Selective cyclooxygenase-2 inhibitors: Heteroaryl modified 1,2-diarylimidazoles are potent, orally active antiinflammatory agents

3168

J . Med. Chem. 2000, 43, 3168-3185

Selective Cyclooxygen a se-2 In h ibitor s: Heter oa r yl Mod ified

1,2-Dia r ylim id a zoles Ar e P oten t, Or a lly Active An tiin fla m m a tor y Agen ts

Ish K. Khanna,* Yi Yu, Renee M. Huff, Richard M. Weier,* Xiangdong Xu, Francis J . Koszyk, Paul W. Collins,

J . Nita Cogburn, Peter C. Isakson, Carol M. Koboldt, J aime L. Masferrer, William E. Perkins, Karen Seibert,

Amy W. Veenhuizen, J inhua Yuan, Dai-Chang Yang, and Yan Y. Zhang

Discovery Medicinal Chemistry and Inflammatory Disease Research, Pharmacia Corporation, 4901 Searle Parkway,

Skokie, Illinois 60077

Received February 18, 2000

A series of heteroaryl modified 1,2-diarylimidazoles has been synthesized and found to be potent

and highly selective (1000-9000-fold) inhibitors of the human COX-2. 3-Pyridyl derived COX-2

selective inhibitor (25) exhibited excellent activity in acute (carrageenan induced paw edema,

ED₅₀) 5.4 mg/kg) and chronic (adjuvant induced arthritis, ED₅₀) 0.25 mg/kg) models of

inflammation. The relatively long half-life of 25 in rat and dog prompted investigation of the

pyridyl and other heteroaromatic systems containing potential metabolic functionalities. A

number of substituted pyridyl and thiazole containing compounds (e.g., 44, 46, 54, 76, and 78)

demonstrated excellent oral activity in every efficacy model evaluated. Several orally active

diarylimidazoles exhibited desirable pharmacokinetics profiles and showed no GI toxicity in

the rat up to 100 mg/kg in both acute and chronic models. The paper describes facile and

practical syntheses of the targeted diarylimidazoles. The structure-activity relationships and

antiinflammatory properties of a series of diarylimidazoles are discussed.

In tr od u ction

quent publications reinforced that cyclooxygenase activ-

ity was also increased substantially by bacterial li-

popolysaccharide (LPS) in human monocytes¹⁰in vitro

and in murine peritoneal macrophages¹¹in vivo. This

increase was associated with de novo synthesis of a new

COX protein. It was observed that the glucocorticoid

dexamethasone blocked LPS induced prostaglandin

release by inhibiting the induction of COX expression

while having no effect on basal prostaglandin produc-

tion.^10,11Needleman and coauthors postulated the exist-

ence of an inducible, second isoform of COX enzyme and

hypothesized on its potential benefits.¹¹A year later,

molecular cloning experiments identified a distinct

isoform known as cyclooxygenase-2 (COX-2).¹²

The discovery of inducible enzyme (COX-2) and the

accumulating evidence that it may be possible to

separate its role from constitutive enzyme (COX-1)

spurred the search for a “super NSAID” with improved

therapeutic potential. A potent and selective COX-2

inhibitor should block the PG’s production in inflam-

matory cells while not interfering with the homeostatic

(COX-1 mediated) production of PG’s in the gastrointes-

tinal tract. The enormity of the COX-2 discovery is

reflected in the unprecedented speed at which research

laboratories have sought to validate its clinical implica-

tions. Recently, celecoxib¹³and refecoxib¹⁴became the

first cyclooxygenase-2 selective inhibitors to enter the

market.

Nonsteroidal antiinflammatory drugs (NSAIDs) such

as aspirin have been in existence for about a century

and have been used as first line therapy for relieving

inflammation and pain associated with a number of

arthritic conditions.¹Chronic usage of these drugs has

been associated with the propensity for side effects such

as gastrointestinal irritation²and suppression of renal

function³in part of the population. Without a handle

on the mechanism(s), common strategies that attempted

to modulate the adverse effect profile of NSAIDs have

varied from developing prodrugs⁴to modifications of the

marketed formulations.⁵In conjunction with broad

screening of the congeners of the marketed or lead

compounds in models of gastric damage, these ap-

proaches have helped identify compounds (e.g., DuP

697, meloxicam)^6,7with lower incidence of gastric le-

sions. The empirical nature of this approach has,

however, been less successful in stimulating researchers

in the field. Alternately, co-therapy of an NSAID with

a cytoprotective agent such as misoprostol has proven

beneficial in minimizing gastrointestinal damage in-

duced by selected antiinflammatory drugs.

In 1971, it was discovered that aspirin and other

NSAIDs exhibit their antiinflammatory effect by inhibi-

tion of the cyclooxygenase (COX) enzyme and blockage

of the synthesis of proinflammatory prostaglandins.⁸

This theory, however, did not discriminate the thera-

peutic from the toxic effects of these drugs. In the late

1980s, a major breakthrough in antiinflammatory re-

search occurred when it was reported⁹that cytokine

interleukin-1 (IL-1) stimulated the synthesis of the COX

enzyme in cultured human dermal fibroblasts. Subse-

Earlier we reported¹⁵our results on the syntheses and

antiinflammatory activity of a series of 1,2-diarylimi-

dazoles. These compounds (1) exhibited excellent

potency (IC₅₀) 10-100 nM) and selectivity (COX-1/

COX-2 ) 10³-10⁴) for the human cyclooxygenase-2

enzyme. Many of these compounds also displayed

impressive in vivo pharmacology in models of inflam-

mation. During these studies, it was observed that

* Address correspondence to Ish K. Khanna. Tel: 847 982 7727.

Fax: 847 982 4714. E-mail: ish.k.khanna@monsanto.com.

Published on Web 07/21/2000

Selective Cyclooxygenase-2 Inhibitors

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3169

Sch em e 1

arylsulfonamides (1, R₁) NH₂) generally displayed a

superior in vivo profile compared to the corresponding

aryl sulfones (1, R₁) Me). It was hypothesized that the

lower logP of arylsulfonamide vs the aryl sulfone (∆logP

∼ 0.5) contributed to its improved absorption and

bioavailability. In our continuing efforts to seek agents

with better oral activity, we explored the replacement

of the aromatic ring A in the lead template 1 by other

aromatic heterocycles. It was postulated that heteroaro-

matic analogues with improved water solubility would

also influence the observed plasma levels and bioavail-

ability in animal models. This paper describes the

syntheses, cyclooxygenase inhibitory activity, and the

antiinflammatory properties of a series of heteroaryl

modified 1,2-diarylimidazoles.

Sch em e 2

Ch em istr y

The 1,2-diarylimidazoles reported in this paper were

synthesized using Schemes 1-9. A number of analogues

containing a 4-(methylsulfonyl)phenyl group directly

attached to the imidazole nitrogen were synthesized

adopting the general methodology (Scheme 1) reported

by us earlier.¹⁵However, in certain instances, the step

involving amidine (5) formation gave inconsistent re-

sults during scale-up. Low solubility of some amidines

in organic solvents and the presence of aluminum salts

occasionally led to emulsion formation during the reac-

tion work up. This made the isolation of pure amidines

tedious. To improve organic solubility and to facilitate

amidine formation, the process was modified and 4-(me-

thylmercapto)aniline was used as the starting amine

(Scheme 2). This variation generally led to incremental

improvement in yield, but the problems associated with

work up of relatively less soluble amidines continued

to give erratic results on scale-up of the reaction. After

limited success with alternate Lewis acids and solvents,

base catalyzed amidine formation was studied on 3-cy-

anopyridine and 4-(methylmercapto) aniline. The results

reported in Scheme 3 clearly indicate that the base and

the reaction conditions significantly influence the out-

come of the reaction. The reactions using lithium

derived bases (examples 7 and 8) generally did not give

as good yields as obtained from bases containing sodium

counterion (e.g., 1-4, 9). Sodium methoxide proved to

be less efficient (examples 5 and 6) possibly because of

its stronger nucleophilicity and potential generation of

less reactive imidate on reaction with 3-cyanopyridine.

Best results were obtained when the amidine formation

was carried out in tetrahydrofuran with sodium bis-

(trimethylsilyl)amide as base. After completion, the

product (8, Scheme 2) was precipitated from the reaction

mixture by pouring over ice-water and collected by

filtration. The improved nucleophilicity of amidine 8 (vs

5, Scheme 1) also influenced the alkylation/cyclization

step. The reaction time for the synthesis of 9 (Scheme

2) was significantly shorter (3-6 h) in comparison to

18-36 h needed for the synthesis of 6 (Scheme 1). Use

of these modifications simplified the preparation and

scale-up of many target compounds. The isomeric com-

pound (34), wherein the pyridyl moiety is switched to

the imidazole N-1 position, was synthesized as in

Scheme 1 using 3-aminopyridine and 4-methylsulfonyl-

benzonitriles as starting materials.

Syn th esis of Ar yl Nitr iles. A number of aryl nitriles

used in the Schemes 1, 2, and 6 were purchased

3170 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16

Khanna et al.

Sch em e 3

Sch em e 4

commercially or synthesized using the reported proce-

dures. Some of the aryl nitriles were prepared from

commercially available intermediates by displacement

reactions or by functional group transformations (Scheme

4). For example, a number of 3-cyanopyridyl intermedi-

ates (3a -3d ) were made from substituted nicotinic acid

by conversion to the corresponding nicotinamides fol-

lowed by dehydration using trifluoroacetic anhydride/

triethylamine (see Experimental Section). 3-Cyano-4-

methyl pyridine (3e) was prepared¹⁷from 2,6-dihydroxy-

pyridine compound 4a by conversion to its 2,6-dichloro

derivative using POCl₃followed by hydrogenolysis

(NaOAc, PdCl₂). The intermediate 3f containing a

6-methoxy substituent was synthesized by cyanation

(DMF, CuCN, 120 °C) of the corresponding 3-bromopy-

ridine compound 4b.¹⁸Syntheses of 2-cyanopyridine

compounds (3g-3i) were accomplished readily from

commercially available intermediates. For example, the

cyano substituent in intermediates 3g and 3h was

incorporated by conversion of the corresponding 2-formyl

(via oxime) and 2-fluoro (NaCN, DMSO) derivatives,

respectively. 4-Picoline N-oxide was reacted with trim-

ethylsilyl cyanide to give 3i in a single pot process.¹⁹

Several heteroaromatic nitriles (3j-3p ) derived from

thiophene, thiazoles, and isoxazole were synthesized by

transformation of the corresponding formyl derivatives

using the standard literature procedures (see Experi-

mental Section). The aldehydes required for the syn-

thesis of 3j-3m were obtained commercially, while

those needed for 3n -3p were synthesized in the fol-

lowing manner. The intermediate 5-thiazolecarboxal-

dehyde (4c) was obtained by condensation of bromoma-

lonaldehyde with thioacetamide in the presence of

Hunig’s base. Metalation²⁰of 4-methylthiazole followed

by quenching with dimethylformamide proceeded in a

regioselective manner to give 4-methylthiazole-2-car-

boxaldehyde in 72% yield. The commercially available

isoxazole intermediate (4d ) was oxidized (oxalyl chlo-

ride, DMSO; 59%) to give the corresponding isoxazole-

3-carboxaldehyde. The oxazole derivative 3q was syn-

thesized using the methodology reported²¹for similar

compounds. The reaction of ethylacetimidate hydrochlo-

ride with aminoacetonitrile hydrochloride gave the

imidate 4e which was elaborated to the desired oxazole

3q by treatment with ethyl formate and potassium tert-

butoxide.

Syn th esis of Ar yl Su lfon a m id es. Diarylimidazoles

containing the sulfonamide group were prepared utiliz-

ing the methodologies outlined in Schemes 5 and 6. A

one-pot conversion of aryl methyl sulfone to aryl sul-

fonamide developed by Huang et al.²²was utilized to

synthesize a number of 1,2-diarylimidazoles.¹⁵This

direct process (7-10, Scheme 5), however, gave low

reaction yields (<10%) with pyridyl derived diarylimi-

dazoles. Because of the longer reaction times (>72 h)

and difficulties encountered in monitoring the progress

of the reaction, a modified two-step process based on

the methodology reported by Harring²³was explored

(Scheme 5). Regioselective generation of the carbanion

(LDA, -78 °C) on aryl methyl sulfone 7, followed by

quenching with (iodomethyl)trimethylsilane, gave the

trimethylsilylethyl sulfone intermediate (11) generally

in high yields (>70%). Desilylation (Bu₄N⁺F^-, THF,

reflux, 1 h) to the sulfinic acid salts followed by

treatment with hydroxylamine-O-sulfonic acid gave the

desired arylsulfonamide (10) in good yield (50-85%).

Selective Cyclooxygenase-2 Inhibitors

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3171

Sch em e 5

resulting intermediate 13 gave the desired aniline 14

in a combined yield of >70%. Base catalyzed (NaHMDS,

THF) amidine formation, alkylation, cyclization, and

dehydration steps proceeded efficiently to give the

intermediates in customary high yields. The sulfona-

mide (10) was generated in very high yield (>80%) from

the intermediate 16, by refluxing with aqueous trifluo-

roacetic acid.

Syn th esis of Su bstitu ted Im id a zoles. 1,2-Dia-

rylimidazoles with different substituents (Me, CHF₂,

CN, CO₂R, CH₂OH) at position-4 of the imidazole were

prepared by reacting the useful amidine intermediate

8 with appropriate electrophiles, followed by elaboration

of the sequence as discussed above in Schemes 1 and 2.

For example, reaction of 8 with ethyl bromopyruvate

under standard conditions (i-PrOH, NaHCO₃, reflux,

34%) gave the intermediate 20, which was oxidized

(oxone, 41%, Scheme 9) to the target 61. The analogue

62 with a hydroxymethyl group at C-4 was obtained by

reduction (DIBAL, 56%) of the corresponding ester

compound 61 (Scheme 9). Similarly, the reaction of

amidine 8 with 1-chloro-3,3-difluoroacetone²⁵gave the

cyclic intermediate 21, which was dehydrated (Ac₂O,

DMAP, reflux) to 22 and oxidized to the desired com-

pound 58.

Sch em e 6

The compound containing a 4-methyl substituent in

the imidazole ring was prepared as shown in Scheme

7. Direct alkylation/cyclization of the amidine 8 with

2-chloroacetone (2-PrOH, NaHCO₃, reflux, 24 h) was

very sluggish and gave low yield (<20%) of the inter-

mediate 18. After several unsatisfactory attempts at

modifying conditions, 1-bromo-2-methoxy-propene was

found to be an effective reagent. The reaction of 8 with

1-bromo-2-methoxy-2-propene in THF using sodium bis-

(trimethylsilyl)amide as a base gave the N-alkylated

product 17 in a regioselective fashion. Treatment of 17

with pyridinium p-toluenesulfonate (aqueous THF, re-

flux, 78%) gave 18, identical to the product obtained

from the 2-chloroacetone reaction. Unlike our experi-

ences with other analogues with different substitutions

at C-4 of the imidazole ring (e.g., CF₃, CHF₂, CN),

attempted oxidation of SMe group in 18 with oxone gave

significant amounts of pyridine N-oxide (19). A two-step

process involving oxidation (m-CPBA) of 18 to 19

followed by deoxygenation (cyclohexene, Pd/C) was

utilized to prepare the target compound 60.

Alternately, the desired arylsulfonamides (10) were

prepared following the reaction sequence outlined in

Scheme 6. The methodology is built on the successful

features of Schemes 1-3. The aniline 14 using 2,5-

dimethylpyrrole as the masked amino protecting group²⁴

was synthesized readily in two steps by starting with

4-nitrobenzenesulfonamide (12). Condensation of 12

with acetonylacetone (toluene, TsOH, reflux, 77%) fol-

lowed by reduction (Raney-nickel, MeOH, H₂) of the

The compound 59 with a cyano substituent at posi-

tion-4 of the imidazole was synthesized as shown in

Scheme 8. The reaction of amidine 8 with 2-chloroacryl-

onitrile using Hunig’s base gave the imidazoline 23 in

79% yield. Sulfur oxidation (oxone, 67%) followed by

aromatization (cumene, 10% Pd/C, reflux, 72%) of the

3172 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16

Khanna et al.

Sch em e 7

Sch em e 9

to “the reversed analogues” wherein the aryl ring B was

attached at the C-2 position of the imidazole. In

complementary work done on 1,2-diarylpyrroles, we

established¹⁶that COX-2 inhibitory activity was sensi-

tive to the manipulation of the aryl sulfone ring.

Specifically, addition of substituents to the aryl ring or

modification of the SO₂R group yielded less potent

inhibitors of the COX-2 enzyme. Similarly, our studies

demonstrated that the presence of a trifluoromethyl

group at C-4 position (R₂) CF₃) of the imidazole ring

contributes to excellent in vitro and in vivo properties

observed with this class of compounds.¹⁵Utilizing these

results, we selected the framework 2 to initiate hetero-

cyclic exploration of the aryl ring A.

Sch em e 8

On the basis of our experience¹⁵with the modifica-

tions of aryl ring A in structure 1, we had concluded

that while there was flexibility and tolerance of a variety

of substituents in the aryl ring, the C-3 position seemed

to offer the optimum combination of potency and

selectivity for human COX-2 enzyme. Thus, the 3-py-

ridyl analogue (25) was chosen as the first target for

biological evaluation.

The compound 25 inhibited human cyclooxygenase-2

enzyme with an IC₅₀of 1.85 µM and selectivity (IC₅₀

COX-1/IC₅₀COX-2) of >5000. In the human whole blood

assay, the compound exhibited much superior potency,

inhibiting LPS induced PGE₂production with an IC₅₀

of 0.2 µM. Similarly, the compound inhibited ionophore

A-23187 induced TXB₂production with an IC₅₀of 42

µM, indicating good selectivity for COX-2 enzyme. The

compound 25 was also very potent orally in the rat air-

pouch model and inhibited PGE₂production with an

ED₅₀of 0.2 mpk.

resulting dihydro intermediate 24 gave the desired

compound 59.

Resu lts a n d Discu ssion

Our SAR studies¹⁵on 1,2-diarylimidazoles (1) dem-

onstrated that the attachment of a methyl sulfone (or

sulfonamide) bearing aryl ring B to the imidazole

nucleus at N-1 gave superior COX-2 inhibitors compared

Selective Cyclooxygenase-2 Inhibitors

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3173

Ta ble 1. Isomeric Pyridines

moiety is switched to the N-1 position was significantly

less potent (IC_50,COX-2 ) >100 µM).

HWB,

PGE₂

HWB, air-pouch

TXB₂(% inhib.,

compd (IC₅₀, µM)^a(IC₅₀, µM)^a(IC₅₀, µM) (IC₅₀, µM) 2 mg/kg)

COX-2

COX-1

25 1.69 ( 0.39 >10000 0.20 ( 0.14 41.6 ( 0

100

26 1.5 ( 0.87

27 >100

>1000 0.24

>100

>10

a

Each result is the mean ( SD (n g 2).

The promising activity of 25 in human whole blood

and air-pouch model prompted us to examine the

isomeric pyridyl compounds 26 and 27. As apparent by

the data reported in Table 1, 4-pyridyl analogue 27 is a

significantly less potent inhibitor of COX-2 (IC₅₀) >100

µM). 2-Pyridyl compound 26 seems very similar to the

3-pyridyl compound 25 in its in vitro profile. Both

compounds showed 100% inhibition in the air-pouch

model at a screening dosage of 2 mg/kg. However,

further investigation of their behavior in in vivo models

of inflammation demonstrated 3-pyridyl isomer 25 to

be a superior compound. For example, in the carrag-

eenan induced paw edema rat model, compound 26

showed 37% inhibition of edema at 30 mg/kg. The

3-pyridyl compound 25 performed significantly better

controlling edema with an ED₅₀of 5.4 mg/kg. None of

the compounds reported in Table 1 showed appreciable

inhibition of LPS induced TNF production by human

peripheral blood monocytes at 10 µM, further confirming

the mechanism of action of these antiinflammatory

agents.

Compound 25 was evaluated in the acute (carrag-

eenan induced paw edema) and the chronic (adjuvant

induced arthritis) models of inflammation in the rat.

The details of these assays are reported in the Experi-

mental Section. The results, shown in Table 2, compare

its profile with non-pyridyl compound 35.¹⁵Diarylimi-

dazoles 25 and 35 showed excellent selectivity for COX-2

enzyme, and both of them showed potency comparable

with celecoxib in the chronic model of inflammation.

However, in the acute model (carrageenan induced

edema and hyperalgesia), compound 25 appears to be

4-7 times more potent than 35. On oral exposure in

rat at 10 mg/kg, compound 25 gave excellent blood levels

(C_maxof 10.5 µg/mL at 4.25 h). The observed plasma

levels and potential tissue distribution can at least offer

partial explanation to the superior effectiveness of 25

in acute models. The lower logP value of 25 compared

to 35 (2.0 vs 2.8) may have contributed to its improved

absorption and the observed plasma levels.

To probe the important structural features respon-

sible for enzyme activity, 3-pyridyl compound 25 was

derivatized and the resulting products evaluated against

COX-2 enzyme. Pyridine N-oxide analogue 28 was a less

potent inhibitor of COX-2 enzyme (IC₅₀) >100 µM),

and N-methylpyridinium analogue 29 was weakly active

(IC₅₀) 69 µM). Of the pyridone compounds examined,

isomeric pyridones 30 and 31 showed poor activity for

COX-2 (IC₅₀) >100 µM). The N-methylpyridone 32

showed some activity (IC₅₀, COX-2 ) 7 µM) and was

moderately potent in the air-pouch model (45% inhibi-

tion of PGE₂at 2 mg/kg). Interestingly, although 2- or

3-pyridyl derived compounds (25 and 26) are good

inhibitors of the COX-2 enzyme, the pyrazine compound

33 was a relatively weak inhibitor (IC_50,) >100 µM).

The results elaborated in Table 1 clearly show 25 as

a very potent antiinflammatory and analgesic agent. To

evaluate the GI safety, compound 25 was given orally

(100 mg/kg/day) to rats in an adjuvant induced arthritis

assay. No lesions or undesirable gastrointestinal toxicity

were seen with this compound after chronic dosage for

10 days. The compound seems remarkably stable to

metabolism and has a half-life of about 12 h in rat and

approximately 88 h in dog. The longer half-life in dog

stimulated us to probe compounds with built-in meta-

bolic functionalities.

Mod ifica tion of th e P yr id yl Su bstitu en ts. Based

on our experience with 1,2-diarylimidazoles,¹⁵it was

apparent that a variety of substituents (such as halo-

gens, Me, OMe, SMe, CH₂OMe, NO₂, CF₃, NR₂) could

be added to ring A to secure potent COX-2 inhibitors.

Examination of these data indicated that introduction

of a methyl or a OMe group might lead to a useful

combination of potency, selectivity, and desirable phar-

macokinetic properties. A number of substituted 3-py-

ridyl and 2-pyridyl derived compounds were synthesized

and evaluated (Tables 3 and 4) for inhibitory activity

vs the cyclooxygenase enzymes.

The arylsulfonamide compound 43 was a very potent

(IC₅₀) 0.4 µM) and selective (COX-1/COX-2 ) >2500)

inhibitor of recombinant human COX-2 enzyme. The

compound also caused complete blockage of PG produc-

tion in the air-pouch assay at the screening dose of 2

mg/kg. However, because of the observed long half-life

of 25 in dog and the lack of potential metabolic sites,

no additional testing was done on this compound. The

data reported in Table 3 suggest that a methyl sub-

stituent at the 2-, 5-, or 6-position in the pyridyl ring is

well tolerated. The sulfonamide analogues (44-46) seem

to be 3-5 times more potent than the corresponding

Consistent with our observations in the 1,2-diarylimi-

dazoles series,¹⁵the analogue 34 in which the pyridyl

3174 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16

Ta ble 2. In Vivo Pharmacology of 1,2-Diarylimidazoles

Khanna et al.

COX-2

COX-1

selectivity

COX-1/COX-2

edema

(ED₅₀, mg/kg)

adj. arthr.

(ED₅₀, mg/kg)

hyperalgesia

(ED₅₀, mg/kg)

compd

(IC₅₀, µM)^a

25

1.69 ( 0.39

0.13 ( 0

>10000

755 ( 231

>5000

5992

5.4 ( 2.9

20.8 ( 0

0.25 ( 0.14

0.15

8.2 ( 6.9

56 ( 0

35¹⁵

a

Each result is the mean ( SD (n g 2).

Ta ble 3. Pyridyl Modifications

Ta ble 5. Imidazole Substitutions

COX-2

COX-1

air-pouch

COX-2

COX-1

air-pouch

compd

R₄

R

(IC₅₀, µM)^a(IC₅₀, µM)^a(% inhib., 2 mg/kg)

compd

R

X

(IC₅₀, µM)^a(IC₅₀, µM)^a(% inhib., 2 mg/kg)

25

36

37

38

39

40

41

42

43

44

45

46

47

48

49

H

Me 1.69 ( 0.39 >10000

100

81

93

25 Me CF₃

1.69 ( 0.39 >10000

100

2-Me Me 9.6 ( 7.7

6-Me Me 1.8 ( 0.1

5-Me Me 1.8 ( 1.6

4-Me Me 54

6-OMe Me 1.2 ( 0.3

5-OMe Me 37.6

>100

>1000

>100

49

58 Me CHF₂20.7 ( 17.4

59 Me CN

60 Me Me

61 Me CO₂Et >100

62 Me CH₂OH 934

>100

>1000

>100

24.4 ( 24.8

79

75

100

>100

>1000

89

63 NH₂CHF₂1.83 ( 0.69

19

5-Br

H

Me 0.95 ( 0.21

NH₂0.44 ( 0.18

90

100

96

a

Each result is the mean ( SD (n g 2).

2-Me NH₂2.8 ( 0.64

6-Me NH₂0.29 ( 0.07

5-Me NH₂0.51 ( 0.02

4-Me NH₂51

5-OMe NH₂>100

5-Br

and 49) containing a 5-bromo substituent were very

potent and selective COX-2 inhibitors.

>1000

>100

>1000

As an extension of the encouraging in vitro and in

vivo results observed with methyl substituted 3-pyridyl

compounds, isomeric methyl substituted 2-pyridyl ana-

logues (Table 4) were also evaluated. Several analogues

show good inhibitory potency against the COX-2 en-

zyme. None of the aryl sulfones (50-53) showed sig-

nificant activity against COX-1 up to concentration of

1000 µM, indicating excellent selectivity for COX-2

enzyme. The affinity of sulfonamides 54-57 for COX-1

varies with the position of the methyl group in the aryl

ring. Interestingly, 3-methyl analogues (53 and 57) were

significantly more potent than similarly substituted

analogues (39 and 47) in the 3-pyridyl series. All of these

compounds also showed excellent inhibition (75-100%)

of prostaglandin production in the air-pouch model.

Mod ifica tion of th e Im id a zole Su bstitu en ts. To

study SAR and to potentially lower the half-life of lead

compound 25, the trifluoromethyl group in the imidazole

ring was substituted by a number of metabolizable

groups. These substituents had demonstrated good to

excellent potency vs COX-2 enzyme in a previously

reported¹⁵1,2-diarylimidazole series. As shown in Table

5, most of the analogues tested were significantly less

active than the lead compound 25. A difluoromethyl

analogue 63 was as potent as 25 in the human recom-

binant COX-2 enzyme assay but was only weakly active

in the air-pouch model. The results reaffirm that CF₃

is very critical component of the pharmacophore in this

series.

NH₂0.34 ( 0.11

26

a

Each result is the mean ( SD (n g 2).

Ta ble 4. Pyridyl Modifications

COX-2

COX-1

air-pouch

compd R₄

R

(IC₅₀, µM)^a(IC₅₀, µM)^a(% inhib., 2 mg/kg)

25

50

51

52

53

54

55

56

57

H

Me 1.69 ( 0.39 >10000

100

92

97

6-Me Me 2.9 ( 2.6 >1000

5-Me Me 1.3 ( 0.68 >1000

4-Me Me 0.53 ( 0.13 >1000

3-Me Me 5.8 ( 0.47 >1000

6-Me NH₂0.42 ( 0.13 >1000

5-Me NH₂0.73 ( 0.32 302

4-Me NH₂0.44 ( 0.19 84 ( 1.4

3-Me NH₂1.54 ( 0.15 338

84

100

75

100

a

Each result is the mean ( SD (n g 2).

sulfones (36-38) in their inhibition of COX-2 enzyme.

The sulfonamide analogues (44-46) performed very well

in the air-pouch model, showing excellent inhibition

(>95%) of PG production at 2 mg/kg. The analogues 39

and 47 containing a 4-methyl substituent were signifi-

cantly less potent against COX-2 enzyme. 5-Methoxy

analogues (41 and 48) were weak inhibitors of the

human COX-2 enzyme. The results reflect a noteworthy

deviation from our experiences with non-heteroaryl

imidazoles¹⁵wherein a methoxy at the 3- or 5- position

gave very potent COX-2 inhibitors. The compounds (42

Heter oa r yl Mod ifica tion s. The research done on

pyridyl and pyrazine derived analogues (vide supra)

strongly suggests that the position of heteroatom in the

ring and the orientation of the substituents greatly

influence the potency versus COX-2 enzyme. The excel-

lent properties demonstrated by some of these com-

pounds swayed us to probe other heteroaromatic sys-

Selective Cyclooxygenase-2 Inhibitors

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3175

Ta ble 6. Heteroaryl Modifications

a

Each result is the mean ( SD (n g 2).

tems. A number of compounds derived from five-member

and bicyclic heterocyclic ring systems were synthesized

and evaluated (Table 6). Many of these compounds carry

a methyl substituent to facilitate metabolism. The

isomeric quinoline compounds (64-66), which mimic

2-pyridyl (26) or 3-pyridyl (25) analogues, showed

similar affinity for COX-2 enzyme, but the selectivity

ratio (COX-1/COX-2) varied between 30 and >500. Of

these compounds, 66 showed excellent blockage of

prostaglandin production (90%) at 2 mg/kg in the air-

pouch model. N-Methyl indole analogue 67 showed

potency against COX-2, which was comparable with 25

and 26. Compound 67, however, performed poorly in the

air-pouch assay. Benzodioxole derived compounds (68

and 69) were very potent inhibitors of COX-2 enzyme

(IC₅₀) 0.28 and 0.47 µM, respectively). Compound 68

did not show good selectivity (COX-1/COX-2 ) 4), and

69 showed poor inhibition of PG production in the air-

pouch model. Among thiophene analogues, 2-thiophene

derived compounds (71, 72) were >100 times more

3176 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16

Ta ble 7. In Vivo Pharmacology of Selected 1,2-Diarylimidazoles

Khanna et al.

COX-2

COX-1

selectivity

COX-1/COX-2

adj. arthr.

edema

hyperalgesia

(ED₅₀, mg/kg)

compd

(IC₅₀, µM)^a

(ED₅₀, mg/kg)^b

(ED₅₀, mg/kg)^c

25

37

44

46

51

53

54

76

1.69 ( 0.39

1.8 ( 0.1

>10000

>5000

>550

>350

>2000

>600

>150

>2000

>9000

721

0.25 ( 0.14

0.20

1.00 ( 0.08

0.67

1.00

0.30

0.64

0.57

5.4 ( 2.9

41

6.9

8.2 ( 6.9

33% (30)

18

32

20% (30)

>1000

2.8 ( 0.64

0.51 ( 0.02

1.3 ( 0.68

5.8 ( 0.47

0.42 ( 0.13

0.52 ( 0.13

0.11 ( 0.05

0.79 ( 0.17

0.08 ( 0.03

0.18 ( 0.8

0.9

7.5

35% (30)

8.2

13.4

18

23

35.8

60% (20)

20.3

14.0

18.5

43

46

99

78

0.33

0.14

0.36 ( 0.16

35b

35c

35d

indomethacin

naproxen

789 ( 299

78 ( 19.8

25.9 ( 0.8

0.1

1500

162

0.1

0.94

66% (10)

a

b

Each result is the mean ( SD (n g 2). ED₅₀values were determined using a minimum of four dose points, 8-10 animals/group.

^cED₅₀values were determined using a minimum of four dose points and using 5 animals/group.

Ta ble 8. Pharmacokinetics of Selected 1,2-Diarylimidazoles in

Rat

potent (vs COX-2 enzyme) than the corresponding

3-thiophene analogue (70). Compound 72 also caused

route of

administration

elimination

half-life^a(h)

95% inhibition of prostaglandin production in the air-

pouch model. Of the heterocycles evaluated, thiazole

derived compounds demonstrated an excellent profile

overall. For example, compound 76 was a potent (IC₅₀,

COX-2 ) 0.5 µM), selective (COX-1/COX-2 ) >2000)

inhibitor and also blocked PG production completely at

a screening dosage of 2 mg/kg in the air-pouch model.

Compound 78 was an even more potent (IC₅₀) 0.11 µM)

and selective inhibitor. It also showed complete inhibi-

tion of prostaglandin production in the air-pouch model.

For reasons not apparent, oxazole (79) did not show

encouraging potency against the COX-2 enzyme. Isox-

azole derived compound 80 was a potent, selective

inhibitor of COX-2 and gave excellent inhibition (>90%)

in the air-pouch model at 2 mg/kg.

compd

dose (mg/kg)

25

44

46

76

10

2

iv

11.6

4.85 ( 1.26

4.96 ( 0.75

3.4

35d

2

7.1

a

Each result is the mean ( SD, 3-4 animals/group.

In Vivo P h a r m a cologica l Stu d ies. The potent and

selective COX-2 inhibitors emerging from the SAR

studies were evaluated in the acute (carrageenan in-

duced rat paw edema) and the chronic (adjuvant in-

duced arthritis in the rat) models of inflammation (Table

7). Most of the compounds examined in adjuvant

induced arthritis model showed excellent potency (ED₅₀

) 0.2-1 mg/kg) in controlling inflammation. The be-

havior of these compounds in acute models of edema

and hyperalgesia showed more variability with the

structures. As is evident from the data in Table 7,

several pyridyl compounds (e.g., 25, 44, 46, 54) showed

excellent in vivo potency in every efficacy model evalu-

ated. Consistent with results given in Table 2, selected

methyl substituted pyridyl compounds (e.g., 44, 46, and

54) were superior to the corresponding non-pyridyl

analogues (35b, 35c, and 35d )¹⁵in edema and particu-

larly in hyperalgesia models. Thiazole containing com-

pounds 76 and 78 also showed excellent selectivity (for

human COX-2) and superb potency in all the models of

inflammation and pain.

P h a r m a cok in etics Stu d ies in Ra t. Several com-

pounds with excellent pharmacological properties were

examined in the rat to assess their pharmacokinetics

(Table 8). Compound 25, with a half-life of 11.6 h in rat,

showed a longer life in dog (88 h). On the other hand,

compounds such as (44, 46, and 76) demonstrated an

excellent pharmacology profile and a very favorable

terminal phase elimination half-life (3-5 h) in rat

(Figure 1). On oral exposure in rat, heteroaromatic

F igu r e 1. Pharmacokinetics of selected diarylimidazoles in

rat.

compounds (e.g., 25, 44, 46, 76) generally exhibited

higher plasma levels (C_max) than observed with 35d .

These compounds (25, 44, 76) demonstrated excellent

bioavailability (>90%) in rat on oral dosing at 20 mg/

kg.

Ga str oin testin a l Toxicity Stu d ies. To test the

COX-2 hypothesis and to establish their safety profile,

the selected compounds from Table 7 were evaluated

in acute gastric and intestinal toxicity studies (Table

Selective Cyclooxygenase-2 Inhibitors

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3177

Ta ble 9. Gastric and Intestinal Toxicity Studies

Exp er im en ta l Section

dose

mg/kg (ig)

gastric^a

fasted rat

intestinal^a

fed rat

Biologica l Meth od s. Expression and purification of human

COX-1 and COX-2 enzymes and in vitro COX-1 and COX-2

enzyme assays have been described previously.²⁶The experi-

mental details of the carrageenan induced paw edema and

hyperalgesia models in the rat have also been published.²⁹The

rat adjuvant induced arthritis model was carried out using

the procedures described earlier.²⁸The gastric and intestinal

toxicity studies in the rat and the mouse were conducted using

the literature methods.^27,29

compd

vehicle^b

25

44

46

54

76

0/6

6/6

0/6

6/6

100

16

indomethacin

a

Ch em istr y (Gen er a l). NMR spectra were recorded in

CDCl₃, DMSO-d₆, or MeOH-d₄solution in 5-mm o.d. tubes

(Wilmad-535) at 20 °C and were collected on either a General

Electric QE-300, a Varian VXR-400, or a Varian VXR-500

spectrometer at 300, 400, or 500 MHz for ¹H (75, 100, or 125

MHz for ¹³C). Nuclear Overhauser effect (NOE) difference

spectra and two-dimensional NMR spectra were determined

on the VXR-400. The chemical shifts (δ) are relative to

tetramethylsilane (TMS, δ ) 0.00 ppm) and expressed in ppm.

Infrared spectra were recorded on a Perkin-Elmer model 681

or a Perkin-Elmer model 685 grating spectrophotometer in

CHCl₃solution or using KBr pellets; frequencies are expressed

in cm^-1. MIR were recorded on a Bio-Rad FTS-45 spectropho-

tometer. Melting points were determined on a Thomas-Hoover

capillary melting point apparatus. DSC measurements were

performed on a DuPont model 912 dual DSC system and run

under nitrogen. Mass spectra were obtained on either a

Finnigan-MAT model 4500 or a Finnigan-MAT 8430 system.

Microanalyses (C, H, N, S) were performed by the Microana-

lytical Group of the Physical Methodology Department at

Searle.

Number of animals with damage/number of animals treated.

A total of 0.5% aqueous methylcellulose.

b

9). No gastric lesions were observed in the fasted rat

after 5 h when the listed compounds (25, 44, 46, 54,

and 76) were administered intragastrically at 100 mg/

kg. Similarly no intestinal bleeding was detected in fed

rats after 72 h when these compounds were adminis-

tered intragastrically at 100 mg/kg. In contrast, in-

domethacin caused gastric and intestinal lesions in all

the animals examined at 16 mg/kg. The compounds 25

and 76 were also evaluated in the chronic model

(adjuvant induced arthritis) in rat at 100 mg/kg orally.

Neither compound showed any gastrointestinal damage

after dosing for 10 days, endorsing the safe profile of

these compounds.

Con clu sion

Trimethylaluminum, triethylaluminum, acetonylacetone,

triethylborane, 3-bromo-1,1,1-trifluoroacetone, iodomethyltri-

methylsilane, sodium bis(trimethylsilyl)amide, 2-chloroacryl-

onitrile, oxone, ethyl bromopyruvate, 1-bromo-2-methoxy-

propene, m-chloroperbenzoic acid, 4-(methylsulfonyl)aniline,

4-(methylmercapto)aniline, 4-nitro benzenesulfonamide, 5-bro-

monicotinic acid, methyl 5-hydroxynicotinate, 2-methyl-nico-

tinic acid, 2-fluoro-5-methyl pyridine, 4-picoline N-oxide,

5-methyl isoxazole-3-methanol, 4-methylthiazole-2-carboxalde-

hyde, and other starting materials and reagents, unless

otherwise specified, were all commercial products. Solvents

used were reagent grade or were dried using conventional

procedures. The reactions were routinely carried out under an

inert atmosphere unless otherwise indicated. Analytical chro-

matography was performed on EM Reagents 0.25 mm silica

gel 60-F plates. Preparative chromatographic separations were

carried out on Merck silica gel 60 (230-400 mesh).

Gen er a l P r oced u r e for th e P r ep a r a tion of 1,2- Dia r -

ylim id a zoles Con ta in in g a Meth yl Su lfon e Su bstitu en t.

All diarylimidazoles containing a methyl sulfone group were

prepared following the general Schemes 1-3. The synthesis

of 3-[1-{4-(methylsulfonyl) phenyl-4-trifluoromethyl-1H-imi-

dazol-2-yl]pyridine (25) is described below as an example for

methods A and B.

The series of 1,2-diarylimidazoles described in this

paper are potent and highly selective inhibitors of

human cyclooxygenase-2 enzyme. The enzymatic and in

vivo data (air-pouch model) on isomeric pyridyl ana-

logues indicates that 2- and 3- pyridyl compounds (25

and 26) are significantly more potent than 4-pyridyl

analogue 27. Pyridyl compound 25 also shows excellent

antiinflammatory and analgesic properties in every

efficacy model. The studies aimed at modulating the

extended half-life of 25 resulted in a number of meth-

ylated pyridine analogues (e.g., 44, 46, 54) that dem-

onstrate an excellent overall profile in all in vitro and

in vivo models (Table 7). Selected pyridyl compounds

(e.g., 25, 44, 46, and 54) were superior to the corre-

sponding non-pyridyl analogues (35, 35b, 35c, and 35d )

in edema and particularly in the hyperalgesia model

(Tables 2, 7). Detailed investigation of the analogues

derived from other heteroaromatic systems shows that

their potency, selectivity, and in vivo profile are greatly

influenced by the substitution pattern. Thiazole derived

compounds (e.g., 76 and 78) are very potent (IC₅₀) 0.5

and 0.1 µM, respectively) and selective (IC₅₀COX-1/

COX-2 ) >2000-9000) inhibitors of the human cy-

clooxygenase-2 enzyme. These compounds also exhibit

superb potency in the adjuvant induced arthritis model

(ED₅₀∼ 0.6 mg/kg) as well as in the carrageenan

induced model of inflammation and hyperalgesia (ED₅₀

) 13-18 mg/kg, Table 7). In imidazole substitutions,

the CF₃group at C-4 position (Table 5) gives the

optimum potency and antiinflammatory properties.

Excellent in vivo properties exhibited by a number of

compounds (e.g, 44, 46, 54, 76, 78) and the absence of

GI toxicity in the selected compounds up to 100 mg/kg

in rat demonstrates that heteroaryl modified 1,2-

dairylimidazoles represent a series of potent antiin-

flammatory agents with an improved side effect profile.

3-[1-{4-(Meth ylsu lfon yl)p h en yl}-4-tr iflu or om eth yl-1H-

im id a zol-2-yl]p yr id in e (25, Meth od A). Step 1: P r ep a r a -

tion of N-[4-(Meth ylth io)p h en yl]-3-p yr id in eca r boxa m id -

a m id e (Ba se Ca ta lyzed ). To a solution of sodium bis(trimeth-

ylsilyl) amide in THF (380 mL, 1 M solution, 0.38 mol) was

added dropwise at room temperature a solution of 4-(meth-

ylmercapto)aniline (50.0 g, 0.36 mol) in 50 mL of dry THF.

After the mixture was stirred for 20 min, a solution of

3-cyanopyridine (39.4 g, 0.38 mol) in 20 mL of dry THF was

added. The reaction mixture was stirred for 4 h then poured

into 2 L of ice-water. The precipitate was collected by

filtration, washed with a solution of ether and hexane (3/7,

300 mL), and air-dried to give 83.7 g of product as a light

yellow solid (96% yield): mp (DSC) 157-159 °C; MIR 3275,

1

3072, 2918, 1661, 1604, 1561, 1482, 1376; H NMR (CD₃OD)

8.88 (d, J ) 2 Hz, 1H), 8.65 (dd, J ) 5, 2 Hz, 1H), 8.24 (dd, J

) 8, 2 Hz, 1H), 7.52 (dd, J ) 8, 5 Hz, 1H), 7.32 (d, J ) 8 Hz,

2H), 6.97 (d, J ) 8 Hz, 2H), 2.47 (s, 3H); MS (CI) 244 (MH⁺).

Anal. (C₁₃H₁₃N₃S) C, H, N.

3178 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16

Khanna et al.

Step 1: P r ep a r a tion of N-[4-(Meth ylth io)p h en yl]-3-

p yr id in eca r boxim id a m id e (Acid Ca ta lyzed ). To a suspen-

sion of 4-(methylmercapto)aniline (50 g, 0.36 mol) in 1,2-

dichloroethane (2 L) at 0 °C was added triethylaluminum (284

mL, 1.9 M solution in toluene, 0.47 mol) over 1 h. The reaction

mixture was warmed to room temperature and stirred for 2

h. A solution of 3-cyanopyridine (56.1 g, 0.47 mol) in 1,2-

dichloroethane (300 mL) was added over 10 min, and the

reaction mixture heated to 70-80 °C. After 18 h, the reaction

mixture was cooled to room temperature and poured over a

slurry of silica gel (110 g) in chloroform/methanol (4/1, 1 L).

After being stirred for 1 h, the mixture was filtered and the

residue washed with a mixture of methylene chloride/methanol

(4/1, 2 L). The combined filtrates were concentrated in vacuo,

and the resulting brownish yellow solid was stirred with a

solution of ethyl acetate/ether (4/1, 600 mL). The intermediate

was filtered and washed with additional ethyl acetate/ether

(4/1). The yellowish solid (53.0 g, 61%), identical to the product

obtained above, was used in the next reaction without further

purification.

1H), 8.06 (d, J ) 8 Hz, 2H), 7.82 (dd, J ) 8, 2 Hz, 1H), 7.58 (s,

1H), 7.47 (d, J ) 8 Hz, 2H), 7.31 (dd, J ) 8, 5 Hz, 1H), 3.12 (s,

3H); MS (DCI) 368 (MH⁺). Anal. (C₁₆H₁₂N₃SO₂F₃) C, H, N, S.

3-[1-{4-(Meth ylsu lfon yl)p h en yl}-4-tr iflu or om eth yl-1H-

im id a zol-2-yl]p yr id in e (25, Meth od B). Step 1: P r ep a r a -

tion of N-[4-(Meth ylsu lfon yl)p h en yl]-3-p yr id in eca r box-

a m id a m id e. To a suspension of 4-(methylsulfonyl)aniline

hydrochloride (6 g, 28.8 mmol) in toluene (150 mL) at 0 °C

was added trimethylaluminum (21.6 mL, 2 M solution in

toluene, 43.2 mmol) over 15 min. The reaction mixture was

warmed to room temperature and stirred for 2.5 h. A solution

of 3-cyanopyridine (6.0 g, 57.6 mmol) in toluene (150 mL) was

added over 10 min and the reaction mixture heated to 90-95

°C. After 24 h, the reaction mixture was cooled to room

temperature and poured over a slurry of silica gel in chloroform/

methanol (2/1). After filtration, the residue was washed with

a mixture of methylene chloride/methanol (2/1). The combined

filtrates were concentrated in vacuo, and the resulting yel-

lowish solid was stirred with ethyl acetate (1000 mL). The

intermediate was filtered and washed with additional ethyl

acetate. The pale yellowish solid (4.5 g, 34%) was used in the

next reaction without further purification: mp (DSC) 265 °C;

Step 2: P r ep a r a tion of 4,5-Dih yd r o-1-[4-(m eth ylth io)-

p h en yl]-2-(3-p yr id in yl)-4-(tr iflu or om eth yl)-1H-im id a zol-

4-ol. To a mixture of N-[4-(methylthio)phenyl]-3-pyridinecar-

boximidamide (65.0 g, 0.27 mol) and sodium bicarbonate (33.6

g, 0.40 mol) in 2-propanol (2.3 L) was added 3-bromo-1,1,1-

trifluoroacetone (81.6 g, 0.43 mol). The reaction mixture was

heated at 50 °C for 1.5 h and at 75-80 °C for 3 h. The reaction

mixture was cooled to room temperature and filtered. Part of

the solvent (1.5 L) was removed under reduced pressure, and

the mixture cooled to room temperature. The precipitated solid

was filtered and washed with 2-propanol (200 mL) and

acetonitrile (100 mL) to give 4,5-dihydro-1-[4-(methylthio)-

phenyl]-2-(3-pyridinyl)-4-(trifluoromethyl)-1H-imidazol-4-ol as

a pale yellow solid (60.1 g, 64%): mp (DSC) 192 °C; IR (KBr)

3412, 3034, 2826, 1601, 1581, 1550, 1495, 1400; ¹H NMR

(DMSO-d₆) 8.60-8.66 (complex band, 2H), 7.84 (dd, J ) 8, 2

Hz, 1H), 7.43 (dd, J ) 8, 5 Hz, 1H), 7.32 (s, 1H), 7.17 (d, J )

8 Hz, 2H), 6.96 (d, J ) 8 Hz, 2H), 4.36 (d, J ) 11 Hz, 1H), 3.87

(d, J ) 11 Hz, 1H), 2.43 (s, 3H); MS (EI) 353 (M⁺). Anal.

(C₁₆H₁₄N₃SOF₃) C, H, N, S.

1

IR (KBr) 3898, 2991, 2916, 1618, 1593, 1564, 1506, 1491; H

NMR (DMSO-d₆) 9.10 (d, J ) 2 Hz, 1H), 8.90 (dd, J ) 5, 2 Hz,

1H), 8.37 (dd, J ) 8, 5 Hz, 1H), 8.07 (d, J ) 8 Hz, 2H), 7.66-

7.76 (complex band, 3H), 3.27 (s, 3H); MS (DCI) 276 (MH⁺).

Anal. (C₁₃H₁₃N₃SO₂‚HCl‚0.5H₂O) C, H, N.

Step 2: P r ep a r a tion of 4,5-Dih yd r o-1-[4-(m eth ylsu lfo-

n yl)p h en yl]-2-(3-p yr id in yl)-4-(t r iflu or om et h yl)-1H -im i-

d a zol-4-ol. To a mixture of amidine of step 1 (4.4 g, 16 mmol)

and sodium bicarbonate (2.7 g, 32 mmol) in 2-propanol (400

mL) was added 3-bromo-1,1,1-trifluoroacetone (2.5 mL, 24

mmol). The reaction mixture was heated at 70-75 °C for 36

h, cooled to room temperature, and filtered. The residue was

washed with methylene chloride, and the combined organic

fractions were dried over sodium sulfate, filtered, and concen-

trated. The crude mixture (16.2 g) was chromatographed (silica

gel, ethyl acetate/acetone (98:2) to give 4,5-dihydro-1-[4-

(methylsulfonyl)phenyl]-2-(3-pyridinyl)-4-(trifluoromethyl)-1H-

imidazol-4-ol (3.7 g, 60%) as a white solid: IR (KBr) 3854,

3752, 3676, 1585, 1498, 1466, 1419; ¹H NMR (CDCl₃) 9.12 (d,

J ) 2 Hz, 1H), 8.72 (dd, J ) 5, 2 Hz, 1H), 7.82 (d, J ) 8 Hz,

2H), 7.76 (dt, J ) 8, 2 Hz, 1H), 7.34 (dd, J ) 8, 5 Hz, 1H), 7.02

(d, J ) 8 Hz, 2H), 4.40 (d, J ) 11 Hz, 1H), 4.13 (d, J ) 11 Hz,

1H), 3.04 (s, 3H); MS (EI) 385 (M⁺). Anal. (C₁₆H₁₄N₃SO₃F₃‚

0.75H₂O) C, H, N.

Step 3: P r ep a r a tion of 3-[1-{4-(Meth ylsu lfon yl)p h en -

yl}-4-tr iflu or om eth yl-1H-im id a zol-2-yl]p yr id in e (25). A

mixture of the product of step 2 (4.3 g, 11.2 mmol) and

p-toluenesulfonic acid monohydrate (0.9 g, 4.73 mmol) in

toluene (300 mL) was heated to reflux for 48 h. The reaction

mixture was cooled and the solvent removed under reduced

pressure. The crude residue was purified by chromatography

on silica gel using ethyl acetate/acetone (98/2) to give pure 25

(2.3 g, 56%) as a white solid, identical in properties to the

product described in step 4, method A.

Step 3: P r ep a r a tion of 3-[1-{4-(Meth ylth io)p h en yl}-4-

t r iflu or om et h yl-1H -im id a zol-2-yl]p yr id in e.

A mixture

of 4,5-dihydro-1-[4-(methylthio)phenyl]-2-(3-pyridinyl)-4-(tri-

fluoromethyl)-1H-imidazol-4-ol (103.3 g, 8.7 mmol) and p-

toluenesulfonic acid monohydrate (15.5 g) in toluene (2.2 L)

was heated to reflux for 4 h. The reaction mixture was cooled

and the solvent removed under reduced pressure. The crude

residue was redissolved in methylene chloride (900 mL) and

treated with aqueous ammonium hydroxide (10%, 1.2 L). The

mixture was stirred for 1 h and the organic layer separated.

After drying (Na₂SO₄), filtration, and concentration in vacuo,

the crude mixture (5.2 g) was purified by chromatography on

silica gel using hexane/ethyl acetate (55/45) as eluent to give

3-[1-{4-(methylthio)phenyl}-4-trifluoromethyl-1H-imidazol-2-

yl]pyridine (92.1 g, 94%) as a brown solid: mp (DSC) 93 °C;

1

IR (KBr) 3850, 3152, 3080, 2932, 1633, 1574, 1500, 1452; H

All diarylimidazoles (25-27, 33-42, 50-53, 64-71, 73-

75, and 79) containing a methylsulfonyl group and a CF₃group

at position-4 of the imidazole ring were prepared by utilizing

one of the methods described above. The experimental proce-

dures given for method A generally gave superior yields and

were preferred. The amidine formation was carried preferen-

tially using the base-catalyzed process detailed in step 1,

method A. Diarylimidazoles (58-62) containing different

substituents at C-4 of imidazole ring were prepared by

modifications of these conditions (vide infra).

Gen er a l P r oced u r e for th e P r ep a r a tion of 1,2-Dia r -

ylim id a zoles Con ta in in g a Su lfon a m id e Su bstitu en t. All

1,2-diarylimidazoles with a sulfonamide group in the aryl rings

were prepared following the general Schemes 5 and 6. The

syntheses of 43, 76, and 46 are used as examples to describe

the procedures (methods A, B, and C, respectively).

NMR (CDCl₃) 8.52-8.61 (complex band, 2H), 7.82 (dd, J ) 8,

2 Hz, 1H), 7.48 (s, 1H), 7.26 (d, J ) 8 Hz, 2H), 7.22-7.30

(complex band, 1H), 7.17 (d, J ) 8 Hz, 2H), 2.52 (s, 3H); MS

(CI) 336 (MH⁺). Anal. (C₁₆H₁₂N₃SF₃‚0.1H₂O) C, H, N, S.

Step 4: P r ep a r a tion of 3-[1-{4-(Meth ylsu lfon yl)p h en -

yl}-4-tr iflu or om eth yl-1H-im id a zol-2-yl]p yr id in e (25). A

solution of oxone (379 g, 0.62 mol) in water (1.8 L) was added

to the product of step 3 (103.2 g, 0.31 mol) in methanol (950

mL). The reaction is slightly exothermic, and the temperature

of the reaction was prevented from rising by a surrounding

water bath. After being stirred at room temperature for 1 h,

the mixture was treated with dilute ammonium hydroxide

(10%, 1 L). The contents were stirred for an hour and the

precipitated solid filtered and washed with water. The crude

mixture was chromatographed (silica gel, ethyl acetate/acetone

98/2) to give pure 1 (90.3 g, 79%) as a white solid: mp (DSC)

193 °C; IR (KBr) 3850, 3155, 3005, 1934, 1578, 1456, 1024;

¹H NMR (CDCl₃) 8.61 (dd, J ) 5, 2 Hz, 1H), 8.53 (d, J ) 2 Hz,

4-[2-(3-P yr id in yl)-4-(t r iflu or om et h yl)-1H -im id a zol-1-

yl]ben zen esu lfon a m id e (43, Meth od A). Step 1: P r ep a r a -

Selective Cyclooxygenase-2 Inhibitors

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3179

tion of 3-[4-(Tr iflu or om eth yl)-1-[4-{(2-tr im eth yl silyl)-

et h yl}su lfon yl]p h en yl]-1H -im id a zol-2-yl]p yr id in e. To

diisopropylamine (2.48 mL, 18 mmol) in 20 mL of dry THF at

0 °C was added BuLi (8.6 mL, 1.90 M solution in hexane, 16

mmol). The solution was stirred for 5 min and then cooled to

-78 °C with dry ice/2-propanol bath. A solution of 25 (5.0 g,

14 mmol) in 30 mL of dry THF was added over 10 min and

the reaction mixture stirred for 1 h. (Iodomethyl)trimethylsi-

lane (4.37 g, 20 mmol) was added dropwise and the mixture

stirred overnight while allowing to warm to room temperature.

The reaction was quenched with 200 mL of 1 N HCl and the

aqueous phase extracted with ethyl acetate (3 × 60 mL). The

combined organic fractions were washed with brine, dried over

MgSO₄, filtered, and concentrated. The crude residue was

purified by chromatography on silica gel (ethyl acetate/hexane,

65:35) to give 4.36 g of 3-[4-(trifluoromethyl)-1-[4-{(2-trimeth-

ylsilyl)ethyl}sulfonyl]phenyl]-1H-imidazol-2-yl]pyridine as a

crude mixture was chromatographed (silica gel, ethyl acetate/

toluene 1:1) to give 1-[[4-{4,5-dihydro-4-hydroxy-2-(2-methyl-

4-thiazolyl)-4-(trifluoromethyl)-1H-imidazol-1-yl}phenyl]sulfonyl-

2,5-dimethyl-1H-pyrrole (0.32 g, 49%) as a brownish solid: mp

(DSC) 221 °C; MIR 3123, 1593, 1581, 1517, 1499, 1363; ¹H

NMR (DMSO-d₆) 8.14 (s, 1H), 7.58 (d, J ) 8 Hz, 2H), 7.43 (br

s, 1H), 6.97 (d, J ) 8 Hz, 2H), 5.93 (s, 2H), 4.47 (d, J ) 12 Hz,

1H), 3.94 (d, J ) 12 Hz, 1H), 2.49 (s, 3H), 2.30 (s, 6H); MS

(CI) 485 (MH⁺). Anal. (C₂₀H₁₉N₄S₂O₃F₃) C, H, N, S.

Step 3: P r ep a r a tion of 2,5-Dim eth yl-1-[[4-{2-(2-m eth yl-

4-th ia zolyl)-4-(tr iflu or om eth yl)-1H-im id a zol-1-yl}p h en yl]-

su lfon yl]-1H-p yr r ole. A mixture of the product from step 2

(6.1 g, 12.6 mmol) and p-toluenesulfonic acid monohydrate

(0.91 g) in toluene (50 mL) was refluxed with a Dean-Stark

trap for 19 h. The reaction mixture was cooled and the solvent

removed under reduced pressure. The crude residue was

dissolved in methylene chloride and washed with saturated

sodium bicarbonate solution, dried over sodium sulfate, and

filtered. The combined organic fractions were concentrated and

the crude mixture purified by chromatography on silica gel

(ethyl acetate/toluene, 3/7) to give 2,5-dimethyl-1-[[4-{2-(2-

methyl-4-thiazolyl)-4-(trifluoromethyl)-1H-imidazol-1-yl}phenyl]-

sulfonyl]-1H-pyrrole as a brownish solid (4.9 g, 83%): mp

(DSC) 205 °C; MIR 3157, 3120, 2958, 2927, 1597, 1576, 1500,

1

white solid (71%): mp (DSC) 177-178 °C; H NMR (CDCl₃)

8.57 (dd, J ) 5, 2 Hz, 1H), 8.53 (dd, J ) 2, 1 Hz, 1H), 7.96 (d,

J ) 8.5 Hz, 2H), 7.73 (m, 1H), 7.54 (m, 1H), 7.42 (d, J ) 8.5

Hz, 2H), 7.25 (dd, J ) 8, 5 Hz, 1H), 3.00 (m, 2H), 0.92 (m,

2H). Anal. (C₂₁H₂₄F₃N₃O₂SSi) C, H, N.

Step 2: P r ep a r a tion of 4-[2-(3-P yr id in yl)-4-(tr iflu or o-

m eth yl)-1H-im id a zol-1-yl]ben zen esu lfon a m id e (43). To a

solution of the product of step 1 (4.28 g, 9.4 mmol) in 25 mL of

dry THF was added tetrabutylammonium fluoride (28.3 mL,

1 M solution in THF, 28 mmol). The mixture was refluxed for

1 h and cooled to room temperature. A solution of sodium

acetate (3.66 g, 47 mmol) in 10 mL of water and hydroxyl-

amine-O-sulfonic acid (5.56 g, 47 mmol) were added sequen-

tially, and the mixture was stirred for 1 h. The reaction

mixture was quenched by adding water (50 mL) and extracted

with ethyl acetate. The organic fractions were washed sequen-

tially with saturated NaHCO₃solution, water, and brine. After

drying (MgSO₄) and filtration, the mixture was concentrated

and the residue purified by chromatography on silica gel (ethyl

acetate/acetone, 95:5) to give 2.77 g of 43 as a colorless solid

(80%): mp 219-221 °C; IR (KBr) 3319, 3177, 3092, 3013, 1599,

1

1360; H NMR (CDCl₃) 7.72 (d, J ) 8 Hz, 2H), 7.67 (s, 1H),

7.43 (s, 1H), 7.40 (d, J ) 8 Hz, 2H), 5.90 (s, 2H), 2.47 (s, 3H),

2.42 (s, 6H); MS (CI) 467 (MH⁺). Anal. (C₂₀H₁₇N₄S₂O₂F₃) C,

H, N, S.

Step 4: P r epar ation of 4-[2-(2-Meth ylth iazol-4-yl)-4-(tr i-

flu or om eth yl)-1H-im idazol-1-yl]ben zen esu lfon am ide (76).

A mixture of the product from step 3 (5.6 g, 12 mmol) in

trifluoroacetic acid (90 mL) and water (30 mL) was refluxed

for 3 h. Trifluoroacetic acid was removed by distillation and

the residue neutralized with saturated aqueous potassium

carbonate. The product was extracted with methylene chloride

(3 × 500 mL) and later with ether/acetone 8/2 (3 × 200 mL).

The combined organic fractions were combined, dried over

MgSO₄, and filtered. The filtrate was concentrated and the

resulting crude residue purified by chromatography (silica gel,

ethyl acetate/toluene, 6/4) to give 76 as a white solid (3.6 g,

77%): mp (DSC) 252 °C; IR (KBr) 3314, 1582, 1501, 1454,

1

1579, 1516, 1498; H NMR (CD₃OD) 8.53 (br s, 2H), 8.07 (m,

1H), 7.97 (d, J ) 8.5 Hz, 2H), 7.81 (ddd, J ) 8, 2, 1.6 Hz, 1H),

7.53 (d, J ) 8.5 Hz, 2H), 7.40 (dd, J ) 8, 5 Hz, 1H); MS (DCI)

369 (MH⁺). Anal. (C₁₅H₁₁F₃N₄O₂S) C, H, N, S.

4-[2-(2-Meth ylth ia zol-4-yl)-4-(tr iflu or om eth yl)-1H-im i-

d a zol-1-yl]ben zen esu lfon a m id e (76, Meth od B). The pro-

cess shown in Scheme 6 utilizes 14 for amidine formation. A

two-step preparation of 14 is shown following the synthesis

of the target compound 76.

1

1404, 1364; H NMR (CDCl₃) 8.02 (d, J ) 8 Hz, 2H), 7.58 (s,

1H), 7.46 (d, J ) 8 Hz, 2H), 7.43 (s, 1H), 2.54 (s, 3H); MS

(APCI) 389 (MH⁺). Anal. (C₁₄H₁₁N₄S₂O₂F₃) C, H, N, S.

The synthesis of intermediate 1-[(4-aminophenyl)sulfonyl]-

2,5-dimethyl-1H-pyrrole (14) used in the preparation above

(step 1) is shown below.

Step 1: P r ep a r a tion of N-[4-{(2,5-Dim eth yl-1H-p yr r ol-

1-yl)su lfon yl} p h en yl]-2-m et h yl-4-t h ia zoleca r b oxim id -

a m im id e. To sodium bis(trimethylsilyl)amide (80 mL, 1 M

solution in THF, 80 mmol) was added dropwise at room

temperature a solution of 14 (20 g, 80 mmol) in 200 mL of dry

THF. After the darkened reaction mixture was stirred for 10

min, a solution of 2-methylthiazole-4-carbonitrile (10.6 g, 84.8

mmol) in 50 mL of dry THF was added. The reaction mixture

was stirred for 16 h and poured into 500 mL of ice-water and

stirred for 10 min. The brownish solid precipitated and was

filtered, washed with hexane, and dried to give N-[4-{(2,5-

dimethyl-1H-pyrrol-1-yl)sulfonyl}phenyl]-2-methyl-4-thiazole-

carboximidamimide (25.6 g, 85%). The product obtained was

used in the next step without additional purification: mp

(DSC) 197 °C; MIR 3491, 3374, 3082, 2923, 1654, 1581, 1484,

1357; ¹H NMR (DMSO-d₆) 8.07 (s, 1H), 7.63 (d, J ) 8 Hz, 2H),

7.04 (d, J ) 8 Hz, 2H), 6.72 (br s, 1H), 5.93 (s, 2H), 2.68 (s,

3H), 2.36 (s, 6H); MS (CI) 375 (MH⁺). Anal. (C₁₇H₁₈N₄S₂O₂) C,

H, N, S.

Step 2: P r ep a r a tion of 1-[[4-{4,5-Dih yd r o-4-h yd r oxy-

2-(2-m eth yl-4-th ia zolyl)-4-(tr iflu or om eth yl)-1H-im id a zol-

1-yl}p h en yl]su lfon yl]-2,5-d im eth yl-1H-p yr r ole. To a sus-

pension of the amidine obtained in step 1 (0.5 g, 1.3 mmol)

and sodium bicarbonate (110 mg, 1.3 mmol) in 2-propanol (3

mL) was added 3-bromo-1,1,1-trifluoroacetone (200 mL, 1.9

mmol). The reaction mixture was heated at 80 °C for 16 h,

cooled to room temperature, filtered, and concentrated. The

Step 1: P r ep a r a tion of 2,5-Dim eth yl-1-[(4-n itr op h en -

yl)su lfon yl]-1H-p yr r ole (13). A mixture of 4-nitrobenzene-

sulfonamide (30.3 g, 0.15 mol), acetonylacetone (34.2 g, 0.30

mol), and p-toluenesulfonic acid (3.0 g) in 200 mL of toluene

was refluxed under nitrogen using a Dean-Stark trap for 18

h. The reaction was cooled and then filtered through a silica

gel column (700 g) followed by elution with ethyl acetate/

hexane (3/7). The combined organic fractions containing the

desired product were concentrated to give crude product as a

brown solid. The crude solid was dissolved in hot ethyl acetate

and boiled with activated charcoal. After filtration and con-

centration, the crude obtained was recrystallized from ethyl

acetate/hexane to afford 13 as a light yellow solid (32.5 g,

1

77%): mp (DSC) 101-103 °C; H NMR (CDCl₃) 8.34 (d, J )

8.5 Hz, 2H), 7.80 (d, J ) 8.5 Hz, 2H), 5.92 (s, 2H), 2.38 (s,

6H). Anal. (C₁₂H₁₂N₂O₄S) C, H, N, S.

Step 2: P r ep a r a tion of 1-[(4-Am in op h en yl)su lfon yl]-

2,5-d im eth yl-1H-p yr r ole (14). A mixture of 13 (7.3 g, 26

mmol) and Raney-nickel (0.7 g) in 70 mL of methanol was

hydrogenated using a Parr apparatus at 50 psi. After 3 h, the

catalyst was filtered and the filtrate concentrated to give 14

as a pale yellow solid (6.4 g, 98%): mp (DSC) 114 °C; MIR

3487, 3388, 1630, 1594, 1504, 1351, 1166; ¹H NMR (CDCl₃)

7.48 (d, J ) 8.5 Hz, 2H), 6.63 (d, J ) 8.5 Hz, 2H), 5.81 (s, 2H),

4.17 (br s, 2H), 2.40 (s, 6H); MS (APCI) 251 (MH⁺). Anal.

(C₁₂H₁₄N₂O₂S) C, H, N, S.

3180 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16

Khanna et al.

Meth od C, Syn th esis of 4-[2-(3-Meth yln icotin yl)-4-(tr i-

flu or om eth yl)-1H-im idazol-1-yl}ben zen esu lfon am ide (46).

To a clear solution of 38 (0.75 g, 1.9 mmol) in tetrahydrofuran

(25 mL) at 0 °C was added n-BuMgCl (24.8 mL, 2 M solution

in THF, 49.6 mmol) slowly. After the mixture was stirred for

an additional 15 min, the ice bath was removed and the

solution stirred at room temperature for 2 h. The reaction

mixture was re-cooled to 0 °C and triethylborane (9.5 mL, 1

M solution in THF, 9.5 mmol) was added. After being stirred

for 2 h, the reaction was refluxed for 72 h. The reaction mixture

was cooled to room temperature and treated with aqueous

sodium acetate (2.3 g in 10 mL water). After the mixture was

stirred for 5 min, solid hydroxylamine-O-sulfonic acid (2.3 g)

was added in small portions over 10 min. The reaction mixture

was stirred for 20 h and extracted with ether. The ethereal

layer was dried over magnesium sulfate, filtered, and concen-

trated. The crude solid was purified by chromatography (silica

gel, toluene/2-propanol, 95/5) to give 46 (0.07 g, 8%) as a white

solid: mp 242-243 °C; IR (KBr) 3320, 3177, 3092, 3013, 1599,

1580, 1516, 1499, 1441, 1406, 1361, 1346, 1288, 1255, 1219,

1167, 1122, 1028; ¹H NMR (CD₃OD) 8.48 (s, 1H), 8.33 (s, 1H),

8.16 (t, J ) 1.2 Hz, 1H), 8.07 (d, J ) 8.8 Hz, 2H), 7.82 (m,

1H), 7.62 (d, J ) 8.8 Hz, 2H), 2.48 (s, 3H); MS (CI) 383 (MH⁺).

Anal. (C₁₆H₁₃F₃N₄O₂S) C, H, N, S.

(11.07 g, 0.078 mol) was added and the reaction mixture stirred

overnight. The solvent was removed under vacuum and the

residue partitioned between water and ethyl acetate. The

organic layer was washed with brine, dried over magnesium

sulfate, and filtered. The filtrate was concentrated to give 4.1

g of product as a pale yellow solid (33% yield). A mixture of

the above product (4.0 g, 0.024 mol) and sodium hydroxide (3.8

g, 0.096 mol) in 200 mL of ethanol was refluxed for 3 h. After

removal of the solvent, the residue was dissolved in 40 mL of

water and acidified with 2 N HCl. The precipitate was filtered

to give 3.65 g of 5-methoxynicotinic acid as a white solid

1

(quantitative): mp 235-237 °C; H NMR (CD₃OD) 8.62 (d, J

) 1.5 Hz, 1H), 8.38 (d, J ) 3.0 Hz, 1H), 7.33 (dd, J ) 3, 1.5

Hz, 1H), 3.94 (s, 3H). Anal. (C₇H₇NO₃‚0.1H₂O) C, H, N.

St ep 2: P r ep a r a t ion of 3-Cya n o-5-m et h oxyp yr id in e

(3c). A suspension of methyl 5-methoxynicotinic acid (3.6 g,

0.024 mol) in 50 mL of thionyl chloride was refluxed overnight.

After removal of the excess thionyl chloride, the residue was

suspended in 40 mL of dichloroethane. Ammonia gas was

bubbled into the reaction mixture at -30 °C for 15 min and

the mixture warmed to room temperature. The solvent was

removed under vacuum and the residue treated with hot

ethanol. After filtration, the filtrate was concentrated to give

3.0 g of 5-methoxynicotinamide as a yellow solid. To a mixture

of the crude amide (3.0 g, 0.02 mol) and triethylamine (6.61 g,

0.06 mol) in 125 mL of dichloromethane was added trifluoro-

acetic anhydride (5.38 g, 0.026 mol) rapidly at 0 °C. After the

mixture was stirred for 30 min, the reaction was quenched by

adding 200 mL of water. The aqueous phase was extracted

with more dichloromethane. The combined organic layers were

washed with brine, dried over magnesium sulfate, and filtered.

The filtrate was concentrated to give 2.5 g of product as a

brown solid (93% yield): mp 98-100 °C; ¹H NMR (CDCl₃) 8.52

(d, J ) 2 Hz, 1H), 8.49 (d, J ) 3.0 Hz, 1H), 7.42 (dd, J ) 3, 2

Hz, 1H), 3.92 (s, 3H).

All diarylimidazoles (43-49, 54-57, 63, 72, 76-78, 80)

containing a sulfonamide group in the aryl ring were prepared

using one of the methods shown above. Methods A and B

generally gave superior yields and were preferred.

Syn th eses of Ar yl Nitr iles (3a-3q). The aryl nitriles used

in the Schemes 1, 2, and 6 were either purchased commercially

or prepared (Scheme 4) as follows:

3-Cyan o-2-m eth ylpyr idin e (3a) was prepared from 2-meth-

ylnicotinic acid as described below.

Step 1: P r ep a r a tion of 2-Meth yln icotin a m id e. To a

stirred mixture of 2-methylnicotinic acid (15.0 g, 0.11 mol) and

1,1′-carbonyldiimidazole (36.0 g, 0.22 mol) was slowly added

300 mL of methylene chloride, and the mixture was stirred at

room temperature overnight. Excess of ammonia gas was

passed through the reaction using a dry ice condenser for about

half an hour. After the reaction mixture was stirred at room

temperature for an additional hour, the solvent was removed

under vacuum. The residue obtained was dissolved in 500 mL

of acetonitrile. The solution was concentrated to about half

the volume and cooled. The precipitated white solid was

filtered and recrystallized from ethanol/ether to give pure

2-methylnicotinamide as a colorless crystal (11.5 g, 76%): mp

The intermediate 3d was prepared from 5-bromonicotininc

acid using procedures described for 3a . Similarly the inter-

mediate 3e was prepared following the reported methodology.¹⁷

3-Cya n o-6-m eth oxyp yr id in e (3f). To a solution of 6-meth-

oxy-3-bromopyridine¹⁸(11 g, 58.5 mmol) in DMF (250 mL) was

added CuCN (7.8 g, 87.8 mmol), and the mixture was heated

to 120 °C for 24 h. The reaction mixture was cooled and

filtered. The crude residue was washed with methylene

chloride, and combined organic fractions were washed succes-

sively with water and brine. After drying over sodium sulfate,

the organic fractions were filtered and concentrated. The crude

greenish solid (12.7 g) was purified by chromatography (silica

gel, hexane/ethyl acetate, 9/1) to give the recovered starting

6-methoxy-3-bromo pyridine (2.5 g, 23%) and the desired 3f

(1.85 g, 24%): mp (DSC) 97 °C; IR (KBr) 3429, 3080, 3011,

2569, 2229, 1996, 1603, 1562, 1495, 1448; ¹H NMR (CDCl₃)

8.50 (d, J ) 2 Hz, 1H), 7.77 (dd, J ) 8, 2 Hz, 1H), 6.82 (d, J )

5 Hz, 1H), 4.02 (s, 3H); MS (EI) 134 (M⁺). Anal. (C₇H₆N₂O) C,

H, N.

1

160-163 °C; H NMR (DMSO-d₆) 8.48 (dd, J ) 5, 2 Hz, 2H),

7.90 (br s, 1H), 7.74 (dd, J ) 8, 2 Hz, 1H), 7.55 (br s, 1H), 7.26

(dd, J ) 8, 5 Hz, 2H), 2.54 (s, 3H). Anal. (C₇H₈N₂O) C, H, N.

Step 2: P r ep a r a tion of 3-Cya n o-2-m eth ylp yr id in e (3a ).

To a suspension of 2-methylnicotinamide (11.1 g, 0.08 mol) in

triethylamine (24.8 g, 0.24 mol) and 400 mL of methylene

chloride was added trifluoroacetic anhydride (21.0 g, 0.10 mol)

rapidly at 0 °C. The reaction was completed within minutes.

The reaction was quenched by adding water and extracted

with methylene chloride. The combined organic layers were

washed with water and brine and dried over magnesium

sulfate. After filtration, the filtrate was concentrated and the

residue purified by chromatography on silica gel (ethyl acetate/

hexane, 1:1) to give 3-cyano-2-methylpyridine (3a ) as a pale

yellow solid (7.2 g, 75%): mp 56-58 °C; ¹H NMR (CDCl₃) 8.72

(dd, J ) 5, 2 Hz, 1H), 7.94 (dd, J ) 8, 2 Hz, 1H), 7.29 (dd, J )

8, 5 Hz, 1H), 2.28 (s, 3H).

3-Cya n o-6-m eth ylp yr id in e (3g) was prepared in two steps

by starting with 6-methyl-2-pyridinecarboxaldehyde and using

the following procedure.

Step 1: P r epar ation of 6-Meth yl-2-pyr idin ecar boxalde-

h yd e, Oxim e. To a mixture of hydroxylamine hydrochloride

(2.89 g, 41.5 mmol) and pyridine (3.4 mL, 41.5 mmol) was

added 6-methyl-2-pyridinecarboxaldehyde (5.0 g, 41.5 mmol)

in installments over 5 min. The reaction mixture was stirred

at room temperature for 20 min. Toluene (100 mL) was then

added and the solution refluxed for 4 h using a Dean-Stark

water trap. The reaction mixture was cooled, filtered, and

concentrated. The residue obtained was suspended in water

and extracted with ether. The combined ether fractions were

dried over sodium sulfate, filtered, and concentrated. The

crude mixture (4.45 g) was chromatographed (silica gel,

hexane/ethyl acetate 8/2) to give 6-methyl-2-pyridine carbox-

aldehyde, oxime (3.9 g, 69%) as a white solid: IR (KBr) 3429,

3-Cyan o-5-m eth ylpyr idin e (3b) was prepared from 5-meth-

ylnicotinamide³⁰using the procedure described for preparation

of 3a (step 2).

3-Cya n o-5-m eth oxyp yr id in e (3c) was prepared from

methyl 5-hydroxy nicotinic acid using the procedure described

below.

Step 1: P r ep a r a tion of 5-Meth oxyn icotin ic Acid . To a

suspension of sodium methoxide (4.21 g, 0.078 mol) in 125 mL

of DMF was added dropwise at room temperature a solution

of methyl 5-hydroxynicotinate (11.34 g, 0.074 mol) in DMF (25

mL). After the mixture was stirred for 30 min, iodomethane

1

3273, 2990, 2712, 1907, 1682, 1590, 1577; H NMR (CD₃OD)

8.07 (s, 1H), 7.62-7.74 (complex band, 2H), 7.24 (dd, J ) 8, 2

Selective Cyclooxygenase-2 Inhibitors

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3181

Hz, 1H), 2.52 (s, 3H); MS (EI) 136 (M⁺). Anal. (C₇H₆N₂O‚

0.2H₂O) C, H, N.

warmed slowly to 16 °C over a 12 h period and quenched

carefully with ice and 72 mL of 4 N hydrochloric acid. The

reaction mixture was transferred to a separatory funnel and

diluted with an additional 100 mL of ether. The ether layer

was washed with an additional 2 × 50 mL of 4 N hydrochloric

acid. The pH of the aqueous layer was adjusted to 7.5 with

solid sodium bicarbonate and extracted with 2 × 150 mL of

ether. The organic extracts were dried (MgSO₄), filtered, and

concentrated at room temperature to give 4-methyl-2-thiaz-

olecarboxaldehyde as a yellow oil (9.1 g, 72%): MIR 3101, 2960,

2928, 1684, 1596, 1500, 1439, 1300, 1259, 1239, 1154; ¹H NMR

(CDCl₃) 9.96 (s, 1H), 7.34 (s, 1H), 2.58 (s, 3H); MS (EI) 127

(M⁺).

Step 2: P r ep a r a tion of 4-Meth yl-2-th ia zoleca r boxa ld e-

h yd e, Oxim e. To a solution of 4-methyl-2-thiazolecarboxal-

dehyde (14.2 g, 110 mmol) in 8.89 mL of pyridine (8.70 g, 110

mmol) was added hydroxylamine hydrochloride (7.64 g, 110

mmol). After being stirred at room temperature for 12 h, the

reaction mixture was diluted with 200 mL of methylene

chloride and extracted with 2 × 50 mL of water. The organic

extracts were dried (MgSO₄), filtered, and concentrated under

reduced pressure to provide an orange solid, which was washed

with methylene chloride to remove the pyridinium hydrochlo-

ride. The crude, obtained (7.2 g, 46%) as mixture of syn- and

anti-oximes, was used in the next reaction without further

purification: mp 125 °C; MIR 2989, 1442, 1231, 1018; ¹H NMR

(DMSO-d₆) 12.35 (br s, 1H), 11.96 (br s, 1H), 8.26 (s, 1H), 7.93

(s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 2.42 (s, 3H), 2.38 (s, 3H); MS

(DCI) 143 (MH⁺). Anal. (C₅H₆N₂OS) C, H, N.

Step 2: P r ep a r a tion of 3-Cya n o-6-m eth ylp yr id in e (3g).

The oxime (3.5 g, 25.7 mmol) obtained in step 1 was refluxed

in acetic anhydride (20 mL) for 48 h. The solvent was removed

under reduced pressure, and the resulting dark residue was

treated with cold aqueous potassium carbonate. After extrac-

tion with methylene chloride (2 × 100 mL), the combined

organic fractions were dried (sodium sulfate), filtered, and

concentrated. The resulting dark brown solid (2.8 g) was

chromatographed (silica gel, hexane/ethyl acetate 75/25) to give

3g (2.3 g, 76%) as a white solid: mp (DSC) 74 °C; IR (KBr)

3439, 3063, 2359, 2233, 1990, 1589, 1460, 1446, 1379; ¹H NMR

(CDCl₃) 7.74 (t, J ) 8 Hz, 1H), 7.52 (dd, J ) 8, 2 Hz, 1H), 7.38

(dd, J ) 8, 2 Hz, 1H), 2.62 (s, 3H); MS (EI) 118 (M⁺). Anal.

(C₇H₆N₂‚0.15H₂O) C, H, N.

2-Cya n o-5-m eth ylp yr id in e (3h ). 2-Fluoro-5-methylpyri-

dine (39 g, 0.35 mol) and sodium cyanide (17.23 g, 0.35 mol)

were added to 141 mL of DMSO and heated to 150 °C for 3

days. An additional 3 g (61.2 mmol) of sodium cyanide was

added, and heating was continued for 5 h. The reaction was

cooled and poured into 525 mL of ice water. The solution was

filtered through a coarse fritted funnel. A dark brown solid

was collected and air-dried. The solid was dissolved in meth-

ylene chloride, dried over MgSO₄, filtered, and concentrated

to give 17 g (41%) of 3h which was used in the next step

without further purification: ¹H NMR (CDCl₃) 8.54 (s, 1H),

7.58-7.64 (complex band, 2H), 2.43 (s, 3H). Anal. (C₇H₆N₂‚

0.1H₂O) C, H, N.

Step 3: P r ep a r a tion of 4-Meth yl-2-th ia zoleca r bon i-

tr ile (3o). The oxime (6.37 g, 51 mmol) obtained in step 2 was

dissolved in 25 mL of dioxane and 18 mL of anhydrous

pyridine. The solution was cooled to 0 °C, and 7.9 mL of

trifluoroacetic anhydride (11.7 g, 56 mmol) was added dropwise

so that the reaction temperature did not rise above 7 °C. The

reaction mixture was warmed to room temperature and stirred

for 12 h. The reaction was diluted with 200 mL of methylene

chloride and washed with 8 × 35 mL of water. The organic

extracts were washed with brine (35 mL), dried (MgSO₄),

filtered, and concentrated under reduced pressure to provide

an oil. The crude mixture was chromatographed (silica gel,

ethyl acetate/hexane 1/3) to provide 3o as a yellow solid (4.56

g, 72%): mp (DSC) 196 °C; MIR 3123, 2929, 2227, 1700, 1501,

1491, 1406, 1169, 1115; ¹H NMR (CDCl₃) 7.26 (s, 1H), 2.55 (s,

3H); MS (EI) 124 (M⁺).

2-Cya n o-4-m eth ylp yr id in e (3i). 4-Picoline N-oxide (13.6

g; 0.124 mole) was suspended in 82 mL of THF under an inert

atmosphere. To this solution were added cyanotrimethylsilane

(20.1 mL, 0.15 mol) and DBU (4.32 g, 0.028 mol) in succession.

The reaction mixture was stirred at 25 °C for 12 h and then

refluxed for 4-5 h. After cooling to room temperature, the

solvent was removed under reduced pressure. The resulting

dark solid was dissolved in methylene chloride and applied to

a bed of florisil in a 600 mL coarse-fritted funnel eluting with

methylene chloride. The desired organic fractions were com-

bined and concentrated to give 3i (6.4 g, 44%): MIR 3049,

3026, 2979, 2926, 2234, 1599, 1470, 1444, 1297; ¹H NMR

(CDCl₃) 8.56 (d, J ) 5 Hz, 1H), 7.52 (s, 1H), 7.3 3 (d, J ) 4 Hz,

1H), 2.44 (s, 3H). Anal. (C₇H₆N₂) C, H, N.

The compounds 3j-3m were synthesized using the proce-

dure described for 3g. The aldehyde intermediates needed for

their synthesis were purchased commercially.

5-Meth yl-3-isoxa zoleca r bon itr ile (3p ). Step 1: P r ep a -

r a tion of 5-Meth yl-3- isoxa zoleca r boxa ld eh yd e. To a

three-neck flask equipped with nitrogen inlet, addition funnel,

and temperature probe were added oxalyl chloride (102 mL,

2.0 M solution in methylene chloride, 204 mmol) and 305 mL

of methylene chloride. After cooling to -78 °C, a solution of

DMSO (34.9 g, 447 mmol) in 88 mL of methylene chloride was

added slowly so that the temperature did not rise above -68

°C. After 10 min, a solution of 5-methylisoxazole-3-methanol

(21 g, 186 mmol) in 168 mL of methylene chloride was added

and the reaction stirred at -78 °C. The reaction was stirred

for 15 min, and triethylamine (130 mL, 931 mmol) was added

all at once. The reaction was warmed to room temperature,

poured into 400 mL of water, and extracted with 400 mL of

methylene chloride. The organic extracts were dried (MgSO₄),

filtered, and concentrated to provide 5-methyl-3-isoxazolecar-

boxaldehyde as a brown oil (13.5 g, 59%). The compound was

stored at -78 °C and was used in the next step without

additional purification: ¹H NMR (CDCl₃) 10.12 (s, 1H), 6.41

(s, 1H), 2.54 (s, 3H).

Step 2: P r ep a r a tion of 5-Meth yl-3-isoxa zoleca r bon i-

tr ile (3p ). 5-Methylisoxazole-3-carboxaldehyde was converted

to 3p using procedures described in steps 2 and 3 of compound

3o: MIR 3142, 2258, 1591, 1434, 1407, 1245, 1005, 931, 803;

¹H NMR (CDCl₃) 6.35 (s, 1H), 2.51 (s, 3H); MS (EI) 108 (M⁺).

2-Meth yl-4-oxa zoleca r bon itr ile (3q). Step 1: P r ep a r a -

tion of Eth yl N-(Cya n om eth yl)eth a n im id a te (4e). To a

suspension of ethyl acetimidate hydrochloride (24.6 g, 20

mmol) in ether (50 mL) was added anhydrous potassium

2-Meth yl-5-cya n oth ia zole (3n ). Step 1: P r ep a r a tion of

2-Meth yl-5-th ia zoleca r boxa ld eh yd e (4c). To a solution of

thioacetamide (9.6 g, 63.6 mmol) in tetrahydrofuran (100 mL)

were added N,N-diisopropylethylamine (11 mL, 63.6 mmol)

and bromomalonaldehyde.³¹After the reaction mixture was

stirred at room temperature for 36 h, the solvent was removed.

The residue was dissolved in methylene chloride and washed

with aqueous sodium bicarbonate and water. The combined

organic fractions were dried (MgSO₄), filtered, and concen-

trated to give a dark brown liquid (10.9 g). Chromatography

(silica gel, ethyl acetate/acetone 98/2) of the crude mixture gave

pure 4c (2.3 g, 28%): ¹H NMR (CDCl₃) 9.92 (s, 1H), 8.82 (s,

1H), 2.74 (s, 3H). Anal. (C₅H₅NOS‚0.75H₂O) C, H, N.

Step 2: P r ep a r a tion of 2-Meth yl-5-cya n oth ia zole (3n ).

The compound was prepared from 4c by following the proce-

1

dure described for 3g: H NMR (CDCl₃) 8.08 (s, 1H), 2.72 (s,

3H). Anal. (C₅H₄N₂S‚0.25H₂O) C, H, N.

4-Meth ylth ia zole-2-ca r bon itr ile (3o). Step 1: P r ep a r a -

tion of 4-Meth yl-2- th ia zoleca r boxa ld eh yd e. To an oven-

dried, three-neck flask equipped with a nitrogen inlet and an

addition funnel were added butyllithium (42 mL, 2.5 M

solution in THF, 100.5 mmol) and 100 mL of anhydrous ether.

A solution of 4-methylthiazole (10 g, 100 mmol) in 25 mL of

anhydrous ether was added over a 30 min period. At no time

during the addition was the temperature allowed to rise above

-68 °C. After the mixture was stirred at -78 °C for 1.5 h, a

solution of N,N-dimethylformamide (10.6 g, 150 mmol) in 24

mL of ether was added all at once. The reaction solution was

3182 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16

Khanna et al.

carbonate (27.6 g, 20 mmol). After stirring for 5 min, a solution

of aminoacetonitrile hydrochloride (18. 5 g, 20 mmol) in water

(40 mL) was added and the mixture stirred for additional 90

min. The reaction was diluted with water (100 mL) and

extracted with ether (2 × 300 mL). The combined organic

fractions were dried (Na₂SO₄), filtered, and concentrated to

give a crude liquid (14.8 g). Distillation of the crude mixture

under reduced pressure (<65 °C) gave 4e (10.2 g, 40%) as a

colorless liquid which solidifies on standing in the refrigera-

tor: MIR (KBr) 3995, 3970, 3945, 3380, 2395, 1650, 1601, 1512,

) 2 Hz, 1H), 7.33 (dd, J ) 8, 2 Hz, 1H), 6.48 (d, J ) 8 Hz, 1H),

3.16 (s, 3H); MS (DCI) 384 (MH⁺). Anal. (C₁₆H₁₂N₃SO₃F₃‚

0.25H₂O) C, H, N.

4-[1-{4-(Meth ylsu lfon yl)p h en yl}-4-tr iflu or om eth yl-1H-

im id a zol-2-yl]-2(1H)-p yr id on e (31). Step 1: P r ep a r a tion

of 4-[1-{4-(Meth ylsu lfon yl)p h en yl}-4-tr iflu or om eth yl-1H-

im id a zol-2-yl]p yr id in e 1-Oxid e (24b). This intermediate

(24b) was prepared by oxidation of 27 using the procedure

described for the preparation of 28: mp (DSC) 279 °C; IR (KBr)

3431, 3069, 1601, 1574, 1518, 1500, 1466, 1441; ¹H NMR

(CDCl₃) 8.16 (d, J ) 8 Hz, 2H), 8.08 (d, J ) 8 Hz, 2H), 7.54 (s,

1H), 7.51 (d, J ) 8 Hz, 2H), 7.26 (d, J ) 8 Hz, 2H), 3.16 (s,

3H); MS (CI) 384 (MH⁺). Anal. (C₁₆H₁₂N₃SO₃F₃) C, H, N, S.

1

1409, 1373, 1283; H NMR (CDCl₃) 4.16 (s, 2H), 4.10 (q, J )

7 Hz, 2H), 1.97 (s, 3H), 1.26 (t, J ) 7 Hz, 3H).

Step 2: P r ep a r a tion of 2-Meth yl-4-oxa zoleca r bon itr ile

(3q). To a solution of 4e (13 g, 0.1 mol) in THF (150 mL) at

-10 °C were added potassium tert-butoxide (3.38 g, 0.1 mol)

and ethyl formate (8.5 mL, 0.1 mol) successively. After being

stirred at -10 °C for 3 h, the reaction mixture was left in the

refrigerator overnight and then diluted with ether. The

precipitated brown solid was filtered and dried under vacuum.

The vacuum-dried solid was added to boiling acetic acid (60

mL) and refluxed for 2 min. The reaction mixture was cooled

to room temperature, diluted with water, and adjusted to pH

7 by adding 1 N sodium hydroxide. The reaction mixture was

extracted with ether (2 × 2 L). The combined organic fractions

were dried (MgSO₄), filtered, and concentrated. The crude

brownish solid was chromatographed (silica gel, hexane/ethyl

acetate 1/1, detection KMnO₄spray) to give 3q (2.3 g, 21%) as

a colorless liquid: MIR 3158, 3095, 2243, 1665, 1589, 1306;

¹H NMR (CDCl₃) 8.08 (s, 1H), 2.54 (s, 3H). Anal. (C₅H₄N₂O)

C, H, N.

Step 2: P r ep a r a tion of 4-[1-{4-(Meth ylsu lfon yl)p h en -

yl}-4-t r iflu or om et h yl-1H-im id a zol-2-yl]-2(1H)-p yr id on e

(31). A solution of 24b in acetic anhydride was refluxed for

72 h. The reaction mixture was cooled and the precipitated

product filtered. Chromatography of the crude mixture (silica

gel, methylene chloride/methanol/ammonium hydroxide 95/5/

0.5) gave the desired product 31 (250 mg, 51%) as a white

solid: mp (DSC) 293 °C; IR (KBr) 3424, 3111, 3028, 2934, 1657,

1

1628, 1576, 1558, 1541, 1462; H NMR (CD₃OD) 8.12 (d, J )

8 Hz, 2H), 8.07 (s, 1H), 7.73 (d, J ) 8 Hz, 2H), 7.44 (d, J ) 7

Hz, 1H), 6.48 (dd, J ) 7, 2 Hz, 1H), 6.38 (d, J ) 2 Hz, 1H),

3.18 (s, 3H); MS (APCI) 384 (MH⁺). Anal. (C₁₆H₁₂N₃SO₃F₃) C,

H, N.

1-Meth yl-5-[1-{4-(m eth ylsu lfon yl)p h en yl}-4-(tr iflu or o-

m eth yl)-1H-im id a zol-2-yl]-2(1H)-p yr id on e (32). A solution

of 40 (140 mg, 0.35 mmol) in methylene chloride (10 mL) and

iodomethane (0.22 mL, 3.5 mmol) was stirred at 40-45 °C.

The reaction progressed very slowly, and additional quantities

of iodomethane and methylene chloride were added intermit-

tently to the reaction mixture. After 7 days, the reaction

mixture was concentrated to remove the solvents, and the

crude mixture was purified on a silica gel column using ethyl

acetate/acetone 9/2 to give 32 (71 mg, 50%): mp (DSC) 199

°C; IR (KBr) 3441, 3101, 2922, 2359, 2222, 1667, 1619, 1578,

P yr id in e Mod ifica tion s. Number of pyridinium and pyri-

done containing analogues (28-32) were prepared by modifi-

cation of compounds 25 and 27.

3-[1-{4-(Meth ylsu lfon yl)p h en yl}-4-tr iflu or om eth yl-1H-

im id a zol-2-yl]p yr id in e 1-oxid e (28). To a solution of 25 (120

mg, 0.33 mmol) in methylene chloride (10 mL) was added

m-chloroperoxybenzoic acid (120 mg, 0.39 mmol). After being

stirred for 16 h, the reaction mixture was diluted with

methylene chloride (100 mL) and washed with saturated

aqueous sodium bicarbonate (60 mL). The combined organic

fractions were dried (Na₂SO₄), filtered, and concentrated.

Chromatography of the crude mixture using methylene chloride/

ethanol 92/8 gave 28 (102 mg, 82%) as a pale yellow solid: mp

(DSC) 258 °C; IR (KBr) 3437, 3117, 2992, 2912, 1657, 1639,

1

1535; H NMR (CDCl₃) 8.13 (d, J ) 8 Hz, 2H), 7.87 (d, J ) 2

Hz, 1H), 7.55 (d, J ) 8 Hz, 2H), 7.48 (s, 1H), 6.87 (dd, J ) 8,

2 Hz, 1H), 6.48 (d, J ) 8 Hz, 1H), 3.57 (s, 3H), 3.14 (s, 3H);

MS (DCI) 398 (MH⁺). Anal. (C₁₇H₁₄N₃SO₃F₃‚0.25H₂O) C, H,

N.

P r ep a r a tion of 1,2-Dia r ylim id a zoles w ith Differ en t

Su bstitu en ts in Im id a zole Rin g. 1,2-Diarylimidazoles (58-

62) with different substituents at position-4 of the imidazole

ring were prepared as shown below. The compound 63 was

prepared from 58 by using the conditions described for the

synthesis of compound 43 (method A).

1

1601, 1572; H NMR (CDCl₃) 8.12-8.20 (complex band, 2H),

8.08 (d, J ) 8 Hz, 2H), 7.58 (s, 1H), 7.48 (d, J ) 8 Hz, 2H),

7.22-7.35 (complex band, 2H), 3.17 (s, 3H); MS (CI) 384

(MH⁺). Anal. (C₁₆H₁₂N₃SO₃F₃‚0.75H₂O) C, H, N, S.

1-Meth yl-3-[1-{4-(m eth ylsu lfon yl)p h en yl}-4-tr iflu or o-

m eth yl-1H-im id a zol-2-yl]p yr id in iu m Iod id e (29). A solu-

tion of 1 (200 mg, 0.54 mmol) in methylene chloride (10 mL)

and iodomethane (0.35 mL, 5.4 mmol) was refluxed for 18 h.

The precipitated white solid was filtered, washed with meth-

ylene chloride, and dried under vacuum to give 29 (250 mg,

91%): mp (DSC) 243 °C; IR (KBr) 3431, 3032, 2909, 1639,

3-[4-(Diflu or om et h yl)-1-[4-(m et h ylsu lfon yl)p h en yl]-

1H-im id a zol-2-yl] p yr id in e (58). Step 1: P r ep a r a tion of

1-Ch lor o-3,3-d iflu or oa ceton e. To a solution of difluoroacetic

acid (2.0 mL, 31 mmol) in THF (100 mL) was added triethy-

lamine (4.1 mL, 31 mmol). After cooling the reaction solution

in an ice bath under nitrogen, isobutyl chloroformate (4.1 mL,

31 mmol) was added in a dropwise fashion, and the resulting

mixture was stirred while allowing to warm to room temper-

ature. The mixed anhydride was freed of Et₃N-HCl by

filtration and cooled in an ice bath. To this solution was added

a solution of 2.8 g of diazomethane in ether, and the solution

was allowed to warm to room temperature. After the mixture

was stirred for 1 h, a solution of hydrogen chloride in dioxane

(16.8 mL, 4 N solution) was added, and the mixture was stirred

overnight. The solution was filtered and used in the next step

without further processing.

Step 2: P r epar ation of 3-[4-(Diflu or om eth yl)-1-[4-(m eth -

ylsu lfon yl)p h en yl]-1H-im id a zol-2-yl]p yr id in e (58). To a

solution of 1-chloro-3,3-difluoroacetone as prepared above were

added 2-propanol (75 mL), 8 (1.88 g, 7.75 mmol), and sodium

bicarbonate (12.6 g, 150 mmol). The mixture was subjected to

distillation through a Vigreaux column to a head temperature

of 65 °C, and then a reflux condenser was fitted. The mixture

was refluxed for 6 h, cooled, and concentrated. The residue

was partitioned between dichloromethane and water, and the

aqueous layer was re-extracted with dichloromethane. The

1

1574, 1531, 1500; H NMR (CD₃OD) 9.29 (d, J ) 2 Hz, 1H),

8.93 (dd, J ) 5, 2 Hz, 1H), 8.27 (s, 1H), 8.19 (dd, J ) 8, 2 Hz,

1H), 8.14 (d, J ) 8 Hz, 2H), 7.99 (dd, J ) 8, 5 Hz, 1H), 7.77 (d,

J ) 8 Hz, 2H), 4.46 (s, 3H), 3.22 (s, 3H). Anal. (C₁₇H₁₅N₃SO₂F₃I)

C, H, N, I.

5-[1-{4-(Meth ylsu lfon yl)p h en yl}-4-tr iflu or om eth yl-1H-

im id a zol-2-yl]-2(1H)-p yr id on e (30). A solution of 40 (140

mg, 0.35 mmol) in methanol (10 mL) and hydrogen chloride

in dioxane (7 mL, 6 N solution) was stirred at room temper-

ature for 80 h. The reaction mixture was concentrated to

remove the solvents. After neutralization with ammonium

hydroxide, the product was extracted with methylene chloride.

The organic fractions were dried (Na₂SO₄), filtered, and

concentrated to give 72 mg of the crude product. Chromatog-

raphy of the crude mixture (silica gel, methylene chloride/

methanol/ ammonium hydroxide 98/2/0.2) gave 30 (42 mg,

31%) as a white solid: mp (DSC) 268 °C; IR (KBr) 3433, 3111,

1626, 1579, 1549, 1500, 1469, 1410; ¹H NMR (CDCl₃) 8.12 (d,

J ) 8 Hz, 2H), 7.52 (d, J ) 8 Hz, 2H), 7.51 (s, 1H), 7.46 (d, J

Selective Cyclooxygenase-2 Inhibitors

J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3183

combined organic fractions were dried (Na₂SO₄), filtered, and

concentrated. Chromatography of the residue over silica gel

using 10% methanol in ethyl acetate as eluent gave 920 mg of

4-(difluoromethyl)-4,5-dihydro-1-[4-(methylsulfonyl) phenyl]-

2-(3-pyridinyl)-1H-imidazol-4-ol (21) contaminated with some

starting amidine.

The crude product as obtained above was mixed with 25 mL

of acetic anhydride and 50 mg of 4-(dimethylamino)pyridine.

The mixture was refluxed for 2 h, cooled, and concentrated.

The residue was partitioned between dichloromethane and

water and the aqueous layer re-extracted with dichloro-

methane. The combined organic fractions were dried (Na₂SO₄),

filtered, and concentrated. Chromatography using 80% ethyl

acetate in hexane gave 307 mg of 22 contaminated with about

10% of 4-(methylmercapto) acetanilide: ¹H NMR (CD₂Cl₂) 8.63

(dd, J ) 4, 2 Hz, 1H), 8.58 (dd, J ) 6, 2 Hz, 1H), 7.82 (dt, J )

9, 2 Hz, 1H), 7.44 (t, J ) 4, 2 Hz, 1H), 7.29 (d, J ) 9 Hz, 2H),

7.26 (d, J ) 9 Hz, 1H), 7.17 (d, J ) 9 Hz, 2H), 6.80 (t, J ) 58

Hz, 1H), 2.54 (s, 3H).

A solution of 22 (307 mg) as obtained above in methanol

(10 mL) and water (3 mL) was cooled in an ice bath, and oxone

(1.31 g, 2.13 mmol) was added. The resulting mixture was

stirred rapidly for 1 h. The mixture was diluted with water,

neutralized with aqueous ammonium hydroxide, and extracted

with ethyl acetate. The combined organic fractions were dried

(Na₂SO₄), filtered, and concentrated. Chromatography using

a gradient of 0-5% MeOH-EtOAc gave 58 (250 mg, 74%) as

a pure white crystalline solid: ¹H NMR (CDCl₃) 8.64 (dd, J )

6, 2 Hz, 1H), 8.57 (d, J ) 2 Hz, 1H), 8.08 (d, J ) 9 Hz, 2H),

7.84 (dt, J ) 9, 2 Hz, 1H), 7.53 (t, J ) 2 Hz, 1H), 7.48 (d, J )

9 Hz, 2H), 7.34 (dd, J ) 9, 5 Hz, 1H), 6.83 (t, J ) 50 Hz, 1H),

3.17 (s, 3H). Anal. (C₁₆H₁₃F₂N₃O₂S) C, H, N.

1-[4-(Meth ylsu lfon yl)p h en yl]-2-(3-p yr id in yl)-1H-im id a -

zole-4-ca r bon itr ile (59). Step 1: P r ep a r a tion of 4,5-Di-

h yd r o-1-[4-(m et h ylt h io)p h en yl]-2-(3-p yr id in yl)-1H -im i-

d a zole-4-ca r bon itr ile (23). To a suspension of 8 (1.00 g, 4.1

mmol) in THF (20 mL) were added 2-chloroacrylonitrile (540

mg, 6.2 mmol) and diisopropylethylamine (796 mg, 6.2 mmol)

successively. The reaction mixture was slowly heated to reflux.

After refluxing for 6 h, an additional 540 mg of 2-chloroacrylo-

nitrile was added. After refluxing overnight, the solvent was

removed and the crude mixture chromatographed (silica gel,

ethyl acetate) to give 23 (951 mg, 79%): ¹H NMR (CDCl₃) 8.73

(d, J ) 2 Hz, 1H), 8.67 (dd, J ) 5, 2 Hz, 1H), 7.85 (dt, J ) 8,

2 Hz, 1H), 7.26 (dd, J ) 9, 5 Hz, 1H), 7.15 (d, J ) 9 Hz, 2H),

6.85 (d, J ) 9 Hz, 2H), 5.10 (dd, J ) 11, 7 Hz, 2H), 4.34 (dd,

J ) 11, 11 Hz, 1H), 4.28 (dd, J ) 11, 7 Hz, 1H), 2.46 (s, 3H).

Step 2: P r ep a r a tion of 4,5-Dih yd r o-1-[4-(m eth ylsu l-

fon yl)p h en yl]-2-(3-p yr id in yl)-1H -im id a zole-4-ca r b on i-

tr ile (24). A solution of 23 (950 mg, 2.65 mmol) in methanol

(25 mL) and water (10 mL) was cooled in an ice bath, and

oxone (3.6 g, 5.8 mmol) was added. The resulting mixture was

stirred for 2 h. The mixture was diluted with water, neutral-

ized with aqueous ammonium hydroxide, and extracted with

ethyl acetate. The combined organic fractions were dried (Na₂-

SO₄), filtered, and concentrated. Chromatography on silica gel

using 10% methanol in ethyl acetate gave 24 (532 mg, 67%)

as a pure white crystalline solid: ¹H NMR (CDCl₃) 8.75 (m,

2H), 7.89 (dt, J ) 8, 2 Hz, 1H), 7.82 (d, J ) 9 Hz, 2H), 7.38

(dd, J ) 9, 5 Hz, 1H), 6.95 (d, J ) 9 Hz, 2H), 5.13 (dd, J ) 11,

7 Hz, 1H), 4.51 (dd, J ) 11, 11 Hz, 1H), 4.42 (dd, J ) 11, 7 Hz,

1H), 3.07 (s, 3H). Anal. (C₁₆H₁₄N₄O₂S) C, H, N.

Step 3: P r ep a r a tion of 1-[4-(Meth ylsu lfon yl)p h en yl]-

2-(3-pyr idin yl)-1H-im id a zole-4-ca r bon itr ile (59). To a mix-

ture of 24 (512 mg, 1.6 mmol) in cumene (30 mL) was added

100 mg of 10% Pd/C. The reaction mixture was refluxed under

a drying tube for 2 h. After cooling, the mixture was diluted

with dichloromethane and methanol and filtered through a

Celite bed. The organic fractions were concentrated and

chromatographed on silica gel using a gradient of 0-10%

MeOH-EtOAc as eluent to give 59 (275 mg, 72% based on

conversion) in addition to the recovered 24 (114 mg): mp (DSC)

194 °C; MIR 2925, 2236, 1596, 1574, 1496, 1432, 1311; ¹H

NMR (CDCl₃-CD₃OD) 8.53 (dd, J ) 5, 2 Hz, 1H), 8.43 (d, J )

2 Hz, 1H), 8.00 (d, J ) 9 Hz, 2H), 7.86 (s, 1H), 7.69 (dt, J ) 9,

2 Hz, 1H), 7.44 (d, J ) 9 Hz, 2H), 7.28 (dd, J ) 9, 5 Hz, 1H),

3.08 (s, 3H). Anal. (C₁₆H₁₂N₄O₂S‚0.25H₂O) C, H, N.

3-[4-Meth yl-1-{4-(m eth ylsu lfon yl)ph en yl}-1H-im id a zol-

2-yl]p yr id in e (60). Step 1: P r ep a r a tion of N-(2-Meth oxy-

2-p r op en yl)-N-[4-(m eth ylth io)p h en yl]-3-p yr id in eca r box-

im id a m id e (17). To a solution of 8 (5.0 g, 20.6 mmol) in dry

THF (175 mL) was added sodium bis(trimethylsilyl)amide

(22.6 mL, 1.0 M solution in THF, 22.6 mmol) over 10 min. After

the mixture was stirred for an additional 15 min, 1-bromo-2-

methoxy-2-propene³²(10.6 mL, 10.3 mmol) was added and the

mixture stirred overnight at room temperature. The reaction

mixture was poured into ice-water and extracted with di-

chloromethane. The organic layer was washed with brine,

dried over MgSO₄, and filtered. The filtrate was concentrated

and the residue chromatographed (silica gel, hexane/ethyl

acetate 2/8) to give 17 (1.55 g, 24%; 40% based on 8 consumed)

as a pale orange liquid, and recovered 8 (2.01 g, 40%): ¹H NMR

(CD₂Cl₂) 8.50 (m, 2H), 7.51 (d, J ) 6 Hz, 1H), 7.21 (dd, J ) 6,

2 Hz, 1H), 7.01 (d, J ) 8 Hz, 2H), 6.54 (d, J ) 8 Hz, 2H), 4.25

(s, 2H), 4.18 (d, J ) 9 Hz, 1H), 4.06 (d, J ) 9 Hz, 1H), 3.62 (s,

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

Step 2: P r ep a r a tion of 3-[4-Meth yl-1-{4-(m eth ylth io)-

p h en yl}-1H-im id a zol-2-yl]p yr id in e (18). To a solution of

17 (1.55 g, 4.95 mmol) in THF (90 mL) was added a solution

of pyridinium p-toluenesulfonate (582 mg, 2.32 mmol) in water

(10 mL). After being stirred overnight at room temperature,

the mixture was refluxed for 4 h. The reaction mixture was

cooled and the solvent removed under reduced pressure.

Chromatography of the resulting residue over silica gel using

a gradient of 5-10% methanol in ethyl acetate gave 18 (1.09

g, 78%) as a white solid: mp (DSC) 123 °C; MIR 1497, 1431,

1389, 1096, 957, 806, 704; ¹H NMR (CD₂Cl₂) 8.55 (d, J ) 2

Hz, 1H), 8.40 (dd, J ) 5, 2 Hz, 1H), 7.64 (dt, J ) 8, 2 Hz, 1H),

7.32 (d, J ) 8 Hz, 2H), 7.13 (dd, J ) 9, 5 Hz, 1H), 7.12 (d, J )

8 Hz, 2H), 6.96 (s, 1H), 2.52 (s, 3H), 2.08 (s, 3H). Anal.

(C₁₆H₁₅N₃S‚0.125H₂O) C, H, N.

Step 3: P r ep a r a tion of 3-[4-Meth yl-1-{4-(m eth ylsu lfo-

n yl)p h en yl}-1H-im id a zol-2yl]p yr id in e (60). A solution of

18 (567 mg, 1.80 mmol) in dichloromethane (14 mL) was cooled

(0-5 °C, ice-bath) and m-chloroperoxybenzoic acid (1.33 g, 80-

85% purity) added. After the mixture was stirred for 30 min,

additional m-chloroperoxybenzoic acid (1.33 g) and dichloro-

methane (5 mL) were added. After being stirred for 1 h, the

mixture was diluted with dichloromethane, and a white solid

was isolated by filtration. The filtrate was washed with

aqueous NaHCO₃and the aqueous layer extracted with

dichloromethane. The combined organic extracts were dried

(Na₂SO₄), filtered, and concentrated. Chromatography of the

residue using a gradient of 0-50% MeOH-EtOAc gave 19 (213

mg) as a white solid.

A solution of 19 (213 mg) in absolute ethanol (20 mL) and

cyclohexene (3 mL) was treated with 50 mg of 10% Pd/C. The

reaction mixture was refluxed for 1 h, diluted with dichloro-

methane, and filtered through Celite. The combined organic

fractions were concentrated to give 60 (184 mg, 29% from 18)

as a white solid: ¹H NMR (CD₂Cl₂) 8.58 (d, J ) 5 Hz, 1H),

8.52 (dd, J ) 5, 2 Hz, 1H), 7.94 (d, J ) 8 Hz, 2H), 7.69 (m,

1H), 7.42 (d, J ) 8 Hz, 2H), 7.24 (m, 1H), 7.01 (s, 1H), 3.12 (s,

3H), 2.32 (s, 3H). Anal. (C₁₆H₁₅N₃SO₂‚H₂O) C, H, N.

Eth yl-1-[4-(m eth ylsu lfon yl)p h en yl]-2-(3-p yr id in yl)-1H-

im id a zole-4-ca r boxyla te (61). Step 1: P r ep a r a tion of

Eth yl-1-[4-(m eth ylth io)p h en yl]-2-(3-p yr id in yl)-1H-im id a -

zole-4-ca r boxyla te (20). A mixture of 8 (5.00 g, 20.6 mmol),

ethyl bromopyruvate (8.93 g, 90% purity, 41.2 mmol), and

sodium bicarbonate (3.46 g) in 2-propanol (200 mL) was stirred

at reflux for 18 h. After cooling to room temperature, the

mixture was concentrated and the residue suspended in

dichloromethane and washed with water and brine. The

aqueous layer was extracted with dichloromethane again. The

combined organic fractions were dried (Na₂SO₄), filtered, and

concentrated. Chromatography of the residue using ethyl

acetate as eluent gave a brownish product 20 (2.39 g, 34%).

An analytical sample was crystallized from ethyl acetate to

3184 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16

Khanna et al.

(4) (a) Brogden, R. N.; Heel, R. C.; Speight, T. M.; Avery, G. S.

Sulindac: A Review of its Pharmacological Properties and

Therapeutic Efficacy in Rheumatic Diseases. Drugs 1978, 16,

97-114. (b) Matsuda, K.; Tanaka, Y.; Ushiyama, S.; Ohnishi,

K.; Yamazaki, M. Inhibition of Prostaglandin Synthesis By

Sodium 2-[4-(2-Oxocyclopentylmethyl)phenyl]propionate Dihy-

drate (CS-600), A New Antiinflammatory Drug, and Its Active

Metabolite In Vitro And In Vivo. Biochem. Pharm. 1984, 33,

give 20 as a pale tan crystalline solid: mp (DSC) 150-151

°C; IR (KBr) 1700, 1543, 1499, 1325, 1258, 1223; ¹H NMR (CD₂-

Cl₂) 8.61 (d, J ) 2 Hz, 1H), 8.53 (dd, J ) 5, 2 Hz, 1H), 7.81 (s,

1H), 7.75 (dt, J ) 8, 2 Hz, 1H), 7.28 (d, J ) 8 Hz, 2H), 7.22

(dd, J ) 9, 5 Hz, 1H), 7.16 (d, J ) 8 Hz, 2H), 4.36 (q, J ) 6 Hz,

2H), 2.50 (s, 3H), 1.37 (t, J ) 6 Hz, 3H). Anal. (C₁₈H₁₇N₃O₂S)

C, H, N.

2473-2478. (c) Friedel, H. A.; Todd, P. A. Nabumetone:

A

Step 2: P r ep a r a tion of Eth yl-1-[4-(m eth ylsu lfon yl)-

p h en yl]-2-(3-p yr id in yl)-1H-im id a zole-4-ca r boxyla te (61).

The compound was prepared by following the experimental

procedure described for 59, step 2: mp (DSC) 165 °C; IR

(CHCl₃) 1727, 1555, 1323, 1156; ¹H NMR (CD₂Cl₂) 8.62 (dd, J

) 5, 2 Hz, 1H), 8.52 (d, J ) 2 Hz, 1H) 8.07 (d, J ) 9 Hz, 2H),

7.92 (s, 1H), 7.88 (dd, J ) 8, 2 Hz, 1H), 7.45 (d, J ) 9 Hz, 2H),

7.33 (dd, J ) 9, 5 Hz, 1H), 4.36 (q, J ) 6 Hz, 2H), 3.09 (s, 3H),

1.38 (t, J ) 6 Hz, 3H). Anal. (C₁₈H₁₇N₃O₄S‚0.25H₂O) C, H, N.

1-[4-(Meth ylsu lfon yl)p h en yl]-2-(3-p yr id in yl)-1H-im id a -

zole-4-m eth a n ol (62). To a cold solution (-70 °C, dry ice-2-

propanol bath) of 61 (1.05 g, 2.8 mmol) in dichloromethane

(35 mL) was added diisobutylaluminum hydride (7.1 mL, 1 M

solution in toluene, 7.1 mmol) dropwise. The mixture was

allowed to warm to room temperature and stirred overnight.

The reaction mixture was quenched by adding methanol, and

the resulting pasty mixture was diluted with dichloromethane

and 10% aqueous acetic acid. The layers were separated, and

the aqueous layer was extracted with additional dichloro-

methane. The combined organic extracts were dried (Na₂SO₄),

filtered, and concentrated. Chromatography of the crude

mixture using 25% methanol in ethyl acetate as eluent gave

62 (520 mg, 56%) as shining pale yellow plates: mp 210-211

°C; MIR 2954, 2919, 2850, 1305, 1288, 1149; ¹H NMR (AcOH-

d₄) 8.69 (d, J ) 5 Hz, 1H), 8.61 (d, J ) 2 Hz, 1H), 8.10 (d, J )

9 Hz, 2H), 8.05 (dt, J ) 8, 2 Hz, 1H), 7.62 (d, J ) 9 Hz, 2H),

7.60 (dd, J ) 8, 5 Hz, 1H), 7.55 (s, 1H), 4.81 (s, 2H), 3.17 (s,

3H). Anal. (C₁₆H₁₅N₃O₃S‚0.375H₂O) C, H, N.

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Ack n ow led gm en t. The authors are grateful to

J acquelyn J . Casler and Concepcion M. Ponte for

assistance in generating data in the adjuvant arthritis

model. The authors are thankful to Dr. Dutt Vinjamori

and J erry C. Mohammed for help in determining the

physical properties and studying the pharmacokinetics

of selected compounds. The authors thank Professors

Paul Grieco (Montana State University) and Lester A.

Mitscher (University of Kansas) for useful discussions.

The support of Physical Methodology, Preparative Chro-

matography, Hydrogenation Department and Informa-

tion Services is gratefully acknowledged.

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J M0000719

Article Doi

Selective cyclooxygenase-2 inhibitors: Heteroaryl modified 1,2-diarylimidazoles are potent, orally active antiinflammatory agents

DOI: 10.1021/jm0000719

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Full text of DOI:10.1021/jm0000719

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