Development of orally active oxytocin antagonists: Studies on 1-(1-{4- [1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy].2methoxybenzoyl}- 4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines

2146

J . Med. Chem. 1998, 41, 2146-2163

Develop m en t of Or a lly Active Oxytocin An ta gon ists: Stu d ies on

1-(1-{4-[1-(2-Meth yl-1-oxid op yr id in -3-ylm eth yl)p ip er id in -4-yloxy]-2-

m eth oxyben zoyl}p ip er id in -4-yl)-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e (L-372,662)

a n d Rela ted P yr id in es

Ian M. Bell,*^,†J ill M. Erb,^†Roger M. Freidinger,^†Steven N. Gallicchio,^†J ames P. Guare,^†Maribeth T. Guidotti,^‡

Rita A. Halpin,^∇Doug W. Hobbs,^†Carl F. Homnick,^†Michelle S. Kuo,^†Edward V. Lis,^‡David J . Mathre,^§

Stuart R. Michelson,^†J oseph M. Pawluczyk,^†Douglas J . Pettibone,^‡Duane R. Reiss,^‡Stanley Vickers,^∇

Peter D. Williams,^†and Carla J . Woyden^‡

Departments of Drug Metabolism, Medicinal Chemistry, Pharmacology, and Process Research, Merck Research Laboratories,

West Point, Pennsylvania 19486, and Rahway, New J ersey 07065

Received February 5, 1998

The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpi-

peridine terminus to incorporate various pyridine N-oxide groups. This modification has led

to the identification of compounds with improved pharmacokinetics and excellent oral

bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed

good potency in vitro (K_i) 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous

AD₅₀) 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog),

good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv

administration, and excellent selectivity against the human arginine vasopressin receptors.

Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin

antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic

profiles of these compounds. Although lipophilic substitution around the pyridine ring of

compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and

caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic

constraint and incorporation of trifluoromethyl groups, were examined. The former approach

was ineffective because of metabolic hydroxylation on the constrained ring system, whereas

the latter showed improvement in plasma pharmacokinetics in some cases.

In tr od u ction

Preterm labor continues to be a serious problem in

industrialized nations. Premature birth can have grave

consequences for the newborn, with rates of morbidity

and mortality increasing rapidly as gestational age

decreases.^1-3Furthermore, the perinatal care required

for preterm babies is extremely expensive, and they

often incur additional medical costs resulting from long-

term health complications.^2-4The only approved thera-

peutic treatment for premature labor in the United

States is the â-agonist ritodrine, and it has clear

limitations,⁵in terms of both efficacy and maternal

safety. Thus, it is of considerable interest to investigate

new approaches to tocolytic therapy. One such ap-

proach is the development of selective antagonists for

the oxytocin receptor, following the observation that the

nonapeptide hormone oxytocin (OT; Figure 1) plays a

key role in the initiation and maintenance of labor.^6-9

Recently, the utility of such agents has been demon-

strated clinically by using intravenously administered

atosiban (ORF 22164; Figure 1).¹⁰This peptidyl an-

tagonist was shown to inhibit uterine contractions in

F igu r e 1. Structures of oxytocin, the oxytocin antagonists

atosiban (ORF 22164) and L-368,899, and the arginine V_1a

vasopressin antagonist OPC 21268.

women with threatened and established preterm labor

and displayed an improved safety profile compared with

^∇Department of Drug Metabolism, West Point.

^†Department of Medicinal Chemistry, West Point.

^‡Department of Pharmacology, West Point.

^§Department of Process Research, Rahway.

ritodrine. We have been interested in developing an OT

antagonist which could be administered by either an

intravenous (iv) or an oral route. Such a compound

Published on Web 05/20/1998

Development of Orally Active Oxytocin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2147

were protruding from the receptor into solvent. Simple

removal of the acetyl group led to L-371,209 (1; Figure

2) which possessed improved aqueous solubility but

reduced affinity for the OT receptor. Presumably the

charged nature of the piperidine nitrogen is not toler-

ated at this relatively short distance from the benzoyl

group. Thus, a pyridylmethyl substituent was employed

to simultaneously place a polar heterocycle at a suitable

distance from the benzoyl ring and attenuate the pK_a

of the terminal piperidine nitrogen. These consider-

ations led to L-371,377 (3; Figure 2), which possessed

excellent aqueous solubility and even greater oral

plasma levels than its progenitor compound, 2. We now

report the further development of such compounds to

give highly potent OT antagonists with improved phar-

macokinetic properties.

F igu r e 2. Structures of the oxytocin antagonists L-371,209,

L-371,257, and L-371,377 with K_ivalues shown for the cloned

human oxytocin receptor.

Ch em ica l Meth od s

The pyridine derivatives described herein were gener-

ally synthesized via the piperidinyl ether 1 (Figure 2)

or its fluorinated analogue 12 (Scheme 2). Scheme 1

details the synthesis of 1, starting from commercially

available N-(tert-butyloxycarbonyl)-4-piperidinone (4),

which was used to reductively alkylate 2-aminobenzyl

alcohol. Ring closure with triphosgene gave the ben-

zoxazinone derivative, and deprotection afforded com-

pound 6. Methyl 2,4-dihydroxybenzoate (7) was selec-

tively alkylated at the 4-hydroxy group to give its

N-(tert-butyloxycarbonyl)-4-piperidinyl ether under Mit-

sunobu conditions.¹⁵Alkylation of the 2-hydroxyl moi-

ety with iodomethane followed by saponification gave

the carboxylic acid 8, which was coupled with 6 to give,

after removal of the Boc group, the desired intermediate.

Upon discovery that a 5-fluoro substituent on the

benzoyl ring of 1 was desirable for OT receptor affinity,

a route to this alternative key intermediate was devel-

oped (see Scheme 2). This started from 2,4,5-trifluo-

robenzonitrile, which was reacted at low temperature

with the anion of N-(tert-butyloxycarbonyl)-4-piperidinol

in THF to give 10 using methods described by Wells et

al.¹⁶A similar fluoride displacement at the 2-position

of the benzonitrile by potassium methoxide, followed by

saponification, gave acid 11. Activation of 11 with EDC

and 1-hydroxybenzotriazole (HOBT) allowed acylation

of the piperidinylbenzoxazinone 6, and deprotection of

would allow iv use for acute management of uterine

contractions in a clinical setting, coupled with the

potential for oral dosing on an outpatient basis.

A

number of structurally distinct classes of peptidyl OT

antagonists have been identified,¹¹but as a group, they

have been hampered by poor oral bioavailability. Our

laboratory has therefore focused on the design of non-

peptide antagonists of OT.

We have previously described the identification of a

potent, orally bioavailable non-peptide OT antagonist

(L-371,257; Figure 2),¹²which was developed from the

Otsuka arginine vasopressin (AVP) antagonist OPC

21268 (Figure 1).¹³While the overall properties of

L-371,257 (2) were encouraging, modifications that

would enhance its pharmacokinetic half-life, bioavail-

ability, potency, and aqueous solubility were sought.

Improved solubility was required to allow formulation

for intravenous administration. It had been observed

in systematic structure-activity studies that alteration

of the piperidinylbenzoxazinone or benzoyl moieties

usually caused decreases in OT receptor affinity. The

piperidinyl ether terminus, on the other hand, was

relatively tolerant to change and was therefore chosen

as the focus for efforts to introduce solubilizing groups.

It was discovered that a variety of acidic or basic groups

could be appended to the acetyl group with little effect

on OT receptor affinity,¹⁴suggesting that these groups

Sch em e 1^a

a

Reagents: (a) 2-aminobenzyl alcohol, AcOH, toluene, reflux; (b) NaCNBH₃, AcOH, toluene, THF; (c) triphosgene, DIEA, THF; (d)

HCl, EtOAc; (e) N-(tert-butyloxycarbonyl)piperidin-4-ol, Ph₃P, DEAD, THF; (f) NaH, MeI, DMF; (g) NaOH, MeOH, H₂O; (h) EDC, HOBT,

DIEA, DMF.

2148 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12

Bell et al.

Sch em e 2^a

roperoxybenzoic acid (mCPBA), and the resulting N-

oxides were found to be relatively stable: most could

be stored for several months under anhydrous condi-

tions without significant decomposition. The final alky-

lation step of the piperidine with the chloride 15 in DMF

at 50 °C usually proceeded smoothly and in good yield.

It was found that degassing of the DMF reduced the

incidence of side products and improved yields. For

more sterically hindered chlorides, such as those used

to provide the trialkylated pyridines in Table 2 and the

tetrahydroquinolines in Table 3, addition of sodium

iodide to the alkylation mixture improved reaction rates

and yields.

Some of the pyridines were obtained directly as the

alcohol or chloride intermediate for use in the above

route, as described in the Experimental Section. The

2-(trifluoromethyl)pyridine derivatives 44 and 45 (Table

2) were synthesized via 3-(trifluoroacetyl)-2-(trifluoro-

methyl)pyridine, which has been described by Hojo and

co-workers.^17-19This trifluoromethyl ketone was con-

verted to the corresponding ethyl ester by the method

of Delgado and Clardy,²⁰and the ester was carried

forward in the standard route. The ethylpyridine

derivative 48 (Table 3) was provided by reductive

alkylation of piperidine 1 with 3-acetylpyridine. Stan-

dard EDC-mediated coupling of 1 with 2-methylnicotinic

acid followed by oxidation with mCPBA gave the pyri-

dine N-oxide 49 (Table 3).

a

Reagents: (a) N-(tert-butyloxycarbonyl)piperidin-4-ol, t-BuOK,

THF; (b) MeOH, t-BuOK, THF; (c) NaOH, EtOH, H₂O; (d) EDC,

HOBT, DIEA, DMF; (e) HCl, EtOAc.

The quinoline compound 55 (Table 3) was derived

from alkylation of 5-aminoquinoline with 1,5-dichloro-

pentan-3-ol in analogy with work by Reese and Thomp-

son.^21,22The resulting 5-(4-hydroxypiperidin-1-yl)-

quinoline was coupled to the requisite phenol under

Mitsunobu conditions¹⁵to give the desired product. The

other bicyclic systems in Table 3 were realized via

condensation of propynal²³with the appropriate â-amino

enone system. For example, 3-amino-2-cyclohexen-1-

one (20) was reacted with propynal to give 7,8-dihydro-

6H-quinolin-5-one²⁴(21) (see Scheme 4). Reduction of

this ketone with NaBH₄gave the corresponding racemic

alcohol, which was converted to the corresponding

chloride and thence to the desired compounds 50 and

51 via the standard route described above. Alkylation

of the piperidine 1 with this chloride gave the tetrahy-

droquinoline 54. In analogy with the syntheses of these

tetrahydroquinolines, condensation of propynal with

3-amino-2-cyclopenten-1-one²⁵ultimately afforded the

ring-contracted analogues 52 and 53.

Sch em e 3^a

a

Reagents: (a) DIBAL, THF; (b) SOCl₂, CH₂Cl₂; (c) mCPBA,

CHCl₃; (d) 1 (X ) H) or 12 (X ) F), DIEA, DMF.

the resulting amide afforded the desired piperidine

intermediate 12.

Because of the interesting activities of the racemic

tetrahydroquinoline derivative 51, it was necessary to

have an asymmetric synthesis which could provide

multigram quantities of its individual enantiomers for

future study. The synthetic route is outlined in Scheme

4. Methyl dihydroxybenzoate (7) was converted to

methyl 4-hydroxy-2-methoxybenzoate (17) using a ben-

zyl protecting group for the 4-hydroxy group. Fluorina-

tion of phenol 17 with 3,5-dichloro-1-fluoropyridinium

triflate²⁶followed by saponification gave the carboxylic

acid 18, which was coupled with the piperidinyl ben-

zoxazinone 6 to give the key phenolic intermediate 19.

The other key fragment was synthesized from the same

ketone 21 that was used to make the racemic com-

pounds. In this case, however, the oxazaborolidine

(OAB) catalyst derived from R,R-diphenyl-2-pyrroli-

The general route to the pyridine N-oxide OT antago-

nists, utilizing either piperidine 1 or 12, is shown in

Scheme 3. Most of the pyridines were obtained from a

nicotinate ester derivative 13 which was either com-

mercially available or described in the literature. The

nicotinate was subjected to reduction with diisobutyl-

aluminum hydride (DIBAL) at 0 °C to give the corre-

sponding carbinol, which was chlorinated with thionyl

chloride to yield 14 as its hydrochloride salt. These salts

were quite stable, but the corresponding free bases were

prone to self-alkylation. Those containing multiple

alkyl substituents were found to decompose more slowly,

presumably due to steric hindrance of the chloride and

pyridine functionalities. As a consequence of the in-

stability of their free bases, the pyridine salts were

deprotonated immediately before reaction with 3-chlo-

Development of Orally Active Oxytocin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2149

Sch em e 4^a

confirmed by comparison of its optical rotation with the

reported value of (S)-22.²⁸Treatment of (R)-22 with

diphenyl phosphorazidate (DPPA) and 1,8-diazabicyclo-

[5.4.0]undec-7-ene (DBU) in toluene, with THF added

to aid solubility, provided the corresponding azide with

clean stereochemical inversion, in analogy with work

by Thompson et al.²⁹The pyridine was converted to its

N-oxide with mCPBA, and catalytic hydrogenation of

the 5-azidotetrahydroquinoline N-oxide over Pd-C

yielded the desired amine (S)-23 but caused a slight loss

in stereochemical integrity, giving (S)-23 in 97% ee.

Alkylation of the amine with 1,5-dichloropentan-3-ol²²

in butanol with catalytic NaI provided piperidinol (S)-

24 in 41% yield which, while disappointing compared

with the near-quantitative yields of the preceding steps,

allowed access to the necessary intermediate in one

transformation from amine (S)-23. The final Mitsunobu

coupling proceeded smoothly, giving the desired (S)-51

in good overall yield and 97% ee.

Biologica l Meth od s

The radioligand binding assays and the in vivo

functional assay measuring blockade of OT-induced

uterine contractions have been described in detail

previously.^30,31

Radioligand competition experiments with the test

compounds of interest were used to determine their

receptor affinities. The high-affinity binding of [³H]OT

to uterine tissue (OT site) taken from DES-treated rats

or pregnant rats (days 22-23 of gestation) and that of

[³H]AVP to rat liver (V_1asite) and rat kidney medulla

(V₂site) taken from male rats were used to determine

affinities for these rat receptors.³⁰Similar competition

experiments were also performed using uterine, liver,

or kidney tissue taken from human surgical or early

postmortem donors.³¹The human OT receptor was

stably expressed in 293 embryonic kidney cells (293/

OTR),³²and plasma membrane fractions prepared from

these cells were used for competition experiments with

[³H]OT to determine affinities for the cloned human OT

receptor. Results are reported as K_ivalues for the test

compounds to inhibit binding of the radioligand. Most

of the K_ivalues are reported as the mean of several

independent experiments with the standard error from

the mean (SEM) being reported for at least three

determinations; typical variation was less than 50%

between experiments.

The in vivo functional assay measured the ability of

test compounds to antagonize OT-stimulated contrac-

tions of the in situ rat uterus³¹and was performed on

anesthetized, DES-pretreated rats prepared for record-

ing of isometric uterine contractions. An approximate

ED₅₀dose of OT (1 µg/kg) was administered intrave-

nously at 35-min intervals. The uterine contraction in

response to the third injection of OT was set at 100%,

and a solution of the test compound (in saline, saline-

2% DMSO, or saline-15% DMSO-15% emulphor) was

infused intravenously over 10 min or a suspension (in

saline-1% methocel) was injected intraduodenally (id).

A fourth injection of OT was then administered, and the

dose of compound which reduced the contractile re-

sponse of the uterus to OT by 50%, compared to the

vehicle-treated group, was determined to be the AD₅₀

value. The reported numbers are the mean values for

a

Reagents: (a) PhCH₂Br, K₂CO₃, acetone; (b) NaH, MeI, DMF;

(c) H₂, Pd-C, MeOH, AcOH; (d) 3,5-dichloro-1-fluoropyridinium

triflate, CH₂Cl₂; (e) NaOH, MeOH, H₂O; (f) 6, EDC, HOBT, DIEA,

DMF; (g) propynal, DMF; (h) (S)-OAB-BH₃, CH₂Cl₂; (i) DPPA,

DBU, toluene, THF; (j) mCPBA, CHCl₃; (k) H₂, Pd-C, EtOH; (l)

1,5-dichloropentan-3-ol, K₂CO₃, NaI, 1-BuOH; (m) Ph₃P, DEAD,

THF.

dinemethanol was used to effect the asymmetric reduc-

tion of the ketone.²⁷In Scheme 4, the (S)-OAB catalyst

was used stoichiometrically to yield the tetrahydro-

quinolinol (R)-22. In this procedure, an extra equiva-

lent of borane was used to complex with the pyridine

nitrogen, and (R)-22 was obtained in excellent yield and

>99% ee. The absolute stereochemistry of this alcohol

was predicted based upon chemical precedent and

2150 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12

Bell et al.

4-6 animals per dose group; typical SEM was less than

20% of the mean for individual dose-response data

points.

the attractive features of L-371,377 (3), we decided to

focus on such 3-picolyl-containing structures and specif-

ically sought to address the latter two issues.

Pharmacokinetic studies in rats and dogs were per-

formed as previously described.³¹Compounds were

dosed at 3 mg/kg intravenously and 10 mg/kg per os (po),

except as noted. For rats, a solution of the test

compound (in saline, saline-2% DMSO, or saline-15%

DMSO-15% emulphor) was administered to conscious

adult female rats intravenously via the tail vein, or a

suspension (in saline-1% methocel) was given orally.

Blood samples were collected (n ) 3 rats/time point) and

analyzed by either radioreceptor assay or HPLC with

UV or MS detection. For the radioreceptor assay,

plasma samples were subjected to methanol extraction

and dilution prior to assaying for ability to inhibit [³H]-

OT binding to the OT receptor. A standard curve was

generated by spiking untreated plasma with known

concentrations of the test compound and working these

samples up identically to the experimental plasma

isolates. HPLC analysis of plasma samples was per-

formed analogously. To correlate bioactivity with par-

ent compound, plasma samples were pooled across the

sampling time course, extracted, and subjected to

reversed-phase HPLC fractionation. Collected fractions

were analyzed by radioreceptor assay for bioactivity,

and the bioactivity profile was compared with the HPLC

(UV detection) profile. For dog studies, adult female

dogs with implanted arterial catheters were adminis-

tered a solution of the test compound (in saline) intra-

venously or a suspension of the test compound (in

saline-0.5% methocel) orally. Blood samples were

collected from the arterial catheter and analyzed as

described above. Pharmacokinetic data was analyzed

by using the noncompartmental analysis program

NCOMP.³³

As part of a structure-activity exploration of com-

pound 3, the 2-methyl analogue (29) was synthesized

and plasma bioactivity was examined following oral

administration to rats. This indicated a superior plasma

half-life for analogue 29, and it was also found to have

improved duration of action and a 2-fold improvement

in potency for inhibiting OT-induced uterine contrac-

tions in the rat, compared with compound 3. Interest-

ingly, in vitro binding assays did not reproduce this

increased in vivo potency but showed 29 to be es-

sentially equipotent with pyridine 3 (see Table 1).

Examination of the pharmacokinetics of compound 29

in rats using HPLC analysis revealed it to have a

shorter half-life and lower plasma levels than the

bioassay experiments had indicated and thus implied

the presence of one or more active metabolites. Pooled

rat plasma samples were fractionated by HPLC, and the

bioactivity in the fractions was assayed to reveal two

major metabolites, the less active piperidine 1 (K_i) 82

nM at the chOTr), resulting from loss of the terminal

2-methylpyridin-3-ylmethyl group, and the more active

pyridine N-oxide of 29, the metabolite responsible for

the pharmacodynamic disparity, L-372,662 (30, chOTr

K_i) 4.1 nM; see Table 1).

The identity of L-372,662 (30) was independently

verified by resynthesis, and more detailed examination

of this N-oxide showed it to have an interesting overall

profile. Although its affinity for the rat OT receptor (K_i

) 15 nM) was only twice that of pyridine 3 (K_i) 28

nM), it was 8 times more potent at blocking OT-induced

uterine contractions in the rat (iv AD₅₀) 0.71 mg/kg

compared with 5.7 mg/kg for 3). This disparity between

intrinsic receptor affinity and efficacy in the rat for these

two compounds may be due to differences in clearance

(CL) or volume of distribution (V_d), or perhaps avail-

Resu lts a n d Discu ssion

ability of the antagonist at the site of action.

A

L-371,377 (3; see Table 1) was targeted as an attrac-

tive structure for further study because of its good

aqueous solubility (11.5 mg/mL at pH 5.2) and promis-

ing absorption profile. The related pyridyl isomers 26

and 27 were synthesized, in addition to the phenyl

analogue 25 (see Table 1). The 3- and 4-pyridyl deriva-

tives (3 and 27, respectively) had some advantage in

terms of receptor affinity and had similar absorption

properties in the rat. A number of analogues of each

were investigated, and these preliminary studies indi-

cated that the 3-pyridyl analogues were more promising

with respect to OTr affinity.¹⁴Moreover, following

intraduodenal (id) administration in the rat, 3 blocked

OT-induced uterine contractions with an AD₅₀) 13 mg/

kg, compared with an intravenous (iv) AD₅₀) 5.7 mg/

kg. This id/iv ratio of 2.3 for the AD₅₀values suggested

that the compound was well-absorbed from the gut and

compared very favorably with previous lead compounds

such as the camphorsulfonamide L-368,899 (see Figure

1). This sulfonamide, which had entered phase I clinical

studies, had an id/iv ratio of 20.³⁴However, compound

3 had two major liabilities: first its receptor affinity was

suboptimal (K_i) 10 nM at the cloned human OT

receptor (chOTr)); second it had a short half-life in rats

as judged by the rapid decrease in plasma bioactivity

following po administration. Nonetheless, because of

difference in clearance could be explained by differential

rates of metabolism for the compounds, and the N-oxide

30 did indeed exhibit greater resistance to metabolism

than free pyridines such as 29 as judged by in vitro

microsome studies. Following a 60-min incubation with

rat liver microsomes, only 2% of compound 30 was

metabolized compared with 24% of 29. Both incubations

produced piperidine 1 as the major metabolite, but the

pyridine 29 also gave a significant amount of N-oxide

30. Moreover, HPLC fractionation of plasma samples

after administration of 30 to rats showed that almost

all the bioactivity was associated with the parent

compound, in contrast to analogue 29 (vide supra).

Therefore, the N-oxide 30 has increased metabolic

stability in rats compared with compound 29, and based

on the close structural similarity between pyridines 29

and 3, this may partially explain the disparity between

the in vitro and in vivo data above. L-372,662 (30) had

good pharmacokinetic properties in rats (C_max) 8 µg/

mL following a 10 mpk po dose, iv t_1/2) 112 min, F )

90%) and dogs (C_max) 11 µg/mL following a 10 mpk po

dose, iv t_1/2) 107 min, F ) 96%). The high oral

bioavailabilities are notable for OT antagonists: L-368,-

899, for example, had oral bioavailabilities of 35% in

the rat and 25% in the dog. Compound 30 also

Development of Orally Active Oxytocin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2151

Ta ble 1

maintained a favorable id/iv ratio of 7 for its AD₅₀values

in the rat, as may be expected for a highly bioavailable

compound, and had good solubility in water at pH 5.2

(>8.5 mg/mL). Selectivity against the related AVP

2152 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12

Bell et al.

receptors (V_1aand V₂) has often been an issue for OT

antagonists, but N-oxide 30 represented a significant

improvement over L-368,899 in this regard. For com-

pound 30 at the human V_1areceptor, K_i) 2 500 ( 620

nM (selectivity vs the chOTr ) 600-fold), while at the

human V₂receptor, K_i) 28 000 ( 9 100 nM (selectivity

vs the chOTr ) 6800-fold). For L-368,899 the corre-

sponding selectivities vs the chOTr were 20-fold (V_1a

receptor) and 70-fold (V₂receptor). Moreover, all the

compounds in this N-oxide class of OT antagonists

exhibited excellent (>100-fold) selectivity for the human

OT receptor vs the human V_1aand V₂receptors. A more

complete description of the pharmacology of L-372,662

(30) will be presented in a separate publication.

at the rat uterus in vivo (iv AD₅₀) 0.31 mg/kg compared

with 0.71 mg/kg for 30), and this somewhat disappoint-

ing performance led to speculation that the additional

methyl group may have introduced a metabolic liability.

As noted above, alkyl substitution at the 6-position

of the pyridine ring led to small losses in intrinsic

potency. Such 6-substituted derivatives, however, ex-

hibited an improved duration of action for in vivo

blockade of OT-induced contractions in the rat uterus.

This could be rationalized in terms of the increased

steric hindrance around the pyridine N-oxide moiety

which may help block metabolic conjugation reactions

with this potentially labile group. The 2,4,6-trisubsti-

tuted analogues (entries 40-43 in Table 2) were made

in an effort to combine this enhanced duration with the

improved OT receptor affinity of the 2,4-disubstituted

pyridines.

Overall, compound 30 had an impressive profile,

maintaining the attractive features of L-371,377 (3)

while demonstrating excellent oral bioavailability with

significantly improved plasma half-life and having

increased potency in vitro and in vivo. It became the

focus of continued structure-activity exploration with

the aim of further enhancing potency. One of the first

areas of study was simple alkyl substitution on the

pyridine ring. The various monomethyl isomers were

prepared (see Table 1), and examination of the binding

data at the chOTr revealed a preference for 2- and

4-substitution (compare compounds 30 and 31 with 32

and 33 in Table 1). Elongation of the 2-methyl group

to ethyl (compound 34; Table 1) or propyl (compound

35; Table 1) gave little improvement in chOTr affinity.

Table 2 details analogues in which the pyridine ring was

substituted with two or three alkyl groups. Based on

the observations with monomethyl compounds, effort

was concentrated on 2- and 4-substitution, and gratify-

ingly, it was found that the enhancements seen in

receptor affinity with these individual modifications

were additive. Thus, the 2,4-dimethyl analogue (37;

Table 2) had a K_i) 1.0 nM at the chOTr, an improve-

ment of 4-fold compared with compound 30. Other

dimethylated pyridines offered no advantage over 30

(see analogues 38 and 39; Table 2), and in general, alkyl

substitution at the 6-position of the pyridine ring caused

some reduction in affinity for the OT receptor. Con-

comitant with these studies on alkylated pyridines, a

systematic exploration of substitution of the central

benzoyl moiety was undertaken. This aromatic ring

was found to be quite intolerant of modification in terms

of OT receptor affinity, and the only advantageous

change discovered was the addition of a 5-fluoro sub-

stituent, which usually provided a 3-5-fold improve-

ment in K_i. Substitution at the benzoyl 5-position with

other halogens, such as chloro or bromo, caused a

marked decrease in affinity for the OT receptor.¹⁴

Tables 2 and 3 detail a number of compounds which

illustrate the advantage of this fluorine atom in terms

of intrinsic potency.

An example of such a structure is analogue 43 (Table

2), in which a 2-ethyl substituent on the pyridine ring

appears to give some advantage over methyl in terms

of receptor affinity (compare with compound 41; Table

2). Examination of bioactivity in plasma following

administration of this compound to rats revealed a good

iv half-life (142 min) and reasonable plasma levels (C_max

) 2.6 µg equiv/mL following a 10 mpk dose po).

However, the in vivo AD₅₀values were again disap-

pointing: while compound 43 was more than 4 times

as potent as L-372,662 (30) at the rat OT receptor in

vitro, the iv AD₅₀in the rat only improved fractionally,

from 0.71 to 0.50 mg/kg. It seemed possible that either

high plasma protein binding or more rapid clearance of

these trisubstituted pyridine compounds might account

for their relatively poor performance in vivo. To address

the latter possibility, 43 was administered to rats, and

HPLC-fractionated plasma samples were examined for

binding to the OT receptor. The bioactivity was clearly

distributed through several fractions which did not

correspond to the parent antagonist, demonstrating the

formation of active metabolites. Indeed, examination

of the rat plasma pharmacokinetics by HPLC revealed

that N-oxide 43 had only a 43-min iv half-life (see Table

2), and therefore the 142-min half-life seen by radiore-

ceptor assay reflects the presence of such active me-

tabolites. This difference between compound 43 and its

monosubstituted analogue 36 (Table 2) is illustrated in

Figure 3 which compares their plasma profiles in terms

of bioactivity and actual concentration of the parent

compound. It was concluded, therefore, that although

additional alkyl groups on the pyridine moiety had

effected an improvement in intrinsic receptor affinity

with respect to compound 30, they had introduced a

serious metabolic liability, presumably involving oxida-

tive metabolism of the substituted pyridine ring.

This realization led to a reexamination of a more

simple alkylpyridine, the 4-methyl derivative 31 (Table

1). While this compound had similar in vitro binding

affinities to its regioisomer 30, it had a much poorer in

vivo profile. The two analogues differed only in the

position of a methyl group on the terminal pyridine ring

and had similar physical properties: their log P coef-

ficients, for example, were 1.95 (30) and 1.85 (31).

Despite being so closely related, they exhibited very

different pharmacokinetic profiles in the rat (see Table

1) with analogue 31 having less than a 20-min plasma

Thus, addition of simple alkyl groups and incorpora-

tion of a fluoro substituent on the benzoyl ring demon-

strated improvements in intrinsic potency at the OT

receptor, and the effects of such modifications on in vivo

properties were investigated. The dimethyl analogue

37, for example, exhibited a 4-fold improvement in K_i

at the chOTr compared with N-oxide 30 and had a

similarly enhanced affinity for the rat OT receptor.

However, it showed an improvement of only about 2-fold

Development of Orally Active Oxytocin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2153

Ta ble 2

2154 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12

Bell et al.

nation of their pharmacokinetic properties in rats.

Gratifyingly, the first analogue tested, 46, exhibited a

much improved profile over its nonfluorinated counter-

part, 31, as analyzed by bioassay. The plasma levels

following oral dosing of these two compounds in rats are

shown in Figure 4 (C and F) which clearly illustrates a

significantly higher C_max(9.6 µg equiv/mL) and longer

half-life (113 min) for analogue 46. These data suggest

that oxidative metabolism of the 4-methyl group on the

terminal pyridine ring of compound 31 is responsible

for its poor pharmacokinetic profile and that perfluori-

nation of this methyl group alleviates this problem. It

is not possible to be certain, however, since the conver-

sion of methyl to trifluoromethyl alters the electronic

properties of the pyridine ring. It is possible that this

would perturb metabolic conjugation reactions involving

the pyridine N-oxide and hence offer protection from

such metabolism. The electronic change in the pyridine

ring also causes the fluoroalkyl compounds to become

more lipophilic than their alkyl analogues: compare, for

example, compound 44 (log P ) 2.75) with compound

30 (log P ) 1.95). Such a change in physical properties

could account for changes in clearance or absorption of

the compounds which might affect their pharmacoki-

netic properties.

An argument against a role for physical properties,

or a change in pyridine electronics reducing metabolism

of the N-oxide, is that the trifluoromethyl analogues 44

and 45 exhibit similar pharmacokinetic profiles to their

methylated counterparts 30 and 36, respectively (com-

pare A with D and B with E in Figure 4). If protection

of the N-oxide or increased lipophilicity were responsible

for the enhanced profile of compound 46, it would be

expected that these 2-(trifluoromethyl)pyridyl analogues

would have a similar advantage over the 2-methylpyr-

idyl compounds, since they would presumably also

benefit from such an effect. In conclusion, then, it ap-

pears that the 2-methyl group is not a primary site for

oxidative metabolism in such molecules and hence that

perfluorination of this substituent has little effect on

the plasma profiles of such compounds. A 4-methyl

substituent, on the other hand, seems to be a serious

liability, and conversion of such a group to trifluoro-

methyl apparently offers substantial protection from

such metabolism.

F igu r e 3. Comparison of plasma levels of (A) 36 and (B) 43

following po administration (10 mpk) in rats, as determined

by bioassay (0) and HPLC (O).

half-life by bioassay. Since t_1/2) (0.693V_d)/CL and it is

improbable that there is a significant difference in V_d

between the two compounds, this observation seemed

most likely due to a high rate of clearance for compound

31, and a metabolic explanation for this was sought.

Two possibilities in which the position of the methyl

group may play a role are either a conjugation reaction

involving the N-oxide or direct oxidation of the methyl

substituent. In the former example, it is conceivable

that a 2-methyl substituent affords the N-oxide better

protection than a 4-methyl group and hence shields

compound 30 from such metabolism. In the latter case,

it is possible that a methyl group at the 4-position of

such a pyridine ring is a preferential site for oxidative

attack by cytochrome P-450 enzymes and that a methyl

substituent at the 2-position is relatively inert to such

a process. To examine these possibilities, trifluorometh-

yl-containing analogues of 30 and 31 were synthesized

(see Table 2, structures 44 and 46). Presumably, such

compounds would be protected from P-450-mediated

hydroxylation of the alkyl substituents on the pyridine

ring and would therefore allow the importance of such

processes for these analogues to be examined.

Addition of a fluorine atom to the central benzoyl ring

of such trifluoromethylated antagonists affords some

improvement in affinity for the OT receptor, as seen in

the change from analogue 46 (chOTr K_i) 6.6 nM) to

47 (chOTr K_i) 1.1 nM). Unfortunately, this improve-

ment in intrinsic potency seems to be accompanied by

some losses in the pharmacokinetic profiles of these

structures. The 5-fluorobenzoyl compound 45, for in-

stance, appears to have an inferior profile (iv t_1/2) 66

min, F ) 66%) when compared to the corresponding

analogue 44 (iv t_1/2) 86 min, F ) 82%), and this is

illustrated in Figure 4 (D and E). A similar trend is

seen in the comparison of compounds 30 and 36 (see

Table 2 and Figure 4A,B), and this, to some extent,

undermines the advantages of the substituent in terms

of affinity. It is possible that the 5-fluoro substituent

leads to more rapid elimination of the molecules, either

due to slightly increasing their overall lipophilicity and

hence propensity to be good substrates for metabolizing

enzymes (for reference, log P (30) ) 1.95, log P (36) )

The trifluoromethyl-containing analogues detailed in

Table 2 (entries 44-47) exhibit in vitro binding affinities

that are broadly similar to their methyl-containing

counterparts. The more important issue was an exami-

Development of Orally Active Oxytocin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2155

F igu r e 4. Plasma profiles following po dosing in rats, as analyzed by HPLC or radioreceptor assay for (A) 30 (10 mpk, HPLC),

(B) 36 (10 mpk, HPLC), (C) 31 (10 mpk, bioassay), (D) 44 (3 mpk, HPLC), (E) 45 (10 mpk, HPLC), (F) 46 (10 mpk, bioassay).

Plasma concentration axis for 44 is normalized to compensate for lower dose (3 mpk vs 10 mpk).

2.16) or by specifically enhancing some metabolic pro-

cess such as demethylation of the aryl methyl ether.

As described above, it was discovered that addition

of a pyridine N-oxide end group to the piperidinylben-

zoxazinone class of oxytocin antagonists led to potent,

orally bioavailable compounds. The OT receptor affinity

could be modulated by substitution around the pyridine

ring, although some of the structures with the highest

in vitro affinity did not manifest this in vivo due to

metabolic liabilities. In the case of analogue 31, re-

placement of the pyridine methyl substituent with a

trifluoromethyl group offered a solution to its apparent

metabolic problems. In addition to oxidation of alkyl

substituents on the pyridine ring, a major metabolic

pathway for this class of OT antagonists was N-

dealkylation at the (pyridylmethyl)piperidine, as ob-

served in the in vitro metabolism studies on compounds

29 and 30 (vide supra). To address this mode of

metabolism, modification of the linker between the

piperidinyl ether and the terminal pyridine moiety and

incorporation of cyclic constraints into this region of the

molecule were explored.

The first linker modification investigated was simple

conversion of the pyridylmethyl group to a nicotinamide,

to give structure 49 (Table 3). While receptor binding

affinity is almost unaffected by this substitution, the

duration of action in rats following iv administration of

a 3 mpk dose was much shorter (falling to 50% of the

initial response after 0.5 h) than that observed with

compound 30 (50% at 2 h), suggesting that the amide

linker gave rise to higher rates of clearance in vivo. This

observation was not surprising since a number of

similar amides, such as L-371,257 (1; Figure 2), had

been investigated previously and found to have short

duration in the rat. Therefore, the effects of blocking

the pseudobenzylic position with a methyl group were

investigated with compound 48 (Table 3), the methy-

lated analogue of pyridine 3. The modification caused

a modest loss of receptor binding affinity and offered

no advantage in terms of plasma half-life. Nonetheless,

this result demonstrated that branching at this linker

carbon was not very deleterious for potency at the OT

receptor, and it encouraged the study of molecules in

which the 2-methyl substituent on the pyridine ring of

L-372,662 (30) was attached to this linker via a 1- or

2-atom tether.

The racemic tetrahydroquinolines 50 and 51 (see

Table 3) were initially investigated, to determine whether

such a cyclic constraint might imbue these molecules

with a pharmacokinetic advantage by hindering me-

tabolism at the pseudobenzylic position. The addition

of the ethylene linker to compound 36 (Table 3) to give

51 caused a slight reduction in receptor affinity (from

K_i) 1.1 nM to K_i) 2.0 nM at the chOTr) and also a

reduction in potency in the rat (from iv AD₅₀) 0.32 mg/

kg to iv AD₅₀) 0.91 mg/kg). A similar trend can be

seen in the comparison of analogues 30 and 50. Ex-

amination of the metabolic stability of such compounds

in vitro by incubation of compound 30 or 51 with rat

liver microsomes revealed essentially no metabolism

(<5%) after 60 min in both cases. The initial pharma-

cokinetic results on 51 were also encouraging, revealing

a po C_max) 8.1 µg equiv/mL (10 mpk) and iv t_1/2) 158

min, as analyzed by plasma bioactivity in rats (for

comparison, the analogous data for compound 36 are

po C_max) 4.2 µg equiv/mL and iv t_1/2) 66 min), and it

was decided to investigate the individual enantiomers

in more detail.

2156 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12

Bell et al.

Ta ble 3

The enantiomers, (R)-51 and (S)-51 (Table 3), were

found to be quite similar in terms of intrinsic potency:

at the chOTr, for example, K_i) 2.3 and 1.7 nM,

respectively. Other related analogues were also very

similar in affinity at the cloned human receptor (see

Table 3). Reduction of the N-oxide in analogue 51 gave

Development of Orally Active Oxytocin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2157

the racemic tetrahydroquinoline 54, K_i) 2.5 nM, while

aromatization of this ring system provided the quinoline

55, K_i) 2.3 nM. Contraction of the cyclohexenyl ring

in compound 51 to give analogue 52, K_i) 3.3 nM,

caused less than a 2-fold drop in receptor affinity. The

lack of variation in intrinsic potency for the enantiomers

of 51 as well as for these other analogues was in

agreement with the hypothesis that this pyridine ring

system is close to the mouth of the receptor in the bound

state, rather than being buried deep in the binding site

where such changes would be expected to have a more

pronounced effect on affinity.

ability, superior aqueous solubility, and very high

selectivity for the human OT receptor vs human AVP

receptors. Incorporation of a 5-fluoro substituent on the

central benzoyl ring routinely offered an enhancement

in terms of in vitro and in vivo potency, but it appeared

to be somewhat detrimental to the pharmacokinetic

profiles of these compounds. While increased lipophilic

substitution around the pyridine ring gave higher

affinity compounds in vitro, such substituents were a

metabolic liability and caused shortfalls in vivo. Two

approaches to prevent this metabolism, addition of a

cyclic constraint and incorporation of trifluoromethyl

groups, were examined. The former approach was

ineffective due to metabolic hydroxylation on the con-

strained ring system, in a manner similar to that

observed with other substituted pyridines. The latter

showed improvement in plasma pharmacokinetics for

a 4-substituted pyridyl group, apparently by blocking

oxidative metabolism.

Examination of (R)-51 and (S)-51 in the rat revealed

the latter compound was slightly more potent (iv AD₅₀

) 1.1 and 0.41 mg/kg, respectively), and monitoring of

plasma bioactivity following administration of the iso-

mers to rats suggested that (S)-51 had a small advan-

tage in terms of half-life (iv t_1/2) 114 min vs 103 min

for (R)-51) and plasma levels (po C_max) 8.3 µg equiv/

mL vs 6.6 µg equiv/mL for (R)-51). Further studies on

(S)-51 examined its pharmacokinetic profile in rats (see

Table 3) and dogs (iv t_1/2) 246 min, po C_max) 2.2 µg/

mL) by HPLC. Unfortunately, although previous in

vitro metabolism studies on compound 51 had indicated

no significant metabolism by rat or dog liver mi-

crosomes, comparison of the HPLC plasma profiles with

those obtained by bioassay indicated the presence of

significant amounts of at least one active metabolite in

both rats and dogs. The major metabolite identified was

shown to be hydroxylated on the tetrahydroquinoline

ring by LCMS studies, and since its UV absorption

spectrum was very similar to that of 51, the hydroxyl

group was inferred to be on the alkyl portion of this

heterocycle. This was apparently responsible for the

promising appearance of the bioassay plasma profiles,

and it was concluded that the concentrations of parent

compound in rat plasma following po administration of

either analogue 36 or the tetrahydroquinoline (S)-51

were similar (see Table 3) and, as such, the cyclic

constraint had not offered a significant advantage from

a metabolic standpoint. It seems that the methyl group

on the pyridyl ring of compound 30 is protected from

metabolism, perhaps by the neighboring N-oxide moiety,

but elongation of this alkyl group adds sites for me-

tabolism even if the side chain is constrained in the form

of a ring. Equally, addition of alkyl groups at other

positions on the pyridine ring apparently provides

metabolizing enzymes with prime sites for oxidation to

give both active and inactive metabolites. Therefore,

from a pharmacokinetic viewpoint, L-372,662 (30) and

the trifluoromethyl-substituted pyridine N-oxides rep-

resent the optimal compounds discovered in this class

of OT antagonists, and they exhibit the best plasma

half-lives.

Exp er im en ta l Section

Gen er a l Meth od s. Proton NMR spectra were run at 300

MHz on a Varian VXR-300 or at 400 MHz on a Varian Unity

400 or VXR-400 spectrometer, and chemical shifts are reported

in parts per million (δ) downfield from tetramethylsilane as

internal standard. Fast atom bombardment mass spectra

were recorded on a VG-ZAB-HF spectrometer using glycerol

as matrix. Elemental analyses were performed using a Perkin-

Elmer 2400 model II elemental analyzer. Silica gel 60 (230-

400 mesh) from EM Science was used for column chromatog-

raphy, and analytical or preparative thin-layer chromatography

was conducted using EM Science Kieselgel 60 F₂₅₄plates.

Thermoseparations HPLC equipment with

a Vydac C18

reversed-phase column was used for analytical or preparative

HPLC. The elution used either a gradient of 95/5 to 0/100 A/B,

A ) H₂O-0.1% TFA, B ) CH₃CN-0.1% TFA (method A), or a

gradient of 95/5 to 5/95 A/B, A ) H₂O-0.1% H₃PO₄, B ) CH₃-

CN (method B). Enantiomeric purity was established by

HPLC on a Chiralpak AD column. Optical rotations were

determined on a Perkin-Elmer 241 polarimeter. Melting

points are uncorrected. For reactions performed under anhy-

drous conditions, glassware was either oven- or flame-dried

and the reaction was run under a positive pressure of argon.

Tetrahydrofuran was freshly distilled from sodium/benzophe-

none; all other anhydrous solvents were used as purchased

from Aldrich. Except where noted, reagents were purchased

from Aldrich and used without further purification. The

reported yields are the actual isolated yields of purified

material and are not optimized.

1-{1-[2-Meth oxy-4-(piper idin -4-yloxy)ben zoyl]piper idin -

4-yl}-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e Hyd r och lor id e

(1). 1-(ter t-Bu tyloxycar bon yl)-4-((2-h ydr oxym eth yl)ph en -

yla m in o)p ip er id in e (5). 1-(tert-Butyloxycarbonyl)-4-piperi-

dinone (4) (20 g, 0.10 mol), 2-aminobenzyl alcohol (13 g, 0.11

mol), and acetic acid (14 mL, 0.22 mol) were dissolved in dry

toluene (500 mL). The solution was refluxed with azeotropic

removal of water for 6 h, then cooled to ambient temperature,

and concentrated under reduced pressure to about one-half of

the original volume. To the solution were added NaBH₃CN

(20 g, 0.32 mol) and dry THF (300 mL). Acetic acid (10 mL,

0.17 mol) was added dropwise over a period of about 1 h. The

reaction was stirred at ambient temperature for 24 h. The

reaction mixture was concentrated under reduced pressure,

and the residue was dissolved in EtOAc (750 mL). The EtOAc

layer was washed with saturated aqueous NaHCO₃(4 × 250

mL) and brine (250 mL). The EtOAc layer was dried (MgSO₄)

and filtered, and the solvent was removed under reduced

pressure. The residue was purified by flash chromatography

using a gradient elution of 15-30% EtOAc in hexanes. The

title compound was obtained as a gum (24 g, 78%): ¹H NMR

(CDCl₃) δ 7.22 (1H, t, J ) 7 Hz), 7.09 (1H, d, J ) 7 Hz), 6.80-

Con clu sion

The introduction of a pyridine N-oxide group to the

benzoxazinone class of oxytocin antagonists developed

from L-371,257 (2) has provided potent compounds with

an excellent overall profile, as exemplified by L-372,-

662 (30). As a class, these pyridine N-oxides exhibit a

number of advantages over camphorsulfonamide com-

pounds such as L-368,899, including improved affinity

for the human oxytocin receptor, higher oral bioavail-

2158 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12

Bell et al.

6.60 (2H, m), 4.68 (2H, s), 4.00 (2H, m), 3.50 (1H, m), 3.00

(2H, m), 2.05 (2H, m), 1.47 (9H, s).

gradient elution of 20-40% EtOAc in hexanes. Methyl 4-(N-

(tert-butyloxycarbonyl)-4-piperidinyloxy)-2-methoxybenzoate was

obtained as a gum that solidified on standing (43 g, 89%): ¹H

NMR (CDCl₃) δ 7.83 (1H, d, J ) 7 Hz), 6.50 (2H, m), 4.56 (1H,

m), 3.90 (3H, s), 3.87 (3H, s), 3.70 (2H, m), 3.35 (2H, m), 1.95

(2H, m), 1.78 (2H, m), 1.45 (9H, s).

1-(4-P ip e r id in yl)-1,4-d ih yd r ob e n z[d ][1,3]oxa zin -2-

on e Hyd r och lor id e (6). Aniline 5 (24 g, 78 mmol) was

dissolved in dry THF (250 mL) and cooled to 0 °C. To the

solution were added N,N-diisopropylethylamine (DIEA) (41

mL, 0.24 mol) and triphosgene (8.54 g, 28.8 mmol). The

reaction was stirred at 0 °C for 1 h and then at ambient

temperature for 72 h. Ether (250 mL) was added, the mixture

was cooled to 0 °C for 3 h, and the hydrochloride salt of DIEA

was removed by filtration. The filtrate solvents were removed

under reduced pressure, and the residue was dissolved in

EtOAc (750 mL). The EtOAc solution was washed with 5%

aqueous citric acid (2 × 500 mL), water (250 mL), and

saturated aqueous NaHCO₃(2 × 500 mL). The EtOAc layer

was dried (MgSO₄) and filtered, and the solvent was removed

under reduced pressure. The residue was boiled in ether (ca.

200 mL) until the solid had dissolved. Cooling overnight gave

1-(N-(tert-butyloxycarbonyl)-4-piperidinyl)-1,4-dihydrobenz[d]-

[1,3]oxazin-2-one as off-white crystals (mp 143-145 °C; 19 g,

75%): ¹H NMR (CDCl₃) δ 7.34 (1H, t, J ) 7 Hz), 7.16 (1H, d,

J ) 7 Hz), 7.10-7.00 (2H, m), 5.09 (2H, s), 4.30 (2H, br s),

4.02 (1H, tt, J ) 12, 3 Hz), 2.80 (2H, m), 2.61 (2H, qd, J ) 12,

4 Hz), 1.83 (2H, m), 1.48 (9H, s).

A stirred solution of 1-(N-(tert-butyloxycarbonyl)-4-piperi-

dinyl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (19 g, 57 mmol) in

EtOAc (500 mL) was cooled to 0 °C. HCl gas was bubbled

through the solution for 30 min. Stirring was continued at 0

°C for 1 h, during which time a precipitate had formed, and

the reaction was warmed to ambient temperature for 1 h. The

stirred suspension was cooled to 0 °C, and cold ether (250 mL)

was added. After 1 h at 0 °C, the solid was collected by

filtration and washed with ether. The solid was dried in vacuo

for 18 h, giving the title compound as a white amorphous solid

(14.5 g, 95%): ¹H NMR (CD₃OD) δ 7.42 (1H, t, J ) 7 Hz), 7.51

(1H, d, J ) 7 Hz), 7.47 (1H, d, J ) 7 Hz), 7.18 (1H, t, J ) 7

Hz), 5.19 (2H, s), 4.30 (1H, m), 3.60 (2H, m), 3.45 (2H, m, J )

12 Hz), 2.90 (2H, qd, J ) 12, 4 Hz), 2.25 (2H, m).

4-(N-(ter t-Bu tyloxycar bon yl)-4-piper idin yloxy)-2-m eth -

oxyben zoic Acid (8). Methyl 2,4-dihydroxybenzoate (7) (41.6

g, 248 mmol) and triphenylphosphine (84.4 g, 322 mmol) were

dissolved in 800 mL of dry THF at 0 °C. To the stirred mixture

was added dropwise, over a period of 2 h, a solution of N-(tert-

butyloxycarbonyl)piperidin-4-ol (64.8 g, 322 mmol) and diethyl

azodicarboxylate (56 g, 322 mmol) in THF (600 mL). The

reaction mixture was stirred for 6 h at 0 °C and then warmed

to ambient temperature for 18 h. The reaction mixture was

diluted with 1 L of EtOAc. The organic phase was washed

with saturated aqueous NaHCO₃(2 × 200 mL), dried (Na₂-

SO₄), and concentrated to give 300 g of a semisolid. This

material was suspended in 1 L of hexanes-EtOAc (9:1 v/v),

stirred, and filtered to remove triphenylphosphine oxide.

Evaporation of the filtrate solvents under reduced pressure

yielded 125 g of a yellow oil which was purified by flash

chromatography using 10% EtOAc in hexanes as eluant. The

product-containing fractions were concentrated under reduced

pressure to give methyl 4-(N-(tert-butyloxycarbonyl)-4-piper-

idinyloxy)-2-hydroxybenzoate as an oil which solidified on

standing (68.6 g, 79%): ¹H NMR (CDCl₃) δ 10.96 (1H, s), 7.75

(1H, d, J ) 7 Hz), 6.42 (2H, m), 4.50 (1H, m), 3.90 (3H, s),

3.70 (2H, m), 3.35 (2H, m), 1.95 (2H, m), 1.75 (2H, m), 1.45

(9H, s).

To a solution of methyl 4-(N-(tert-butyloxycarbonyl)-4-piper-

idinyloxy)-2-hydroxybenzoate (50 g, 0.14 mol) and iodomethane

(17.4 mL, 0.28 mol) in DMF (400 mL) at 0 °C was added NaH

(6.55 g of a 60% suspension in mineral oil, 0.164 mol) in several

portions over a period of 2 h. The resulting suspension was

warmed to ambient temperature and stirred for 18 h. The

reaction was quenched with MeOH (5 mL), and the mixture

was concentrated under reduced pressure. The residue was

suspended in EtOAc (500 mL) and washed with water (2 ×

250 mL) and brine (250 mL). The EtOAc layer was dried

(MgSO₄), filtered, and concentrated under reduced pressure.

The residue was purified by flash chromatography using a

Methyl 4-(N-(tert-butyloxycarbonyl)-4-piperidinyloxy)-2-

methoxybenzoate (35 g, 96 mmol) was dissolved in MeOH (250

mL), and to the solution was added 2 N NaOH (100 mL, 0.20

mol). The mixture was warmed to 70 °C for 3 h. The solution

was cooled to ambient temperature, concentrated under

reduced pressure, and cooled to 0 °C, and 0.5 M aqueous citric

acid solution (300 mL) was added. To the suspension were

added EtOAc (500 mL) and water (300 mL). The EtOAc layer

was separated, and the aqueous phase was washed with

EtOAc (200 mL). The combined EtOAc layers were washed

with brine (250 mL), dried (MgSO₄), and filtered, and the

solvent was removed under reduced pressure to give the title

compound as a gum that solidified on standing (30.7 g, 95%):

¹H NMR (CDCl₃) δ 8.12 (1H, d, J ) 7 Hz), 6.65 (1H, dd, J ) 7,

2 Hz), 6.55 (1H, d, J ) 2 Hz), 4.60 (1H, m), 4.05 (3H, s), 3.70

(2H, m), 3.35 (2H, m), 1.95 (2H, m), 1.78 (2H, m), 1.48 (9H, s).

1-{1-[2-Meth oxy-4-(piper idin -4-yloxy)ben zoyl]piper idin -

4-yl}-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e Hyd r och lor id e

(1). The acid 8 (5.00 g, 14.2 mmol), piperidine 6 (4.02 g, 15.0

mmol), HOBT (2.52 g, 16.5 mmol), and EDC (3.27 g, 17.0

mmol) were combined in DMF (75 mL). DIEA (2.87 mL, 16.5

mmol) was added dropwise to the stirred solution. After 1 h,

more DIEA (approximately 1 mL) was added to bring the

mixture to pH 6-7 (wetted E. Merck pH 0-14 “colorpHast”

indicator strips). The reaction was stirred at ambient tem-

perature for 24 h. The solvent was removed under reduced

pressure, and the residue was dissolved in EtOAc (150 mL)

and washed with 5% aqueous citric acid solution (2 × 100 mL),

water (100 mL), and saturated aqueous NaHCO₃solution (2

× 100 mL). The EtOAc layer was dried (MgSO₄) and filtered,

and the solvent was removed under reduced pressure. The

crude product was purified by flash chromatography using a

gradient elution of 1-3% MeOH in CH₂Cl₂. 1-(1-(4-(N-(tert-

Butyloxycarbonyl)-4-piperidinyloxy)-2-methoxybenzoyl)piperi-

din-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one was obtained as

a white foam by evaporation of a CH₂Cl₂solution under

reduced pressure (7.22 g, 90%): ¹H NMR (CDCl₃) δ 7.35 (1H,

t, J ) 7 Hz), 7.20-7.05 (4H, m), 6.50 (2H, m), 5.10 (2H, s),

4.97 (1H, br d), 4.50 (1H, m), 4.20-4.10 (1H, m), 3.88-3.81

(3H, m), 3.70 (4H, m), 3.35 (3H, m), 3.20-3.00 (2H, m), 2.80-

2.50 (2H, m), 1.95 (2H, m), 1.75 (2H, m), 1.48 (9H, s).

1-(1-(4-(N-(tert-Butyloxycarbonyl)-4-piperidinyloxy)-2-meth-

oxybenzoyl)piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-

one (5.0 g, 8.8 mmol) was dissolved in EtOAc (125 mL) and

cooled to 0 °C. HCl gas was bubbled through the stirred

solution for 20 min. A gummy precipitate formed. Excess HCl

was purged by bubbling nitrogen through the solution, and

the reaction was warmed to ambient temperature with stirring

for 1 h. The solvent was removed under reduced pressure,

and the residue was dried in vacuo for 24 h at 50 °C to give

the title compound as an amorphous solid (4.37 g, 99%): ¹H

NMR (CDCl₃) δ 7.37 (1H, t, J ) 7 Hz), 7.20-7.05 (4H, m),

6.53 (1H, br s), 6.48 (1H, s), 5.10 (2H, s), 4.98 (1H, br d), 4.42

(1H, m), 4.20-4.10 (1H, m), 3.88-3.81 (3H, m), 3.70 (1H, br

d), 3.20 (3H, m), 3.20-3.00 (3H, m), 2.80-2.50 (5H, m), 1.95

(3H, m), 1.75 (3H, m); MS (FAB) m/z ) 466 (M⁺+ H); HPLC

purity ) 99.0% (method A; 215 nm). Anal. (C₂₆H₃₁N₃O₅‚HCl‚

0.6H₂O) C, H, N.

1-{1-[5-Flu or o-2-m eth oxy-4-(piper idin -4-yloxy)ben zoyl]-

p ip er id in -4-yl}-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e Hy-

d r och lor id e (12). 4-(N-(ter t-Bu tyloxyca r bon yl)-4-p ip er -

id in yloxy)-2,5-d iflu or oben zon itr ile (10). A solution of

t-BuOK in THF (1.0 M, 25 mL, 25 mmol) was slowly added to

a solution of N-(tert-butyloxycarbonyl)-4-piperidinol (5.0 g, 24.9

mmol) in THF (40 mL) at 0 °C. The resulting mixture was

stirred for 0.5 h, then cannulated into a cold solution of 2,4,5-

trifluorobenzonitrile (9) (4.7 g, 30 mmol) in THF (40 mL) at

-65 °C. The reaction mixture was stirred at -65 °C for 3 h,

Development of Orally Active Oxytocin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2159

then warmed to ambient temperature over 2 h, and stirred

for 18 h. Water (200 mL) and EtOAc (200 mL) were added.

The organic layer was separated, washed with water (50 mL)

and brine (50 mL), dried over MgSO₄, and evaporated under

reduced pressure. The residue was purified by flash chroma-

tography using 20% EtOAc in hexanes as eluant to give the

title compound as a white solid (mp 120-121 °C; 7.1 g, 84%):

¹H NMR (CDCl₃) δ 7.31 (1H, dd, J ) 9.1, 6.0 Hz), 6.80 (1H,

dd, J ) 10.1, 7.6 Hz), 4.56 (1H, m), 3.70 (2H, m), 3.40 (2H, m),

1.95 (2H, m), 1.80 (2H, m), 1.47 (9H, s).

m/z ) 484 (M⁺+ H); HPLC purity ) 98.6% (method A; 215

nm). Anal. (C₂₆H₃₀FN₃O₅‚HCl‚1.95H₂O) C, H, N.

Gen er a l P r oced u r e for th e Syn th esis of P yr id in e

N-Oxid e Der iva tives: 1-(1-{2-Meth oxy-4-[1-(2-m eth yl-1-

oxidopyr idin -3-ylm eth yl)piper idin -4-yloxy]ben zoyl}piper -

id in -4-yl)-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e (30). To a

stirred solution of ethyl 2-methylnicotinate (10.0 g, 60 mmol)

in dry THF (180 mL) at 0 °C was added DIBAL (120 mL of a

1.0 M solution in THF, 120 mmol). The mixture was allowed

to slowly warm to ambient temperature and stirred for 18 h.

Saturated NaHCO₃was added, the precipitate was removed

by filtration, and the filtrate was concentrated under reduced

pressure. The residue was partitioned between saturated

NaHCO₃(100 mL) and CHCl₃(200 mL). The organic layer

was removed and the aqueous layer extracted further with

CHCl₃(5 × 100 mL). The combined organic extracts were

dried (MgSO₄), filtered, and concentrated in vacuo to give

3-(hydroxymethyl)-2-methylpyridine (7.6 g, 100%): ¹H NMR

(CDCl₃) δ 8.41 (1H, d, J ) 5 Hz), 7.70 (1H, d, J ) 8 Hz), 7.15

(1H, dd, J ) 8, 5 Hz), 4.73 (2H, s), 2.54 (3H, s).

To a stirred solution of 3-(hydroxymethyl)-2-methylpyridine

(5.8 g, 47 mmol) in CH₂Cl₂(250 mL) was added thionyl chloride

(97.9 g, 0.823 mol), and the resulting mixture was stirred for

4 h at ambient temperature and then concentrated in vacuo.

The residue was partitioned between saturated NaHCO₃(150

mL) and CH₂Cl₂(150 mL). The organic layer was removed

and the aqueous layer extracted further with CH₂Cl₂(2 × 150

mL). The combined organic extracts were dried (MgSO₄),

filtered, and concentrated in vacuo to give 3-(chloromethyl)-

2-methylpyridine (4.9 g, 74%). This compound could be stored

as the hydrochloride salt: ¹H NMR (CD₃OD) δ 8.70 (1H, dd, J

) 6, 2 Hz), 8.65 (1H, dd, J ) 8, 2 Hz), 7.95 (1H, dd, J ) 8, 6

Hz), 4.94 (2H, s), 2.88 (3H, s).

4-(N-(ter t-Bu tyloxycar bon yl)-4-piper idin yloxy)-5-flu or o-

2-m eth oxyben zoic Acid , Sod iu m Sa lt (11). MeOH (1.21

mL, 30 mmol) was added to a solution of t-BuOK in THF (1.0

M, 30 mL, 30 mmol) at 0 °C under an inert atmosphere to

give a suspension. The suspension was stirred for 0.5 h and

then cannulated into a cold solution of nitrile 10 (7.1 g, 21

mmol) in THF (100 mL) at -50 °C. The reaction mixture was

stirred at -50 °C for 1 h, warmed to 0 °C over 0.5 h, and stirred

at 0 °C for 6 h. Water (250 mL) and EtOAc (200 mL) were

added, and the organic layer was washed with water (100 mL)

and brine (100 mL), dried over MgSO₄, filtered, and evaporated

to dryness under reduced pressure. The residue was purified

by flash chromatography using 50% EtOAc in hexanes as

eluant to provide 4-(N-(tert-butyloxycarbonyl)-4-piperidinyl-

oxy)-5-fluoro-2-methoxybenzonitrile as a white solid (mp 112-

113 °C; 7.0 g, 92%): ¹H NMR (CDCl₃) δ 7.25 (1H, d, J ) 10.4

Hz), 6.53 (1H, d, J ) 6.6 Hz), 4.60 (1H, m), 3.90 (3H, s), 3.70

(2H, m), 3.40 (2H, m), 1.95 (2H, m), 1.80 (2H, m), 1.47 (9H, s).

To a solution of 4-(N-(tert-butyloxycarbonyl)-4-piperidinyl-

oxy)-5-fluoro-2-methoxybenzonitrile (7.0 g, 20 mmol) in EtOH

(50 mL) was added a solution of NaOH (3.2 g, 80 mmol, in 25

mL of water). The resulting slurry was heated to reflux for

18 h and then cooled to 0 °C. The precipitate was collected by

filtration, washed with 5:1 EtOH-H₂O, and dried in vacuo to

give the title compound as a flaky white solid (6.8 g, 87%): ¹H

NMR (DMSO-d₆) δ 7.07 (1H, d, J ) 11.7 Hz), 6.68 (1H, d, J )

7.0 Hz), 4.50 (1H, m), 3.70 (3H, s), 3.60 (3H, s), 3.20 (2H, m),

1.90 (2H, m), 1.55 (2H, m), 1.41 (9H, s).

To a stirred solution of 3-(chloromethyl)-2-methylpyridine

(500 mg, 3.53 mmol) in CHCl₃(40 mL) was added mCPBA

(1.11 g, 55 wt %, 3.53 mmol), and the resulting mixture was

stirred for 2 h at ambient temperature. The reaction was

quenched with saturated NaHCO₃(25 mL), and the organic

layer was washed with water (25 mL), then dried (MgSO₄),

filtered, and concentrated in vacuo. The residue was purified

by flash column chromatography, eluting with 3% MeOH in

CH₂Cl₂to give 3-(chloromethyl)-2-methylpyridine N-oxide (495

mg, 89%): ¹H NMR (CDCl₃) δ 8.27 (1H, d, J ) 6.3 Hz), 7.26

(1H, d, J ) 7.8 Hz), 7.15 (1H, t, J ) 7.2 Hz), 4.59 (2H, s), 2.61

(3H, s).

1-{1-[5-Flu or o-2-m eth oxy-4-(piper idin -4-yloxy)ben zoyl]-

p ip er id in -4-yl}-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e Hy-

d r och lor id e (12). To a solution of piperidine 6 (2.7 g, 10

mmol) in DMF (25 mL) were added acid 11 (3.9 g, 10 mmol),

HOBT (1.5 g, 10 mmol), and EDC (3.8 g, 13 mmol). To the

stirred solution was added DIEA (approximately 1.3 mL) until

the reaction mixture was pH 7 (wetted E. Merck “colorpHast”

pH 1-14 indicator strips). The reaction was stirred at ambient

temperature for 18 h, and the solvent was removed under

reduced pressure. The residue was dissolved in EtOAc (200

mL) and washed with 5% aqueous citric acid (75 mL), water

(50 mL), and saturated aqueous NaHCO₃(50 mL). The EtOAc

layer was dried (MgSO₄) and filtered, and the solvent was

removed under reduced pressure. The residue was purified

by flash chromatography using EtOAc as eluant to give 1-(1-

(4-(N-(tert-butyloxycarbonyl)-4-piperidinyloxy)-5-fluoro-2-meth-

oxybenzoyl)piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-

one as an amorphous solid (5.4 g, 93%): ¹H NMR (CDCl₃) δ

7.37 (1H, t, J ) 6 Hz), 7.20-7.00 (4H, m), 6.57 (1H, d, J ) 6

Hz), 5.10 (2H, s), 4.96 (1H, d, J ) 7 Hz), 4.48 (1H, m), 4.15

(1H, m), 3.86-3.79 (3H, m), 3.70 (4H, m), 3.35 (2H, m), 3.20-

3.00 (1H, m), 3.80 (4H, m), 1.95 (2H, m), 1.80 (2H, m), 1.47

(9H, s).

To a solution of piperidine 1 (1.00 g, 2.15 mmol) and

3-(chloromethyl)-2-methylpyridine N-oxide (407 mg, 2.58 mmol)

in dry, degassed DMF (25 mL) was added DIEA until the

mixture was pH 7.5, as measured by moistened indicator

paper. The reaction mixture was heated to 50 °C for 48 h;

then the solvent was removed under reduced pressure. The

residue was partitioned between saturated NaHCO₃(100 mL)

and CHCl₃(100 mL). The organic layer was removed and the

aqueous layer extracted further with CHCl₃(2 × 100 mL). The

combined organic extracts were dried (MgSO₄), filtered, and

concentrated in vacuo. The residue was purified by flash

column chromatography, eluting with 3% MeOH-0.3% NH₄-

OH in CH₂Cl₂to give the title compound which was converted

to the corresponding hydrochloride salt (880 mg, 59%): ¹H

NMR (CD₃OD) δ 8.59 (1H, br s), 8.02 (1H, br s), 7.63 (1H, br

s), 7.40 (1H, t, J ) 7.8 Hz), 7.29-7.11 (4H, m), 6.80-6.64 (2H,

m), 5.14 (2H, s), 4.80 (2H, m), 4.63 (2H, s), 4.23 (1H, m), 3.92-

3.84 (3H, m), 3.75-3.16 (7H, m), 3.01-2.56 (5H, m), 2.53-

Into a solution of 1-(1-(4-(N-(tert-butyloxycarbonyl)-4-piper-

idinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-1,4-dihy-

drobenz[d][1,3]oxazin-2-one (5.4 g, 9.3 mmol) in EtOAc (100

mL) was bubbled HCl gas for 20 min. The mixture was stirred

at 0 °C for 1 h and then at ambient temperature for 1 h. The

precipitate was collected by filtration, washed with EtOAc, and

dried in vacuo to give the title compound as an amorphous

solid (4.7 g, 97%): ¹H NMR (CD₃OD) δ 7.40 (1H, t, J ) 7.0

Hz), 7.28 (1H, d, J ) 8.2 Hz), 7.20-7.00 (3H, m), 6.91 (1H, d,

J ) 6.8 Hz), 5.14 (2H, s), 4.80 (1H, m), 4.22 (1H, m), 3.90-

3.85 (3H, m), 3.62 (1H, m), 3.50-3.20 (6H, m), 3.00-2.50 (4H,

m), 2.20-2.00 (4H, m), 2.00 (1H, m), 1.83 (1H, m); MS (FAB)

2.20 (4H, m), 2.05-1.75 (2H, m); MS (FAB) m/z ) 587 (M⁺

+

H); HPLC purity ) 99.7% (method A; 215 nm). Anal.

(C₃₃H₃₈N₄O₆‚HCl‚H₂O) C, H, N.

The following compounds were made in analogy with

pyridine N-oxide 30, utilizing the appropriate ester,^35-38,40

alcohol,³⁹or halide: 3, 25-29, 31, 33-41, 46, and 47. The

following compounds were made by a similar method, with the

exceptions as shown and yields quoted for the final step.

1-(1-{2-Me t h oxy-4-[1-(5-m e t h yl-1-oxid op yr id in -3-yl-

m et h yl)p ip er id in -4-yloxy]b en zoyl}p ip er id in -4-yl)-1,4-

d ih yd r oben z[d ][1,3]oxa zin -2-on e (32). A mixture of 3,5-

2160 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12

Bell et al.

lutidine (10.0 g, 93.3 mmol), N-chlorosuccinimide (15.0 g, 112

mmol), and 2,2′-azobis(isobutyronitrile) (AIBN) (187 mg, 1.1

mmol) was heated to reflux in CCl₄(120 mL) for 18 h. The

reaction mixture was poured into saturated NaHCO₃(200 mL)

and CH₂Cl₂(500 mL). The organic layer was separated, dried

over MgSO₄, filtered, and concentrated in vacuo to give a crude

sample of 3-(chloromethyl)-5-methylpyridine (2.5 g, 19%): ¹H

NMR (CDCl₃) δ 8.43 (1H, s), 8.40 (1H, s), 7.56 (1H, s), 4.56

(2H, s), 2.37 (3H, s).

Using 3-(chloromethyl)-5-methylpyridine for the oxidation

step gave the title compound (125 mg, 43%). For the hydro-

chloride salt: ¹H NMR (CD₃OD) δ 8.62 (1H, s), 8.53 (1H, s),

7.93 (1H, br s), 7.40 (1H, t, J ) 7.9 Hz), 7.31-7.13 (4H, m),

6.79-6.64 (2H, m), 5.14 (2H, s), 4.81 (2H, m), 4.49 (2H, s), 4.22

(1H, m), 3.94-3.83 (3H, m), 3.68-3.14 (6H, m), 3.01-2.13 (7H,

m), 2.48 (3H, s), 2.03-1.75 (2H, m); MS (FAB) m/z ) 587 (M⁺

+ H); HPLC purity ) 98.0% (method A; 215 nm). Anal.

(C₃₃H₃₈N₄O₆‚HCl‚1.65H₂O‚0.25CH₂Cl₂) C, H, N.

1-(1-{4-[1-(2-E t h yl-4,6-d im et h yl-1-oxid op yr id in -3-yl-

m eth yl)p ip er id in -4-yloxy]-2-m eth oxyben zoyl}p ip er id in -

4-yl)-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e (42). A mixture

of 2,4-pentanedione (15 g, 0.150 mol), ethyl 3-oxovalerate (25

g, 0.173 mol), and ammonium acetate (51 g, 0.662 mol) was

heated at 110 °C for 96 h and then allowed to cool to ambient

temperature. The crude product was purified by flash column

chromatography, eluting with 5% EtOAc in hexane to give

ethyl 2-ethyl-4,6-dimethylnicotinate as a yellow oil (6.5 g,

21%): ¹H NMR (CDCl₃) δ 6.86 (1H, s), 4.40 (2H, q, J ) 7 Hz),

2.77 (2H, q, J ) 7 Hz), 2.50 (3H, s), 2.28 (3H, s), 1.40 (3H, t,

J ) 7 Hz), 1.26 (3H, t, J ) 7 Hz).

Using ethyl 2-ethyl-4,6-dimethylnicotinate for the reduction

step gave the title compound (131 mg, 41%). For the hydro-

chloride salt: ¹H NMR (CD₃OD) δ 7.57 (1H, s), 7.40 (1H, t, J

) 7.4 Hz), 7.31-7.11 (4H, m), 6.82-6.67 (2H, m), 5.14 (2H, s),

4.82 (2H, m), 4.61 (2H, br s), 4.22 (1H, tt, J ) 11.8, 3.9 Hz),

3.94-3.83 (3H, m), 3.73-3.14 (8H, m), 3.00-2.20 (7H, m), 2.61

(3H, s), 2.61 (3H, s), 2.03-1.76 (2H, m), 1.28 (3H, t, J ) 7.3

Hz); MS (FAB) m/z ) 629 (M⁺+ H); HPLC purity ) 99.0%

(method A; 215 nm). Anal. (C₃₆H₄₄N₄O₆‚HCl‚1.75H₂O‚0.65CH₂-

Cl₂) C, H, N.

1-(1-{4-[1-(2-E t h yl-4,6-d im et h yl-1-oxid op yr id in -3-yl-

m eth yl)p ip er id in -4-yloxy]-5-flu or o-2-m eth oxyben zoyl}-

p ip er id in -4-yl)-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e (43).

Using ethyl 2-ethyl-4,6-dimethylnicotinate for the reduction

step and piperidine 12 in the alkylation reaction gave the title

compound (108 mg, 34%). For the hydrochloride salt: ¹H NMR

(CD₃OD) δ 7.61 (1H, s), 7.40 (1H, t, J ) 7.2 Hz), 7.30-7.05

(4H, m), 6.95 (1H, m), 5.14 (2H, s), 4.80 (2H, m), 4.63 (2H, br

s), 4.23 (1H, m), 3.94-3.84 (3H, m), 3.75-3.16 (8H, m), 3.01-

2.23 (7H, m), 2.63 (3H, s), 2.62 (3H, s), 2.03-1.78 (2H, m), 1.29

(3H, t, J ) 7.4 Hz); MS (FAB) m/z ) 647 (M⁺+ H); HPLC

purity ) 99.5% (method A; 215 nm). Anal. (C₃₆H₄₃FN₄O₆‚

HCl‚1.4H₂O‚0.85CH₂Cl₂) C, H, N.

1-(1-{2-Meth oxy-4-[1-(1-oxid o-2-(tr iflu or om eth yl)p yr i-

d in -3-ylm et h yl)p ip er id in -4-yloxy]b en zoyl}p ip er id in -4-

yl)-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e (44). To a stirred

suspension of NaH (1.97 g of a 60% dispersion in mineral oil,

49.4 mmol) in DMF (30 mL) was added 3-(trifluoroacetyl)-2-

(trifluoromethyl)pyridine¹⁹(3.00 g, 12.3 mmol) in wet DMF (75

mL + 75 µL of H₂O), dropwise. The mixture was stirred at

60 °C for 45 min; then iodoethane (7.70 g, 49.4 mmol) was

added. Stirring was continued at 60 °C for 1 h; then the

mixture was cooled to ambient temperature, quenched with

saturated NaHCO₃(300 mL), and extracted with EtOAc (2 ×

500 mL). The combined organic extracts were dried (Na₂SO₄)

and concentrated in vacuo. The residue was purified by flash

column chromatography, eluting with 20% EtOAc in hexane,

to give ethyl 2-(trifluoromethyl)nicotinate (1.74 g, 65%): ¹H

NMR (CDCl₃) δ 8.81 (1H, dd, J ) 4.6, 1.2 Hz), 8.12 (1H, dd, J

) 7.8, 1.2 Hz), 7.58 (1H, dd, J ) 7.8, 4.6 Hz), 4.43 (2H, q, J )

7.2 Hz), 1.41 (3H, t, J ) 7.2 Hz).

Hz), 7.83-7.76 (2H, m), 7.40 (1H, t, J ) 7.3 Hz), 7.32-7.11

(4H, m), 6.81-6.65 (2H, m), 5.14 (2H, s), 4.82 (2H, m), 4.67

(2H, s), 4.22 (1H, tt, J ) 11.9, 3.9 Hz), 3.95-3.83 (3H, m),

3.75-3.13 (6H, m), 3.01-2.14 (7H, m), 2.04-1.76 (2H, m); MS

(FAB) m/z ) 641 (M⁺+ H); HPLC purity ) 99.0% (method A;

215 nm). Anal. (C₃₃H₃₅F₃N₄O₆‚0.9HCl‚2.45H₂O) C, H, N.

1-(1-{5-Flu or o-2-m eth oxy-4-[1-(1-oxido-2-(tr iflu or om eth -

yl)p yr id in -3-ylm eth yl)p ip er id in -4-yloxy]ben zoyl}p ip er -

id in -4-yl)-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e (45). Us-

ing ethyl 2-(trifluoromethyl)nicotinate for the reduction step

and piperidine 12 in the alkylation reaction gave the title

compound (227 mg, 79%). For the hydrochloride salt: ¹H NMR

(CD₃OD) δ 8.55 (1H, dd, J ) 5.1, 2.2 Hz), 7.83-7.76 (2H, m),

7.40 (1H, t, J ) 7.2 Hz), 7.31-7.04 (4H, m), 6.95 (1H, d, J )

6.1 Hz), 5.14 (2H, s), 4.80 (2H, m), 4.66 (2H, s), 4.22 (1H, m),

3.94-3.83 (3H, m), 3.70-3.16 (6H, m), 3.01-2.15 (7H, m),

2.03-1.78 (2H, m); MS (FAB) m/z ) 659 (M⁺+ H); HPLC

purity ) 99.7% (method A; 215 nm). Anal. (C₃₃H₃₄F₄N₄O₆‚

HCl‚2.25H₂O) C, H, N.

1-(1-{2-Meth oxy-4-[1-(1-p yr id in -3-yleth yl)p ip er id in -4-

yloxy]b en zoyl}p ip er id in -4-yl)-1,4-d ih yd r ob en z[d ][1,3]-

oxa zin -2-on e (48). To a stirred solution of piperidine 1 (0.20

g, 0.43 mmol) in dichloroethane (2.2 mL) were added 3-acetyl-

pyridine (94.5 mL, 0.86 mmol) and sodium triacetoxyborohy-

dride (182 mg, 0.86 mmol). The solution was stirred at

ambient temperature for 5 days. Everyday an additional 2

equiv each of the 3-acetylpyridine and sodium triacetoxyboro-

hydride were added to the reaction mixture. The reaction

solvent was removed under reduced pressure to afford a crude

oil. The residue was purified by flash column chromatography

using 5% MeOH-0.5% NH₄OH in CH₂Cl₂and then further

purified on a semipreparative HPLC column (method A).

Removal of solvent gave the title compound as an amorphous

powder. The sample was taken up in CH₃CN with 5 equiv of

aqueous HCl and lyophilized to afford the hydrochloride salt

of the title compound (240 mg, 82% yield): ¹H NMR (CDCl₃)

δ 8.54 (1H, d, J ) 1.7 Hz), 8.48 (1H, dd, J ) 6.3, 1.6 Hz), 7.66

(1H, dt, J ) 7.7, 1.9 Hz), 7.32 (1H, t, J ) 7.4 Hz), 7.27-7.22

(2H, m), 7.14 (1H, t, J ) 7.1 Hz), 7.10-7.03 (2H, m), 6.46-

6.42 (1H, m), 6.42 (1H, s), 5.06 (2H, s), 4.95 (1H, d, J ) 11.1

Hz), 4.29-4.25 (1H, m), 4.17-4.06 (1H, m), 3.85-3.76 (3H,

m), 3.67 (1H, d, J ) 12.8 Hz), 3.52 (1H, q, J ) 7.0 Hz), 3.15-

2.99 (1H, m), 2.83-2.67 (4H, m), 2.55-2.50 (1H, m), 2.34-

2.22 (2H, m), 2.10-1.80 (4H, m), 1.80-1.74 (4H, m), 1.38 (3H,

d, J ) 7.0 Hz); MS (FAB) m/z ) 571 (M⁺+ H); HPLC purity

) 98.8% (method A; 215 nm). Anal. (C₃₃H₃₈F₄N₄O₅‚2HCl‚

1.95H₂O) C, H, N.

1-(1-{2-Me t h oxy-4-[1-(2-m e t h yl-1-oxid op yr id in -3-yl-

ca r bon yl)p ip er id in -4-yloxy]ben zoyl}p ip er id in -4-yl)-1,4-

d ih yd r oben z[d ][1,3]oxa zin -2-on e (49). A solution of 2-

methylnicotinic acid (118 mg, 0.86 mmol), piperidine 1 (431

mg, 0.86 mmol), HOBT (116 mg, 0.86 mmol), EDC (198 mg,

1.03 mmol), and DIEA (245 mg, 1.89 mmol) in dry, degassed

DMF was stirred for 18 h at ambient temperature. The

solvent was removed under reduced pressure, and the residue

was partitioned between CH₂Cl₂(20 mL) and saturated

NaHCO₃(20 mL). The aqueous phase was extracted further

with CH₂Cl₂(2 × 10 mL). The combined organic layers were

dried (MgSO₄) and filtered, and the solvent was removed under

reduced pressure. The crude product was purified by flash

chromatography, eluting with 2% MeOH in CH₂Cl₂, to give

1-(1-{2-methoxy-4-[1-(2-methylpyridin-3-ylcarbonyl)piperidin-

4-yloxy]benzoyl}piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-

2-one (450 mg, 89%): ¹H NMR (CD₃OD) δ 8.68 (1H, dd, J )

5.5, 1.4 Hz), 8.24 (1H, d, J ) 7.4 Hz), 7.76 (1H, dd, J ) 7.4,

5.9 Hz), 7.40 (1H, t, J ) 7.4 Hz), 7.30-7.11 (4H, m), 6.71-

6.63 (2H, m), 5.14 (2H, s), 4.78 (2H, m), 4.22 (1H, m), 3.99

(1H, br s), 3.92-3.80 (3H, m), 3.67-3.52 (2H, m), 3.35-3.12

(2H, m), 3.00-2.42 (4H, m), 2.67 (3H, s), 2.17-1.74 (6H, m).

To a stirred solution of 1-(1-{2-methoxy-4-[1-(2-methylpyr-

idin-3-ylcarbonyl)piperidin-4-yloxy]benzoyl}piperidin-4-yl)-1,4-

dihydrobenz[d][1,3]oxazin-2-one (225 mg, 0.385 mmol) in

CHCl₃(5 mL) was added mCPBA (275 mg, 55 wt %, 0.87

mmol), and the resulting mixture was stirred for 18 h at

Using ethyl 2-(trifluoromethyl)nicotinate for the reduction

step gave the title compound (124 mg, 57%). For the hydro-

chloride salt: ¹H NMR (CD₃OD) δ 8.55 (1H, dd, J ) 5.0, 2.4

Development of Orally Active Oxytocin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2161

ambient temperature. The solvent was removed under re-

duced pressure, and the residue was purified by flash chro-

matography, eluting with 5% MeOH in CH₂Cl₂. Further

purification by semipreparative HPLC (method A) gave the

title compound (88 mg, 38%): ¹H NMR (CDCl₃) δ 8.31 (1H, d,

J ) 6.2 Hz), 7.35 (1H, t, J ) 7.2 Hz), 7.32-7.04 (6H, m), 6.55-

6.46 (2H, m), 5.09 (2H, s), 4.99 (1H, d, J ) 10.9 Hz), 4.64 (1H,

d, J ) 4.0 Hz), 4.23-3.79 (6H, m), 3.70 (1H, d, J ) 13.1 Hz),

3.52 (1H, m), 3.26-2.98 (2H, m), 2.89-2.50 (6H, m), 2.10-

1.73 (6H, m); MS (FAB) m/z ) 601 (M⁺+ H); HPLC purity )

99.8% (method A; 215 nm). Anal. (C₃₃H₃₆N₄O₇‚EtOAc) C, H,

N.

1-(1-{2-Meth oxy-4-[1-(1-oxid o-5,6,7,8-tetr a h yd r oqu in o-

lin -5-yl)p ip er id in -4-yloxy]b en zoyl}p ip er id in -4-yl)-1,4-

d ih yd r oben z[d ][1,3]oxa zin -2-on e (50). 7,8-Dih yd r o-6H-

qu in olin -5-on e (21). To a stirred solution of 3-amino-2-

cyclohexen-1-one (Fluka) (12 g, 0.108 mol) in dry, degassed

DMF (500 mL) was added propynal²³(13.7 g, 0.25 mol)

dropwise. The resulting mixture was stirred at ambient

temperature for 48 h; then the solvent was removed under

reduced pressure. The residual brown solid was heated to 140

°C for 5 min, and the cooled residue was purified by flash

chromatography, eluting with 3% MeOH in CH₂Cl₂, to give

the title compound as a dark oil (8.5 g, 53%): ¹H NMR (CDCl₃)

δ 8.68 (1H, dd, J ) 5, 2 Hz), 8.29 (1H, dd, J ) 8, 2 Hz), 7.29

(1H, dd, J ) 8, 5 Hz), 3.17 (2H, t, J ) 6 Hz), 2.71 (2H, t, J )

7 Hz), 2.22 (2H, m).

4-(benzyloxy)-2-hydroxybenzoate as a white powder (44.5 g,

58%): ¹H NMR (CDCl₃) δ 7.75 (1H, d, J ) 7.8 Hz), 7.44-7.30

(5H, m), 6.54-6.48 (2H, m), 5.08 (2H, s), 3.91 (3H, s).

To a stirred, 0 °C solution of methyl 4-(benzyloxy)-2-

hydroxybenzoate (12 g, 46 mmol) in DMF (150 mL) were added

NaH (2.76 g, 69 mmol) and methyl iodide (16.5 g, 116 mmol).

The solution was allowed to warm to ambient temperature and

stirred for 18 h. The reaction mixture was poured onto ice

and the resulting aqueous solution extracted with Et₂O (3 ×

200 mL). The organic phase was dried (MgSO₄) and filtered

and the Et₂O removed under reduced pressure. The crude

white solid was purified by flash column chromatography,

eluting with 20% EtOAc in hexanes, to give methyl 4-(benzyl-

oxy)-2-methoxybenzoate as a white powder (12 g, 96%): ¹H

NMR (CDCl₃) δ 7.85 (1H, d, J ) 9.3 Hz), 7.46-7.32 (5H, m),

6.58-6.54 (2H, m), 5.10 (2H, s), 3.87 (3H, s), 3.85 (3H, s).

A solution of methyl 4-(benzyloxy)-2-methoxybenzoate (8.2

g, 30 mmol), palladium catalyst (10% Pd-C, 1 g), and AcOH

(1 mL) in methanol (100 mL) was stirred under an atmosphere

of hydrogen (ca. 1 atm) at ambient temperature for 18 h. The

methanol solution was filtered through Celite and the crude

reaction solution stripped down to afford an oil. The product

was purified by flash column chromatography, eluting with

50% EtOAc in hexanes, to give the title compound as a white

powder (4.7 g, 86%): ¹H NMR (CDCl₃) δ 7.79 (1H, d, J ) 8.4

Hz), 6.47-6.42 (2H, m), 6.25 (1H, br s), 3.86 (3H, s), 3.82 (3H,

s).

5-Hyd r oxy-5,6,7,8-tetr a h yd r oqu in olin e (22). Sodium

borohydride (7.7 g, 0.204 mol) was added in portions, over 40

min, to a stirred solution of ketone 21 (10.0 g, 68 mmol) in

MeOH (350 mL) at 0 °C. The reaction mixture was stirred

for 18 h, allowing it to warm to ambient temperature. The

solvent was evaporated under reduced pressure, and the

residue was partitioned between saturated NaHCO₃(450 mL)

and EtOAc (500 mL). The organic layer was removed and the

aqueous phase extracted further with EtOAc (2 × 500 mL).

The combined organic extracts were dried (MgSO₄), filtered,

and concentrated in vacuo. The residue was chromatographed

on silica gel, eluting with EtOAc, to give the title compound

as a pale solid (9.20 g, 91%): ¹H NMR (CDCl₃) δ 8.44 (1H, dd,

J ) 4.8, 1.6 Hz), 7.78 (1H, dd, J ) 7.7, 1.3 Hz), 7.14 (1H, dd,

J ) 7.7, 4.8 Hz), 4.83 (1H, br s), 3.04-2.86 (2H, m), 2.15-2.00

(3H, m), 1.95-1.82 (2H, m).

1-(1-{2-Meth oxy-4-[1-(1-oxid o-5,6,7,8-tetr a h yd r oqu in o-

lin -5-yl)p ip er id in -4-yloxy]b en zoyl}p ip er id in -4-yl)-1,4-

d ih yd r oben z[d ][1,3]oxa zin -2-on e (50). Using alcohol 22 for

the chlorination step and adding sodium iodide in the alky-

lation reaction gave the title compound (131 mg, 36%). For

the TFA salt: ¹H NMR (CD₃OD) δ 8.46 (1H, d, J ) 6.4 Hz),

7.76 (1H, d, J ) 8.1 Hz), 7.52 (1H, t, J ) 7.2 Hz), 7.40 (1H, t,

J ) 7.6 Hz), 7.31-7.11 (4H, m), 6.77-6.66 (2H, m), 5.14 (2H,

s), 4.81 (2H, m), 4.76 (1H, t, J ) 4.2 Hz), 4.22 (1H, tt, J )

11.8, 3.8 Hz), 3.92-3.83 (3H, m), 3.64-3.12 (7H, m), 3.04 (2H,

t, J ) 6.4 Hz), 3.01-2.02 (10H, m), 2.02-1.75 (2H, m); MS

(FAB) m/z ) 613 (M⁺+ H); HPLC purity ) 99.8% (method A;

215 nm). Anal. (C₃₅H₄₀N₄O₆‚1.9CF₃CO₂H‚1.35H₂O) C, H, N.

5-F lu or o-4-h yd r oxy-2-m eth oxyben zoic Acid (18).

A

mixture of ester 17 (3.7 g, 21 mmol) and 3,5-dichloro-1-

fluoropyridinium triflate (8.4 g, 85 wt %, 23 mmol) in dry CH₂-

Cl₂(80 mL) was heated to reflux for 18 h and then concen-

trated to dryness under reduced pressure. The residue was

partially purified by flash column chromatography, eluting

with a gradient of 0-2% MeOH in CH₂Cl₂, to give a solid which

was recrystallized from hot Et₂O to give methyl 5-fluoro-4-

hydroxy-2-methoxybenzoate (1.57 g, 38%): ¹H NMR (CDCl₃)

δ 7.65 (1H, d, J ) 11.0 Hz), 6.62 (1H, d, J ) 7.3 Hz), 5.82 (1H,

br s), 3.86 (6H, s).

To a stirred solution of methyl 5-fluoro-4-hydroxy-2-meth-

oxybenzoate (500 mg, 2.50 mmol) in MeOH (5 mL) was added

aqueous NaOH (2 N, 6.25 mL, 12.5 mmol). The resulting

solution was heated to reflux for 3 h, then allowed to cool, and

concentrated in vacuo. The residue was partitioned between

20% citric acid (20 mL) and EtOAc (50 mL). The organic layer

was washed with water (2 × 20 mL), dried (MgSO₄), filtered,

and evaporated under reduced pressure to give the title

compound as a yellow solid (460 mg, 99%): ¹H NMR (CDCl₃)

δ 7.65 (1H, d, J ) 10.7 Hz), 6.62 (1H, d, J ) 7.1 Hz), 5.73 (1H,

br s), 4.04 (3H, s).

1-(1-{5-Flu or o-4-h ydr oxy-2-m eth oxyben zoyl}piper idin -

4-yl)-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e (19). A solution

of acid 18 (460 mg, 2.47 mmol), piperidine 6 (730 mg, 2.72

mmol), EDC (947 mg, 4.94 mmol), HOBT (367 mg, 2.72 mmol),

and DIEA (479 mg, 3.71 mmol) in dry, degassed DMF was

stirred for 18 h at ambient temperature. The solvent was

evaporated under reduced pressure and the residue partitioned

between 10% citric acid (75 mL) and EtOAc (75 mL). The citric

acid layer was extracted with a further portion of EtOAc (25

mL), and the combined organic extracts were washed with

water (2 × 50 mL), dried (MgSO₄), filtered, and concentrated

in vacuo. The residue was purified by flash column chroma-

tography, eluting with 3% MeOH in CH₂Cl₂, to yield the title

compound (500 mg, 51%): ¹H NMR (CDCl₃) δ 7.35 (1H, t, J )

7.2 Hz), 7.18-6.92 (3H, m), 6.51 (1H, d, J ) 7.0 Hz), 5.09 (2H,

s), 4.95 (1H, d, J ) 11.7 Hz), 4.13 (1H, m), 3.79-3.73 (3H, m),

3.72 (2H, m), 3.19-3.03 (1H, m), 2.89-2.56 (3H, m), 1.98-

1.77 (2H, m).

The following compounds were made in analogy with

pyridine N-oxide 50, utilizing the appropriate ketone,²⁵alcohol,

or chloride: 51-54.

(S)-1-(1-{5-F lu or o-2-m et h oxy-4-[1-(1-oxid o-5,6,7,8-t et -

r a h yd r oqu in olin -5-yl)p ip er id in -4-yloxy]ben zoyl}p ip er -

id in -4-yl)-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e [(S)-51].

Meth yl 4-Hyd r oxy-2-m eth oxyben zoa te (17). To a stirred,

0 °C solution of methyl 2,4-dihydroxybenzoate (7) (50 g, 0.30

mol) in acetone (1 L) were added K₂CO₃(150 g, 1 mol) and

benzyl bromide (56 g, 0.33 mol). The solution was allowed to

warm to ambient temperature over 48 h. The reaction solution

was filtered through Celite and the acetone solution stripped

down under reduced pressure. The crude oil was dissolved in

EtOAc (1 L) and washed with water (250 mL) and saturated

NaHCO₃(500 mL). The EtOAc layer was dried (MgSO₄) and

filtered, and the EtOAc was removed under reduced pressure.

The crude product was purified by flash column chromatog-

raphy, eluting with 15% EtOAc in hexanes, to give methyl

(R)-5-Hyd r oxy-5,6,7,8-tetr a h yd r oqu in olin e [(R)-22]. To

a

stirred solution of (S)-tetrahydro-1-methyl-3,3-diphenyl-

1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole-borane⁴¹(5.0 g, 17.1

mmol) and borane-methyl sulfide (10 M, 1.7 mL, 17 mmol)

in dry CH₂Cl₂(40 mL) at ambient temperature was added a

solution of ketone 21 (2.5 g, 17 mmol) in CH₂Cl₂(10 mL) over

5 min, during which time the temperature rose to 36 °C. The

2162 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12

Bell et al.

reaction was carefully quenched into MeOH (250 mL), and the

resulting solution was concentrated by distillation (1 atm) to

remove volatile impurities. The MeOH addition/distillation

was repeated (3×), and the crude residue was purified by flash

column chromatography, eluting with 87:12:1 hexane-EtOH-

triethylamine to remove diphenylprolinol and then with 40:

47:12:1 hexane-CH₂Cl₂-EtOH-triethylamine to elute the

product. Concentration of the product-containing fractions in

vacuo followed by trituration with tert-butyl methyl ether gave

the title compound as a white solid (2.2 g, 88%): ¹H NMR

(CDCl₃) δ 8.44 (1H, dd, J ) 4.8, 1.6 Hz), 7.77 (1H, dd, J ) 7.7,

1.3 Hz), 7.14 (1H, dd, J ) 7.7, 4.8 Hz), 4.82 (1H, br s), 3.03-

2.85 (2H, m), 2.15-2.02 (2H, m), 1.94-1.83 (3H, m); MS (FAB)

m/z ) 150 (M⁺+ H); HPLC (Chiralpak) >99% ee; [R]²⁰_D) -40°

(c ) 0.8, MeOH).

reduced pressure, and the residue was purified by flash column

chromatography, eluting with 5% MeOH-0.5% NH₄OH in

CH₂Cl₂, to give the title compound as a pale solid (188 mg,

41%): ¹H NMR (CDCl₃) δ 8.16 (1H, d, J ) 6.4 Hz), 7.69 (1H,

d, J ) 8.1 Hz), 7.12 (1H, t, J ) 7.1 Hz), 3.80 (1H, dd, J ) 10.5,

4.7 Hz), 3.71 (1H, m), 3.15 (1H, dd, J ) 19.1, 5.2 Hz), 2.79-

2.67 (2H, m), 2.60-2.53 (2H, m), 2.27-2.13 (2H, m), 2.04-

1.84 (3H, m), 1.73-1.46 (4H, m); MS (FAB) m/z ) 249 (M⁺

+

)

H); HRMS (FAB) m/z ) 249.1601 (M⁺+ H), C₁₄H₂₁N₂O₂

249.1603; HPLC (Chiralpak) 96.4% ee; [R]²⁰) +84° (c ) 0.8,

D

MeOH).

(S)-1-(1-{5-F lu or o-2-m et h oxy-4-[1-(1-oxid o-5,6,7,8-t et -

r a h yd r oqu in olin -5-yl)p ip er id in -4-yloxy]ben zoyl}p ip er -

id in -4-yl)-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e [(S)-51].

To a stirred solution of phenol 19 (178 mg, 0.44 mmol) and

triphenylphosphine (157 mg, 0.60 mmol) in dry THF (5 mL)

at 0 °C was added a solution of alcohol (S)-24 (100 mg, 0.40

mmol) and diethyl azodicarboxylate (77 mg, 0.44 mmol) in dry

THF (5 mL), dropwise. The reaction mixture was stirred at

ambient temperature for 18 h, the solvent was evaporated in

vacuo, and the residue was partitioned between saturated

NaHCO₃(10 mL) and CH₂Cl₂(5 mL). The organic layer was

removed and the aqueous phase extracted further with CH₂-

Cl₂(2 × 5 mL). The combined organic extracts were dried

(MgSO₄), filtered, and concentrated in vacuo to give a crude

residue which was chromatographed on silica gel, eluting with

3% MeOH-0.3% NH₄OH in CH₂Cl₂, to give the title compound

as a pale solid (175 mg, 69%). For the hydrochloride salt: ¹H

NMR (CD₃OD) δ 8.60 (1H, d, J ) 6.4 Hz), 8.16-8.00 (1H, m),

7.64 (1H, t, J ) 7.2 Hz), 7.40 (1H, td, J ) 7.8, 1.4 Hz), 7.31-

7.23 (2H, m), 7.21-6.89 (2H, m), 7.14 (1H, t, J ) 7.4 Hz), 5.14

(2H, s), 4.90-4.65 (3H, m), 4.23 (1H, m), 3.94-3.83 (3H, m),

3.61 (2H, m), 3.48 (2H, m), 3.33-3.04 (5H, m), 3.01-2.05 (10H,

m), 2.03-1.77 (2H, m); MS (FAB) m/z ) 631 (M⁺+ H); HRMS

(FAB) m/z ) 631.2912 (M⁺+ H), C₃₅H₄₀FN₄O₆) 631.2926;

HPLC purity ) 99.6% (method A; 215 nm); HPLC (Chiralpak)

(S)-5-Am in o-1-oxid o-5,6,7,8-tetr a h yd r oqu in olin e [(S)-

23]. A solution of alcohol (R)-22 (1.00 g, 6.70 mmol), diphenyl

phosphorazidate (2.77 g, 10.1 mmol), and DBU (1.53 g, 10.1

mmol) in dry toluene (10 mL) and dry THF (1 mL) was stirred

at ambient temperature for 18 h. The solvent was evaporated

under reduced pressure, and the residue was partitioned

between saturated NaHCO₃(75 mL) and CH₂Cl₂(75 mL). The

organic layer was removed and the aqueous phase extracted

further with CH₂Cl₂(2 × 50 mL). The combined organic

extracts were dried (MgSO₄), filtered, and concentrated in

vacuo to give a dark oil which was chromatographed on silica

gel, eluting with 30% EtOAc in hexane, to give (S)-5-azido-

5,6,7,8-tetrahydroquinoline as a colorless oil (1.05 g, 90%): ¹H

NMR (CDCl₃) δ 8.50 (1H, dd, J ) 4.8, 1.7 Hz), 7.63 (1H, dd, J

) 7.7, 1.1 Hz), 7.17 (1H, dd, J ) 7.7, 4.8 Hz), 4.59 (1H, t, J )

4.7 Hz), 3.02 (1H, m), 2.91 (1H, m), 2.15-1.97 (3H, m), 1.93

(1H, m); MS (FAB) m/z ) 175 (M⁺+ H); HPLC (Chiralpak)

99.1% ee; [R]²⁰) -36° (c ) 0.9, MeOH).

D

To a stirred solution of (S)-5-azido-5,6,7,8-tetrahydroquino-

line (1.02 g, 5.86 mmol) in CHCl₃(35 mL) was added mCPBA

(1.19 g, 85 wt %, 5.86 mmol), and the resulting mixture was

stirred at ambient temperature for 18 h. The reaction was

quenched with saturated NaHCO₃(75 mL) and the organic

layer extracted. The aqueous phase was extracted further

with CHCl₃(2 × 15 mL). The combined organic extracts were

dried (MgSO₄), filtered, and concentrated in vacuo to give an

oil which was chromatographed on silica gel, eluting with 5%

MeOH in EtOAc, to give (S)-5-azido-1-oxido-5,6,7,8-tetrahy-

droquinoline as a colorless oil (1.11 g, 100%): ¹H NMR (CDCl₃)

δ 8.25 (1H, d, J ) 6.4 Hz), 7.28 (1H, dd, J ) 7.7 Hz), 7.17 (1H,

dd, J ) 7.7, 6.4 Hz), 4.60 (1H, t, J ) 4.9 Hz), 3.05 (1H, dt, J

) 19.8, 5.8 Hz), 2.88 (1H, dt, J ) 19.8, 6.8 Hz), 2.16-1.88 (4H,

m); MS (FAB) m/z ) 191 (M⁺+ H); HRMS (FAB) m/z )

191.0957 (M⁺+ H), C₉H₁₁N₄O ) 191.0933; HPLC (Chiralpak)

96.8% ee; [R]²⁰) -27° (c ) 0.8, MeOH). Anal. (C₃₅H₃₉

-

D

FN₄O₆‚HCl‚2.25H₂O‚0.2CH₂Cl₂) C, H, N.

1-(1-{5-F lu or o-2-m eth oxy-4-[1-(qu in olin -5-yl)p ip er id in -

4-yloxy]ben zoyl}p ip er id in -4-yl)-1,4-d ih yd r oben z[d ][1,3]-

oxa zin -2-on e (55). To a stirred solution of 5-aminoquinoline

(222 mg, 1.54 mmol) in dry DMF (1 mL) was added 1,5-

dichloropentan-3-ol²²(220 mg, 1.40 mmol), anhydrous K₂CO₃

(426 mg, 3.08 mmol), and anhydrous NaI (115 mg, 0.77 mmol).

The reaction mixture was stirred at 100 °C for 4 h and then

partitioned between EtOAc (15 mL) and water (15 mL). The

aqueous layer was extracted with a further portion of EtOAc

(15 mL), and the combined organic extracts were dried (Na₂-

SO₄), filtered, and concentrated in vacuo. The residue was

purified by flash column chromatography, eluting with 40%

hexane in EtOAc, to give 5-(4-hydroxypiperidin-1-yl)quinoline

as a pale solid (67 mg, 21%): ¹H NMR (CDCl₃) δ 8.88 (1H, dd,

J ) 4.2, 1.7 Hz), 8.49 (1H, dt, J ) 7.7, 0.8 Hz), 7.81 (1H, d, J

) 8.4 Hz), 7.61 (1H, dd, J ) 8.3, 7.6 Hz), 7.39 (1H, dd, J )

8.4, 4.2 Hz), 7.12 (1H, dd, J ) 7.5, 0.7 Hz), 3.95 (1H, m), 3.32

(2H, dt, J ) 11.9, 4.0 Hz), 2.90 (2H, td, J ) 10.8, 2.3 Hz), 2.61

(1H, br s), 2.13 (2H, m), 1.91 (2H, m).

To a stirred solution of phenol 19 (58 mg, 0.145 mmol), 5-(4-

hydroxypiperidin-1-yl)quinoline (30 mg, 0.13 mmol), and tri-

phenylphosphine (52 mg, 0.197 mmol) in dry THF (2 mL) at 0

°C was added a solution of diethyl azodicarboxylate (25 mg,

0.145 mmol) in dry THF (2 mL), dropwise. The reaction

mixture was stirred at ambient temperature for 18 h and then

partitioned between saturated NaHCO₃(10 mL) and EtOAc

(10 mL). The organic layer was removed and the aqueous

phase extracted further with EtOAc (10 mL). The combined

organic extracts were dried (Na₂SO₄), filtered, and concen-

trated in vacuo to give a crude residue which was purified by

preparative TLC, eluting with EtOAc to give the title com-

pound as a pale solid (38 mg, 48%): ¹H NMR (CDCl₃) δ 8.90

(1H, dd, J ) 4.1, 1.6 Hz), 8.50 (1H, dd, J ) 8.1, 0.7 Hz), 7.81

(1H, d, J ) 8.4 Hz), 7.63 (1H, dd, J ) 8.4, 7.5 Hz), 7.40 (1H,

dd, J ) 8.6, 4.2 Hz), 7.35 (1H, td, J ) 7.8, 1.3 Hz), 7.20-7.03

(5H, m), 6.64 (1H, d, J ) 6.4 Hz), 5.09 (2H, s), 4.97 (1H, d, J

99.5% ee; [R]²⁰) -94° (c ) 0.8, MeOH).

D

A mixture of (S)-5-azido-1-oxido-5,6,7,8-tetrahydroquinoline

(1.00 g, 5.26 mmol) and 10% Pd-C (100 mg) in EtOH (50 mL)

was stirred under an atmosphere of hydrogen (ca. 1 atm) at

ambient temperature for 2 h. The reaction mixture was

filtered through a pad of Celite, and the filtrate was concen-

trated in vacuo to give a crude solid. Purification by flash

column chromatography, eluting with 7% MeOH-0.5% NH₄-

OH in CH₂Cl₂, gave the title compound as a pale solid (820

mg, 95%): ¹H NMR (CDCl₃) δ 8.18 (1H, d, J ) 6.4 Hz), 7.43

(1H, dd, J ) 8.1 Hz), 7.13 (1H, dd, J ) 8.1, 6.4 Hz), 3.99 (1H,

dd, J ) 6.9, 4.7 Hz), 2.96 (2H, t, J ) 6.4 Hz), 2.10-2.04 (2H,

m), 1.87 (1H, m), 1.73-1.54 (3H, m); MS (FAB) m/z ) 165 (M⁺

+ H); HRMS (FAB) m/z ) 165.1009 (M⁺+ H), C₉H₁₃N₂O )

165.1009; HPLC (Chiralpak) 96.7% ee; [R]²⁰_D) -4.0° (c ) 0.8,

MeOH).

(S)-5-(4-Hydr oxyp iper id in -1-yl)-1-oxido-5,6,7,8-tetr a h y-

d r oqu in olin e [(S)-24]. To a stirred solution of amine (S)-

23 (300 mg, 1.83 mmol) in 1-butanol were added 1,5-

dichloropentan-3-ol²²(260 mg, 1.66 mmol), anhydrous K₂CO₃

(505 mg, 3.65 mmol), and anhydrous NaI (274 mg, 1.83 mmol).

The reaction mixture was stirred at 75 °C for 18 h, then

additional portions of 1,5-dichloropentan-3-ol (57 mg, 0.37

mmol) and NaI (27 mg, 0.18 mmol) were added, and heating

was continued for 8 h. The solvent was evaporated under

Development of Orally Active Oxytocin Antagonists

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) 10.1 Hz), 4.58 (1H, br s), 4.15 (1H, m), 3.93-3.78 (3H, m),

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m), 2.30-2.09 (4H, m), 2.02-1.75 (2H, m); MS (FAB) m/z )

611 (M⁺+ H); HPLC purity ) 98.0% (method B; 215 nm).

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Su p p or tin g In for m a tion Ava ila ble: ¹H NMR and MS

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J M9800797

Article Doi

Development of orally active oxytocin antagonists: Studies on 1-(1-{4- [1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy].2methoxybenzoyl}- 4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines

DOI: 10.1021/jm9800797

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Full text of DOI:10.1021/jm9800797

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