J. Med. Chem. 1993,36, 58Ch590
580
Analogues of Platelet Activating Factor. 8. Antagonists of PAF Containing an Aromatic Ring Linked to a Pyridinium Ring Michael P. nova,' Allan Wissner, Marion L. Carroll, Suresh S.Kerwar, Walter C. Pickett, Robert E.Schaub, Lawrence W. Torley, and Constance A. Kohler Oncology and Immunology Section, Medical Research Division, American Cyanamid Company, Lederle hboratories, Pearl River, New York 1OW Received October 13, 1992
A series of platelet activating factor (PAF) antagonists containing a quaternary pyridinium ring connected through an amide, imide, or carbamate linkage to a substituted aromatic ring was prepared. Of these compounds, those containing a branched imide linkage of the form (CON(COCHs)CH2, 37-61, and 59) generally showed excellent PAF antagonist properties in vitro. Structure-activity relationships within thie series of compounds were studied extensively with respect to substituents and the position of substitution in both the aromatic and pyridinium ringa. Several of these compounds (40 and 44)showed in vitro PAF antagonism at leee than 0.1 pM and are as potent as CV-6209, the most potent PAF antagonist reported in the literature. Leas active PAF antagonists were those bearing simple amide linkages (20-23,27-29, and 31-36), linear imide linkages (62-63), or carbamate linkages (66 and 68), between the two aromatic ringa. A number of our PAF antagonists were tested in vivo in mice and rabbits for their ability to protect these animals against a lethal injection of PAF. Those antagonists that are particularly potent (ICs0 , 1.03 (s,9 H, SiC(CH&, 172.58,164.01, 154.51, 147.14, 145.80, 131.98, 127.14,126.76, 0.35 (e, 6H, Si(CHd2);l3C NMR (CDCb) 6 174.35,173.48,158.83, 125.11,115.17,68.59,47.71,46.98,31.82,29.57,29.50,29.46,29.26, 156.91, 149.30, 140.01,136.49, 128.82, 128.56, 126.88, 121.99, 28.95,26.09,25.87,22.56,and 14.01 ppm; ma^ spectrum (FAB) 121.30,118.72,51.23,34.84,29.49,26.20,26.95,18.76, and -3.53 m/e 481 (M+- I). Anal. (C&&031) C, H, I; N calcd, 4.60; ppm; maw spectrum (EI) m/e 440 (M+). Anal. ( c 2 a H d ~ O ~ S i ) found, 4.11. N-Acetyld-(l,l-cUmethylethyl)-N-(2-pyridinylrnethyl)-4- C, H, N, Si. N-Acet yl-t- (1,l -dim& hy lethy1)-4-hydroxy-N-(2-pyridi(tetradecy1oxy)benEde"-Oxide (61). A solution of 86d nylmethy1)benEamide (67). To a 0 OC solution of 66 (13.52g, (0.25g, 0.48 mmol), 3-chloroperbenzoic acid (165mg of a 50% 30.7 mmol) dissolved in dry THF (50 mL) was added tetrabuby weight solid, 0.48 mmol), and glacial acetic acid (2mL) waa tylammonium fluoride (TBAF, 46 mL of a 1 M THF solution, heated at 50 OC for 18h. The reaction mixture waa diluted with 46 mmol). The reaction mixture was stirred at 0 "C for 15 min saturated aqueous sodium bicarbonate (100mL) and extracted and at room temperature for 3 h, diluted with water (600mL), with chloroform (4X 50 mL). The combined organic layers were and extraded with methylene chloride (4 X 500 mL). T h e waahed with brine (50 mL),dried over anhydroussodium sulfate, combined organic phases were washed with brine (600mL), dried filtered, and concentrated. The residue was purified on silicagel over anhydrous sodium sulfate, fiitered, concentrated in vacuo, (50g,elutionwithW% EtOAc/hexane)togiveSl asapaleyellow and purified on silica gel (600 g, gradient elution with 4040% oil, 0.102 g (39%): IR (neat) 2924, 2854, 1696, 1599 cm-l; lH EtOAc/hexane), to provide 67as colorleee crystals, 8.10 g (81% 1: NMR (CDCb) 8 8.30-8.28 (m, 1 H, aromatic),7.67-7.54 (m, 2 H, mp 150-151 OC; IR (neat) 1693,1598cm-l; lH NMR (CDCb) 6 aromatic), 7.45-7.40 (m, 1 H, aromatic), 7.30-7.20 (m, 2 H, 9.05 (br, 1 H, OH), 8.51-8.49 (m, 1 H, aromatic), 7.73 (td, 1 H, aromatic),6.90-6.86 (m, 1 H, aromatic),5.11 (s,2H, NCHn), 4.05 J = 7.7, 1.5 Hz,aromatic), 7.56 (d, 1 H, J = 2.1 Hz,aromatic), (t, 2 H, J = 7 Hz, OCHz), 2.29 (~,3 H, COCHa), 1.86 (quintet, 2 7.35-7.21 (m, 3 H, aromatic), 6.44 (d, 1 H, J = 8.3 Hz,aromatic), H, J = 7 Hz,OCHZCHZ), 1.37 (s,9 H, C(CH&), 1.53-1.26 (m, 22 5.13 (8,2H, NCHz), 2.31 (8, 3 H, COCHs), 1.32 (e, 9 H, C(CHs)s); H), 0.88 (t,3 H, J = 7 Hz,CH3); maes spectrum (FAB)m/e 539 '9c NMR (CDCls)b 174.45,173.74,160.75,156.72,148.41,137.57, (M+ + H). Anal. (C~H&?O~*l.OHZO) C, H; N: calcd, 5.03; 137.01,128.89,128.86,124.55,122.55,121.88,116.15,51.03,34.70, found, 4.52. 29.13,and 26.50 ppm; maw spectrum (EI)m/e 326 (M+). Anal. 8-(1,1-Dimethylethyl)-4-[ [(1,l-dimethylethy1)dimethylrilyl]o.y]benmic Acid (1.1-Dimethylethy1)dimethylrilyl (Ci8&!&Os) C, H, N. 44[Acetyl(2-pyridinylmethyl)~ino]car~n~l]-2-(1,1Eater (64). To a 0 OC solution of 63 (8.0 g, 41.2 mmol), dimethylethy1)phenyl Octadecylcarbamate (MI). To a 80. commercially available or prepared by hydrolysis of 62according lution of phenol 67 (2.0g, 6.13mmol), freehly dmtilled octadecyl to the procedure described earlier? dry methylene chloride (50 isocyanate (2.14mL, 6.13 mmol), and dry THF (30 mL) waa mL), dry DMF (3 mL), D W (252 mg, 2.1 mmol), and addedtriethylamine (0.85 mL,6.13mmol). The reaction mixture triethylamine (28.7 mL, 206 mmol) waa added a solution of tertwas stirred at room temperature for 22 h, diluted with saturated butyldmethylaiiyl chloride (TBDMS-Cl, 13.04 g, 86.5 mmol) aqueous sodium bicarbonate (100 mL), and extracted with d h l v e d in dry methylene chloride (50 mL). The cooling bath methylene chloride (3 X 50 mL). T h e combined methylene waa removed, and the reaction mixture waa stirred at room chloride layers were washed with brine (50 mL), dried over temperature for 18 h and then at reflux temperature for 18 h. anhydrous sodium sulfate, and filtered, and the fitrate waa The cooled reaction mixture waa diluted with half-saturated concentrated in vacuo. The reaidue was purified on silica gel aqueous d u m bicarbonate (200 mL) and extraded with (250 g, elution with 50% EtOAc/hexane) to provide MI aa a methylene chloride (3X 50 mL). T h e combined organic phaees colorleaa oil,3.36g (88%): IR (neat) 2923,2853,1748,1704,1665, were dried over anhydrous d i u m sulfate, fiitered, and con1593 cm-1; 1H NMR (CDCS) 6 8.52-8.50(m, 1 H, aromatic), 7.75 centrated. The residue waa purified on silica gel (250g, elution
-
Analogues of Platelet Activating Factor (d, 1H, J = 2 Hz,aromatic), 7.66-7.58 (m, 2 H, aromatic), 7.217.11 (m, 3 H, aromatic), 5.08 (e, 2 H, NCHz), 3.32-3.26 (m, 2 H, NHCH2), 2.30 (8, 3 H, COCH,), 1.6tH.50 (m, 2 H, NCHZCHZ), 1.30 (e, 9 H, C(CH3)3), 1.36-1.26 (m, 30 HI, 0.88 (t, 3 H, J = 7 Hz, CH3); '3c N M R (CDCb) 6 174.00, 173.57, 156.48, 153.72, 152.82, 149.31, 141.96, 136.47, 131.98, 128.05, 127.43, 124.44,
122.06,121.40,50.96,41.39,34.74,31.91,29.98,29.86,29.68,29.55, 29.34,29.22,26.68, 26.25,22.67, and 14.11 ppm; mass spectrum (EI) m/e 326 (M+ - ClgHnNO). Anal. (C&&304) C, H, N.
2-[[Acety1[3-( l,l-dimethylethyl)-4-[[(octadecy1amino)carbonyl]oxy]benzoyl]amino]met hyll-1-methylpyridinium Iodide (59). 59 was prepared by the procedure described for 20 by the reaction of 58 and iodoethane. Compound 59 was isolated as pale yellow crystals (100%): mp (softanddec) 110130 OC; IR (KBr) 2922, 2851,1723, 1667, 1631 cm-l; lH NMR (da-DMSO/TFA) 6 9.02 (d, 1H, J = 5.6 Hz, aromatic), 8.55 (td, 1H, J = 8,1.2 Hz, aromatic), 8.067.94 (m, 2 H, aromatic), 7.707.65 (m, 1H, aromatic), 7.12-7.16 (m, 2 H, aromatic), 5.34 (s,2 H, NCH2), 4.34 (e, 3 H, NCH3), 3.4Ck3.06 (m,2 H, NCH2), 2.17 (e, 3 H, COCH,), 1.53-1.44 (m, 2 H, NCH~CHZ), 1.33 (8, 9 H, C(CH3)s),1.37-1.24 (m, 30 H), 0.85 (t,3 H, J = 6.7 Hz, CHd; mass spectrum (FAB) m/e 636 (M+- I). Anal. (Cd&2N3041) C, H, N, I. N-[3-Methoxy-4-(tetradecyloxy)benzoyl]-4-pyridinecarboxamide (61a). To a room temperature slurry of NaH (0.864 g of a 50% oil dispersion, 18 mmol) in dry THF (10 mL) was added 60a (1.0 g, 8.2 mmol) in one portion. HMPA (1.4 mL, 8.2 mmol) was added to the reaction mixture after a 30-min period. After an additional stirring period of 30 min, acid chloride 12b (3.14 g, 8.2 mmol) dissolved in dry THF (10 mL) was added. The reaction mixture was stirred at room temperature for 1.5 h, poured into saturated aqueous ammonium chloride (200 mL), and extracted with methylene chloride (3 X 100 mL). The combined organic phases were washed with brine (75 mL), dried over anhydrous sodium sulfate, fiitered, concentrated in vacuo, and purified on silica gel (250 g, elution with 90% EtOAdhexane) to provide 61a as a colorless solid, 2.73 g (71%): mp 116-117 OC; IR (KBr) 2922,2853,1727,1681,1599 cm-l; lH NMR (CDCl3) 6 9.11 (e, 1H, NH), 8.80 (d, 2 H, J = 5.5 Hz, aromatic), 7.62-7.60 (m, 2 H, aromatic), 7.46-7.43 (m, 2 H, aromatic), 6.91 (d, 1H, J = 8.6 Hz, aromatic), 4.08 (t,2 H, J = 7 Hz, OCHz), 3.91 (a, 3 H, OCH3),1.88 (quintet, 2 H, J = 7 Hz, OCH2CH2),1.4H.26 (m, 22 H), 0.88 (t, 3 H, J = 6.5 Hz, CHzCHs); 13C NMR (CDCls) 6 167.39, 165.44, 153.37, 150.36, 149.49, 141.33, 124.21, 121.60, 121.38, 111.56, 111.29, 69.16, 56.10, 31.86, 29.60, 29.54, 29.49, 29.30, 28.88, 25.85, 22.63, and 14.07 ppm; mass spectrum (EI) m/e 468 (M+). Anal. (CzeHd204) C, H, N.
4 4[[%Met hoxy-4-(tetradecyloxy)benzoyl]amino]carbonyll-1-propylpyridiniumIodide(62). A solutionof 61a (0.75 g, 1.6 mmol) and 1-iodopropane (5.5 mL, 56 mmol) was heated at 90-95 OC for 4.5 h and then maintained at room temperature for 18 h. The unreacted 1-iodopropane was removed in vacuo, and the residue was recrystallized from methanol to give 62 as orange-colored crystals, 1.02 g (100%): mp (softens/dec) 68-88 "C; IR (KBr) 2921,2851, 1735, 1678,1599 cm-l; lH NMR (deDMSO/TFA) 6 9.27 (d, 2 H, J = 6.7 Hz, aromatic), 8.41 (d, 2 H, J = 6.7 Hz, aromatic), 7.69 (dd, 1H, J = 8.5,2.1 Hz, aromatic), 7.60 (d, 2 H, J = 2.1 Hz, aromatic), 7.10 (d, 1H, J = 8.6 Hz, aromatic), 4.67 (t, 2 H, J = 7 Hz, NCH2), 4.08 (t,2 H, J = 7 Hz, OCHz),3.86(s,3H,0CHS),2.02(hextet,2H,J= 7Hz,NCHzCH2), 1.77 (quintet, 2 H, J = 7 Hz, OCHZCH~), 1.46-1.26 (m, 22 H), 0.95 (t, 3 H, J = 7.3 Hz, NCH~CHZCH~), 0.87 (t, 3 H, J = 6.7 Hz, CHzCH,); mass spectrum (FAB) m/e 511 (M+ - I). Anal. ( C S ~ H ~ ~ N ZC,OH, ~ IN; ) I calcd, 19.87; found, 18.81. Phenyl [4-(Tetradecyloxy)phenyl]methyl Carbonate (64). T o a 0 OC slurry of benzyl alcohol 16b (9.0g, 28 mmol), pyridine (4.5 mL, 56 mmol), and dry methylene chloride (70 mL) was added phenyl chloroformate (4.2 mL, 33.7 mmol) by syringe. The reaction mixture was stirred at 0 OC for 15 min and room temperature for 30 min, prior to dilution with saturated aqueous sodium bicarbonate (200 mL). The aqueous phase was extracted with methylene chloride (4 X 100 mL); the combined organic phases were washed with brine (200 mL), dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and purified on silica gel (250 g, gradient elution with 0-5% EtOAc/hexane) to give 64 as colorless prisms, 12.4 g (100%): mp 34-35 OC; IR
Journal of Medicinal Chemistry, 1993, Vol. 36, NO.5 S89 (KBr) 2917,2849,1758 cm-l; lH NMR (CDCb) 6 7.40-7.35 (m, 4 H, aromatic), 7.26-7.15 (m, 3 H, aromatic), 6.926.89 (m, 2 H, aromatic), 5.20 (s,2 H, C02CH2),3.96 (t,2 H, J = 6.5 Hz, OCH2), 1.79(quintet,2H,J=7Hz,OCH~CH~),1.46-1.26(m,22H),O.88 (t, 3 H, J = 6.6 Hz, CH3); '3c NMR (CDCb) 8 159.61, 153.66, 151.11,130.50,129.39,126.60,125.93,121.01,114.54,70.27,68.02, 31.90, 29.64, 29.58, 29.37, 29.35, 29.20, 26.01, 22.68, and 14.11 ppm; mass spectrum (EI)m/e 440 (M+). Anal. (C&04) C, H. [4-(Tetradecyloxy)phenyl]methyl(2-Pyridinylmethyl)carbamate (65). A mixture of carbonate 64 (3.0 g, 6.8 mmol) and 13a (1.1g, 10.2 mmol) was heated at 100 OC for 80 min. The crude reaction mixture was purified on silica gel (250 g, elution to give 6S as colorleas crystals, 2.99 g with 50% EtOAc/he-e) (96%): mp 67-68 OC; IR (KBr) 3336,2917,2850,1690 cm-1; 1H NMR (CDCl3) 6 8.53 (d, 1H, J = 4 Hz,aromatic), 7.68-7.63 (m, 1H, aromatic), 7.31-7.16 (m, 4 H, aromatic), 6.87 (d, 2 H, J = 8.5 Hz, aromatic), 5.79 (br s, 1H, NH), 5.07 (8, 2 H, COZCHZ), 4.51 (d, 2 H, J = 5 Hz, NCHz), 3.94 (t,2 H, J 6.5 Hz,OCHz), 1.82-1.72 (m, 2 H, OCHZCHZ),1.46-1.26 (m, 22 H), 0.88 (t, 3 H, J = 6.5 Hz,CH3); '3c NMR (CDCb) 6 159.08,156.88,156.70, 149.05,136.69,129.93,128.31,122.27,121.67,114.40,67.98,66.69, 45.99, 31.89, 29.64, 29.57, 29.36, 29.33, 29.20, 25.99, 22.67, and 14.10 ppm; mass spectrum (E11 m/e 454 (M+). Anal. (Cz~&zNz03) C, H, N.
l-Etayl-2-[[[[[4(tetraaecylo~)P~Yl~~~~~~lIamino]methyl]pyridinium Salt with TrifluoromethanesulfonicAcid (1:l) (66). A solution of carbamate 66 (1.0 g, 2.2 mmol), ethyl trifluoromethanesulfonate (EtOTf, 0.31 mL, 2.4 mmol), and dry toluene (3 mL) was heated at 65-70 OC for 12 h. The cooled reaction mixture was concentrated in vacuo and purified on silica gel (70 g, elution with 50% EtOAc/hexane followed by MeOH) to give 66 as a gummy solid, 0.255 g (18% ): IR (neat) 2918,2850,1711,1674,1631,1615,1584 cm-l; lH NMR (drDMSO/TFA) 6 9.07 (d, 1H, J = 5.6 Hz,aromatic), 8.73-8.55 (m, 1H, aromatic), 8.09-8.00 (m, 2 H, aromatic), 7.32-7.29 (m, 2 H, aromatic), 6.94-6.91 (m, 2 H, aromatic), 5.02 (8, 2 H, COr CHz), 4.71-4.61 (m, 4 H, NCH2, NHCHZ),3.95 (t,2 H, J = 6.4 Hz,OCHz), 1.71 (quintet, 2 H, J = 7 Hz,OCH~CHS),1.52 (t, 3 H, J = 7 Hz,NCHzCH3),1.46-1.26 (m, 22 H), 0.86 (t, 3 H, J = 6.6 Hz, CH3); mass spectrum (FAB) m/e 483 (M+- O M . Anal. (Cz.iH47N2OeSFs) C, H, N, S,F. [4-(Tetradecyloxy)phenyl]methyl Acetyl(2-pyridinylmethy1)carbamate (67). A mixture of carbamate 66 (3.0 g, 6.6 mmol), acetic anhydride (12.5 mL, 132 mmol), DMAF' (80 mg, 0.66 mmol), triethylamine (4.6 mL, 33 mmol), and dry methylene chloride (25 mL) was heated at 100 OC for 54 h in a sealed glass veseel. The crude reaction mixture was shaken with saturated aqueous sodium bicarbonate (100 mL); the organic phase was dried over anhydrous sodium sulfate, fiitered, and concentrated in vacuo. The residue was p d i e d on silica gel (150 g, elution to give 67 as colorleas crystals, 1.42 g with 20% EtOAc/he-e) (43%): mp 52-53 "C; IR (KBr) 2919, 2850, 1738, 1698, 1614 cm-l; lH NMR (CDCl3) 6 8.50-8.49 (m, 1H, aromatic), 7.56 (td, 1H, J = 7.7, 1.8 Hz, aromatic), 7.167.02 (m, 4 H, aromatic), 6.81-6.77 (m, 2 H, aromatic), 5.09,5.08 (2 s,4 H, NCHz + OCHz), 3.92 (t,2 H, J = 6.6 Hz, OCHd, 2.61 (s,3 H, COCb), 1.77 (quintet, 2 H, J = 7 Hz, OCHzCHz),1.46-1.26 (m, 22 HI, 0.88 (t, 3 H, J = 6.7 Hz, CH3); 13CNMR (CDCls) 6 172.97,159.29,156.94,154.47, 149.21,136.34,129.93,126.75,121.83,120.41,114.35,68.43,67.98, 48.48, 31.88, 29.63, 29.57, 29.35, 29.18, 26.57, 25.99, 22.66, and 14.09 ppm; mass spectrum (EI) m/e 320 (M+- CeHeNzOz). Anal. (CmH~N204)C, H, N.
Acknowledgment. We thank Dr.J. James, Dr.M. Siegel, Mr. G. 0. Morton, and staff for the spectral data and Dr. J. B. Medwid and stafffor the analyticaldata. We would also like to thank Mr. M. Jennings for his technical
assistance.
Rsfeerencee (1)
Benveniete, J.; Hewn, P. M.; Cochrane, C. G. Imukocyt4Dependent Hietamine Release From Rabbit Plateleta. The Role of IgE, B w p W , and a PlateletActivating Factor. J. Ezp. Add. 1972,1s6,136&-1377.
690 Journal of Medicinal Chemistry, 1993, Vol. 36, No.5
(2) Benveniste, J.; Tence, M.; Varenne, P.; Bidault, J.; Bodlet, C.; Poloneky, J. Semiayntheda and Propoeed Structure of Platelet Activating Factor (P.A.F.): PAF an Akyl Ether Analogue of Lyrophosphatidylcholine. C. R. Hebd. Seances Acad. Sci., Ser. D 1979,zsS,1037-1040. (3) Demopoulos, C. A.; Pinchd, R. N.; Hanahan, D. J. Platelet Activating Factor. Evidence for 1-OAkyl-2-acetyl-sn-glycerylEphonphorylcholine ae The Active Component (A New C h of Lipid Chemical Mediitors). J.Biol. Chem. 1979,254,9356-9358. (4) For some recent reviews of the biological properties of PAF and its involvement in human ,-d nee: (a) Platelet Activating Factor and Human Direme; Bamea, P. J.; Page, C. P., Henson, P. M.,Ede.; Blackwell Scientific: Oxford, 1989. (b) Page, C. P. Developments in Asthma. A View of Current Research; PJB Publicatione: Richmond, 1987. (c) Feuerstein, G.; Siren, A.-L. PlateletActivatingFactor and Shock. Pmg. Biochem. Pharmacol. 1988, 23, 181-190. (d) Braquet, P.; Touqui, L.; Shen, T. Y.; V ,B. B. Perspectiwin Plate1e.t-ActivatingFacbrReeearch. Pharmacol. Rev. 1987,39,97-145. (e)Beck,T.; Bielenberg, G. W.; Sauer,D. PlateletActivathgFactorAntagonists. New Therapeutic Pmibilitiea For Cerebral Ischemia. Pharm. Ztg. 1991,1369-18. (f) Koltai, M:; Hoeford, D.; Guinot,P.; m u , A,;Braquet, P. PAF: A Review of its Effecta, Antagonists and Pmible Future Clinical I m p l i ~ ~ t(Part i o ~I). Drugs 1991,42,9-29. (5) For reviews see: (a) Handley, D. A. Developmentand Therapeutic Indicatiom For PAF Racaptor Antagonists. Drugs Future 1988, M.N. PAF and PAF Antagonists. Drug8 13,137-152. (b) Future 1986,11,869-875. (c) Miyazalri,H.; N h u r a , N.; Ito, T.; Sada, T.; Oehima, T.; Koike, H. Syntheais and Antagonistic Activities of Enantiomers of Cyclic PlateletActivating Factor Analogs. Chem. Pharm. Bull. 1989,37,2391-2397 and reference therein. (d)Handbook of PAFand PAFAntagonbte; Braquet. P., Ed.; CRC Press: Boca Raton, 1991. (e) Koltai, M.; Hoeford, D.; Guinot, P.; EMnu, A; Braquet, P. PAF: A Review of its Effects, Antagonists and Pmible Future Clinical Implicatione (Part 11). Drugs 1991,42,174-204. (6) Teraehita, Z.; Tsuhima, S.; Yoshioh, Y.;Nomura, H.; Inada, Y.; Niahikawa,N. CV-3988-AS p d kAntagomst of Platelet Activating Factor (PAF). Life SCL1988, 32, 1975. (7) Wmer, A.; Carroll, M. L.; Green, K. E.; Kerwar, S.; Pickett, W.
u,
C.;Schaub,RE.;Torley,L.W.;Wrenn,S.;Kohler,C.A.Analogues Of Platelet Activating Factor. 6. Mono-and Bis-Aryl Phosphate Antagonists of Platelet Activating Factor. J. Med. Chem. 1992,
36,160-1662.
N.;Termhita, Z.;Yoehioka, Y.;Tsuehima, S. Discovery Of aspecific PAF Antagonist CV-3988,And an Analysis of The Pathophysiological Rolea of PAF. J. Take& Res. Lab. 1987,46,1-19. (b)T d t a , Q-Imura, Y.;Taketani,M.;T~uebima, 9.; Nmhiknwa, N. CV-6209, a H ~ h l Potent y Antagomstof Platelet Activating Factor in vitro and in Vivo. J. Pharmacol. Exp. Ther. 1987,242,285-268. (c) Miyamoto,T.; Ohno, H.; Yano, H.; Ohda, T.; Hama~ka,N.; Kawasalri, A. ON0-620: A New Potent Antagonist of PlateletActivating Factor. Adu. Prostagbndin, Thromboxane, Leukotriene Res. 1986, 15,719-720. (d)Taltatani, M.; Yoshioka,Y.;T&, A;Teranhita, Z.4.; Imura, Y.;NmhiLawa, K.; Tsuahirmr, 5.Platelet Activating Factor (PAF) Antagonists: Synthesis and StructuncActivityStudies of Novel PAF Analogs Modified in the Phosphorylcholine Moiety. J. Med. Chem. 1989, 32,6644. (e)Corey, E. J.; Chen, C. P.; Parry, M.J. Dual Binding Modes to the Receptor for Platelet Activating Factor (PAF) of Anti-PAF trana-2,CDiarylfura. Tetrahedron Lett. 1988, 29, 28e.F. (f) Handley, D. A.; Andereon, R. C.; Saunders, R. N. Inhibition By SRI 63-072 and SRI 63-119 of PAF-Acether and Immune Complex Effecta in the Guinea Pig. Eur. J. Pharmacol. 1987,141,409-416.
(8) (a) N-wa,
Trova et al.
(9) W i n e r , A.; Carroll, M. L.;Johnson, B. D.; Karwar, 8.;PicLett, W. C.; Schaub, R E.; Torley, L. W.;Trow, EA. P.; Kohler, C. A. Analogues Of Platelet Activating Factor. 7. BbAryl Amide and Urea Antagonh of PAF. J. Med. Chem. 1992,36,4779-4789. (10) (a) Bartroli, J.; Carder, E.; Merlos, M.; Garcia-Rdhnell,J.; Forn, J. Diaubntituted Tetrahydrofurans and Dioxohea m PAF Antagonists. J. Med. Chem. 1991, 34, 373-386. (b) Bartroli, J.; Carder, E.; Merlos, M.;Gual, M.;Gucir-M~eU, J.; Forn, J. Deaign of Potent Linear PAF Antagonists. J. Med. Chem. 1991, 34,3328-3334. (c)Carceller, E.; Merlos, M.;Giral,M.;Butroli, J.; Garcia-Manell, J.; Forn, J. 4Subtituted 2-Alkoxytetrahydm ha aa Potent and Long-Lasting PAF Antagonists. J. Med. Chem. 1992,35,676483. (11) Page, C.; Abbott, A. PAF. New Antagonists,New Rolea in D h and a W o r Role in Reproductive Biology. Trends Pharmacol. Sei. 1989, 10, 265-267. (12) ( a ) T a l r e t a n i , M . ; ~ , N . ; I m u r a , Y . ; T e ~ ~ Z . - I ; N ~ ~ K.; Teuehimn, S. Platelet Activating Factor (PAF) Antagoniste: Developmentof a H ~ h l Potent y PAF Antagonist, TCV-309. Adv. Prostaglandin, Thromboxane, Leuhotriene Res. 1990, ZIB, 943946. (b) Teraehita. Z.4.: TaLatani. M.:N&wa. K. Pharmacological Profde of WV-309-A Potent PAF Antagonist. J. Lipid Med. 1992,5183-186. (13) Wmner,A.;GRldEinekae,C. V. Rsactionof tert-Butyldiithy&l Esters with Oxalyl Chloride-Dmethylfonnamide: Preparation of Carboxylic Acid Chloridw Under Neutral Conditione. J. Org. Chem. 1978,43,3972-3974. (14) (a)Inarrea,P.; Gomez-Cambronero, J.; Nieto, M.;SanchezCmpo, M.Characteristicsof the B w of Platelet-Activating Factor to Platelets of Different Animal Speciea. Eur. J. Pharm. 1984,106, 309-315. (b) Hwang, S.-B.; Lam, M.-H. Speciea Difference in the SpsciTcReceptors of PlateletActivatingFaetor. Biochem.Pharm. 1986,36,4511-4618. (c) Stewart,A. G.; h t i n g , 0. J. Characterization of Receptors for PlateletActivating Factor on Platelets, Polymorphonuclear Leukocyb and Mamphagea. Br. J. Phar~ O C O 1988,94,122&1233. ~ . (d) Hwang, 9.-B. Specific Receptors of PlateletActivatingFactor, Receptor Hetercgeneity, and Signal Traduction Mechanism. J. Lipid Med. 1990,2,123-168. (15) K o r n ~ , E . ; E h r l i c h , Y . H . ; L e n o z R H . P l a ~ A ~ ~ ~ F a c t o r Induced Aggregationof Human Plateleta Specifiiy Inhibitedby Triazolobexuodbepin~Science 1984,228,1rlM-1456. (16) Casab-Stenzel, J.; Muacevic, G.; Weber,K. H. Pharmacological Actione of WEB 2086, a New Specific Antagonist of Platelet Activating Factor. J. Pharmacol. Exp. Ther. 1987,241,974-981. (17) Shen, T. Y.; Hwang, 5.-B.; Chang, M.N.; Doebber, T. W.;Lam, M.-H. T.; Wu,M.S.; Wang, X.;Han,G.; Li, R Charlcterization of a PlateletActivatingFactor Receptor Antagoniatblated From Haifenteng (Piper Futokadaura): Specific Inhibition of In Vitro andInVivoPlateletrActivatingFactor-Inducad~ecta Roc.Natl. Acad. Sci. U.S.A. 1986,82,672-676. (18) Biftu, T.; Gamble, N. F.; Doebber, T. W.;Hwang, Sa-B.;Shen, T.Y.;Snyder, J. Conformation and Activity of Tetrahydrofumu Lignem and Analogs ae Specitic PlateletActivating-FactorAntagonists. J . Med. Chem. 1987,29,1917-1921. (19) Handley, D. A; Van Valen, R 0.; Melden, M.K.;Flury,8.;Lee, M. L.; Saunders, R. N. Inhibition and Reversal of Endotoxin-, Aggregated IgG- and PAF-Induced Hypotension in the Rat by SRI 63-072,a PAF Receptor Antagonist. Immunopharmacology 1986, 12,ll-16. (20) Handley,D. A.;Tomeech, J.C.;Saunden,R.N. InhibitionofPAFInduced Systemic Reapom in the Rat, Guinea PQ,Dog, and Primate by the Receptor Antagonist SRI 63-441. Thromb. Hem t a t s b 1986,56, 40-44.
