Second Generation Leukotriene B4 Receptor Antagonists Related to

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J . Med. Chem. 1995,38, 858-868

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Art ides Second-GenerationLeukotriene Bq Receptor Antagonists Related to SC-41930: Heterocyclic Replacement of the Methyl Ketone Pharmacophore Thomas D. Penning,* Stevan W. Djuric, Julie M. Miyashiro, Stella Yu, James P. Snyder,t Dale Spangler,? Charles P. Anglin,$Donald J. Fretland,$ James F. Kachur,* Robert H. Keith,$ Bie Shung Tsai,s Doreen Villani-Price,*Robin E. Walsh,* and Deborah L. Widomski$ Departments of Chemistry, Drug Design, and Inflammatory Diseases, Searle Research and Development, Skokie, Illinois 60077 Received October 21, 1994@

Our previous reports have highlighted the first-generation leukotriene B4 (LTB4) receptor antagonist SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl-3,4-dihydro-8-propylW-1-benzopyran-2-carboxylicacid) which has potent oral, topical, and intracolonic activity in various animal models of inflammation. Extensive structure-activity relationship studies, in which a series of heterocyclic replacements for the methyl ketone functional group of SC-41930 was explored, identified SC-50605 (7-[3-[2-(cyclopropylmethyl)-3-methoxy-4-~4-thiazolyl~phenoxy]propoxy]-3,4-dihydro-8-propyl-W-1-benzopyran-2-carboxylic acid) as a n optimized analog within a series of thiazoles. SC-50605 was found to be significantly more potent than SC41930 in LTB4 receptor binding, chemotaxis, and degranulation assays. It also displayed very good activity in animal models of colitis and epidermal inflammation by oral, topical, intravenous, and intracolonic routes of administration. The resolved enantiomers of SC-50605 were obtained by chiral chromatography and both demonstrated good in vitro and in vivo activity. The (+)-isomer (SC-52798)is currently being evaluated as a potential clinical candidate for psoriasis and ulcerative colitis therapy. Leukotriene B4 (LTBd, a 5-lipoxygenase-derivedmetabolite of arachidonic acid, has been shown t o possess potent chemotactic and degranulatory properties for human neutrophils. Elevated levels of LTB4 have been reported in a number of inflammatory disease states characterized by PMN accumulation, including psoriasisl and ulcerative colitis (UC).2 In addition, clinical remission appears to correlate well with diminished LTB4 levels in this p~pulation.~ Substantial efforts have been underway in the pharmaceutical industry to modulate LTB4 function, particularly in the area of LTB4 receptor antagonist r e ~ e a r c h .As ~ part of our program directed toward the identification of novel therapeutic agents for inflammatory diseases, we discovered the orally active, pharmacologically selective LTB4 receptor antagonist SC-41930.5,6In this report we describe our efforts t o identify a second-generation back-up compound for SC-41930with improved potency and selectivity. During our early efforts to identify a successor to SC41930, we found through extensive structure-activity relationship (SAR) studies that the primary amide, SC48928, demonstrated enhanced potency relative t o SC41930 in a number of our i n vitro biological assays. Exploitation of this lead led t o the discovery of the very potent and selective LTB4 receptor antagonist SC-53228, a monomethyl amide that has recently been discl~sed',~ and is currently in preclinical development. Concurrently, the work described herein has sought to exploit this lead by introduction of various nitrogen-containing 5-membered ring heterocycles as surrogates of the amide fun~tionality.~ It has been found that the thia+

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Department of Drug Design. Department of Inflammatory Diseases. Abstract published in Advance ACS Abstracts, February 15, 1995.

0022-262319511838-0858$09.00/0

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zole moiety is a particularly effective replacement for the amide group, leading to the discovery of SC-50605 as a relatively optimized analog within the thiazole series.

Chemistry Because of the ready availability of SC-41930 and other acetophenone analogs from our analog program, the heterocyclic analogs described were constructed from these compounds rather than a de novo synthesis of each. The method of preparation of acetophenones la-f has been previously described.l0 The initial SAR work in this series was carried out with la (the methyl ester of SC-41930). Scheme 1illustrates the synthesis of isoxazole 4 and pyrazole 5. The methyl ketone l a was condensed with DMF-dimethyl acetal or tris(dimethy1amino)methane in DMF at 120 "C t o provide enamino ketone 2.11 Reaction with either hydroxylamine or hydrazine gave 4 and 5, respectively.12 The synthesis of imidazole analogs is shown in Scheme 2. Acetophenone l a was converted to the silyl enol ether, which was chlorinated to provide a-chloro ketone 6. Reaction with 2-benzyl-2-thiopseudourea hydro~hloridel~ in the presence of NaI and Na2C03 furnished imidazole 7, which was saponified with LiOH

0 1995 American Chemical Society

Second-Generation LTBs Receptor Antagonists

Journal of Medicinal Chemistry, 1995, Vol. 38, No. 6 859

Scheme la

la

2

4

& o o :& w N-#

5

(a) (MeO)ZCHNMez,DMF, 120 "C; (b) NH20H-HCl, MeOH, HzO; (c) LiOH; (d) NHzNHz, MeOH, HzO.

Scheme 2"

la

a

CI &o-o&co2Me

b

~

N&o-o&m2R

0

8, 7, R=H R-Mx 0

6 BllS

C

Id 3&

N'

-o&m2n

"#

B

(a) 1. LiHMDS, 2. TMSC1, 3. NCS, 4.TBAF; (b) NH=C(NHz)SBn.HCl, NaI, KzCO3, DMF, 80 "C; (c) LiOH; (d) Ra Ni, NaOH, EtOH.

Scheme 3"

'

.m 2 &oN, :o&

"-1 a

13

(a)Oxalyl chloride, benzene; (b) LDA, THF; (c) TMSN3, toluene

120-160 "C; (d) LiOH.

to give the carboxylic acid 8. Desulfurization of 7 using Raney nickel proceeded with concomitant hydrolysis of the methyl ester to provide the monosubstituted imidazole carboxylic acid 9. A triazole analog was constructed as described in Scheme 3. Again, starting with ketone la and reaction with oxalyl chloride gave the vinyl chloride. Dehydrohalogenation with LDA provided acetylene 11. Triazole 13 was obtained by reaction with trimethylsilyl azide14 followed by saponification with LiOH. As shown in Scheme 4, acetophenone la was converted to the silyl enol ether, which was oxidized with m-CPBA to give hydroxy ketone 14.15 Oxazole 15 was

obtained by conversion of alcohol 14 to the triflate with triflic anhydride followed by reaction with formamide in DMF at 170 "C.lGaSaponification with LiOH provided the carboxylic acid 16. It was necessary to use the triflate in this sequence since reaction of the corresponding chloride with formamide failed to provide any substantial amounts of the desired oxazole. In an attempt to synthesize the 2-aminooxazole, a-chloro ketone 6 was heated in AcOH at 120 "C with urea. Instead of the 2-aminooxazole, 2-methyloxazole 17 was obtained, apparently via generation of acetamide from acetic acid and urea at this temperature.16bTreatment with LiOH furnished acid 18. The synthesis of thiazole analogs is shown in Scheme 5. Reaction of the previously described a-chloro ketone 6 with thiourea in ethanoVwaterl' yielded, after NaOH workup, the 2-aminothiazole 19. Likewise, the 2-mercaptothiazole 21 was obtained by reaction of 6 with ammonium dithiocarbamatels in ethanoywater followed by LiOH treatment. S-Methylation of methyl ester 20 with methyl iodide, followed by treatment with LiOH, provided the 2-(methy1thio)thiazole 23. The 2-(benzy1thio)thiazole analog 24 was obtained by benzylation of acid 21 with benzyl bromide. A 2-methoxy analog was produced via a thi0~yanate.l~ Treatment of 6 with potassium thiocyanate in refluxing ethanol gave a-thiocyanato ketone 25. Reaction of the thiocyanate with NaOMe provided, after saponification, thiazole 27. The simple monosubstituted thiazole 28 was synthesized by treatment of a-chloro ketone 6 with a freshly prepared solution of thioformamide (formamide/P&) and mag-

860 Journal of Medicinal Chemistry, 1995, Vol. 38, No. 6

Penning et al.

Scheme 4"

a (a) 1. LiHMDS, 2. TMSCl, 3. MCPBA, 4. TsOH; (b) TfzO, 2,6-lutidine, CHzClz; (c) HCONHz, DMF, 170 "C; (d) LiOH; (e) urea, AcOH, 120 "C.

Scheme 5"

6 -

i

S&o-o&C02R

29, 28, R-H R-Me J d

k N

(a) Thiourea, EtOH, HzO, reflux; (b) NaOH; ( c ) NHzC(S)S-NHd+, EtOH, HzO, reflux; (d) LiOH; (e) BnBr, CHsNOz; (0 MeI, CH3NOz; (g) KSCN, EtOH, reflux; (h) NaOMe; (i) HCONH2, PzSS, MgC03, dioxane, 100 "C. a

nesium carbonate in dioxane at 100 0C.20SaDonification with LiOH furnished acid 29. On the basis of promising in vitro biological results obtained with 29,a series of monosubstituted thiazoles was synthesized in an attempt to optimize the in vitro pharmacology. The previously describedlO acetophenones lb-f were each treated with cuprous bromidez1 to provide the corresponding a-bromo ketone. The a-bromo ketones were preferred because they were more convenient to generate and utilize than the analogous a-chloro ketones. The bromides were each treated with freshly prepared thioformamide as described above and saponified in the usual manner to give the corresponding thiazoles 32,35,38,41 and 44.

Results and Discussion

Early S A R studies based on our lead LTBI receptor antagonist, SC-41930, led t o the identification of the primary amide, SC-48928, a compound that demonstrated a 2-&fold enhancement in potency in vitro relative to SC-41930. As a continuation of these studies, we sought to exploit this lead via the introduction of various nitrogen-containing 5-membered ring heterocycles in place of the critical acetyl or carboxamido functional group in SC-41930 and SC-48928. It was presumed that the carbonyl oxygen acted as a hydrogenbond acceptor and that the nitrogen of an appropriate heterocycle would function in a similar manner. A

Second-Generation LTBl Receptor Antagonists

Journal of Medicinal Chemistry, 1995, Vol. 38, No. 6 861

Table 1. Comparison of in Vitro Data for SC-41930 Analogs

compd SC-41930

X

Y

SC-48928

4

CH CH NH NH NH

N NH 8 CSBn 9 CH 13 N 16 0 CH 18 0 CMe 19 S CNH2 21 S CSH 23 S CSMe 24 S CSBn 27 S COMe 29 S CH a Numbers in parentheses are upper and lower-wells. 5

LTBd receptor binding LTB4-induced chemotaxisa LTB4-induced degranulation4 (1C50, nM) ( I C ~ OnM) , ( I C ~ OnM) , 320 f 20 1790 i 490 920 f 50 43 f 17b 832 f 9 l C 140 f 30 350 (2) 920 (2) 0 770 f 20 1600 (1) N 610 (2) 1200 (1) N 750 (2) 430 (1) N 520 (2) 1200 (1) N 5.2 (2Ib 88 (2)C 130 (1) N 100 (2) 430 (2) 230 (2) N 1100 (2) 210 000 (1) N 320 (2) 1500 (1) N 890 380 520 (1) 1200 (2) N 2800 (2) 18 600 (1) N 5800 (2) > 10 000 (1) N 1150 (2) > l o 000 (1) N 93 & 31 287 f 24 90 (2) number of determinations. Experiment conducted in the absence of NDGA. Test compound added to

Z

*

Scheme 6" MW$ O ,C -L~.

0

32 (R3- H) 35 38 41 44

A

a CpMe = cyclopropylmethyl. (a) CuBr2, EtOAc, CHC13, reflux; (b) HCONH2, P2S5, MgC03, dioxane, reflux; (c) LiOH.

series of heterocycles based on the SC-41930148928 structure was evaluated in the LTB4 receptor binding and LTB4-induced chemotaxis and degranulation assays. Table 1 delineates the in vitro biological results for these compounds and compares them to that of SC41930. It should be noted that nordihydroguaiaretic acid (NDGA) was initially added in the binding assay to inhibit endogenous LTB4 production but was omitted in later assays, resulting in an increased potency for these test compounds.22 For the sake of comparison, binding affinity for SC-41930 is shown in the presence and absence of NDGA. Test compounds run in the absence of NDGA are noted in Tables 1and 2. Also, in the chemotaxis assay (modified Boyden chamber), test compound was initially added only to the lower well but was later added t o both upper and lower wells to eliminate the necessity of compound diffusion into the

upper well. These conditions resulted in a small increase in compound potency in the assay. Again, for comparison, values for SC-41930 are given under both assay conditions. Test compounds added to both wells are noted in the tables. As shown in Table 1, the isoxazole, pyrazole, and imidazole analogs 4,5,8, and 9 exhibited no substantial increase in potency in the binding and chemotaxis assays relative to SC-41930. This is in contrast to some pyrazole analogs in a 2,4,5-substituted acetophenone series of LTB4 antagonists recently reported by L i l l ~ ~ ~ which showed significantly enhanced potency relative to the parent acetophenones. Likewise, the substituted oxazoles and thiazoles 18, 23, 24, and 27 were, in general, considerably less potent than SC-41930 in these assays. The only exceptions were aminothiazole 19, which was equipotent in the binding and chemotaxis assays, and 21, which was more potent than SC-41930 only in the chemotaxis assay. However, triazole 13 and unsubstituted oxazole and thiazole 16 and 29 were substantially more potent in all three in vitro assays, with potencies from 3 to 10 times that of SC-41930. It is likely that a combination of conformational and electronic effects plays a role in the enhanced potency of these particular analogs; however, this has not been examined further at this time. Because of its overall biological profile, we performed further SAR studies on thiazole analog 29, based on what we had learned from modifications carried out in our previous studies in this area.7,24From this previous work we found that modifications such as replacement of the n-propyl group on the acetophenone portion of the molecule with allyl or cyclopropylmethyl or insertion of two methylene units between the chroman ring and the carboxylic acid generally resulted in compounds with increased potency. The application of these modifications t o 29 is summarized in Table 2. This study led to the identification of SC-50605 (35) and 41 as

Penning et al.

862 Journal of Medicinal Chemistry, 1995, Vol. 38, No. 6

Table 2. Comparison of in Vitro Data for Thiazole Analogs

I

B

compd

R

n

SC-41930

29

32 SC-50605 (35) SC-52798 ((+)-35) SC-52799 ((-)-35)

38 41 44

propyl allyl CpMed CpMe CpMe propyl CpMe CpMe

LTBd receptor binding" ( I C ~ OnM) ,

LTB4-induced chemotaxisn (1C50, nM)

LTB4-induced degranulationn (1C50,nM)

320 f 20 43 f 176 93 f 31 25 (2) 42 f 5 11.4 f 2b 3.2 f 0.66 4.5 f 0.96 26 (2) 12.3 (2)b 15.5 (2)b

1790 f 490 832 f 9 l C 287 f 24 110 (1) 89 f 6c

920 f 050

67 f 1Oe 188 f 16c 1540 f 582

48 f 16 79 f 25 70 f 31 712 220 (2)

90 (2) 23 (2) 57 f 7

49 (2Y 360 (2Y

Numbers in parentheses are number of determinations. Experiment conducted in the absence of NDGA. Test compound added to upper and lower wells. CpMe = cyclopropylmethyl. e Carbons marked with an asterisk are deleted in this molecule.

Table 3. Comparison of in Vivo Data LTB1-induced cavine intradermal chemotaxis (ED501 compd

topical (ng)

iv (mgkg)

oral (mgkg)

murine epidermal inflammation (topical ED50, mg)

SC-41930 SC-50605 (35) SC-52798 ((+)-35) SC-52799 ((-)-35)

340 f 42 70 i 6.7 18 i 2 98 i 8

0.5 f 0.01 0.02 i 0.009

1.7 f 0.2 0.74 f 0.04 0.20 f 0.02 1.21 i 0.13

1.4 f 0.18 0.8 i 0.07 0.29% 0.04 0.98 f 0.10

SCOA-induced colitis (ED509 mgkg) murine (intracolonic) cavine (oral) 28 f 3.1 12 i 1.3 7.1 f 0.9 11.7 i 1.4

20 f 2.7 3.4 f 0.5 2.3 f 0.3 5.9 f 0.7

optimized analogs within this series. Whereas 4 1 was concentrations up t o 10 pM, SC-50605 displayed no more potent than SC-50605 in vitro, SC-50605 was agonist properties in the PMN chemotaxis assay, nor chosen for further investigation on the basis of its did it inhibit LTD4-stimulated contractions of guinea pig overall pharmacological profile. SC-50605 was signifiileal longitudinal muscle at concentrations up to 1pM. cantly more potent than SC-41930 in the binding, SC-50605 also inhibited eicosanoid production in chemotaxis, and degranulation assays. Resolution of A23187-stimulated human PMN and HL-60 cells. It SC-50605 by chiral HPLC provided the individual inhibited LTB4 production with an ICB0of 520 & 25 nM antipodes, both of which were very potent antagonists in PMNs and 660 nM in HL-60s and inhibited PGEz in all in vitro assays. However, the (+)-isomer (SCproduction in HL-60s with an IC50 of 928 f 221 nM. 52798) was approximately twice as potent as the (-)The mechanisms for these inhibitions have not yet been isomer (SC-52799) in these assays. This is consistent defined. with previous reports that the (+)-isomer of SC-41930 SC-50605 and its individual enantiomers were comand the (+)-isomer of SC-51146 (SC-53228)are slightly pared to SC-41930 in several animal models of inflammore potent than the corresponding (-)-isomers.'~~>~~ mation, and all were substantially more potent than SCSC-52798 and SC-50605 also demonstrated signifi41930, regardless of the route of administration (Table cant selectivity toward LTB4- over fMLP (f-Met-Leu3). In the cavine intradermal chemotaxis assay, SCPhebmediated degranulation and chemotaxis. In the 50605 was 2-25 times more potent than SC-41930, and PMN degranulation assay, SC-52798 inhibited fMLPit was 2-6 times more potent in the short-chain organic induced degranulation with an IC50 of 5900 f 700 nM acid (SC0A)-induced colitis models. Consistent with the compared to 48 nM for LTB4-induced degranulation, a in vitro assay data, the (+)-isomer (SC-52798)was more 123-fold selectivity. In the chemotaxis assay, the IC50 potent than both the (-)-isomer and the racemate (SCratio was 21, with ICBOS of 1410 f 336 nM for fMLP 50605) in all of the animal models. In addition, in the and 67 nM for LTB4. (For SC-50605, these ratios were LTB4-induced intradermal chemotaxis assay, when 54 and 12 for the degranulation and chemotaxis assays, administered orally at a dose of 3 mg/kg, SC-52798 respectively.) In addition, SC-50605 and SC-52798 demonstrated a substantial increased duration of action inhibited 12(R)-HETE (lZ(R)-hydroxyeicosatetraenoic relative to SC-41930, 27 h vs 5.5 h. Furthermore, SCacid)-induced chemotaxis with ICBOS of 106 and 52 nM, 50605 demonstrated oral activity at a dose of 30 mgkg respectively. This could prove to be a beneficial property in a 12(R)-HETE-induced cavine intradermal chemoin the treatment of psoriasis due t o recent evidence that taxis assay (data not shown). 12(R)-HETE may be an important mediator in that Conclusion disease state.26 SC-50605 also demonstrated excellent potency against LTB4 binding to its receptors on eosiWe have succeeded in identifying a potent and selective back-up compound to SC-41930. SC-50605 and its nophils (IC50 = 2.6 f 6 nM) as well as LTB4-induced eosinophil chemotaxis (ICB0= 9 nM (n = 2)). At antipodes, SC-52798and SC-52799,have demonstrated

Second-Generation LTBd Receptor Antagonists

a greater potency and overall efficacy in our panel of in vitro and in vivo pharmacological assays than SC-41930. In our paradigms of dermal inflammation and colitis, these compounds have shown significant efficacy via oral, topical, intravenous, and intracolonic routes of administration. These compounds may well have an application in disease states where LTB4 is thought to play a role, such as inflammatory bowel disease and psoriasis, and, potentially, in asthma, rheumatoid arthritis, cystic fibrosis, and contact and atopic dermatitis. Whether compounds such as these, which target a specific inflammatory mediator such as LTB4, will be effective in the medical management of complex human inflammatory disease states remains t o be determined in clinical trials. Experimental Section Biological Methods. Human Neutrophil Preparation. As described previously,6 human neutrophils were isolated from citrated peripheral blood sedimented in 5% dextran, followed by centrifugation on Ficoll-paque and hypotonic erythrocyte lysis. BSA (0.25%) was present during lysis for degranulation and chemotaxis studies but absent for receptor binding studies. After lysis, neutrophils were washed with HEPES-buffered Hanks balanced salt solution (HBSS) and resuspended in HBSS t o a final concentration of (3-5) x lo6 cells/mL. LTB4 Receptor Binding.6$8 Neutrophils (4 x lo6 cells) and 0.6 nM L3H1LTB4 were incubated in the presence or absence of test compound at 0 "C for 45 min in 1 mL of HBSS (30 pM NDGA (nordihydroguaiaretic acid) was also present in some assays). Following incubation, 5 mL of ice-cold HBSS was added to the incubation mixture followed by vacuum filtration through glass fiber filters (Whatman GF/C) t o separate free from bound [3H]LTB4. The filters were washed with 2 x 5 mL HBSS. Specific binding was calculated as the difference between total binding and binding not displaced by 0.1 pM unlabeled LTB4 (nonspecific binding). LTB4-InducedChemotaxis. The chemotaxis assay was performed in modified Boyden chambers as previously described.6 A neutrophil suspension (3.2 x lo6 cells/0.8 mL) in HBSS was added to the upper well of a modified Boyden chamber. The lower well (0.2 mL), separated by a PVC-coated poly(carbonate) membrane (3pM), contained HBSS or 3 x M LTB4in the presence or absence of test compound (in some assays, test compound was added to the upper as well as the lower well). Following a 90-min incubation at 37 "C, the number of cells from the lower well was quantitated with a Coulter counter. Percent inhibition was calculated from cell counts corrected for random migration by subtracting the mean of the HBSS control. LTB4-InducedDegranulation.6 A neutrophil suspension (3 x IO6 cells) in 1 mL of HBSS was preincubated with cytochalasin B ( 5 pg) at 37 "C for 5 min followed by preincubation with the test compound for 7 min. Neutrophils were then incubated for 2 min with LTB4 ( 5 x M) to induce degranulation. Myeloperoxidase (MPO) activity in the cell pellet and supernatant was determined spectophotometrically via decomposition of peroxide using o-dianisidine hydrochloride. After subtracting the basal MPO activity in the supernatant, data were expressed as the percentage of total MPO activity released into the supernatant induced by LTBI. Cavine LTB4-InducedDermal Chemota~is.~~ A solution of LTB4 (35 ng) in 0.1 mL of 0.9% NaCl was injected intradermally into the shaved backs of lightly anesthetized guinea pigs. Appropriate vehicle controls were used throughout. After 4 h, the animals were killed and the skins removed and frozen (-70 "C). Skin punches (12 mm diameter) of injection sites were mechanically homogenized, and the MPO was extracted with detergent-buffer using sonication and freeze-thaw procedures. After centrifugation, MPO activity in the supernatant was assayed spectrophotometrically. Test

Journal of Medicinal Chemistry, 1995, Vol. 38, No. 6 863 compounds were either coinjected with LTB4 or administered iv 5 min before or orally 1 h prior t o injection of LTB4. Mouse Epidermal Phorbol-12-myristate13-acetate (PMA, 25 pg) in acetone was applied to the dorsal ear surface of one mouse ear and control vehicle to the contralateral ear. After 18 h, the animals were killed and the ears extirpated, weighed, and frozen. Edema was assessed by ear weight gain relative t o the contralateral ear. MPO activity was also assayed as described above for the dermal chemotaxis assay. Test compounds were applied with the PMA topically as a solution in acetone. SCOA-Induced Colitis. The short-chain organic acid (SC0A)-induced colitis model was reported previously.29 Colitis was induced by a single intrarectal (ir) enema of 3%acetic acid in water for mice and 4% for guinea pigs, under light anesthesia. After 24 h the animals were killed and the colonic tissues assessed for MPO activity. Test compounds were given ir in the mouse 1 h before and 1 h after acid instillation and orally 30 min prior to colitis induction in the guinea pig. Chemistry. Melting points were determined using a Thomas Hoover melting point apparatus and are uncorrected. Optical rotations were measured on a Perkin-Elmer PE 241 polarimeter using a 1-dm cell. High-field 'H NMR spectra were recorded on a GE QE-300 spectrometer. Chemical shifts are reported in parts per million relative to internal tetramethylsilane. Microanalyses were performed by the Searle Physical Methodology Department. Mass spectra were recorded on a Finnigan MAT-8430 instrument operating in either the electron impact (EI)or chemical ionization (CI)mode as indicated. Methyl 7-[3-[4-[3-(Dimethyl~mino)-l-oxo-2-propenyll3-methoxy-2-propylphenoxylpropxyl-3,4-dihydro-8-propyl-W-1-benzopyran-2-carboxylate (2). Acetophenone la (0.95 g, 1.90 mmol) was stirred in 1 mL of N,N-dimethylformamide (DMF) and 0.3 mL of DMF-dimethyl acetal at 110120 "C for 23.5 h. The mixture was cooled and poured into EtOAc and 1M HC1 and the organic layer separated, washed with brine, dried over Na2S04, and concentrated. Flash chromatography on silica gel using a gradient of 1:2 hexane/ EtOAc t o 100% EtOAc provided 2 (0.88 g, 84%) as a light yellow oil: 'H NMR (CDC13) 6 0.92 (3H, t), 0.97 (3H, t), 1.55 (4H, m), 2.18 (2H, m), 2.29 (2H, m), 2.63 (4H, m), 2.71 (2H, m), 2.91 (3H, br), 3.07 (3H, br), 3.74 (3H, s), 3.78 (3H, s), 4.14 (2H, t), 4.20 (2H, t), 4.77 (lH, dd), 5.74 ( l H , br d), 6.47 ( l H , d), 6.67 (lH, d), 6.79 (lH, d), 7.42 (lH, d), 7.68 (lH, br d). Anal. (C32H43N07Q.3H20)C, H, N. Methyl 3,4-Dihydro-7-[3-[4-(5-isoxazolyl)-3-methoxy-2propylphenoxy]propoxy]-8-propyl-W-l-benzopyran-2carboxylate (3). Enamino ketone 2 (0.155 g, 0.277 mmol) was stirred in 5 mL of MeOH and 1.25 mL of HzO with NH2OH.HCl(48 mg, 0.7 mmol) at reflux for 1 h. The mixture was cooled and poured into ether and water. The ether layer was separated, washed with brine, dried over Na2S04, and concentrated. Flash chromatography on silica gel using a gradient of 1O:l-5:1 hexane/EtOAc furnished 3 (0.13 g, 90%) as a colorless gum: 'H NMR (CDC13) 6 0.92 (3H, t), 0.98 (3H, t), 1.57 (4H, m), 2.19 (2H, m), 2.31 (2H, m), 2.64 (6H, m), 3.68 (3H, s), 3.74 (3H, s), 4.14 (2H, t), 4.22 (2H, t), 4.75 ( l H , dd), 6.47 (lH, d), 6.68 ( l H , d, J = 2 Hz), 6.78 ( l H , d), 6.80 ( l H , d), 7.75 ( l H , d), 8.29 (lH, d, J = 2 Hz). Anal. (C30H37N07) C, H, N. A. General Procedure for the Saponification of Esters. To a 0.05 M solution of the ester in 4:l MeOW tetrahydrofuran (THF) at 0 "C was added 3-4 equiv of 1 N LiOH, and the solution was stirred at 25 "C until TLC analysis indicated all the starting ester was consumed (generally 1-3 h). The mixture was poured into EtOAc and 0.5 M HC1 and the organic layer separated, washed with brine, dried over NazSO4, and concentrated to give the desired carboxylic acid. 3,4-Dihydro-7-[3-[4-(5-isoxazolyl)-3-methoxy-2-propylphenoxylpropoxy]-8-propyl-W-1-benzopyran-2-carboxylic Acid (4). Ester 3 (60 mg, 0.114 mmol) was saponified as described in general procedure A to afford the crude acid which was flash chromatographed on silica gel using a gradient of 100:20:1-75:25:1 hexane/EtOAc/AcOH to furnish 4 (42 mg, 72%) as a colorless gum: 'H NMR (CDC13)6 0.91 (3H, t), 0.96

864 Journal ofMedicina1 Chemistry, 1995, Vol. 38, No. 6

Penning et al.

boxylic Acid (9). Imidazole 7 (35 mg, 54 pmol) was stirred (3H, t), 1.56 (4H, m), 2.20 (lH, m), 2.29 (3H, m), 2.65 (4H, m), in 1mL of EtOH and 1.25 mL of 20% aqueous NaOH with 0.5 2.76 (ZH, m), 3.67 (3H, s), 4.13 (2H, t), 4.21 (2H, t), 4.76 (lH, g of 50% RaNi in water and the mixture heated at reflux for dd, J = 6.9, 3.8 Hz), 6.49 ( l H , d), 6.67 (lH, d, J = 1.5 Hz), 2.5 h. The mixture was cooled and filtered and the filtrate 6.76 (lH, d), 6.82 (lH, d), 7.74 (lH, d), 8.30 (lH, d, J = 1.5 concentrated, The product was dissolved in EtOAc and the Hz); HRMS (EI) mlz 509.2423 (calcd for C~gH35N07509.2413). solution washed with 0.5 M HC1 and brine, dried over Nan3,4-Dihydro-7-[3-[3-methoxy-2-propyl-4-(pyrazol-3-y1)phenoxy]propoxy]-8-propyl-W1-benzopyran-2-carbox- SO4, and concentrated to provide 9 as a colorless oil: IH NMR (CD3CO2D)6 0.87 (3H, t), 0.98 (3H, t), 1.57 (4H, m), 2.21 (2H, ylic Acid (5). Enamino ketone 2 (0.11 g, 0.20 mmol) was m), 2.32 (2H, m), 2.69 (6H, m), 3.68 (3H, s), 4.21 (2H, t), 4.31 saponified as described in general procedure A. The crude acid (2H, t), 4.83 (lH, dd), 6.52 (lH, d), 6.81 (lH, d), 6.92 (lH, d), was stirred in 4 mL of MeOH and 1 mL of water with 0.1 mL 7.60 (lH, d), 7.78 (lH, s), 9.03 (lH, s). Anal. (CzgH36Nz06' of hydrazine hydrate at reflux for 2 h. The mixture was cooled AcOH.Hz0) C, H, N. and poured into EtOAc and 1 N HC1. The organic layer was Methyl 7-[3-[4-(1-Chloroethenyl)-3-methoxy-2-propylseparated, washed with brine, dried over NazS04, and conphenoxy]propoxy]-3,4-dihydro-&propyl.W- l-benzopyrancentrated. Flash chromatography on silica gel using a gradient 2-carboxylate (10). To acetophenone la (1.1g, 2.2 mmol) of 100:20:1-66:33:1 hexane/EtOAc/AcOH provided 5 (82 mg, in 15 mL of benzene containing 1 drop of DMF was added 81%) as a white solid: mp 156-158 "C; 'H NMR (CDCl3) 6 oxalyl chloride (0.35 mL, 4.0 mmol), and the mixture was 0.93 (3H, t), 0.98 (3H, t), 1.58 (4H, m), 2.28 (4H, m), 2.67 (4H, stirred at 25 "C for 2.5 days. The mixture was poured into m), 2.78 (2H, m), 3.61 (3H, s), 4.16 (2H, t), 4.21 (2H, t), 4.80 ether and water and the ether layer separated, washed with (lH, dd), 6.47 (lH, d), 6.59 (lH, br s), 6.72 (lH, d), 6.82 (lH, brine, dried over Na2SO4, and concentrated. Flash chromad), 7.41 (lH, d), 7.58 (lH, br s). Anal. ( C Z ~ H ~ ~ NC,ZH, O N. ~) Methyl 7-[3-[4-(2-Chloro-1-oxoethyl)-3-methoxy-2-pro-tography on silica gel using 20:l hexane/EtOAc furnished vinyl chloride 10 (0.91 g, 80%)as a colorless gum: 'H NMR (CDC13) pylphenoxy]propoxy]-3,4-dihydro-8-propyl-Wl-benzopy6 0.92 (3H, t), 0.97 (3H, t), 1.53 (4H, m), 2.18 (2H, m), 2.27 ran-2-carboxylate(6). To acetophenone la (2.48 g, 4.97 (2H, m), 2.64 (4H, m), 2.72 (2H, m), 3.75 (3H, s), 3.76 (3H, s), mmol) in 50 mL of dry THF at -78 "C was added 5.5 mL of 1 4.13 (2H, t), 4.18 (ZH, t), 4.75 (lH, dd), 5.61 (lH, s, C=CH), M lithium bis(trimethylsily1)amide (LiHMDS) in THF. The 5.71 (lH, s, C=CH), 6.45 (lH, d), 6.64 (lH, d), 6.80 (lH, d), mixture was stirred at -78 "C for 15 min, and chlorotrimeth7.27 (lH, d). Anal. (CzgH370eCl) C, H, C1. ylsilane (TMSC1; 1.27 mL, 10 mmol) was added. The mixture Methyl 3,4-Dihydro-7-[3-(4-ethynyl-3-methoxy-2-prowas warmed t o 0 "C and stirred for 15 min. The solution was pylphenoxy)propoxyl-8-propyl-W-l-benzopyran-2-carconcentrated and the residue dissolved in hexane, filtered, and boxylate (11). To vinyl chloride 10 (0.108 g, 0.208 mmol) in concentrated. To the crude enol ether in 50 mL of THF at 0 10 mL of dry THF at 0 "C was added 1.5 M lithium diisopro"C was added N-chlorosuccinimide (0.73 g, 5.5 mmol). The pylamide (LDA)in cyclohexane (0.4 mL, 0.6 mmol). After the mixture was warmed to 25 "C, stirred for 15 min, and then mixture was stirred at 0 "C for 30 min and at 25 "C for 1 h, refluxed for 1.5 h. The mixture was cooled, and 4 mL of water the reaction was quenched with aqueous NH4C1. The mixture and 6 mL of 1N Bu4NF in THF were added. After 5 min the was poured into ether and water and the ether layer separated, mixture was poured into ether and water and the ether layer washed with brine, dried over NazS04, and concentrated. separated, washed with brine, dried over Na2S04, and conFlash chromatography on silica gel using a gradient of 20:lcentrated. Flash chromatography on silica gel using a gradient 15:l hexaneiEtOAc gave acetylene 11 (46 mg, 46%) as a of 2O:l-1O:l hexane/EtOAc furnished minor amounts of dicolorless gum: 'H NMR (CDC13) 6 0.92 (3H, t), 0.94 (3H, t), and trichloroacetophenones along with the desired monochlo1.52 (4H, m), 2.19 (2H, m), 2.28 (2H, m), 2.61 (4H, m), 2.72 roacetophenone 6 (1.53 g, 58%) as a white solid: mp 47-49 (2H, m), 3.22 (lH, s, CICH), 3.77 (3H, s), 3.92 (3H, s), 4.13 "C; 'H NMR (CDC13) 6 0.90 (3H, t), 0.95 (3H, t), 1.56 (4H, m), (2H, t), 4.17 (2H, t), 4.78 (lH, dd), 6.46 (lH, d), 6.59 (lH, d), 2.19 (2H, m), 2.31 (ZH, m), 2.61 (4H, m), 2.73 (2H, m), 3.77 C, H. 6.80 (lH, d), 7.28 (lH, d). Anal. (Cz9H360~*0.9Hz0) (6H, SI, 4.13 (2H, t), 4.24 (2H, t),4.76 (2H, S, CHzCl), 4.78 (lH, m), 6.45 (lH, d), 6.74 (lH, d), 6.80 (lH, d), 7.62 (lH, d); HRMS Methyl 3,4-Dihydro-7-[3-[3-methoxy-2-propyl-4-( 1,2,3triazol.4-yl)phenoxylp~po~l-8-propyl-~-l-benzopyr~(EI) mlz 532.2249 (calcd for C29H370735C1532.2228). Methyl 3,4-Dihydro-7-[3-[3-methoxy-4-[2-[(phenylmeth-2-carboxylate (12). A solution of 11 (0.20 g, 0.416 mmol) yl)thio]-lH-imidazol-4-y1] -2-propylphenoxylpropoxyl-8- and excess azidotrimethylsilane (TMSN3) in 7 mL of toluene was heated in a sealed tube at 120 "C for 18 h and at 150propyl-2H-l-benzopyran-2-carboxylate (7). Chloromethyl 160 "C for 24 h. The mixture was cooled and poured into ketone 6 (19 mg, 35.6 pmol) was stirred in 0.5 mL of DMF EtOAc and water. The organic layer was separated, washed with 2-benzyl-2-thiopseudoureahydrochloride (9.0 mg, 44.4 with brine, dried over NazS04, and concentrated. Flash pmol) in the presence of NaI (2.0 mg, 13.3 pmol) and KzCO~ chromatography on silica gel using a gradient of 51-2:l (20 mg, 0.19 pmol) at 80 "C for 5 min. The mixture was cooled hexaneiEt0Ac provided the starting acetylene 11 (160 mg, and poured into ether and water. The ether layer was 80%) along with the desired triazole 12 (30 mg, 14%) as a separated, washed with brine, dried over NazS04, and concolorless gum: 'H NMR (CDC13j 6 0.92 (3H, tj, 0.99 (3H, t), centrated. Flash chromatography on silica gel using 3:l 1.58 (4H, m), 2.19 (2H, m), 2.31 (2H, m), 2.69 (6H, m), 3.63 hexaneiEtOAc furnished imidazole 7 (18 mg, 78%) as a (3H, s), 3.78 (3H, SI, 4.15 (2H, t), 4.22 (2H, t), 4.77 (lH, t), colorless oil: 'H NMR (CDC13)6 0.92 (3H, t), 0.97 (3H, t), 1.54 6.47 (lH, d), 6.78 (lH, d), 6.81 (lH, d), 7.62 (lH, d), 8.06 (lH, (4H, m), 2.19 (2H, m), 2.27 (2H, m), 2.63 (4H, m), 2.72 (2H, s); HRMS (EI) mlz 523.2682 (calcd for CzgH37N306 523.2682). m), 3.40 (3H, br s), 3.76 (3H, s), 4.24 (2H, t), 4.28 (2H, t), 4.30 3,4-Dihydro-7-[3-[3-methoxy-2-propyl-4-(1,2,3-triazol(2H, S, CH2Ph), 4.76 (lH, dd), 6.45 (lH, d), 6.71 (lH, d), 6.80 4-yl)phenoxylpropoxyl-8-propyl-W-l-benzopyran-2-car(lH, d), 7.23 (6H, m), 7.37 (lH, s); HRMS (E11 mlz 644.2918 boxylic Acid (13). Ester 12 (30mg, 57.2 pmol) was saponified (calcd for C ~ & I ~ ~ N 644.2920). ZO~S 3,4-Dihydro-7-[3-[3-methoxy-4-[2-[(phenylmethyl)thiol-as described in general procedure A to afford the crude acid lH-imidazol-4-ylI -2-propylphenoxy]propoxyl-8-propyl- which was flash chromatographed on silica gel using a gradient of 100:20:1-66:33:1 hexane/EtOAc/AcOH to furnish 13 (18 mg, W-1-benzopyran-2-carboxylic Acid (8). Ester 7 (12 mg, 62%)as a colorless gum: 'H NMR (CDC13)6 0.91 (3H, t), 0.98 18.6 pmol) was saponified as described in general procedure (3H, t), 1.56 (4H, mj, 2.22 (lH, m), 2.30 (3H, m), 2.66 (4H, m), A t o afford the crude acid which was flash chromatographed 2.77 (2H, m), 3.61 (3H, s), 4.15 (2H, t), 4.22 (2H, t), 4.80 ( l H , on silica gel using a gradient of 3:1-1:l hexaneiEtOAc to t), 6.47 (lH, d), 6.75 ( l H , d), 6.82 (lH, d), 7.58 (lH, d), 8.09 furnish 8 (12 mg, 100%) as a white solid: mp 90-93 "C; 'H (lH, s); HRMS (E11 mlz 465.2629 (calcd for C27H35N304 (M NMR (CDC13) 6 0.91 (3H, t), 0.96 (3H, t), 1.52 (4H, m), 2.27 COz) 465.2627). (4H, m), 2.53-2.85 (6H, m), 3.35 (3H, s), 4.12 (2H, t), 4.19 (4H, Methyl 7-[3-[4-(2-Hydroxy-l-oxoethyl)-3-methoxy-2m), 4.76 (lH, br), 6.44 (lH, d), 6.66 (lH, d), 6.79 (lH, d), 7.21 (5H, m), 7.37 (lH, d), 7.48 (lH, s); HRMS (CI) mlz 631.2830 propylphenoxy]propoxylyl3,4-dihydro-8-propyl-W-l-benzopyran-2-carboxylate(14). To acetophenone la (3.17 g, (calcd for C36H43N206S (M f 1)631.2842). 6.36 mmol) in 60 mL of dry THF at -78 "C was added 7.0 mL 3,4-Dihydro-7-[3-[4-(~-~i~zol-4-yl)-3-metho~-2-propylphenoxy]propoxy]-8-propyl-W-l-benzopyran-2-car-of 1 M LiHMDS. The mixture was stirred at -78 "C for 10

Second-Generation LTB4 Receptor Antagonists

Journal of Medicinal Chemistry, 1995, Vol. 38, No. 6 865

min, and TMSCl(1.8 mL, 14.2 mmol) was added. The mixture noxy]propoxyl-3,4-dihydro-8-propyl-2Hl-benzopyran-2carboxylic Acid (19). Chloromethyl ketone 6 (0.13 g, 0.244 was warmed to 0 "C and stirred for 15 min. The solution was mmol) and thiourea (22 mg, 0.29 mmol) in 5 mL of EtOH and concentrated and the residue dissolved in hexane, filtered, and 1 mL of water were stirred at reflux for 4 h. The mixture was concentrated. The crude enol ether was stirred in 60 mL of cooled and 1mL of 5 M NaOH added. After stirring at 25 "C CHzClz at 0 "C with 2 g of NaHC03, and 1.4 g of 8 0 4 5 % for 10 min, the mixture was poured into CHzClz and 0.5 M m-chloroperoxybenzoicacid (m-CPBA)was added in portions. HC1. The CHzClz layer was separated, washed with brine, After stirring at 0 "C for 1 h, the mixture was diluted with dried over NazS04, and concentrated. Flash chromatography hexane, filtered, and concentrated. The residue was dissolved on silica gel using a gradient of 66:33:1-33:66:1 hexane/EtOAd in 50 mL of diethyl ether and stirred with catalytic pAcOH afforded acid 19 (0.125 g, 95%) as a tan foam: 'H NMR toluenesulfonic acid (TsOH) at 25 "C for 1.5 h. The mixture (CDC13)6 0.94 (3H, t), 0.97 (3H, t), 1.55 (4H, m), 2.12 (lH, m), was poured into water and the ether layer separated, washed 2.28 (3H, m), 2.58 (2H, m), 2.71 (4H, m), 3.58 (3H, s), 4.17 with brine, dried over NazS04, and concentrated. Flash (2H, m), 4.27 ( l H , m), 4.40 (lH, m), 4.85 (lH, t), 6.39 (lH, d), chromatography on silica gel using a gradient of 1O:l-3:1 6.46 (lH, d), 6.77 (lH, d), 6.88 (lH, s), 7.40 (lH, d); HRMS hexane/ethyl acetate provided recovered la (0.87 g, 27%) along (CI) m/z 541.2379 (calcd for C Z S H ~ ~ N (MZ+~ 1) ~ S541.2372). with of 14 (2.06 g, 63%) as a white solid: mp 87-88 "C; 'H Methyl 3,4-Dihydro-7-[3-[4-(2,3-dihydro-2-thioxo-4-thiNMR (CDC13) 6 0.89 (3H, t), 0.96 (3H, t), 1.56 (4H, m), 2.19 azolyl)-3-methoxy-2-propylphenoxylpropoxyl-8-propyl(2H, m), 2.30 (2H, m), 2.63 (4H, m), 2.71 (2H, m), 3.73 (lH, t, W-1-benzopyran-2-carboxylate (20). Chloro ketone 6 OH), 3.76 (3H, s), 3.79 (3H, s), 4.14 (2H, t, J = 5.9 Hz), 4.25 (2H, t, J = 6 Hz), 4.76 (lH, m), 4.77 (2H, d, J = 4.7 Hz, CH2(0.115 g, 0.216 mmol) and ammonium dithiocarbamate (30 mg, 0.27 mmol) were stirred in 7 mL of EtOH and 0.7 mL of H2O OH), 6.45 ( l H , d, J = 8.4 Hz), 6.76 (lH, d, J = 8.9 Hz), 6.80 ( l H , d , J = 8 . 4 H z ) , 7 . 7 7 ( 1 H , d ,J = 8 . 8 H z ) . Anal. (CZsH3808) at 40-50 "C for 2 h. The mixture was poured into ether and water and the ether layer separated, washed with brine, dried C, H. Methyl 3,4-Dihydro-7-[3-[3-methoxy-4-(4-oxazolyl)-2-over Na2S04, and concentrated. Flash chromatography on propylphenoxy]propoxyl-8-propyl-W-l-benzopyran-2- silica gel using a gradient of 1O:l-5:1 hexane/EtOAc gave thiazole 20 (74 mg, 60%)as a colorless gum: 'H NMR (CDC13) carboxylate (15). To a-hydroxy ketone 14 (0.41g, 0.80mmol) 6 0.91 (3H, t), 0.95 (3H, t), 1.53 (4H, m), 2.17 (2H, m), 2.38 in 6 mL of CHzClz at -78 "C was added trifluoromethane(2H, m), 2.61 (4H, m), 2.72 (2H, m), 3.65 (3H, s), 3.77 (3H, s), sulfonic anhydride (0.2 mL, 1.17 mmol) followed by 2,6-lutidine 4.14 (2H, t), 4.21 (2H, t), 4.75 (lH, dd), 6.47 (lH, d), 6.65 (lH, (0.14 g, 1.17 mmol). The mixture was stirred at -78 "C for s), 6.73 (lH, d), 6.80 (lH, d), 7.26 (lH, d), 10.93 (lH, br); HRMS 45 min and poured into ether and water. The ether layer was (E11 m/z 571.2082 (calcd for C3&7NO& 571.2062). separated, washed with brine, dried over NazS04, and concentrated t o give 0.50 g of a light orange solid. The crude 3,4-Dihydro-7-[3-[4-(2,3-dihydro-2-thioxo-4-thiazolyl)3-methoxy-2-propylphenoxylpropoxyl -8-propyl-W- l-bentriflate (0.13 g, 0.20 mmol) in 2 mL of formamide and 1mL of zopyran-2-carboxylicAcid (21). Ester 20 (47 mg, 82.2 DMF was heated in a sealed tube at 170-180 "C for 3 h. The mixture was cooled and poured into EtOAc and water. The pmol) was saponified as described in general procedure A t o afford the crude acid which was flash chromatographed on organic layer was separated, washed with brine, dried over silica gel using a gradient of 87:12:1-83:16:1 hexane/EtOAc/ Na2SO4,and concentrated. Flash chromatography on silica AcOH to furnish 21 (44 mg, 96%) as a white solid: mp 149gel using 5:l hexane/EtOAc provided 15 (0.03 g, 29%) as a colorless oil: 'H NMR (CDC13)6 0.92 (3H, t), 0.98 (3H, t), 1.58 151 "C; 'H NMR (CDC13)6 0.95 (6H, t), 1.55 (4H, m), 2.13 (lH, m), 2.31 (3H, m), 2.60 (2H, m), 2.76 (4H, m), 3.61 (3H, s), 4.18 (4H, m), 2.19 (2H, m), 2.29 (2H, m), 2.65 (6H, m), 3.68 (3H, s), (2H, t), 4.29 (lH, m), 4.42 (lH, m), 4.99 (lH, t), 6.41 (lH, d), 3.75 (3H, s), 4.15 (2H, t), 4.20 (2H, t), 4.76 (lH, dd), 6.46 (lH, 6.44 (lH, d), 6.78 (lH, d), 6.99 (lH, s), 7.20 (lH, d), 12.00 (lH, d), 6.79 (2H, 2d), 7.84 (lH, d), 7.92 (lH, s), 8.13 (lH, s). Anal. br); HRMS (EI)m/z 557.1895 (calcd for C Z S H ~ ~ N O 557.1906). ~SZ (C3oH37N07)C, H, N. 3,4-Dihydro-7-[3-[3-methoxy-4-(4oxazolyl)-2-propylphe- Methyl 3,4-Dihydro-7-[3-[3-methoxy-4-[2-(methylthio)4-thiazolyll-2-propylphenoxylpropoxyl-8-propyl-W-lnoxy]propoxy]-8-propyl-W1-benzopyran-2-carboxylic benzopyran-2-carboxylate(22). Thiazole 20 (51 mg, 89.1 Acid (16). Ester 15 was saponified as described in general pmol) was stirred in 2.5 mL of nitromethane with 0.7 mL of procedure A to afford acid 16 as a white solid: mp 136-137 Me1 at 25 "C for 1h. The mixture was poured into ether and "C; 'H NMR (CDC13)6 0.92 (3H, t), 0.97 (3H, t), 1.58 (4H, m), water and the ether layer separated, washed with brine, dried 2.21 (lH, m), 2.29 (3H, m), 2.65 (4H, m), 2.77 (2H, m), 3.69 over Na2SO4, and concentrated. Flash chromatography on (3H, s), 4.15 (2H, t, J = 6 Hz), 4.22 (2H, t, J = 6.1 Hz), 4.77 silica gel using a gradient of 2O:l-1O:l hexane/EtOAc gave (lH, dd, J = 7, 3.8 Hz), 6.49 (lH, d, J = 8.4 Hz), 6.75 ( l H , d, thiazole 22 (51 mg, 97.6%) as a colorless gum: 'H NMR J=8.7Hz),6.83(1H,d,J=8.4Hz),7.78(1H,d,J=8.6Hz), (CDC13)6 0.93 (3H, t), 0.99 (3H, t), 1.58 (4H, m), 2.21 (2H, m), 8.00 (lH, s), 8.14 (lH, s). Anal. (C~sH35N07)C, H, N. 2.30 (2H, m), 2.67 (6H, m), 2.77 (3H, SI, 3.64 (3H, s), 3.78 (3H, Methyl 3,4-Dihydr0-7-[3-[3-methoxy-4-(2-methyl-4-0~s), 4.15 (2H, t), 4.22 (2H, t), 4.77 (lH, dd), 6.49 (lH, d), 6.74 azolyl)-2-propylphenoxylpropoxyl-8-propyl-Wl-ben(lH, d), 6.83 (lH, d), 7.66 (lH, s), 7.91 (lH, d); HRMS (EI) zopyran-2-carboxylate(17). Chloromethyl ketone 6 (0.105 m/z 585.2223 (calcd for C ~ ~ H ~ S N O 585.2219). & g, 0.2 mmol) was stirred in 3 mL of AcOH with urea (50 mg, 0.8 mmol) a t 120 "C for 47 h. The mixture was cooled and 3,4-Dihydro-7-[3-[3-methoxy-4-[2-(methylthio)-4-thiazolyl]-2-propylphenoxy]propoxyl-~-propyl-W-l-benzopypoured into EtOAc and water and the organic layer separated, ran-2-carboxylicAcid (23). Ester 22 (48 mg, 81.9 pmol) was washed with brine, dried over NazS04, and concentrated. saponified as described in general procedure A to afford acid Flash chromatography on silica gel using 5:1 hexane/EtOAc 23 (44 mg, 94%) as a colorless gum: 'H NMR (CDC13) 6 0.92 provided 17 (37 mg, 32%) as a colorless oil: 'H NMR (CDC13) (3H, t), 1.00 (3H, t), 1.58 (4H, m), 2.20 (lH, m), 2.30 (3H, m), 6 0.92 (3H, t), 0.98 (3H, t), 1.57 (6H, m), 2.19 (2H, m), 2.28 2.67 (4H, m), 2.75 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 4.16 (2H, (2H, m), 2.51 (3H, s), 2.67 (4H, m), 3.68 (3H, s), 3.77 (3H, s), t), 4.21 (2H, t), 4.78 (lH, dd), 6.51 (lH, d), 6.73 (lH, d), 6.82 4.15 (2H, t), 4.20 (2H, t), 4.76 (lH, dd), 6.46 (lH, d), 6.74 (lH, O ~H,S Z ) ( l H , d), 7.65 (lH, SI, 7.89 (lH, d). Anal. ( C ~ O H ~ ~ N C, d), 6.80 ( l H , d), 7.79 ( l H , d), 7.97 (lH, s); HRMS (EI) m/z N. 537.2728 (calcd for C31H39N07 537.2726). 3,4-Dihydro-7-[3-[3-methoxy-4-(2-methyl-4-oxazolyl)-2- 3,4-Dihydro-7-[3-[3-methoxy-4-[2-[(phenyLmethyl)thiol4-thiazolyl]-2-propylphenoxylpropoxyl-8-propyl-W1propylphenoxylpropoxyl-8-propyl-W-l-benzopyran-2benzopyran-2-carboxylicAcid (24). Thiazole 21 (30 mg, carboxylic Acid (18). Ester 17 (45 mg, 77 pmol) was 53.7 pmol) was stirred in 1.5 mL of nitromethane and 0.5 mL saponified as described in general procedure A to afford acid of THF with BnBr (30 pL, 0.25 mmol) at 25 "C for 1 h. The 18 as a white solid: mp 112-114 "C; 'H NMR (CDC13) 6 0.92 mixture was poured into ether and water and the ether layer (3H, t), 0.97 (3H, t), 1.57 (4H, m), 2.26 (4H, m), 2.54 (3H, s), separated, washed with brine, dried over NazS04, and con2.64 (4H, m), 2.78 (2H, m), 3.66 (3H, s), 4.15 (2H, t), 4.23 (2H, centrated. Flash chromatography on silica gel using a gradient m), 4.80 (lH, dd), 6.46 (lH, d), 6.67 (lH, d), 6.80 (lH, d), 7.67 of 1O:l-7:1 hexane/EtOAc gave thiazole 24 (25 mg, 72%) as a (lH, d), 7.98 (lH, s). Anal. (C30H37N07)C, H, N. 7-[3-[4-(2-Amino-4-thiazolyl)-3-methoxy-2.propylphe-colorless gum: 'H NMR (CDC13) 6 0.93 (3H, t), 0.99 (3H, t),

866 Journal of Medicinal Chemistry, 1995, Vol. 38, No. 6

Penning et al.

(3H, t), 1.55 (4H, m), 2.20 (lH, m), 2.29 (3H, m), 2.65 (4H, m), 1.56 (4H, m), 2.16 (lH, m), 2.29 (3H, m), 2.65 (4H, m), 2.77 2.75 (2H, m), 3.56 (3H, s), 3.76 (3H, SI, 4.14 (2H, t), 4.21 (2H, (2H, m), 3.61 (3H, s), 4.15 (2H, t), 4.21 (2H, t), 4.50 (2H, SI, t), 4.77 (IH, t), 6.48 (lH, d), 6.72 (lH, d), 6.81 (lH, d), 7.80 4.72 (lH, dd), 6.50(1H, d), 6.73 (lH, d), 6.82 (lH, d), 7.29 (3H, (lH, d), 7.82 (lH, d, J = 1.7 Hz), 8.91 (lH, d, J = 1.7 Hz). m), 7.41 (2H, d), 7.64 (lH, s), 7.91 (lH, d). Anal. (C36H41Anal. (C29H35NOsS)C, H, N, S. NOsS2)C, H, N. Methyl 3,4-Dihydr0-7-[3-[3-methoxy-4-(1-0~0-2-thiocy-Methyl 7-[3-[4-(2-Bromo-l-oxoethyl)-3-methoxy.2-(21 anatoethyl)-2-propylphenoxylpropoxyl-8-propyl-W-l- propeny1)phenoxyl propoxyl-3,4-dihydro-8-propyl-Wbenzopyran-2-carboxylate(30). The title compound was benzopyran-2-carboxylate(25). Chloro ketone 6 (0.11 g, prepared by general procedure B from acetophenone lb (0.156 0.206 mmol) and potassium thiocyanate (21 mg, 0.216 mmol) g, 0.314 mmol) to provide 30 (59 mg, 33%) as a colorless gum: were stirred in 2 mL of EtOH at reflux for 4.5 h. The mixture lH NMR (CDCld 6 0.92 (3H, t), 1.52 (2H, m), 2.20 (2H, m), was cooled and poured into ether and water. The ether layer 2.29 (2H, m), 2.67 (4H, m), 3.43 (2H, d), 3.77 (3H, SI, 3.78 (3H, was separated, washed with brine, dried over Na2S04, and s), 4.11 (2H, t), 4.23 (2H, t), 4.58 (2H, s, CHzBr), 4.77 (lH, concentrated to provide thiocyanate 25 (0.111 g, 97%) as a dd), 4.97 (2H, m), 5.95 (lH, m), 6.43 (1H, d), 6.77 (1H, d), 6.80 white solid: 'H NMR (CDC13) 6 0.90 (3H, t), 0.96 (3H, t), 1.53 (lH, d), 7.65 (lH, d). (4H, m), 2.19 (2H, m), 2.31 (2H, m), 2.61 (4H, m), 2.72 (2H, Methyl 3,4-Dihydro-7-[3-[3-methoxy-2-(2-propenyl)-4m), 3.75 (3H, s), 3.79 (3H, s), 4.12 (2H, t), 4.26 (2H, t), 4.71 (thiazol-4-yl)phenoxy]propoxy1-8-propyl-W1-benzopy(2H, S, CHzSCN), 4.77 (lH, dd), 6.45 (lH, d), 6.78 (lH, d), 6.81 ran-2-carboxylate(31). The title compound was prepared (lH, d), 7.72 (lH, d). by general procedure C from bromomethyl ketone 30 (59 mg, Methyl 3,4-Dihydro-7-[3-[3-methoxy-4-(2-methoxy-4thiazolyl)-2-propylphenoxy]propoxyl-8-propyl-W-l-ben- 0.103 mmol) to afford thiazole 31 (38 mg, 68%) as a colorless gum: 'H NMR (CDC13) 6 0.93 (3H, t), 1.55 (2H, m), 2.18 (2H, zopyran-2-carboxylate(26). Thiocyanate 25 (40 mg, 71.8 m), 2.28 (2H, m), 2.69 (4H, m), 3.51 (2H, d), 3.61 (3H, s), 3.77 ymol) was stirred in 2 mL of MeOH with 10 mg of NaOMe at (3H, s), 4.14 (2H, t), 4.22 (2H, t), 4.77 (lH, dd), 4.98 (2H, m), 25 "C for 30 min. The mixture was poured into ether and 6.00 (lH, m), 6.46 (lH, d), 6.80 (2H, 2d), 7.84 (lH, d, J = 1.9 water and the ether layer separated, washed with brine, dried Hz), 7.95 (lH, d), 8.84 (lH, d, J = 1.9 Hz); HRMS (EI) mlz over Na2S04, and concentrated. Flash chromatography on 537.2195 (calcd for C ~ O H ~ ~ N537.2185). OSS silica gel using a gradient of 2O:l-1O:l hexane/EtOAc gave 3,4-Dihydro-7-[3-[3-methoxy-2-(2-propenyl)-4-(thiazolthiazole 26 (24 mg, 39%)as a colorless gum: 'H NMR (CDC13) 4-yl)phenoxy]propoxyl-8-propyl-2H1-benzopyran-2-car6 0.92 (3H, t), 0.98 (3H, t), 1.57 (4H, m), 2.19 (2H, m), 2.30 boxylic Acid (32). Ester 31 (22 mg, 40.9pmol) was saponified (2H, m), 2.69 (6H, m), 3.66 (3H, s), 3.77 (3H, s), 4.13 (3H, s), as described in general procedure A to afford the crude acid 4.15 (2H, t), 4.21 (2H, t), 4.78 (lH, t), 6.48 (lH, d), 6.72 (lH, which was flash chromatographed on silica gel using 83:16:1 d), 6.81 (lH, d), 7.17 (lH, s), 7.82 (lH, d); HRMS (EI) mlz hexane/EtOAc/AcOH to furnish 32 (20 mg, 93%) as a colorless 569.2438 (calcd for C31H39N0,S 569.2443). 3,4-Dihydro-7-[3-[3-methoxy-4(2-methoxy-4-thiazolyl)-gum: lH NMR (CDC13) 6 0.92 (3H, t), 1.52 (2H, m), 2.20 (lH, 2-propylphenoxylpropxy]-8-propyl-W-l-benzopyran-2- m), 2.29 (3H, m), 2.65 (2H, m), 2.77 (2H, m), 3.48 (2H, d), 3.59 (3H, s), 4.13 (2H, t), 4.23 (2H, t), 4.76 (lH, dd), 4.97 (2H, m), carboxylic Acid (27). Ester 26 (20 mg, 35.1 pmol) was 6.00 (1H, m), 6.49 (lH, d), 6.75 (1H, d), 6.82 (1H, d), 7.84 (1H, saponified as described in general procedure A to afford acid d), 7.87 (lH, d), 8.89 (lH, d); HRMS (EI) mlz 479.2114 (calcd 27 (19 mg, 97%) as a colorless gum: 'H NMR (CDC13) 6 0.78 for C~sH33N04S(M - C02) 479.2130). (3H, t), 0.95 (3H, t), 1.42 (2H, m), 1.55 (2H, m), 1.96 (2H, m), Methyl 7-[3-[4-(2-Bromo-1-oxoethyl)-2-(cyclopropyl2.18 (2H, m), 2.59 (6H, m), 3.63 (3H, s), 4.03 (2H, t), 4.10 (3H, methyl)-3-methoxyphenoxy]propoxyl-3,4-dihydro-8-pros), 4.11 (2H, t), 4.30 (lH, m), 6.34 (lH, d), 6.67 (2H, 2d), 7.14 pyl-W-1-benzopyran-2-carboxylate (33). The title com(lH, s), 7.78 (lH, d). pound was prepared by general procedure B from acetopheB. General Procedure for the Bromination of Acnone IC (0.147 g, 0.288 mmol) to provide 33 (107 mg, 63%) as etophenones. A 0.5 M solution of the acetophenone in CHC13 a colorless gum: 'H NMR (CDC13) 6 0.22 (2H, m), 0.37 (2H, was added t o a hot 1.0 M solution of CuBrz (2 equiv) in EtOAc. m), 0.90 (3H, t), 0.99 (lH, m), 1.52 (2H, m), 2.19 (2H, m), 2.31 The mixture was refluxed for 3 h, cooled, stirred with decol(2H, m), 2.59 (4H, m), 2.60 (2H, m), 3.73 (3H, SI, 3.77 (3H, SI, orizing carbon for 30 min, filtered, and concentrated. Flash 4.14 (2H, t), 4.25 (2H, t), 4.58 (2H, s, CHzBr), 4.75 (lH, dd), chromatography on silica gel using 15:l hexane/EtOAc gave 6.44 (1H, d), 6.76 (lH, d), 6.80 (1H, d), 7.61 (1H, d). the desired bromomethyl ketone. Methyl 7-[3-[2-(Cyclopropylmethyl)-3-methoxy-4-(t~aC. General Procedure for the Synthesis of 2-Unsubzol-4-yl)phenoxy]propoxy] -3,4-dihydro-8-propy1-2H-lstituted Thiazoles, A 0.4 M solution of thioformamide in benzopyran-2-carboxylate(34). The title compound was dioxane was generated by stirring P2s5 with 5-6 equiv of prepared by general procedure C from bromomethyl ketone formamide in refluxing dioxane for 2 h. The solution was 33 (107 mg, 0.18 mmol) to afford thiazole 34 (76 mg, 76%) as decanted away from the solids and used without any purificaa colorless gum: 'H NMR (CDC13) 6 0.26 (2H, m), 0.38 (2H, tion. To a 0.1 M solution of the chloromethyl or bromomethyl m), 0.94 (3H, t), 1.06 (lH, m), 1.56 (2H, m), 2.20 (2H, m), 2.31 ketone in dioxane was added 10 equiv of MgC03 followed by (2H, m), 2.67 (6H, m), 3.58 (3H, SI, 3.77 (3H, SI, 4.18 (2H, t), 10 equiv of the thioformamide solution. The mixture was 4.24 (2H, t), 4.77 (lH, dd), 6.47 (1H, d), 6.79 (1H, d), 6.80 (1H, refluxed for 2 h, cooled, and poured into ether and 0.5 M d), 7.83 (lH, d, J = 1.9 Hz), 7.91 (lH, d), 8.84 (lH, d, J = 1.9 NaOH. The ether layer was separated, washed with brine, Hz); HRMS (EI) mlz 551.2346 (calcd for C31H37NOsS 551.2341). dried over NaZS04, and concentrated. Flash chromatography 7-[3-[2-(Cyclopropylmethyl)-3-methoxy-4-(thiazol-4on silica gel using 8:l hexane/EtOAc gave the desired thiazole. Methyl 3,4-Dihydro-7-[3-[3-methoxy-2-propyl-4-(thia- yl)phenoxy]propoxy]-3,4-dihydro-8-propyl-W-l;benzopyzol-4-yl)phenoxy]propoxy]-8-propyl-W1-benzopyran-2- ran-2-carboxylicAcid (35). Ester 34 (43 mg, 77.9pmol) was saponified as described in general procedure A t o afford the carboxylate (28). Reaction of chloromethyl ketone 6 (30 mg, crude acid which was flash chromatographed on silica gel using 56 pmol) with thioformamide as described in general procedure 83:16:1 hexane/EtOAc/AcOH to furnish 35 (41 mg, 98%) as a C furnished thiazole 28 (30 mg, 99%) as a colorless gum: 'H colorless gum: lH NMR (CDC13)6 0.24 (2H, m), 0.39 (2H, m), NMR (CDC13)6 0.92 (3H, t), 0.99 (3H, t), 1.58 (4H, m), 2.20 0.93 (3H, t), 1.04 (lH, m), 1.55 (2H, m), 2.20 (1H, m), 2.30 (3H, (2H, m), 2.30 (2H, m), 2.69 (6H, m), 3.61 (3H, s), 3.76 (3H, s), m), 2.62 (4H, m), 2.77 (2H, m), 3.57 (3H, SI, 4.18 (2H, t), 4.23 4.17 (2H, t), 4.22 (2H, t), 4.77 ( l H , t), 6.49 (lH, d), 6.78 (lH, (2H, t), 4.78 (lH, dd), 6.50 (lH, d), 6.76 (lH, d), 6.82 (lH, d), d), 6.81 (lH, d), 7.82 (lH, d, J = 1.7 Hz), 7.91 (lH, d), 8.84 7.81 (lH, d), 7.83 (lH, d), 8.92 (lH, d). Anal. (C3oH35NOsS) (lH, d, J = 1.7 Hz); HRMS (EI) mlz 539.2335 (calcd for C30H37C, H, N, S. NOsS 539.2341). 3,4-Dihydro-7-[3-[3-methoxy-2-propyl-4-(thiazol-4-y1)- Separation of Enantiomers of 35. Racemic 35 (180 mg, phenoxy]propoxy]-8-propyl-W-l-benzopyran-2-carbox-0.335 mmol) was resolved by chiral HPLC using a Chiracel O.D. column and eluting with 10:90:0.1 2-propanofiexanel ylic Acid (29). Ester 28 (27 mg, 50 ymol) was saponified as trifluoroacetic acid (3 mumin flow rate) to provide (-1-35(31.7 described in general procedure A t o afford acid 29 as a white -17.7" (e 1.585, CHCld, mg, 17.6%), mp 111-112 "C, [a125~ solid: mp 101-103 "C; 'H NMR (CDC13) 6 0.92 (3H, t), 0.98

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Second-Generation LTB4 Receptor Antagonists

Journal of Medicinal Chemistry, 1995, Vol. 38,No. 6 867

Methyl 2-[3-[3-[2-(Cyclopropylmethyl)-3-methoxy-4and (+)-35(25.8 mg, 14.3%),mp 109-110 "C, [aIz5~ +17.8" (c (thiazol-4-yl)phenoxy]propoxyl-2-propylphenoxylace1.29, CHC13). Anal. (C3JI36NO&.0.5HzO) C, H, N. Methyl 7-[3-[4-(2-Bromo-1-oxoethyl)-3-methoxy-2-pro-tate (43). The title compound was prepared by general procedure C from bromomethyl ketone 42 (0.14 g, 0.25 mmol) pylphenoxylpropoxylyl-3,4-dihydro-&propyl-Wl-benzopyto afford thiazole 43 (12 mg, 9%)as a colorless gum: lH NMR ran-2-propionate(36). The title compound was prepared by (CDC13) 6 0.16-0.42 (4H, m), 0.94 (3H, t), 0.96-1.12 (lH, m), general procedure B from acetophenone Id (0.55 g, 1.04 mmol) 1.42-1.60 (2H, m), 2.25-2.48 (2H, m), 2.64 (2H, d), 2.69 (2H, to provide 36 (0.34 g, 54%) as a colorless gum: lH NMR t), 3.48 (3H, s), 3.78 (3H, s), 4.19 (2H, t), 4.24 (2H, t), 4.64 (CDC13)6 0.89 (3H, t), 0.96 (3H, t), 1.40-1.77 (5H, m), 1.98 (2H, s), 6.38 (lH, d), 6.58 (lH, d), 6.78 (lH, d), 7.06 (lH, t), (3H, m), 2.30 (2H, m), 2.46-2.87 (8H, m), 3.68 (3H, s), 3.75 (3H, 7.85 (lH, d, J = 2 Hz), 7.90 (lH, d), 8.85 (lH, d, J = 2 Hz). s), 3.97 (1H, dt), 4.12 (2H, t), 4.23 (2H, t),4.57 (2H, s, CHZBr), 2-[3-[3-[2-(CyclopropyLmethyl)-3-methoxy-4-(thiazo1-46.44 ( l H , d), 6.73 (lH, d), 6.82 (lH, d), 7.60 (lH, d). Acid (44). Methyl 3,4-Dihydro-7-[3-[3-methoxy-2-propyl-4-(thia-yl)phenoxylpropoxyl-2-propylphenoxylacetic Ester 43 (12 mg, 0.091 mmol) was saponified as described in zol-4-yl)phenoxy]propoxy]-8-propyl-W-l-benzopyran-2general procedure A to furnish the acid 44 as a colorless gum: propionate (37). The title compound was prepared by lH NMR (CDC13)6 0.14-0.26 (2H, m), 0.26-0.44 (2H, m), 0.92 general procedure C from bromomethyl ketone 36 (0.22 g, 0.36 t),0.96-1.10 (lH, m), 1.44-1.62 (2H, m), 2.20-2.38 (2H, (3H, mmol) t o afford thiazole 37 (0.16 g, 78%) as a colorless gum: m), 2.64 (2H, d), 2.70 (2H, t), 3.54 (3H, s), 4.19 (2H, t, J = 5.5 'H NMR (CDC13) 6 0.91 (3H, t), 0.98 (3H, t), 1.41-1.78 (5H, Hz), 4.26 (2H, t, J = 5.5 Hz), 4.66 (2H, s), 6.42 (lH, d, J = 8.5 m), 1.98 (3H, m), 2.29 (2H, m), 2.48-2.89 (8H, m), 3.60 (3H, Hz), 6.59 (lH, d, J = 8.5 Hz), 6.72 (lH, d, J = 8.5 Hz), 7.06 s), 3.69 (3H, s), 3.96 (lH, dt), 4.15 (2H, t), 4.21 (2H, t), 6.44 (lH, t, J = 8.6 Hz), 7.76 (lH, d, J = 8.6 Hz), 7.84 (lH, d, J = (1H, d), 6.77 (lH, d), 6.82 (lH, d), 7.83 (1H, d), 7.92 (1H, d), 2 Hz), 8.89 (lH, d, J = 2 Hz). Anal. (CZ&~NO&HZO)C, H, 8.83 ( l H , d). N. 3,4-Dihydro-7-[3-[3-methoxy-2-propyl-4-(thiazol-4-y1)phenoxy]propoxy]-8-propyl-2H1-benzopyran-2-propiAcknowledgment. The authors would like t o thank onic Acid (38). Ester 37 (0.15 g, 0.264 mmol) was saponified the Searle Physical Methodology Department for mass as described in general procedure A to afford the crude acid spectral and microanalytical data and Ms. Patricia which was chromatographed by reverse phase on a C18 column Finnegan for NMR interpretive assistance. We would using 2 5 7 5 1 HzO/CH&N/AcOH to furnish 38 (113 mg, 77%) also like to acknowledge Ms. Dorothy Honda for the as a white solid: mp 110-113 "C; lH NMR (CDCl3) 6 0.90 (3H, t), 0.99 (3H, t), 1.41-1.79 (5H, m), 1.99 (3H, m), 2.30 (2H, m), chromatographic resolution of SC-50605 and Dr. Paul 2.53-2.89 (8H, m), 3.59 (3H, s), 3.98 (lH, m), 4.14 (2H, t),4.21 Collins for his helpful advice. (2H, ti, 6.45 (lH, d), 6.77 (lH, d), 6.82 (lH, d), 7.83 (1H, d), HZ H,ON. ) 7.87 (lH, d), 8.90 (lH, d). Anal. ( C ~ ~ H ~ ~ N O S S -C, References Methyl 7-[3-[4-(2-Bromo-1-oxoethyl)-2-(cyclopropyl- (1) Barr, R. M.; Wong, E.; Mallet, A. I.; Olins, L. A,; Greaves, M. methyl)-3-methoxyphenoxylpropoxy]-3,4-dihydro-8-proW. The Analysis of Arachidonic Acid Metabolites in Normal, Uninvolved and Lesional Psoriatic Skin. Prostaglandins 1984, pyl-W-1-benzopyran-2-propionate (39). The title com28, 57-65. pound was prepared by general procedure B from acetophe(2) Sharon, P.; Stenson, W. F. Enhanced Synthesis of Leukotriene none le (0.56 g, 1.04 mmol) to provide 39 (0.50 g, 77%) as a B4 by Colonic Mucosa in Inflammatory Bowel Disease. Gastrocolorless gum: 'H NMR (CDC13) 6 0.21 (2H, m), 0.38 (2H, m), enterology 1984,86,453-460. 0.91 (3H, t), 1.00 (lH, m), 1.46 (2H, m), 1.70 (lH, m), 1.97 (3H, (3) Kobza-Black, A,; Camp, R. D. R.; Mallet, A,; Cunningham, F. M.; Hofbauer, M.; Greaves, M. W. Pharmacologic and Clinical m), 2.29 (2H, m), 2.46-2.88 (8H, m), 3.70 (3H, SI, 3.76 (3H, SI, Effects of Lonapalene (RS 431791, a 5-Lipoxygenase Inhibitor, 3.98 (1H, m), 4.12 (2H, t), 4.26 (2H, t), 4.58 (2H, s, CHZBr), in Psoriasis. J . Invest. Dermatol. 1990,95, 50-54. 6.43 ( l H , d), 6.77 (lH, d), 6.83 (lH, d), 7.63 (lH, d). (4) (a) Djuric, S. W.; Fretland, D. J.; Penning, T. D. The Leukotriene Methyl 7-[3-[2-(Cyclopropylmethy1)-3-methoxy-4-(thiaB4 Receptor Antagonists - A Most Discriminating Class of Antizol-4-yl)phenoxy]propoxyl-3,4-dihydro-8-propy1-2H-1Inflammatory Agent? Drugs Future 1992, 17, 819-830. (b) Cohen, N.; Yagaloff, K. A. Recent Progress in the Development benzopyran-2-propionate(40). The title compound was of Leukotriene Bq Antagonists. Curr. Opin. Invest. Drugs 1994, prepared by general procedure C from bromomethyl ketone 3, 13-22. 39 (0.45 g, 0.73 mmol) to afford thiazole 40 (0.34 g, 80%) as a (5) Djuric, S. W.; Collins, P. W.; Jones, P. H.; Shone, R. L.; Tsai, B. colorless gum: 'H NMR (CDC13) 6 0.26 (2H, m), 0.39 (2H, m), S.; Fretland, D. J.; Butchko, G. M.; Villani-Price, D.; Keith, R. 0.92 (3H, t), 1.07 (lH, m), 1.48 (2H, m), 1.68 (lH, m), 1.98 (3H, H.; Zemaitis, J. M.; Metcalf, L.; Bauer, R. F. 7-[3-(4-Acetyl-3methoxy-2-propylphenoxy)propoxyl-3,4-dihydro-8-propyl-2H-lm), 2.32 (2H, m), 2.31-2.90 (8H, m), 3.58 (3H, s), 3.70 (3H, s), benzopyran-2-carboxylic acid: An Orally Active Selective Leu3.97 (1H, m), 4.15 (2H, t), 4.23 (2H, t), 6.46 (1H, d), 6.79 (lH, kotriene B4 Receptor Antagonist. J . Med. Chem. 1989,32,1145d), 6.82 (lH, d), 7.83 (lH, d), 7.91 (lH, d), 8.84 (lH, d). 1147. 7-[3-[2-(Cyclopropylmethyl)-3-methoxy-4-(thiazol-4- (6) Tsai, B. S.;Villani-Price, D.; Keith, R. H.; Zemaitis, J. M.; Bauer, R. F.; Leonard, R.; Djuric, S. W.; Shone, R. L. SC-41930: An yl)phenoxylprop0xyl-3,4-dihydro-8-propyl-Wl-benzopyInhibitor of Leukotriene B4-stimulated Human Neutrophil Funcran-2-propionicAcid (41). Ester 40 (0.22 g, 0.379 mmol) tions. Prostaglandins 1989,38, 655-674. was saponified as described in general procedure A to afford (7) Djuric, S. W.; Docter, S. H.; Yu, S. S.; Spangler, D.; Tsai, B. S.; the crude acid which was purified by reverse phase chromaAnglin, C. P.; Gaginella, T. S.; Kachur, J. F.; Keith, R. H.; tography on a C18 column using 25:75:1 HzO/CH3CN/AcOH Maziasz, T. J.; Villani-Price, D.; Rao, T. S.; Walsh, R. E.; t o furnish 41 (90 mg, 42%) as a colorless gum: 'H NMR Widomski, D. L.; Fretland, D. J. Synthesis and Pharmacological Activity of SC-53228, A Leukotriene B4 Antagonist with High (CDC13)6 0.26 (2H, m), 0.38 (2H, m), 0.91 (3H, t), 1.06 (lH, Intrinsic Potency and Selectivity. Biorg. Med. Chem. Lett. 1994, m), 1.51 (2H, m), 1.70 (lH, m), 1.99 (3H, m), 2.29 (2H, m), 4 , 811-816. 2.47-2.89 (8H, m), 3.57 (3H, s), 3.97 (IH, m), 4.15 (2H, t),4.22 (8) Tsai, B. S.; Keith, R. H.; Villani-Price, D.; Kachur, J. F.; Yang, (2H, t), 6.44 (lH, d), 6.78 (lH, d), 6.82 (lH, d), 7.83 (lH, s), D. C.; Djuric, S. W.; Yu, S. The In Vitro Pharmacology of SC7.87 (lH, d), 8.89 (lH, s). Anal. (C3~H3gN06S.0.75Hz0)C, H, 51146: A Potent Antagonist of Leukotriene Bq Receptors. J . N.

Pharmacol. Exp. Ther. 1994,268,1499-1505.

T. D.; Djuric, S. W.; Docter, S. H.; Yu, S. S.; Spangler, Methyl 2-[3-[3-[4-(2-Bromo-1-oxoethyl)-2-(cyclopropyl- (9) Penning, D.; Anglin, C. P.; Fretland, D. J.; Kachur, J. F.; Keith, R. H.; methyl)-3-methoxyphenoxylpropoxyl-2-propylphenoxylTsai, B. S.; Villani-Price, D.; Widomski, D. L. The Design and acetate (42). The title compound was prepared by general Synthesis of Second Generation Leukotriene B4 Receptor Antagonists Related to SC-41930. Agents Actions 1993,39, C11procedure B from acetophenone If (0.32 g, 0.66 mmol) to 13. provide 42 (0.19 g, 51%) as a colorless gum: 'H NMR (CDC13) (10)(a) Miyano, M.; Shone, R. L.; Sohn, D. D. Substituted Dihy6 0.15-0.25 (2H, m), 0.25-0.42 (2H, m), 0.92 (3H, t), 0.94drobenzopyrans Useful as Leukotriene D4 Inhibitors. US Patent 1.08 (lH, m), 1.42-1.58 (2H, m), 2.25-2.40 (2H, m), 2.59 (2H, 4,665,203, 1987. (b)Djuric,S. W.; Shone, R. L.;Yu, S. S.Alkoxyd), 2.68 (2H, t), 3.75 (3H, s), 3.79 (3H, s), 4.16 (2H, t), 4.26 substituted Dihydrobenzopyran-2-carboxylateDerivatives. US Patent 4,889,871, 1989. (c) Djuric, S. W.; Docter, S. H.; Yu, S. S. (2H, t), 4.58 (2H, s), 4.64 (2H, s), 6.38 (lH, d), 6.56 (lH, d), Leukotriene B4 Antagonists. US Patent 5,124,350, 1992. 6.75 (lH, d), 7.06 (lH, t), 7.62 (lH, d).

Penning et al.

868 Journal of Medicinal Chemistry, 1995, Vol. 38, No. 6 (11) Bredereck, H.; Effenberger, F.; Botsch, H. Untersuchungen iiber

die Reaktionsfahigkeit von Formamidinen, Dimethylformamidathylacetal (Amidacetal) und Bis-dimethyl-amino-methoxymethan (Aminalester). (Investigation of the Synthetic Utility of Formamide, Dimethylformamide-Diethylacetaland Bis-dimethylaminomethoxy methane.) Chem. Ber. 1964, 97, 33973406. (12) Garcia, E. E.; Benjamin, L. E.; Fryer, R. I. Enamine Intermediates in the Synthesis of Analogs of Pyrrolnitrin. J . Heterocycl. Chem. 1974,11,275-277. (13) Dodson, R. M. The Reaction of S-Benzylisothiourea with Phenacyl Bromide. J . Am. Chem. SOC.1948, 70, 2753-2755. (14) Birkofer, L.; Ritter, A.; Richter, P. Thermolyse silylierter Tetrazol. (Thermolysis of Silylated Tetrazole.) Chem. Ber. 1963, 96,2750-2757. (15) Brook, A. G.; Macrae, D. M. 1,4-Silyl Rearrangement of Siloxyalkenes to Siloxyketones During Peroxidation. J . Organomet. Chem. 1974, 77, C19-C21. (16) (a) Theilig, G. Untersuchungen in der Oxazolreihe und Umwandlungen von Oxazolen in Imidazole mittels Formamids. (Investigations in the Oxazole Series and Transformations of Oxazoles into Imidazoles via Formamide.) Chem. Ber. 1953,86, 96-109. (b) Cherbuliez, E.; Landolt, F. Sur l’acidolyse des amides. (Concerning the Acidolysis of Amides.) Helv. Chim. Acta 1946,29, 1438-1445. (17) Hantzsch, A.; Traumann, V. Amidothiazole aus Sulfoharnstoff und halogenisirten Ketonen, resp. Aldehyden. (Aminothiazoles from Thiourea and Halogenated Ketones or Aldehydes.) Chem. Ber. 1888,21, 938-941. (18) Mathes, R. A.; Beber, A. J. A Synthesis of 2-Thiazolethiol and its Disulfide. J. Am. Chem. SOC. 1948, 70, 1451-1452. (19) Hantzsch, A.; Weber, J. H. Ueber Verbindungen des Thiazols (Pyridins der Thiophenreihe). (Concerning Thiazole Compounds.) Chem. Ber. 1887,20, 3118-3132. (20) Poite, M.; Metzger, J. Nouvelles Syntheses dans la SBrie des Alcoyl-5 et Dialcoyl-2,5 Thiazoles. (New Synthesis of a Series of 5-Alkyl- and 2,5-Dialkylthiazoles.j Bull. SOC.C h i n . Fr. 1962, 2078-2085. (21) King, L. C.; Ostrum, G. K. Selective Bromination with Copper(11) Bromide. J . Org. Chem. 1964,29, 3459-3461. (22) Tsai, B. S.; Keith, R. H.; Gaginella, T. S. Antagonist Specific Effect of Nordihydroguaiaretic Acid (NDGA) on Human Neutrophil (PMN) Leukotriene B4 Receptors. FASEB J. 1991, 5, A892.

(23) Harper, R. W.; Jackson, W. T.; Froelich, L. L.; Boyd, R. J.; Aldridge, T. E.; Herron, D. K. Leukotriene B4 (LTB4) Receptor Antagonists: A Series of (Hydroxypheny1)pyrazoles. J . Med. Chem. 1994,37, 2411-2420. (24) Djuric, S. W.; Collins, P. W.; Jones, P. H.; Nosal, R. A.; Penning, T. D.; Shone, R. L.; Yu, S. S.; Fretland, D. J.;Keith, R. H.; Price, D. V.; Tsai, B. S.; Widomski, D. L.; Zemaitis, J. M.; Bauer, R. F. SC-41930 A Potent and Selective Antagonist of Leukotriene B4Receptor Binding, Chemotaxis, and Degranulation of Human Neutrophils. 4th Int. Conf. Inflamm. Res. Assoc., Oct. 23-27, 1988; Abstract 42. (25) Fretland, D. J.; Widomski, D. L.; Anglin, C. P.; Yu, S.; Djuric, S. W. Optical Isomers of a Leukotriene Bd Antagonist Have Differential Effects on Granulocyte Diapedesis in the Guinea Pig Dermis. Chirality 1992, 4, 353-355. (26) (a) Cunningham, F. M.; Woollard, P. M. 12(R)-Hydroxy-5,8,10,14-eicosatetraenoic acid is a Chemoattractant for Human Polymorphonuclear Leukocytes In Vivo. Prostuglandins 1987, 34, 71-78. (b)Cunningham, F. M.; Woollard, P. M.; Camp, R. D. R. Proinflammatory Properties of Unsaturated Fatty Acids and Their Monohydroxy Metabolites. Prostaglandins 1985,30,497509. (27) Fretland, D. J.; Widomski, D. L.; Anglin, C. P.; Penning, T. D.; Yu, S.; Djuric, S. W. Leukotriene B4-induced Granulocyte Trafficking in Guinea Pig Dermis: Effect of Second-generation Leukotriene B4 Receptor Antagonists, SC-50605 and SC-51146. Inflammation 1993, 17, 353-360. (28) Fretland, D. J.;Widomski, D. L.; Zemaitis, J. M.; Walsh, R. E.; Levin, S.; Djuric, S. W.; Shone, R. L.; Tsai, B. S.; Gaginella, T. S. Inflammation of Guinea Pig Dermis: Effects of Leukotriene B4 Receptor Antagonist, SC-41930. Inflammation 1990,14,727739. (29) Fretland, D. J.; Widomski, D.; Tsai, B. S.; Zemaitis, J. M.; Levin, S.; Djuric, S. W.; Shone, R. L.; Gaginella, T. S. Effect of Leukotriene Bd Receptor Antagonist SC-41930 on Colonic Inflammation in Rat, Guinea Pig and Rabbit. J. Pharmacol. Exp. Ther. 1990,255,572-576.

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