: C, 54.28; H, 3.61; N,

5

7.91. Found: C, 54.23; H, 3.64; N, 7.54.

5.1.11.

6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(4-ﬂuoro-2-

methylphenyl)-2- methylthio-5,6,7,8,9,10-hexahydropyrim-

ido[4,5-b][1,5]diazocin-5-one (16). The compound 16

(540 mg, 99%) was prepared from 14 (485 mg,

1.00 mmol) in a manner similar to that described for

the preparation of 10a. Foam. ¹H NMR (400 MHz,

5.1.15. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methoxyl-

phenyl)-2-methylsulfonyl-6,7,8,9-tetrahydro-5H-pyrimi-

do[4,5-b][1,5]oxazocin-5-one (12c). The compound 12c

5726

S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

(1.75 g, 85%) was prepared from 10c (1.80 g,

3.23 mmol) in a manner similar to that described for

the preparation of 12a. mp: 202–206 °C. ¹H NMR

(400 MHz, CDCl₃): d 2.06–2.23 (2H, m), 3.35 (6H, s),

3.41–3.48 (1H, m), 3.72–3.82 (2H, m), 4.05 (1H, d,

J = 14.7 Hz), 4.45–4.60 (2H, m), 5.52 (1H, d,

J = 14.7 Hz), 6.73 (1H, d, J = 7.3 Hz), 7.04 (1H, dd,

J = 7.3 and 7.3 Hz), 7.35–7.43 (2H, m), 7.69 (2H, s),

7.86 (1H, s). HRMS (EI) calcd for C₂₅H₂₁F₆N₃O₅S

(M⁺) 589.1106; found, 589.1082. Anal. Calcd for

C₂₅H₂₁F₆N₃O₅S: C, 50.94; H, 3.59; N, 7.13. Found:

C, 50.77; H, 3.43; N, 6.90.

manner similar to that described for the preparation of

12a. mp: 307–310 °C. H NMR (400 MHz, DMSO-d₆):

1

d 2.23 (3H, s), 3.30 (3H, s), 3.51–3.58 (2H, m), 3.76–

3.87 (2H, br), 4.62–4.74 (2H, br), 7.05 (1H, t,

J = 7.3 Hz), 7.17–7.24 (2H, m), 7.27 (1H, ddd, J = 7.3,

7.3, and 1.2 Hz), 7.84 (2H, s), 8.06 (1H, s), 8.68–8.73

(1H, br). HRMS (EI) calcd for C₂₄H₂₀F₆N₄O₃S (M⁺)

558.1160; found, 558.1156. Anal. Calcd for

C₂₄H₂₀F₆N₄O₃S: C, 51.61; H, 3.61; N, 10.03. Found:

C, 51.38; H, 3.45; N, 9.95.

5.1.20. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methylphen-

yl)-2-[4-(1- pyrrolodinyl)piperidino]-6,7,8,9-tetrahydro-5H-

pyrimido[4,5-b][1,5]oxazocin-5-one (3a). To a solution of

12b (1.50 g, 2.62 mmol) in 1,4-dioxane (10 mL) were

added diisopropylethylamine (1 mL) and 4-(pyrrolidi-

nyl)piperidine (485 mg, 3.14 mmol) at room temperature

and the mixture was reﬂuxed for 3 h. The resulting mix-

ture was diluted with ethyl acetate, then washed with

water and brine. The organic layer was dried over anhy-

drous Na₂SO₄, ﬁltered, and then concentrated in vacuo.

Flash chromatography (AcOEt:MeOH = 3:1) of the res-

idue gave 3a as a colorless foam (1.08 g, 64%). ¹H NMR

(400 MHz, CDCl₃): d 1.45–1.58 (2H, m), 1.75–1.87 (4H,

m), 1.87–2.05 (4H, m), 2.05–2.18 (2H, m), 2.18–2.37

(1H, m), 2.25 (3H, s), 2.57–2.69 (3H, m), 2.90–3.01

(2H, m), 3.23–3.32 (1H, m), 3.76–3.89 (1H, m), 3.84

(1H, d, J = 15.3 Hz), 4.27–4.41 (2H, m), 4.67–4.80

(1H, m), 5.32 (1H, d, J = 15.3 Hz), 6.92–6.98 (1H, m),

7.02–7.08 (1H, m), 7.18–7.25 (2H, m), 7.57 (2H, s),

7.80 (1H, s). HRMS (EI) calcd for C₃₃H₃₅F₆N₅O₂

(M⁺) 647.2695; found, 647.2707. Anal. Calcd for

5.1.16. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-ﬂuorophen-

yl)-2-methylsulfonyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-

b][1,5]oxazocin-5-one (12d). The compound 12d (215 mg,

92%) was prepared from 10d (221 mg, 0.405 mmol) in a

manner similar to that described for the preparation of

1

12a. mp: 202–205 °C. H NMR (400 MHz, CDCl₃): d

2.07–2.26 (2H, m), 3.36 (3H, s), 3.43–3.53 (1H, m),

3.71–3.82 (1H, m), 4.06 (1H, d, J = 14.7 Hz), 4.50–4.62

(2H, m), 5.36 (1H, d, J = 14.7 Hz), 6.90–6.97 (1H, m),

7.25 (1H, ddd, J = 7.3, 7.3, and 1.2 Hz), 7.39–7.47

(1H, m), 7.55 (1H, ddd, J = 7.3, 7.3, and 1.8 Hz), 7.75

(2H, s), 7.87 (1H, s). HRMS (FAB⁺) calcd for

C₂₄H₁₉F₇N₃O₄S (M⁺+1) 578.0985; found, 578.1015.

Anal. Calcd for C₂₄H₁₈F₇N₃O₄S: C, 49.92; H, 3.14; N,

7.28. Found: C, 49.91; H, 3.07; N, 7.17.

5.1.17. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methylphen-

yl)-2-methylsulfonyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]-

oxazepin-5-one (13). The compound 13 (1.73 g, 84%) was

prepared from 11 (1.95 g, 3.70 mmol) in a manner simi-

lar to that described for the preparation of 12a. mp:

1

C₃₃H₃₅F₆N₅O₂ꢁ H₂O: C, 60.86; H, 5.42; N, 10.75.

Found: C, 60.47⁵; H, 5.40; N, 10.47.

1

197–200 °C. H NMR (400 MHz, CDCl₃): d 2.33 (3H,

s), 3.37 (3H, s), 3.77 (2H, t, J = 4.9 Hz), 4.71 (2H, t,

J = 4.9 Hz), 4.79 (2H, s), 7.05 (1H, brd, J = 7.3 Hz),

7.23 (1H, t, J = 7.3 Hz), 7.33 (1H, d, J = 7.3 Hz), 7.40

(1H, ddd, J = 7.3, 7.3, and 1.2 Hz), 7.68 (2H, s), 7.88

(1H, s). HRMS (EI) calcd for C₂₄H₁₉F₆N₃O₄S (M⁺)

559.1000; found, 559.1016. Anal. Calcd for

5.1.21. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methylphen-

yl)pyridyl)-1-piperazinyl]-6,7,8,9-tetrahydro-5H-pyrimi-

do[4,5-b][1,5]oxazocin-5-one (3b). The compound 3b

(77.1 mg, 88%) was prepared from 12b (86.0 mg,

0.150 mmol) in a manner similar to that described for

the preparation of 3a. Foam. ¹H NMR (400 MHz,

CDCl₃): d 1.92–2.03 (1H, m), 2.08–2.20 (1H, m), 2.27

(3H, s), 3.29 (1H, dd, J = 15.3 and 4.3 Hz), 3.53–3.66

(4H, m), 3.78–3.89 (1H, m), 3.85 (1H, d, J = 15.3 Hz),

3.92–4.03 (4H, m), 4.30–4.43 (2H, m), 5.33 (1H, d,

J = 15.3 Hz), 6.63–6.69 (2H, m), 6.93–6.99 (1H, m),

7.02–7.08 (1H, m), 7.20–7.28 (2H, m), 7.46–7.53 (1H,

m), 7.57 (2H, s), 7.80 (1H, s), 8.20 (1H, dd, J = 4.9

and 1.2 Hz). HRMS (EI) calcd for C₃₃H₃₀F₆N₆O₂

(M⁺) 656.2334; found, 656.2310. Anal. Calcd for

C₃₃H₃₀F₆N₆O₂: C, 60.36; H, 4.61; N, 12.80. Found: C,

60.25; H, 4.63; N, 12.92.

1

C₂₄H₁₉F₆N₃O₄S ꢁ H₂O: C, 51.36; H, 3.41; N, 7.49.

Found: C, 51.02; ¹H⁰, 3.39; N, 7.19.

5.1.18. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methylphen-

yl)-2-methylsulfonyl-5,6,7,8,9,10-hexahydropyrimido[4,5-b]-

[1,5]diazocin-5-one (18). The compound 18 (335 mg, 65%)

was prepared from 16 (490 mg, 0.907 mmol) in a manner

similar to that described for the preparation of 12a. mp:

1

276–279 °C. H NMR (400 MHz, CDCl₃): d 1.87–2.07

(2H, m), 2.24 (3H, s), 3.27 (3H, s), 3.33–3.46 (3H, m),

3.71–3.83 (1H, m), 3.78 (1H, d, J = 15.3 Hz), 5.32 (1H,

d, J = 15.3 Hz), 6.41 (1H, t, J = 7.3 Hz), 6.85–6.94

(1H, br), 7.02 (1H, t, J = 7.3 Hz), 7.20–7.28 (2H, m),

7.55 (2H, s), 7.82 (1H, s). HRMS (EI) calcd for

C₂₅H₂₂F₆N₄O₃S (M⁺) 572.1317; found, 572.1290. Anal.

5.1.22. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-2-(1-imidazolyl)-

4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]-

[1,5]oxazocin-5-one (3c). The compound 3c (53.8 mg,

64%) was prepared from 12b (86.0 mg, 0.150 mmol) in

a manner similar to that described for the preparation

1

Calcd for C₂₅H₂₂F₆N₄O₃S ꢁ H₂O: C, 52.36; H, 3.87; N,

20

9.77. Found: C, 52.73; H, 3.85; N, 9.37.

1

of 3a. Foam. H NMR (400 MHz, CDCl₃): d 2.01–2.12

5.1.19. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methylphen-

yl)methylsulfonyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-

e][1,4]diazepin-5-one (19). The compound 19 (410 mg,

15%) was prepared from 17 (2.50 g, 4.75 mmol) in a

(1H, m), 2.21–2.32 (4H, m), 3.41 (1H, dd, J = 15.6 and

4.9 Hz), 3.74–3.85 (1H, m), 3.91 (1H, d, J = 14.6 Hz),

4.45–4.57 (2H, m), 5.32 (1H, d, J = 14.6 Hz), 6.94 (1H,

S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

5727

d, J = 7.8 Hz), 7.07 (1H, dd, J = 7.8 and 7.8 Hz), 7.14

(1H, d, J = 1.0 Hz), 7.27–7.33 (2H, m), 7.59 (2H, s),

7.84 (1H, s), 7.86 (1H, d, J = 1.0 Hz), 8.58 (1H, s).

HRMS (EI) calcd for C₂₇H₂₁F₆N₅O₂(M⁺) 561.1599;

found, 561.1597. Anal. Calcd for C₂₇H₂₁F₆N₅O₂: C,

57.76; H, 3.77; N, 12.47. Found: C, 57.53; H, 3.69; N,

12.31.

a manner similar to that described for the preparation

of 3a. mp: 162–164 °C. H NMR (400 MHz, CDCl₃):

1

d 1.92–2.04 (1H, m), 2.10–2.20 (1H, m), 2.13 (3H, s),

2.25 (3H, s), 3.30 (1H, dd, J = 15.1 and 4.4 Hz), 3.50

(2H, dd, J = 4.4 and 4.4 Hz), 3.63–3.70 (2H, m), 3.76–

3.95 (6H, m), 4.30–4.43 (2H, m), 5.32 (1H, d,

J = 15.1 Hz), 6.95 (1H, br d, J = 7.3 Hz), 7.05 (1H, br

dd, J = 7.3 and 7.3 Hz), 7.20–7.25 (2H, m), 7.57 (2H,

s), 7.81 (1H, s). HRMS (EI) calcd for C₃₀H₂₉F₆N₅O₃

(M⁺) 621.217500; found, 621.2192. Anal. Calcd for

C₃₀H₂₉F₆N₅O₃: C, 57.97; H, 4.70; N, 11.27. Found: C,

57.90; H, 4.70; N, 11.33.

5.1.23. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methylphen-

yl)morpholino-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]-

oxazocin-5-one (3d). The compound 3d (50.4 mg, 87%)

was prepared from 12b (57.4 mg, 0.100 mmol) in a man-

ner similar to that described for the preparation of 3a.

1

Foam. H NMR (400 MHz, CDCl₃): d 1.91–2.03 (1H,

5.1.27. 2-(4-Acetamido-1-homopiperazinyl)-6-[3,5-bis(tri-

ﬂuoromethyl)benzyl]-4-(2-methylphenyl)-6,7,8,9-tetrahy-

dro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (3h). To a

solution of 12b (86.0 mg, 0.150 mmol) in 1,4-dioxane

(1 mL) were added diisopropylethylamine (0.1 mL) and

4-(tert-butoxycarbonylamino)homopiperazine (36.1 mg,

0.180 mmol) at room temperature and the mixture was

reﬂuxed for 5 h. The resulting mixture was diluted with

ethyl acetate, then washed with water and brine. The

organic layer was dried over anhydrous Na₂SO₄, ﬁl-

tered, and then concentrated in vacuo. To the resulting

residue was added 3 M HCl–AcOEt (1 mL) under ice

cooling. The mixture was stirred for 30 min at 0 °C

and then for 1 h at room temperature. The resulting

mixture was concentrated in vacuo. To a solution of

the residue in THF (1 mL) were added triethylamine

(0.1 mL) and acetic anhydride (0.05 mL) portion-wise

under ice cooling. The mixture was stirred for 30 min

at 0 °C. The resulting mixture was diluted with ethyl

acetate, then washed with water. The organic layer

was dried over anhydrous Na₂SO₄, ﬁltered, and then

concentrated in vacuo. Flash chromatography (AcOEt)

of the residue gave 3h as a pale yellow foam (39.5 mg,

m), 2.08–2.19 (1H, m), 2.25 (3H, s), 3.28 (1H, dd,

J = 15.3 and 4.3 Hz), 3.68–3.76 (4H, m), 3.76–3.89 (6H,

m), 4.30–4.42 (2H, m), 5.32 (1H, d, J = 15.3 Hz), 6.92–

6.97 (1H, m), 7.01–7.08 (1H, m), 7.19–7.27 (2H, m),

7.57 (2H, s), 7.80 (1H, s). HRMS (EI) calcd for

C₂₈H₂₆F₆N₄O₃(M⁺) 580.1909; found, 580.1948. Anal.

Calcd for C₂₈H₂₆F₆N₄O₃: C, 57.93; H, 4.51; N, 9.65.

Found: C, 57.80; H, 4.41; N, 9.52.

5.1.24. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-2-[4-(ethoxy-

carbonyl)piperidino]-4-(2-methylphenyl)-6,7,8,9-tetrahy-

dro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (3e). The

compound 3e (64.6 mg, 68%) was prepared from 12 b

(86.0 mg, 0.150 mmol) in a manner similar to that de-

scribed for the preparation of 3a. Foam. ¹H NMR

(400 MHz, CDCl₃): d 1.25 (3H, t, J = 7.3 Hz), 1.62–

1.75 (2H, m), 1.87–2.01 (4H, m), 2.07–2.17 (1H, m),

2.26 (3H, s), 2.50–2.60 (1H, m), 3.00–3.11 (2H, m),

3.27 (1H, dd, J = 14.7 and 4.3 Hz), 3.77–3.88 (1H, m),

3.84 (1H, d, J = 15.3 Hz), 4.14 (2H, q, J = 7.3 Hz),

4.28–4.40 (2H, m), 4.60–4.72 (2H, m), 5.32 (1H, d,

J = 15.3 Hz), 6.93–6.98 (1H, m), 7.02–7.08 (1H, m),

7.18–7.28 (1H, m), 7.57 (2H, s), 7.80 (1H, s). HRMS

(EI) calcd for C₃₂H₃₂F₆N₄O₄(M⁺) 650.2328; found,

650.2351. Anal. Calcd for C₃₂H₃₂F₆N₄O₄: C, 59.07; H,

4.96; N, 8.61. Found: C, 58.82; H, 5.00; N, 8.55.

1

41%). H NMR (400 MHz, CDCl₃): d 1.83–2.06 (4H,

m), 2.12 (3H, s), 2.25 (3H, d, J = 3.9 Hz), 3.29 (1H,

dd, J = 15.1 and 4.4 Hz), 3.33–4.15 (10H, m), 4.29–

4.42 (2H, m), 5.31 (1H, d, J = 15.1 Hz), 6.91–6.98 (1H,

m), 7.01–7.08 (1H, m), 7.19–7.25 (2H, m), 7.57 (2H, s),

7.80 (1H, s). HRMS (EI) calcd for C₃₁H₃₁F₆N₅O₃

(M⁺) 635.2331; found, 635.2313. Anal. Calcd for

C₃₁H₃₁F₆N₅O₃: C, 58.58; H, 4.92; N, 11.02. Found: C,

58.25; H, 4.81; N, 10.72.

5.1.25. 2-(4-Carbamoylpiperidino)-6-[3,5-bis(triﬂuorom-

ethyl)benzyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-

pyrimido[4,5-b][1,5]oxazocin-5-one (3f). The compound

3f (70.0 mg, 75%) was prepared from 12b (86.0 mg,

0.150 mmol) in a manner similar to that described for

the preparation of 3a. Foam. ¹H NMR (400 MHz,

CDCl₃): d 1.62–1.77 (2H, m), 1.86–2.02 (3H, m), 2.07–

2.18 (1H, m), 2.25 (3H, s), 2.37–2.47 (1H, m), 2.90–

3.02 (2H, m), 3.28 (1H, dd, J = 15.3 and 4.9 Hz), 3.77–

3.89 (1H, m), 3.85 (1H, d, J = 15.3 Hz), 4.28–4.42 (2H,

m), 4.77–4.88 (2H, m), 5.32 (1H, d, J = 15.3 Hz), 5.38–

5.49 (2H, brs), 6.92–6.99 (1H, m), 7.01–7.09 (1H, m),

7.19–7.25 (2H, m), 7.57 (2H, s), 7.80 (1H, s). HRMS

(EI) calcd for C₃₀H₂₉F₆N₅O₃(M⁺) 621.2175; found,

5.1.28. 2-(3-Acetamido-1-pyrrolidinyl)-6-[3,5-bis(triﬂuo-

romethyl)benzyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-

5H-pyrimido[4,5-b][1,5]oxazocin-5-one (3i). The com-

pound 3i (65.0 mg, 70%) was prepared from 12b

(86.0 mg, 0.150 mmol) in a manner similar to that de-

1

scribed for the preparation of 3a. mp: 134–137 °C. H

NMR (400 MHz, CDCl₃): d 1.90–2.03 (5H, m), 2.07–

2.19 (1H, m), 2.19–2.32 (4H, m), 3.28 (1H, dd,

J = 15.1 and 4.9 Hz), 3.49 (1H, dd, J = 11.7 and

4.4 Hz), 3.69 (2H, dd, J = 6.8 and 6.8 Hz), 3.74–3.91

(3H, m), 4.29–4.42 (2H, m), 4.52–4.62 (1H, m), 5.32

(1H, d, J = 14.6 Hz), 5.63 (1H, br s), 6.91–6.98 (1H,

m), 7.01–7.08 (1H, m), 7.18–7.26 (2H, m), 7.57 (2H, s),

7.80 (1H, s). HRMS (EI) calcd for C₃₀H₂₉F₆N₅O₃

(M⁺) 621.2175; found, 621.2173. Anal. Calcd for

C₃₀H₂₉F₆N₅O₃ÆH₂O: C, 56.34; H, 4.57; N, 10.95.

Found: C, 56.64; H, 4.62; N, 10.96.

1

2

621.2142. Anal. Calcd for C₃₀H₂₉F₆N₅O₃ꢁ H₂O: C,

57.14; H, 4.64; N, 11.11. Found: C, 57.18; H, 4.61; N,

11.02.

5.1.26. piperazinyl)-6-[3,5-bis(triﬂuoromethyl)benzyl]-4-

(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]-

[1,5]oxazocin-5-one (3g). The compound 3g (60.7 mg,

65%) was prepared from 12b (86.0 mg, 0.150 mmol) in

5728

S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

5.1.29. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-2-(1,1-dioxo-

thiomorpholino)-4-(2-methylphenyl)-6,7,8,9-tetrahydro-

5H-pyrimido[4,5-b][1,5]oxazocin-5-one (3j). The com-

pound 3j (12.5 mg, 13%) was prepared from 12b

(86.0 mg, 0.150 mmol) in a manner similar to that de-

scribed for the preparation of 3a. mp: 227–230 °C.

¹H NMR (400 MHz, CDCl₃): d 1.94–2.05 (1H, m),

2.11–2.21 (1H, m), 2.23 (3H, s), 3.00–3.09 (4H, m),

3.29–3.37 (1H, m), 3.75–3.83 (1H, m), 3.86 (1H, d,

J = 14.6 Hz), 4.33–4.44 (6H, m), 5.31 (1H, d,

J = 14.6 Hz), 6.93 (1H, d, J = 6.8 Hz), 7.06 (1H, dd,

J = 6.8 and 6.8 Hz), 7.21–7.30 (2H, m), 7.57 (2H, s),

7.81 (1H, s). HRMS (EI) calcd for C₂₈H₂₆F₆N₄O₄S

(M⁺) 628.1579; found, 628.1523. Anal. Calcd for

C₂₈H₂₆F₆N₄O₄S H₂O: C, 52.01; H, 4.05; N, 8.66.

Found: C, 52.34; H, 4.11; N, 8.80.

5.1.33. 2-(4-Acetyl-1-piperazinyl)-6-[3,5-bis(triﬂuorometh-

yl)benzyl]-4-(2-ﬂuorophenyl)-6,7,8,9-tetrahydro-5H-pyrim-

ido[4,5-b][1,5]oxazocin-5-one (3n). The compound 3n

(65.7 mg, 88%) was prepared from 12d (68.5 mg,

0.119 mmol) in a manner similar to that described for the

1

preparation of 3g. Foam. H NMR (400 MHz, CDCl₃):

d 1.97–2.12 (2H, m), 2.14 (3H, s), 3.30–3.38 (1H, m), 3.52

(2H, t, J = 5.5 Hz), 3.65–3.72 (2H, m), 3.80–3.94 (5H, m),

3.99 (1H, d, J = 15.3 Hz), 4.33–4.45 (2H, m), 5.36 (1H, d,

J = 15.3 Hz), 6.92–6.98 (1H, m), 7.19 (1H, ddd, J = 7.3,

7.3, and 1.2 Hz), 7.32–7.38 (1H, m), 7.46 (1H, ddd,

J = 7.3, 7.3, and 1.8 Hz), 7.73 (2H, s), 7.82 (1H, s). HRMS

(FAB⁺) calcd for C₂₉H₂₇F₇N₅O₃(M⁺+1) 626.2002; found,

1

626.2012. Anal. Calcd for C₂₉H₂₆F₇N₅O₃ꢁ H₂O: C,

5

55.36;H,4.17;N,11.13. Found:C, 54.96;H,4.11;N,10.88.

5.1.34. 2-(4-Acetyl-1-piperazinyl)-6-[3,5-bis(triﬂuorometh-

yl)benzyl]-4-(2-methylphenyl)-5,6,7,8-tetrahydropyrimido-

[5,4-f][1,4]oxazepin-5-one (4). The compound 4 (62.2 mg,

68%) was prepared from 13 (84.0 mg, 0.150 mmol) in a

manner similar to that described for the preparation of

3a. mp: 231–234 °C. ¹H NMR (400 MHz, CDCl₃): d

2.15 (3H, s), 2.31 (3H, s), 3.52 (2H, t, J = 4.9 Hz),

3.64–3.73 (4H, m), 3.86–3.98 (4H, m), 4.54 (2H, t,

J = 4.9 Hz), 4.73 (2H, s), 7.10 (1H, dd, J = 7.3 and

1.2 Hz), 7.22 (1H, t, J = 7.3 Hz), 7.27 (1H, d,

J = 7.3 Hz), 7.32 (1H, ddd, J = 7.3, 7.3, and 1.2 Hz),

7.65 (2H, s), 7.82 (1H, s). HRMS (EI) calcd for

C₂₉H₂₇F₆N₅O₃(M⁺) 607.2018; found, 607.2026. Anal.

Calcd for C₂₉H₂₇F₆N₅O₃: C, 57.33; H, 4.48; N, 11.53.

Found: C, 57.13; H, 4.38; N, 11.41.

5.1.30. 6-[3,5-Bis(triﬂuoromethyl)benzyl]-4-(2-methylphe-

nyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-6,7,8,9-tetrahy-

dro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (3k). The

compound 3k (54.6 mg, 55%) was prepared from 12b

(86.0 mg, 0.150 mmol) in a manner similar to that de-

scribed for the preparation of 3h. Foam. ¹H NMR

(400 MHz, CDCl₃): d 1.92–2.04 (1H, m), 2.07–2.20

(1H, m), 2.24 (3H, s), 2.79 (3H, s), 3.20–3.33 (5H, m),

3.73–3.84 (1H, m), 3.85 (1H, d, J = 15.3 Hz), 3.96–4.03

(4H, m), 4.31–4.43 (2H, m), 5.31 (1H, d, J = 15.3 Hz),

6.92–6.97 (1H, m), 7.03–7.08 (1H, m), 7.19–7.25 (2H,

m), 7.56 (2H, s), 7.80 (1H, s). HRMS (EI) calcd for

C₂₉H₂₉F₆N₅O₄S (M⁺) 657.1844; found, 657.1843. Anal.

Calcd for C₂₉H₂₉F₆N₅O₄S: C, 52.96; H, 4.44; N, 10.65.

Found: C, 52.77; H, 4.32; N, 10.46.

5.1.35.

2-(4-Acetyl-1-piperazinyl)-6-[3,5-bis(triﬂuoro-

5.1.31. 2-(4-Acetyl-1-piperazinyl)-6-[3,5-bis(triﬂuorometh-

yl)benzyl]-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]-

[1,5]oxazocin-5-one (3l). The compound 3l (53.7 mg, 59%)

was prepared from 12a (84.0 mg, 0.150 mmol) in a man-

ner similar to that described for the preparation of 3a.

methyl)benzyl]-4-(2-methylphenyl)-5,6,7,8,9,10-hexahydro-

pyrimido[4,5-b][1,5]diazocin-5-one (5a). The compound 5a

(70.0 g, 75%) was prepared from 18 (85.9 mg, 0.150

mmol) in a manner similar to that described for the prep-

aration of 3a. Foam. ¹H NMR (400 MHz, CDCl₃): d

1.73–1.85 (1H, m), 1.85–1.97 (1H, m), 2.12 (3H, s), 2.18–

2.38 (3H, br), 3.18–3.38 (3H, m), 3.42–3.49 (2H, m),

3.59–3.68 (2H, m), 3.69–3.94 (6H, m), 5.36 (1H, d,

J = 15.3 Hz), 5.47 (1H, t, J = 7.3 Hz), 6.85–7.10 (2H, m),

7.16–7.24 (2H, m), 7.79 (2H, s), 8.02 (1H, s). HRMS (EI)

calcd for C₃₀H₃₀F₆N₆O₂(M⁺) 620.2334; found,

1

mp: 215–218 °C. H NMR (400 MHz, CDCl₃): d 1.97–

2.20 (2H, m), 2.14 (3H, s), 3.40–3.48 (1H, m), 3.48–3.54

(2H, m), 3.65–3.71 (2H, m), 3.84–4.00 (5H, m), 4.03

(1H, d, J = 15.3 Hz), 4.33–4.40 (2H, m), 5.36 (1H, d,

J = 15.3 Hz), 7.24–7.31 (2H, m), 7.35–7.43 (3H, m),

7.76 (2H, s), 7.86 (1H, s). HRMS (EI) calcd for

C₂₉H₂₇F₆N₅O₃(M⁺) 607.2018; found, 607.2049. Anal.

Calcd for C₂₉H₂₇F₆N₅O₃: C, 57.33; H, 4.48; N, 11.53.

Found: C, 56.99; H, 4.36; N, 11.49.

1

620.2319. Anal. Calcd for C₃₀H₃₀F₆N₆O₂ꢁ H₂O: C,

5

57.73;H,4.84;N,13.46. Found:C, 57.40;H,4.82;N,13.22.

5.1.36. 2-(4-Acetyl-1-piperazinyl)-6-[3,5-bis(triﬂuorometh-

yl)benzyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimi-

do[4,5-e][1,4]diazepin-5-one (6). The compound 6 (43.8 g,

46%) was prepared from 19 (83.8 mg, 0.150 mmol) in a

manner similar to that described for the preparation of

3a. mp: 171–173 °C. ¹H NMR (400 MHz, CDCl₃): d

2.14 (3H, s), 2.34 (3H, s), 3.48 (2H, dd, J = 5.5 and

5.5 Hz), 3.61 (4H, s), 3.65 (2H, dd, J = 5.5 and

5.5 Hz), 3.82 (2H, dd, J = 5.5 and 5.5 Hz), 3.88 (2H,

dd, J = 5.5 and 5.5 Hz), 4.68 (2H, br), 5.29 (1H, s),

7.14 (1H, dd, J = 7.3 and 1.2 Hz), 7.20 (1H, ddd,

J = 7.3, 7.3, and 1.2 Hz), 7.23–7.31 (2H, m), 7.63 (2H,

s), 7.80 (1H, s). HRMS (EI) calcd for C₂₉H₂₈F₆N₆O₂

5.1.32. 2-(4-Acetyl-1-piperazinyl)-6-[3,5-bis(triﬂuorom-

ethyl)benzyl]-4-(2-methoxyphenyl)-6,7,8,9-tetrahydro-5H-

pyrimido[4,5-b][1,5]oxazocin-5-one (3m). The compound

3m (86.2 mg, 90%) was prepared from 12c (88.5 mg,

0.150 mmol) in a manner similar to that described for

the preparation of 3a. Foam. ¹H NMR (400 MHz,

CDCl₃): d 1.93–2.12 (2H, m), 2.13 (3H, s), 3.28–3.37

(1H, m), 3.41 (3H, s), 3.48–3.53 (2H, m), 3.63–3.70

(2H, m), 3.82–3.94 (5H, m), 4.04 (1H, d, J = 14.7 Hz),

4.28–4.43 (2H, m), 5.17 (1H, d, J = 14.7 Hz), 6.76 (1H,

d, J = 7.3 Hz), 7.01 (1H, dd, J = 7.3 and 7.3 Hz), 7.27–

7.37 (2H, m), 7.69 (2H, s), 7.82 (1H, s). HRMS (EI) calcd

for C₃₀H₂₉F₆N₅O₄(M⁺) 637.2124; found, 637.2085.

(M⁺) 606.2178; found, 606.2166. Anal. Calcd for

1

Anal. Calcd for C₃₀H₂₉F₆N₅O₄ꢁ H₂O: C, 55.73; H,

C₂₉H₂₈F₆N₆O₂ꢁ H₂O: C, 56.58; H, 4.58; N, 13.65.

4.52; N, 10.83. Found: C, 55.49; H², 4.47; N, 10.87.

Found: C, 56.28²; H, 4.53; N, 13.26.

S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

5729

5.1.37. 2-(4-Acetyl-1-piperazinyl)-6-[3,5-bis(triﬂuorom-

ethyl)benzyl]-10-methyl- 4-(2-methylphenyl)-5,6,7,8,9,10-

hexahydropyrimido[4,5-b][1,5]diazocin-5-one (5b). To a

solution of 5a (25.0 mg, 40.3 lmol) in DMF (0.5 mL)

was added sodium hydride (2.5 mg, 62.5 lmol, 60% oil

suspension) portion-wise under ice cooling. The mixture

was stirred for 30 min at room temperature, and then

iodomethane (4.0 ll, 64.3 lmol) was added and stirred

for 1 h at room temperature. The resulting mixture

was diluted with ethyl acetate, then washed with water.

The organic layer was dried over anhydrous Na₂SO₄, ﬁl-

tered, then concentrated in vacuo. Flash chromatogra-

phy (AcOEt) of the residue gave 5b as a colorless

propanol (10.7 g, 35.5 mmol) and triethylamine

(20 mL) in THF (50 mL) at 0 °C. The mixture was stir-

red for 1 h at 0 °C and then for 2 h at room temperature.

The resulting mixture was diluted with ethyl acetate,

then washed with water and brine. The organic layer

was dried over anhydrous Na₂SO₄, ﬁltered, and then

concentrated in vacuo. Flash chromatography

(AcOEt:hexane = 3:1) of the residue gave 22 as a color-

less solid (15.4 g, 92%). mp: 99–102 °C. ¹H NMR

(400 MHz, CDCl₃): d 1.20–1.30 (1H, m), 1.70–1.90

(2H, m), 3.20–3.85 (4H, m), 4.54 (0.6H, s), 4.90 (0.7H,

d, J = 15.3 Hz), 4.99 (0.7H, d, J = 15.3 Hz), 7.70–8.08

(5H, m). HRMS (EI) calcd for C₁₈H₁₄ClF₆IN₂O₂

(M⁺) 565.9693; found, 565.9731. Anal. Calcd for

C₁₈H₁₄ClF₆IN₂O₂: C, 38.15; H, .2.49; N, 4.94. Found:

C, 37.95; H, 2.35; N, 5.01.

1

foam (10.8 mg, 42%). H NMR (400 MHz, CDCl₃): d

1.74–1.90 (2H, m), 2.13 (3H, s), 2.35 (3H, br s), 3.13–

3.24 (2H, m), 3.26 (3H, s), 3.58 (2H, dd, J = 4.9 and

4.9 Hz), 3.53–3.92 (9H, m), 5.25 (1H, d, J = 14.7 Hz),

6.75–7.00 (2H, br), 7.14–7.25 (2H, m), 7.58 (2H, br s),

7.78 (1H, s). HRMS (EI) calcd for C₃₁H₃₂F₆N₆O₂

5.1.41. 5-[3,5-Bis(triﬂuoromethyl)benzyl]-7-chloro-3,4,5,6-

tetrahydro-2H-pyrido[4,3-b]-1,5-oxazocin-6-one (23). To a

solution of 22 (1.74 g, 3.07 mmol) in EtOH (30 mL) was

(M⁺) 634.2491; found, 634.2451. Anal. Calcd for

1

C₃₁H₃₂F₆N₆O₂ꢁ H₂O: C, 58.50; H, 5.07; N, 13.21.

added K₂CO₃(2.12 g, 15.3 mmol), and the mixture was

stirred under reﬂux for 6 h. The resulting mixture was

extracted with ethyl acetate, and the extract was washed

with brine, then dried over Na₂SO₄. The solvent was evap-

orated, and the residue was puriﬁed by silica gel chroma-

tography (AcOEt:hexane = 2:1 v/v) to give compound 23

Found: C, 58.17¹;⁰H, 5.02; N, 13.01.

5.1.38.

10-Acetyl-2-(4-acetyl-1-piperazinyl)-6-[3,5-bis-

(triﬂuoromethyl)benzyl]-4-(2-methylphenyl)-5,6,7,8,9,10-

hexahydropyrimido[4,5-b][1,5]diazocin-5-one (5c). To a

solution of 5a (25.0 mg, 40.3 lmol) in 1,4-dioxane

(0.5 mL) were added pyridine (0.1 mL) and acetic anhy-

dride (0.2 mL) at room temperature. The mixture was

stirred for 3 h at 100 °C. The resulting mixture was

diluted with ethyl acetate, and then washed with water.

The organic layer was dried over anhydrous Na₂SO₄,

ﬁltered, and then concentrated in vacuo. Flash chroma-

tography (AcOEt) of the residue gave 5c as a colorless

1

(950 mg, 71%). mp: 197–200 °C. H NMR (400 MHz,

CDCl₃): d 1.97–2.18 (2H, m), 3.23–3.32 (1H, m), 3.63–

3.74 (1H, m), 4.06 (1H, d, J = 15.3 Hz), 4.22–4.30 (1H,

m), 4.44–4.53 (1H, m), 5.64 (1H, d, J = 15.3 Hz), 6.80

(1H, d, J = 5.5 Hz), 7.84 (1H, s), 7.88 (2H, s), 8.17 (1H,

d, J = 5.5 Hz). HRMS (EI) calcd for C₁₈H₁₃ClF₆N₂O₂

(M⁺) 438.0570; found, 438.0571. Anal. Calcd for

C₁₈H₁₃ClF₆N₂O₂H₂O: C, 47.33; H, 2.87; N, 6.13. Found:

C, 47.17; H, 2.88; N, 6.33.

1

foam (26.0 mg, 97%). H NMR (400 MHz, CDCl₃): d

1.51–1.64 (1H, m), 1.93 (3H, s), 2.16 (3H, s), 2.22–

2.33 (1H, m), 2.28 (3H, s), 3.02–3.12 (1H, m), 3.24–

3.33 (1H, m), 3.53–3.66 (3H, m), 3.68–3.78 (2H, m),

3.86–4.00 (5H, m), 4.61–4.69 (1H, m), 5.36 (1H, d,

J = 15.9 Hz), 6.98 (1H, d, J = 7.3 Hz), 7.11 (1H, t,

J = 7.3 Hz), 7.27–7.35 (2H, m), 7.49 (2H, s), 7.78 (1H,

s). HRMS (EI) calcd for C₃₂H₃₂F₆N₆O₃(M⁺)

662.2440; found, 662.2435. Anal. Calcd for

C₃₂H₃₂F₆N₆O₃H₂O: C, 56.47; H, 4.74; N, 12.35.

Found: C, 56.76; H, 4.79; N, 12.55.

5.1.42. 5-[3,5-Bis(triﬂuoromethyl)benzyl]-7-iodo-3,4,5,6-

tetrahydro-2H-pyrido[2,3-b]-1,5-oxazocin-6-one (24). To

a solution of 22 (6.86 g, 12.1 mmol) in THF (60 mL)

was added NaH (581 mg, 14.5 mmol) at 0 °C, and the

mixture was stirred for 0.5 h and then at room temper-

ature for 1 h. The reaction mixture was cooled at 0 °C,

and water was added. The subsequent work-up proce-

dure as described above aﬀorded compound 24 (7.69 g,

1

42%). mp: 203–206 °C. H NMR (400 MHz, CDCl₃): d

1.73–1.81 (1H, m), 2.21–2.34 (1H, m), 3.18–3.27 (1H,

m), 3.40–3.50 (1H, m), 4.14 (1H, d, J = 15.6 Hz), 4.22–

4.30 (1H, m), 4.46–4.68 (1H, m), 5.71 (1H, d,

J = 15.6 Hz), 7.69 (1H, d, J = 5.3 Hz), 7.83 (1H, s),

7.94 (2H, s), 8.01 (1H, d, J = 5.3 Hz). HRMS (EI) calcd

for C₁₈H₁₃F₆IN₂O₂(M⁺) 529.9926; found, 529.9907.

Anal. Calcd for C₁₈H₁₃F₆IN₂O₂: C, 40.78; H, 2.47; N,

5.28. Found: C, 40.88; H, 2.30; N, 5.19.

5.1.39. 2-Chloro-4-iodo-3-pyridinecarboxylic acid (21).

The compound 21 (22.7 g, 81%) was prepared from 20

(23.8 g, 99.3 mmol) in a manner similar to that described

for the preparation of 7. mp: 159–161 °C. ¹H NMR

(400 MHz, CDCl₃): d 7.76 (1H, d, J = 5.4 Hz), 8.09

(1H, d, J = 5.4 Hz). HRMS (EI) calcd for C₆H₃ClINO₂

(M⁺) 282.8897; found, 282.8896. Anal. Calcd for

C₆H₃ClINO₂: C, 25.42; H, 1.07; N, 4.94. Found: C,

25.36; H, 0.97; N, 4.71.

5.1.43. 5-[3,5-Bis(triﬂuoromethyl)benzyl]-7-(2-methylphe-

nyl)-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]-1,5-oxazocin-6-

one (25). The compound 25 (330 mg, 98%) was pre-

pared from 23 (300 mg, 0.684 mmol) in a manner simi-

lar to that described for the preparation of 10a. mp:

5.1.40. N-[3,5-Bis(triﬂuoromethyl)benzyl]-2-chloro-N-(3-

hydroxypropyl)-4-iodo-3-pyridinecarboxamide (22). To a

mixture of 21 (8.40 g, 29.6 mmol) and thionyl chloride

(20 mL) was added three drops of DMF and the mixture

was reﬂuxed for 2 h, then concentrated. A solution of

the residue in THF (150 mL) was added dropwise to a

solution of 3-[[3,5-bis(triﬂuoromethyl)benzyl]amino]-1-

1

151–154 °C. H NMR (400 MHz, CDCl₃): d 1.95–2.12

(2H, m), 2.18 (3H, s), 3.24–3.32 (1H, m), 3.75–3.85

(1H, m), 3.91 (1H, d, J = 15.3 Hz), 4.19–4.27 (1H, m),

4.38–4.46 (1H, m), 5.33 (1H, d, J = 15.3 Hz), 6.85 (1H,

5730

S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

d, J = 5.5 Hz), 6.92–7.09 (2H, m), 7.18–7.25 (2H, m),

7.57 (2H, s), 7.81 (1H, s), 8.44 (1H, d, J = 5.5 Hz). HRMS

3.57–3.75 (1H, m), 4.06 (1H, d, J = 15.3 Hz), 4.28–4.39

(1H, m), 4.73–4.81 (1H, m), 5.45 (1H, d, J = 15.3 Hz),

6.68–7.33 (4H, m), 7.01 (1H, d, J = 6.7 Hz), 7.52 (2H,

s), 7.79 (1H, s), 8.31 (1H, d, J = 6.7 Hz). HRMS

(FAB⁺) calcd for C₂₅H₂₁F₆N₂O₃(M⁺+1) 511.1456;

found, 511.1469. Anal. Calcd for C₂₅H₂₀F₆N₂O₃ꢁ

¹₅H₂O: C, 58.41; H, 3.92; N, 5.45. Found: C, 58.03; H,

3.79; N, 5.38.

(EI) calcd for C₂₅H₂₀F₆N₂O₂(M⁺) 494.1429; found,

1

494.1443. Anal. Calcd for C₂₅H₂₀F₆N₂O₂ꢁ H₂O: C,

60.29; H, 4.05; N, 5.62. Found: C, 60.01; H, 4.0⁵7; N, 5.40.

5.1.44. 5-[3,5-Bis(triﬂuoromethyl)benzyl]-7-(2-methylphe-

nyl)-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-1,5-oxazocin-6-

one (26a). The compound 26a (278 mg, 99%) was pre-

pared from 24 (300 mg, 0.566 mmol) in a manner sim-

ilar to that described for the preparation of 10a. mp:

5.1.48. 5-[3,5-Bis(triﬂuoromethyl)benzyl]-10-oxo-7-phen-

yl-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-1,5-oxazocin-6-one

(27b). The compound 27b (411 mg, 54%) was prepared

from 26b (729 mg, 1.52 mmol) in a manner similar to

that described for the preparation of 27. mp: 207–

1

138–142 °C. H NMR (400 MHz, CDCl₃): d 1.75–1.97

(2H, m), 2.17–2.34 (3H, brs), 3.17–3.32 (1H, m), 3.50–

3.73 (1H, m), 4.02 (1H, d, J = 15.3 Hz), 4.31–4.41

(1H, m), 4.60–4.68 (1H, m), 5.44 (1H, d, J = 15.3 Hz),

6.73–7.70 (5H, m), 7.02 (1H, d, J = 4.9 Hz), 7.78

(1H, s), 8.40 (1H, d, J = 4.9 Hz). HRMS (EI) for

C₂₅H₂₀F₆N₂O₂(M⁺): calcd, 494.1429; found,

494.1441. Anal. calcd for C₂₅H₂₀F₆N₂O₂: C, 60.73; H,

4.08; N, 5.67. Found: C, 60.88; H, 4.01; N, 5.32.

1

210 °C. H NMR (400 MHz, CDCl₃): d 1.77–1.84 (1H,

m), 2.35–2.48 (1H, m), 3.46 (1H, dd, J = 15.9 and

6.1 Hz), 3.79 (1H, dd, J = 15.9 and 11.6 Hz), 4.19 (1H,

d, J = 15.3 Hz), 4.30 (1H, ddd, J = 12.8, 12.8, and

3.7 Hz), 4.79 (1H, dd, J = 12.8 and 5.5 Hz), 5.51 (1H,

d, J = 15.3 Hz), 7.16 (1H, d, J = 6.7 Hz), 7.24–7.69

(5H, m), 7.71 (2H, s), 7.85 (1H, s), 8.35 (1H, d, J = 6.7

Hz). HRMS (FAB⁺) calcd for C₂₄H₁₉F₆N₂O₃(M⁺+1)

5.1.45. 5-[3,5-Bis(triﬂuoromethyl)benzyl]-7-phenyl-3,4,5,6-

tetrahydro-2H-pyrido[2,3-b]-1,5-oxazocin-6-one

(26b).

The compound 26b (729 mg, 80%) was prepared from

24 (1.00 g, 1.89 mmol) in a manner similar to that de-

497.1300; found 497.1291. Anal. Calcd for

1

C₂₄H₁₈F₆N₂O₃ꢁ H₂O: C, 57.03; H, 3.59; N, 5.54.

Found: C, 57.43²; H, 3.54; N, 5.39.

1

scribed for the preparation of 10a. mp: 185–186 °C. H

NMR (400 MHz, CDCl₃): d 1.73–1.82 (1H, m), 2.26–

2.39 (1H, m), 3.32–3.40 (1H, m), 3.69–3.78 (1H, m),

4.17 (1H, d, J = 15.3 Hz), 4.27–4.37 (1H, m), 4.63–4.70

(1H, m), 5.51 (1H, d, J = 15.3 Hz), 7.16 (1H, d,

J = 5.5 Hz), 7.25–7.70 (5H, m), 7.71 (2H, s), 7.83 (1H,

s), 8.41 (1H, d, J = 5.5 Hz). HRMS (EI) calcd for

C₂₄H₁₈F₆N₂O₂(M⁺) 480.1272; found 480.1286. Anal.

Calcd for C₂₄H₁₈F₆N₂O₂: C, 60.00; H, 3.78; N, 5.83.

Found: C, 59.83; H, 3.71; N, 5.76.

5.1.49. 5-[3,5-Bis(triﬂuoromethyl)benzyl]-9-chloro-7-(2-

methylphenyl)-3,4,5,6- tetrahydro-2H-pyrido[4,3-b]-1,5-

oxazocin-6-one (29).

A

mixture of 27 (243 mg,

0.476 mmol) and phosphorus oxychloride (2 mL) was

reﬂuxed for 1 h. After concentration in vacuo, the resi-

due was poured into H₂O and ﬁltered in vacuo to give

29 as a yellow foam (252 mg, 99%). ¹H NMR

(400 MHz, CDCl₃): d 1.94–2.31 (2H, m), 2.20 (3H, s),

3.28–3.36 (1H, m), 3.72–3.83 (1H, m), 3.89 (1H, d,

J = 15.3 Hz), 4.27–4.33 (1H, m), 4.39–4.48 (1H, m),

5.27 (1H, d, J = 15.3 Hz), 6.92–6.99 (2H, m), 6.99–7.07

(1H, m), 7.17–7.25 (2H, m), 7.54 (2H, s), 7 81 (1H, s).

HRMS (EI) calcd for C₂₅H₁₉ClF₆N₂O₂(M⁺) 528.1039;

found, 528.1013. Anal. Calcd for C₂₅H₁₉ClF₆N₂O₂Æ7-

H₂O: C, 45.84; H, 2.92; N, 4.28. Found: C, 46.17; H,

3.28; N, 4.14.

5.1.46. 5-[3,5-Bis(triﬂuoromethyl)benzyl]-7-(2-methylphe-

nyl)-8-oxo-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]-1,5-oxazo-

cin-6-one (27). To a solution of 25 (360 mg, 0.728 mmol)

in dichloromethane (2 mL) was added mCPBA (251 mg,

1.45 mmol) portion-wise under ice cooling. The mixture

was stirred for 30 min at 0 °C and then for 24 h at room

temperature.

Flash

chromatography

(AcOEt:-

MeOH = 5:1 v/v) of the mixture gave 27 as a colorless

solid (259 g, 70%). mp: 175–177 °C. ¹H NMR

(400 MHz, CDCl₃): d 1.95–2.15 (2H, m), 2.36 (3H, s),

1.31–3.38 (1H, m), 3.77–3.86 (1H, m), 3.94 (1H, d,

J = 14.7 Hz), 4.12–4.20 (1H, m), 4.44–4.51 (1H, m),

5.25 (1H, d, J = 14.7 Hz), 6.79 (1H, d, J = 7.3 Hz),

6.94 (1H, d, J = 7.3 Hz), 7.01–7.07 (1H, m), 7.24–7.37

(3H, m), 7.53 (2H, s), 7.82 (1H, s), 8.24 (1H, d,

J = 7.3 Hz). HRMS (EI) calcd for C₂₅H₂₀F₆N₂O₃(M⁺)

510.1378; found, 510.1413. Anal. Calcd for

C₂₅H₂₀F₆N₂O₃ÆH₂O: C, 56.82; H, 3.81; N, 5.30. Found:

C, 57.00; H, 3.83; N, 5.27.

5.1.50. 5-[3,5-Bis(triﬂuoromethyl)benzyl]-9-chloro-7-(2-

methylphenyl)-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-1,5-

oxazocin-6-one (30a). The compound 30a (1.80 g, 98%)

was prepared from 28a (1.77 g, 3.47 mmol) in a manner

similar to that described for the preparation of 29.

1

Foam. H NMR (400 MHz, CDCl₃): d 1.81–1.94 (1H,

m), 2.14–2.34 (4H, m), 3.20–3.33 (1H, m), 3.40–3.73

(1H, m), 3.98 (1H, d, J = 15.3 Hz), 4.32–4.42 (1H, m),

4.56–4.65 (1H, m), 5.40 (1H, d, J = 15.3 Hz), 6.68–7.38

(5H, m), 7.52 (2H, s), 7.78 (1H, s). HRMS (EI) calcd

for C₂₅H₁₉ClF₆N₂O₂(M⁺) 528.1039; found, 528.1063.

Anal. Calcd for C₂₅H₁₉ClF₆N₂O₂Æ3H₂O: C, 51.51; H,

3.29; N, 4.81. Found: C, 51.38; H, 3.43; N, 4.74.

5.1.47. 5-[3,5-Bis(triﬂuoromethyl)benzyl]-7-(2-methylphe-

nyl)-10-oxo-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-1,5-oxa-

zocin-6-one (28a). The compound 28a (231 mg, 83%)

was prepared from 26a (270 mg, 0.546 mmol) in a man-

ner similar to that described for the preparation of 27.

5.1.51.

5-[3,5-Bis(triﬂuoromethyl)benzyl]-9-chloro-7-

phenyl-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-1,5-oxazocin-

6-one (30b). The compound 30b (440 mg, 99%) was pre-

pared from 28b (400 mg, 0.806 mmol) in a manner sim-

ilar to that described for the preparation of 29. mp: 177–

1

mp: 188–191 °C. H NMR (400 MHz, CDCl₃): d 1.75–

1.84 (1H, m), 1.90–2.44 (4H, m), 3.27–3.38 (1H, m),

1

178 °C. H NMR (400 MHz, CDCl₃): d 1.78–1.88 (1H,

S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

5731

m), 2.23–2.36 (1H, m), 3.33–3.42 (1H, m), 3.69–3.79

(1H, m), 4.12 (1H, d, J = 15.3 Hz), 4.28–4.37 (1H, m),

4.60–4.68 (1H, m), 5.46 (1H, d, J = 15.3 Hz), 7.19 (1H,

s), 7.23–7.47 (5H, m), 7.69 (2H, s), 7.83 (1H, s). HRMS

(EI) calcd for C₂₄H₁₇ClF₆N₂O₂(M⁺) 514.0883; found,

514.0865. Anal. Calcd for C₂₄H₁₇ClF₆N₂O₂: C, 55.99;

H, 3.33; N, 5.44. Found: C, 55.98; H, 3.24; N, 5.25.

from the carotid artery and the ileum was isolated. The

ileum was mounted in an organ bath containing Tyr-

odeꢀs solution, which was maintained at 32 °C and

gased with 95% O₂and 5% CO₂. The ileum was sub-

jected to a resting tension of 1 g and allowed to equil-

ibrate for 20 min before the experiment was started.

As a control, a concentration–response curve for sub-

stance P obtained in the absence of test compounds

was used. The NK₁receptor antagonist activity of

each test compound was determined from a concentra-

tion–response curve obtained by pretreatment with at

least three concentrations of a test compound in

DMSO solution for 10 min and subsequently applying

substance P in a cumulative manner. The activity was

expressed as a K_Bvalue determined by the Schild

method.²⁴

5.1.52. 9-(4-Acetylpiperazinyl)-5-[3,5-bis(triﬂuorometh-

yl)benzyl]-7-(2-methylphenyl)-3,4,5,6-tetrahydro-2H-pyr-

ido[4,3-b]-1,5-oxazocin-6-one (1b). A mixture of 29

(79.4 mg, 0.150 mmol) and 1-acetylpiperazine (38.5 mg,

0.300 mmol) was heated at 150 °C for 5 h. The resulting

mixture was diluted with ethyl acetate, then washed with

water and brine. The organic layer was dried over anhy-

drous Na₂SO₄, ﬁltered, and then concentrated in vacuo.

Flash chromatography (AcOEt:MeOH = 10:1) of the

1

residue gave 1b as a colorless foam (51.4 mg, 55%). H

5.2.2. Water solubility test. A sample solution of test

compound (10 g/mL) was prepared by adding a test

compound (2.0–4.0 mg) in dimethylsulfoxide (0.2–

0.4 mL). The solution was added to aqueous buﬀer solu-

tion, pH 6.8, and the mixture was shaken vigorously for

15 min at room temperature, followed by ﬁltering oﬀ the

precipitate using a 96-well ﬁlterplate. An HPLC

equipped with a photodiode array detector was used

to measure the concentration of the sample solution.

NMR (400 MHz, CDCl₃): d 1.90–2.10 (2H, m), 2.13

(3H, s), 2.23 (3H, s), 3.21–3.29 (1H, m), 3.45–3.62

(4H, m), 3.62–3.78 (4H, m), 3.78–3.89 (1H, m), 3.92

(1H, d, J = 15.3 Hz), 4.10–4.18 (1H, m), 4.36–4.44

(1H, m), 5.34 (1H, d, J = 15.3 Hz), 6.11 (1H, s), 6.92–

7.01 (1H, m), 7.01–7.08 (1H, m), 7.17–7.24 (2H, m),

7.57 (2H, s), 7.79 (1H, s). HRMS (EI) calcd for

C₃₁H₃₀F₆N₄O₃(M⁺) 620.2222; found, 620.2244. Anal.

1

Calcd for C₃₁H₃₀F₆N₄O₃ꢁ H₂O: C, 59.65; H, 4.84; N,

5

8.98. Found: C, 59.27; H, 4.72; N, 8.76.

5.2.3. Cystometry test²⁵. Guinea pigs were anesthetized

with halothane and the spinal cord was cut at the

tenth cervical vertebra level in each animal. After

restriction in a Ballman cage for more than 2 h,

room-temperature saline was injected through a blad-

der catheter into the bladder at a rate of 6 mL/h to

conduct a cystometry test. After the eﬀective bladder

capacity had stabilized, a DMSO solution of a test

compound was administered intravenously from the

jugular vein. The eﬀective bladder capacity was deﬁned

as the volume of saline injected from the time of one

micturition to the next. The eﬀect of each test com-

pound was regarded as the increase in the average

bladder volume, determined by taking the diﬀerence

between the average bladder volume measured 30 min

prior to administration of the test compound and that

measured every 30 min after administration of the test

compound.

5.1.53. 9-(4-Acetylpiperazinyl)-5-[3,5-bis(triﬂuorometh-

yl)benzyl]-7-(2-methylphenyl)-3,4,5,6-tetrahydro-2H-pyr-

ido[2,3-b]-1,5-oxazocin-6-one (2b). The compound 2b

(44.6 mg, 38%) was prepared from 30a (100 mg,

0.189 mmol) in a manner similar to that described for

the preparation of 1b. Foam. ¹H NMR (400 MHz,

CDCl₃): d 1.81–1.95 (2H, m), 2.05–2.20 (4H, m), 2.27–

2.35 (2H, m), 3.15–3.23 (1H, m), 3.52–3.62 (4H, m),

3.62–3.82 (5H, m), 3.93 (1H, d, J = 15.3 Hz), 4.28–4.36

(1H, m), 4.42–4.52 (1H, m), 5.31–5.43 (1H, m), 6.24

(1H, s), 6.75–7.33 (4H, m), 7.52 (2H, s), 7.77 (1H, s).

HRMS (EI) calcd for C₃₁H₃₀F₆N₄O₃(M⁺) 620.2222;

found, 620.2224. Anal. Calcd for C₃₁H₃₀F₆N₄O₃: C,

60.00; H, 4.87; N, 9.03. Found: C, 59.69; H, 4.73; N, 8.90.

5.1.54. 5-[3,5-bis(triﬂuoromethyl)benzyl]-9-morpholino-7-

phenyl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]-1,5-oxazocin-

6-one (2c). The compound 2c (47.3 mg, 57%) was pre-

pared from 30b (75.0 mg, 0.146 mmol) in a manner sim-

ilar to that described for the preparation of 1b. Foam.

¹H NMR (400 MHz, CDCl₃): d 1.84–1.93 (1H, m),

2.07–2.20 (1H, m), 3.35–3.43 (1H, m), 3.50–3.63 (4H,

m), 3.76–3.83 (4H, m), 3.92–4.01 (1H, m), 4.03–4.10

(1H, m), 4.13 (1H, d, J = 15.3 Hz), 4.40–4.52 (1H, m),

5.40 (1H, d, J = 15.3 Hz), 6.14 (1H, s), 7.24–7.37 (3H,

m), 7.41–7.47 (2H, m), 7.78 (2H, s), 7.84 (1H, s). HRMS

(EI) calcd for C₂₈H₂₅F₆N₃O₃(M⁺) 565.1800; found

565.1761. Anal. Calcd for C₂₈H₂₅F₆N₃O₃: C, 59.47; H,

4.46; N, 7.43. Found: C, 59.45; H, 4.50; N, 7.19.

5.2.4. Rhythmic bladder contraction test. Rhythmic blad-

der contraction was observed when saline (1–2 mL) was

injected into a balloon placed in the bladder of ure-

thane-anesthetized guinea pigs. After rhythmic bladder

contraction had stabilized, a DMSO solution of a test

compound was administered by iv injection. The eﬀect

on rhythmic bladder contraction was evaluated in terms

of frequency and amplitude of contraction.

Acknowledgments

The authors thank Dr. H. Miyachi, currently at the Uni-

versity of Tokyo, for many valuable suggestions and

encouragement, and also Dr. T. Ishizaki, Dr. Y. Fuku-

da, and Dr. M. Segawa of Kyorin Pharmaceutical Co.,

Ltd., for helpful discussion.

5.2. Biology

5.2.1. NK₁receptor antagonist test.²³Guinea pigs were

stunned by a blow on the head and then exsanguinated

5732

S. Seto et al. / Bioorg. Med. Chem. 13 (2005) 5717–5732

11. Gao, Z.; Peet, N. P. Curr. Med. Chem. 1999, 6, 375–388.

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Article Doi

Design, synthesis, and evaluation of novel 2-substituted-4-aryl-6,7,8,9- tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-ones as NK1 antagonists

DOI: 10.1016/j.bmc.2005.06.015

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Article abstract of DOI:10.1016/j.bmc.2005.06.015

Full text of DOI:10.1016/j.bmc.2005.06.015

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