WO1991018889A1 - Leukotriene antagonists - Google Patents
Leukotriene antagonists Download PDFInfo
- Publication number
- WO1991018889A1 WO1991018889A1 PCT/US1991/003922 US9103922W WO9118889A1 WO 1991018889 A1 WO1991018889 A1 WO 1991018889A1 US 9103922 W US9103922 W US 9103922W WO 9118889 A1 WO9118889 A1 WO 9118889A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- mmol
- acid
- phenyloctyl
- mixture
- Prior art date
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- 239000003199 leukotriene receptor blocking agent Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 129
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
- -1 COR3 Chemical group 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- 101100295738 Gallus gallus COR3 gene Proteins 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 150000002431 hydrogen Chemical group 0.000 claims description 8
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 229910006069 SO3H Inorganic materials 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 3
- 125000000565 sulfonamide group Chemical group 0.000 claims description 3
- GFYVABWNFFQRGH-UHFFFAOYSA-N 5-[[2-carboxy-2-hydroxy-1-[2-(8-phenyloctyl)phenyl]ethyl]sulfanylmethyl]thiophene-2-carboxylic acid Chemical compound C=1C=CC=C(CCCCCCCCC=2C=CC=CC=2)C=1C(C(O)C(O)=O)SCC1=CC=C(C(O)=O)S1 GFYVABWNFFQRGH-UHFFFAOYSA-N 0.000 claims description 2
- CJBFUSJOJMBXKH-UHFFFAOYSA-N 5-[[2-carboxy-2-methoxy-1-[2-(8-phenyloctyl)phenyl]ethyl]sulfonylmethyl]thiophene-2-carboxylic acid Chemical compound C=1C=C(C(O)=O)SC=1CS(=O)(=O)C(C(OC)C(O)=O)C1=CC=CC=C1CCCCCCCCC1=CC=CC=C1 CJBFUSJOJMBXKH-UHFFFAOYSA-N 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 84
- 239000002253 acid Substances 0.000 abstract description 20
- 150000002617 leukotrienes Chemical class 0.000 abstract description 12
- 238000000034 method Methods 0.000 abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 176
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 145
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 140
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 89
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 78
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 73
- 239000000243 solution Substances 0.000 description 71
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- 229940093499 ethyl acetate Drugs 0.000 description 58
- 235000019439 ethyl acetate Nutrition 0.000 description 58
- 239000000047 product Substances 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- 229910052786 argon Inorganic materials 0.000 description 39
- 239000002904 solvent Substances 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 32
- 239000000741 silica gel Substances 0.000 description 31
- 229910002027 silica gel Inorganic materials 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 23
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 19
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 16
- 235000019253 formic acid Nutrition 0.000 description 16
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 16
- 239000002243 precursor Substances 0.000 description 15
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 229960000583 acetic acid Drugs 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 13
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 150000001299 aldehydes Chemical class 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 235000019260 propionic acid Nutrition 0.000 description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 9
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000007429 general method Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 8
- 239000003937 drug carrier Substances 0.000 description 7
- 229960001340 histamine Drugs 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000008024 pharmaceutical diluent Substances 0.000 description 7
- 239000002464 receptor antagonist Substances 0.000 description 7
- 229940044551 receptor antagonist Drugs 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- 150000003573 thiols Chemical class 0.000 description 7
- MORHPNKHDKWZHZ-UHFFFAOYSA-N 4-(5-sulfanylidene-2h-tetrazol-1-yl)butanoic acid Chemical compound OC(=O)CCCN1N=NN=C1S MORHPNKHDKWZHZ-UHFFFAOYSA-N 0.000 description 6
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- 238000003818 flash chromatography Methods 0.000 description 6
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- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000003039 volatile agent Substances 0.000 description 6
- 206010002198 Anaphylactic reaction Diseases 0.000 description 5
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 5
- OTZRAYGBFWZKMX-SHSCPDMUSA-N Leukotriene E4 Natural products CCCCCC=C/CC=C/C=C/C=C/C(SCC(N)C(=O)O)C(O)CCCC(=O)O OTZRAYGBFWZKMX-SHSCPDMUSA-N 0.000 description 5
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- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical compound CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 5
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- OTZRAYGBFWZKMX-JUDRUQEKSA-N leukotriene E4 Chemical compound CCCCCC=CCC=C\C=C\C=C\[C@@H](SC[C@H](N)C(O)=O)[C@@H](O)CCCC(O)=O OTZRAYGBFWZKMX-JUDRUQEKSA-N 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
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- ZGDUNGBWVZKWGE-UHFFFAOYSA-N 2-(2-methoxyphenyl)-4,4-dimethyl-5h-1,3-oxazole Chemical compound COC1=CC=CC=C1C1=NC(C)(C)CO1 ZGDUNGBWVZKWGE-UHFFFAOYSA-N 0.000 description 4
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- GWNVDXQDILPJIG-SHSCPDMUSA-N Leukotriene C4 Natural products CCCCCC=C/CC=C/C=C/C=C/C(SCC(NC(=O)CCC(N)C(=O)O)C(=O)NCC(=O)O)C(O)CCCC(=O)O GWNVDXQDILPJIG-SHSCPDMUSA-N 0.000 description 4
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- 229910052783 alkali metal Inorganic materials 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
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- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 4
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- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229910006074 SO2NH2 Inorganic materials 0.000 description 1
- 101100075025 Scheffersomyces stipitis (strain ATCC 58785 / CBS 6054 / NBRC 10063 / NRRL Y-11545) LTA4 gene Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- OGEAASSLWZDQBM-UHFFFAOYSA-N Temelastine Chemical compound C1=NC(C)=CC=C1CC(C(N1)=O)=CN=C1NCCCCC1=NC=C(Br)C=C1C OGEAASSLWZDQBM-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- 230000003435 bronchoconstrictive effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- IFMWVBVPVXRZHE-UHFFFAOYSA-M chlorotitanium(3+);propan-2-olate Chemical compound [Cl-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-] IFMWVBVPVXRZHE-UHFFFAOYSA-M 0.000 description 1
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- PXCXMTKJRYTWQE-UHFFFAOYSA-L disodium;(5-sulfanylidene-2h-tetrazol-1-yl)methanesulfonate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)CN1NN=NC1=S.[O-]S(=O)(=O)CN1NN=NC1=S PXCXMTKJRYTWQE-UHFFFAOYSA-L 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- AFEPBNOTXMBLBD-UHFFFAOYSA-N ethyl 2-methyl-5-sulfanylidenetetrazolidine-1-carboxylate Chemical compound SC1=NNN(N1C(=O)OCC)C AFEPBNOTXMBLBD-UHFFFAOYSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- UFPQIRYSPUYQHK-WAQVJNLQSA-N leukotriene A4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@@H]1O[C@H]1CCCC(O)=O UFPQIRYSPUYQHK-WAQVJNLQSA-N 0.000 description 1
- VNYSSYRCGWBHLG-AMOLWHMGSA-N leukotriene B4 Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O VNYSSYRCGWBHLG-AMOLWHMGSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- MBHQEXPGNCWWBP-UHFFFAOYSA-M magnesium;dodecane;bromide Chemical compound [Mg+2].[Br-].CCCCCCCCCCC[CH2-] MBHQEXPGNCWWBP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- QKKNCFKGAWTLBU-FIRIVFDPSA-N methyl (2s,3r)-2-hydroxy-3-[(4-methoxyphenyl)methylsulfanyl]-3-[2-(8-phenyloctyl)phenyl]propanoate Chemical compound S([C@@H]([C@@H](O)C(=O)OC)C=1C(=CC=CC=1)CCCCCCCCC=1C=CC=CC=1)CC1=CC=C(OC)C=C1 QKKNCFKGAWTLBU-FIRIVFDPSA-N 0.000 description 1
- HULURQJQYGWAQG-UHFFFAOYSA-N methyl 2-(2-dodecylphenyl)-2-[2-(2h-tetrazol-5-yl)ethylsulfanyl]acetate Chemical compound CCCCCCCCCCCCC1=CC=CC=C1C(C(=O)OC)SCCC1=NN=NN1 HULURQJQYGWAQG-UHFFFAOYSA-N 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- ACEONLNNWKIPTM-UHFFFAOYSA-N methyl 2-bromopropanoate Chemical compound COC(=O)C(C)Br ACEONLNNWKIPTM-UHFFFAOYSA-N 0.000 description 1
- CSOCSYGDRZASHM-UHFFFAOYSA-N methyl 2-chloro-2-(2-dodecylphenyl)acetate Chemical compound CCCCCCCCCCCCC1=CC=CC=C1C(Cl)C(=O)OC CSOCSYGDRZASHM-UHFFFAOYSA-N 0.000 description 1
- GSJFXBNYJCXDGI-UHFFFAOYSA-N methyl 2-hydroxyacetate Chemical class COC(=O)CO GSJFXBNYJCXDGI-UHFFFAOYSA-N 0.000 description 1
- SYSBOXNRHCEKRA-UHFFFAOYSA-N methyl 3-[2-(8-phenyloctyl)phenyl]oxirane-2-carboxylate Chemical compound COC(=O)C1OC1C1=CC=CC=C1CCCCCCCCC1=CC=CC=C1 SYSBOXNRHCEKRA-UHFFFAOYSA-N 0.000 description 1
- DVBOFIBBCJQFBE-UHFFFAOYSA-N methyl 4-methyl-2-sulfanylidene-3h-1,3-thiazole-5-carboxylate Chemical compound COC(=O)C=1SC(S)=NC=1C DVBOFIBBCJQFBE-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- OOACYMHHMQUBSD-UHFFFAOYSA-N tert-butyl 3-(2-dodecylphenyl)-3-hydroxypropanoate Chemical compound CCCCCCCCCCCCC1=CC=CC=C1C(O)CC(=O)OC(C)(C)C OOACYMHHMQUBSD-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- SMJRBWINMFUUDS-UHFFFAOYSA-M thien-2-ylacetate Chemical compound [O-]C(=O)CC1=CC=CS1 SMJRBWINMFUUDS-UHFFFAOYSA-M 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
- 229940103494 thiosalicylic acid Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 210000005092 tracheal tissue Anatomy 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- AAAQKTZKLRYKHR-UHFFFAOYSA-N triphenylmethane Chemical compound C1=CC=CC=C1C(C=1C=CC=CC=1)C1=CC=CC=C1 AAAQKTZKLRYKHR-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- SRS-A LEUKOTRIENE ANTAGONISTS BACKGROUND OF THE INVEN ⁇ ON "Slow Reacting Substance of Anaphylaxis"
- SRS-A has been shown to be a highly potent bronchoconstricting substance which is released primarily from mast cells and basophils on antigenic challenge.
- SRS-A has been proposed as a primary mediator in human asthma.
- SRS-A in addition to its pronounced effects on lung tissue, also produces permeability changes in skin and may be involved in acute cutaneous allergic reactions. Further, SRS-A has been shown to effect depression of ventricular contraction and potentiation of the cardiovascular effects of histamine.
- SRS-A derived from mouse, rat, guinea pig and man have all been characterized as mixtures of leukotriene-C4 (LTC4), leukotriene-D4 (LTD4) and leukotriene-E4 (LTE4), the structural formulae of which are represented below.
- the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a factor.
- R l is (L) a -(CH2) b -(T) c -B wherein a is 0 or 1; b is 3 to 14; c is 0 or 1; L and T are independently oxygen, sulfur, or CH 2 with the proviso that L and T are not sulfur when q is 1 or 2;
- B is Ci- 4 alkyl, ethynl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl, or phenyl optionally monosubstituted with Br, Cl, CF3, C 1 - 4 alkyl, C 1 -4 alkoxy, methylthio, or trifluoromethylthio;
- R2 and A are independently selected from H, CF3, C 1 -4 alkyl, C 1 - 4 alkoxy, F, Cl, Br, I, OH, NO2 or NH 2 ; or
- R l and A are H and R 2 is (L) a -(CH 2 ) b -(T) c -B wherein a, b, c, L, T, and B are as defined above;
- Y is COR3 or (CHX) n (CH 2 ) p -Z wherein R3 is OH, NH 2 , aryloxy or Ci- 6 alkoxy; p is 0 or 1; x is H, OH, C 1 - 4 alkyl, C 1 - 4 alkoxy, or F; and Z is COR3, or tetrazolyl; R is
- s m is 0 to 6, but m is 1 to 6 when w is imidazole;
- R 4 and R5 are independently hydrogen or C 1 - 4 alkyl at any position when m is not 0;
- W is a 5-membered ring heteroaryl group selected from tetrazolyl, thiazolyl, triazolyl, thienyl, furyl, oxazolyl, thiadiazolyl, pyrrolyl, imidazolyl or pyrazolyl, unsubstituted or substituted with one to three of the group
- R 4 and R5 are as defined above; j is 0 to 6; and V is hydrogen, C 1 - 4 alkyl, COR 3 , SO3H, S0 H, S0 2 NH 2 , COCH 2 OH,
- This invention further relates to the ester or diester derivatives of the compounds of Formula (I).
- This invention includes all stereoisomers, racemates, or mixtures thereof.
- W can be 1,2,3-triazole; 1,3,4-triazole; 1,2,3-thiadiazole, 1,3,4-thiadiazole, and other possible steroisomers.
- This invention further relates to pharmaceutical compositions comprising a pharmaceutical carrier or diluent and a nontoxic amount of the compound of formula (I). Such compositions are useful for inhibiting the effects of leukotrienes and in treating diseases in which leukotrienes are a factor.
- This invention further relates to pharmaceutical compositions comprising a pharmaceutical carrier or diluent and nontoxic amounts of a compound of formula (I) and a histamine Hj -receptor antagonist.
- compositions are useful in inhibiting antigen-induced respiratory anaphylaxis.
- This invention further relates to methods for inhibiting the effects of leukotrienes.
- This invention also relates to methods for inhibiting antigen -induced respiratory anaphylaxis comprising administration of an effective amount of the above-described pharmaceutical compositions.
- Ri is (L)a-(CH2)b-(T)c-B wherein a is 0 or 1; b is 3 to 14; c is 0 or 1;
- L and T are independently oxygen, sulfur, or CH2 with the proviso that L and T are not sulfur when q is 1 or 2;
- B is Cl-4 alkyl, ethynl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl, or phenyl optionally monosubstituted with Br, Cl, CF3, Cl-4 alkyl, Cl-4 alkoxy, methylthio, or trifluoromethylthio;
- R2 and A are independently selected from H, CF3, Cl-4 alkyl, Cl-4 alkoxy, F, Cl, Br, I, OH, N02 or NH2; or
- Rl and A are H and R2 is (L)a-(CH2)b-(T)c-B wherein a, b, c, L, T, and B are as defined above;
- Y is COR3 or (CHX)n(CH2)p-Z wherein
- R 3 is OH, NH2, aryloxy or Cl-6 alkoxy; n is 0 or 1; p is 0 or 1;
- X is H, OH, Cl-4 alkyl, Cl-4 alkoxy, or F
- Z is COR 3 , or tetrazolyl
- n 0 to 6;
- R 4 and R 5 are independently hydrogen or C 1 - 4 alkyl at any position when m is not 0;
- W is thienyl substituted with one to three of the group
- I 5 j is 0 to 6;
- V is hydrogen, Cl-4 alkyl, COR 3 , S0 3 H, S0 2 H, S0 2 NH 2 , COCH 2 OH, CHOHCH 2 OH, or tetrazolyl, with R 3 as defined above; or a pharmaceutically acceptable salt thereof.
- W can be 1,2,3-triazole; 1,3,4-triazole; 1,2,3-thiadiazole, 1,3,4-thiadiazole, and other possible steroisomers.
- the compounds of this invention further comprise the ester and diester derivatives of the compounds of Formula (I).
- the preferred compounds of this invention are those where m is 0, 1 or 2; thienyl is substituted with one of the groups
- j is 0 or 1 and R 4 and R5 are hydrogen and V is COR 3 , SO 3 H, S0 2 H, SO 2 NH 2 , COCH 2 OH, CHOHCH 2 OH, or tetrazolyl, with R 3 as defined above; or a pharmaceutically acceptable salt thereof.
- a subgeneric class of these compounds are those represented by structural formula (I) wherein Y is CO2H. Particular members of this subgeneric class are exemplified by the following compounds:
- a second subgeneric class of these compounds are those represented by structural formula (I) where Y is CH2COOH.
- Particular members of this subgeneric class are exemplified by the following compounds:
- a third subgeneric class of these compounds are those represented by structural formula (I) where Y is CH(OH)COOH.
- Y is CHXCOOH or derivatives of this acid such as its esters, amides and salts.
- X is C ⁇ -C 4 alkoxy, particularly methoxy.
- Exemplary compounds are:
- Some of the compounds of formula (I) contain one or two asymmetric centers. This leads to the possibility of two or four stereoisomers for each compound.
- the present invention includes all such stereoisomers, racemates, or mixtures thereof.
- the compounds of the present invention are capable of forming salts with known pharmaceutically acceptable bases, according to procedures well known in the art.
- acceptable bases include inorganic and organic bases, such as ammonia, arginine, organic amines, alkaline earth and alkali metal bases.
- a compound of formula (II) is treated with trimethylsilyl cyanide in the presence of zinc iodide at low temperatures in an inert solvent to form the trimethylsilyl-protected cyanohydrin.
- Treatment of this with gaseous hydrogen chloride in methanol provides the methyl 2- hydroxyacetate derivative which is converted to the 2-chloroacetate with thionyl chloride.
- This valuable intermediate is then reacted with an appropriate thiol selected to give, after removal of ester protective groups, the desired product of formula (I).
- the compounds of the formula (I) wherein Y is CH(X)C02H, wherein X is H, C1.4 alkyl, or Cj _4 alkoxy are prepared by reacting the appropriate aldehyde of the formula (II) and an esterified bromoacetate, conveniently t-butyl bromoacetate, with a mixture of diethyl aluminum chloride, zinc dust and a catalytic amount of cuprous bromide at low temperatures in an inert solvent to give the esterified 3-hydroxy-propionate derivative which is reacted directly with a substituted thiol in trifluoroacetic acid.
- an esterified bromoacetate conveniently t-butyl bromoacetate
- the compounds of the formula (I) wherin Y is CH(X)C ⁇ 2H wherein X is H, C1.4 alkyl, Cj _4 alkoxy, or fluoro are prepared from a propionate precursor of the following structural formula (IV)
- RJ O is a conventional ester protective group, such as t-butyl or Cj -4 alkyl
- RJ I is hydrogen, C ⁇ _4 alkyl, C1.4 alkoxy, or fluoro.
- a compound of formula (IV) is reacted with a mixture of alkali metal alkoxide, such as sodium methoxide, and an appropriate thiol to give, after removal of the ester protective group, the desired product of formula (I).
- the propionate precursors of formula (IV) are prepared from the corresponding aldehydes of formula (II) by general procedures such as reaction with an alkyl (triphenylphosphoranylidene)acetate or by conversion of the aldehyde to a 3-hydroxypropionate derivative, as described above, followed by an elimination reaction to form the double bond. Additionally, the propionate precusor is obtained from a 3-methanesulfonyloxypropionate derivative by treatment with triethylamine.
- a compound of formula (V) is reacted in an inert solvent with triethylamine and the appropriate thiol selected to give, after removal of ester protective groups, a desired product of formula (I).
- the epoxide precursors of formula (V) where p is 2 are prepared by reaction of the Grignard derivative of a bromobenzene compound of the formula (VI)
- epoxide precursors of formula (V) where p is 1 can be prepared by Arndt-Eistert homologation of the compound where p is
- the epoxide precursors of formula (V) where p is O are prepared by reaction of an aldehyde of the formula (II) with a lower alkyl chloroacetate and an alkali metal alkoxide, such as sodium methoxide in an appropriate solvent such as diethyl ether or methylene chloride.
- a compound of formula (VII) is reacted with a mixture of zinc iodide and a substituted thiol in an inert solvent or with a substituted thiol in trifluoroacetic acid to give, after removal of any ester protective group, a product of formula (I).
- the tetrahydro-4H-pyran-2-one precursors of formula (VII) are prepared by reaction of the Grignard derivative of the bromobenzene compound of formula (VI) with chlorotitanium triisopropoxide followed by reaction with 5-oxovalerate alkyl ester.
- the aldehydes of the formula (II) are known or readily prepared utilizing the general procedures described as follows.
- the aldehyde precursors to the compounds of the formula (I) wherein Rj is, for example, an alkyl radical containing 8 to 13 carbon atoms are prepared from the appropriate 2-alkylphenyl-4-,4- dimethyloxazoline [see Meyers et al. J. Org. Chem.. 43 1372 (1978)].
- the aldehyde precursors of the compounds of the formula (I) wherein Ri is, for example, an alkoxy radical containing 7 to 12 carbon atoms are prepared by the O-alkylation of the appropriate 2- hydroxybenzaldehyde with the corresponding alkylating agent by standard methods.
- the thioalkyl containing aldehyde precursors of the compounds of the formula (I) are prepared by the reaction of the appropriately substituted o-haloalkylthiobenzene (for example, a compound of formula (III):
- the phenylthioalkyl containing aldehyde precursors of the compounds of the formula (I) are prepared by the reaction of the appropriately substituted haloalkylbenzaldehyde with a thiophenol and triethylamine. .
- the heteroaryl mercaptan precursors necessary to prepare the compounds of formula (I) are known compounds and are conveniently prepared employing standard chemical reactions.
- the mercapto derivatives of these precursors are prepared according to known methods. For example, 5-(2-mercaptoethyl)tetrazole can be prepared by adding ⁇ -merceptopropionitrile to a mixture of sodium azide and aluminium chloride in tetrahydrofuran.
- the leukotriene antagonist activity of the compounds of this invention is measured by the ability of the compounds to inhibit the leukotriene induced contraction of guinea pig tracheal tissues in vitro. The following methodology was employed:
- the compounds of this invention possess biosignificant antagonist activity against leukotrienes.
- the antagonist activ ' ty of representative compounds of this invention is tabulated below in Table I (other data appears in the preparative examples).
- the -log KB values were calculated from the above test protocol. Where compounds were tested more than once, the -log K ⁇ values given herein represent the current average data.
- R is 5 wherein R4 and R5 are H, W is optionally substituted with -(C)jR4R5-V; R2 and A are H; and q is O.
- compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of the formula (I) or a pharmaceutically acceptable salt, such as an alkali metal salt thereof, sufficient to produce the inhibition of the effects of leukotrienes, such as symptoms of asthma and other hypersensitivity diseases.
- examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non- aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoro- methane, chlorotrifluoroethane and compressed carbon dioxide propellants.
- the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
- the nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, i.e. parenterally, topically, orally or by inhalation.
- the compositions will be in a form suitable for administration by inhalation.
- the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer.
- the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container.
- the compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device.
- the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.
- the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
- a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
- topical administration the pharmaceutical composition will be in the form of a cream or ointment.
- a compound of formula I is administered to an animal subject, including humans, in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of an allergic response.
- the dosage of the composition is easily determined by those skilled in the art and are generally selected from the range of from 350 mg. to 700 mg. of active ingredient for each administration.
- equal doses will be administered 1 to 4 times daily with the daily dosage regimen being selected from about 350 mg. to about 2800 mg.
- the pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.
- the method of inhibiting the symptoms of an allergic response which comprises administering to an animal subject a therapeutically effective amount for producing said inhibition of a compound of formula I, preferably in the form of a pharmaceutical composition.
- the administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be practiced when relief of allergic symptoms is specifically required. However, the method is also usefully carried out as continuous or prophylactic treatment. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the allergic condition being treated, and so forth.
- Compounds of this invention alone and in combination with a histamine Hi -receptor antagonist, inhibit antigen induced contraction of isolated, sensitized guinea pig trachea (a model of respiratory anaphylaxis).
- compositions, as described herein-above, of the present invention also comprise a pharmaceutical carrier or diluent and a combination of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a histamine Hi - receptor antagonist in amounts sufficient to inhibit antigen-induced respiratory anaphylaxis.
- histamine Hj -receptor antagonists include mepyramine, 2-[4-(5-bromo-3-methyl-pyrid-2- yl)butylamino]-5-[(6-methyl-pyrid-3-yl) methyl] -4-pyrimidone and other known Hj -receptor antagonists.
- the above-defined dosage of a compound of formula I is conveniently employed for this purpose with the known effective dosage for the histamine Hj -receptor antagonist.
- the methods of administration described above for the single active ingredient can similarly be employed for the combination with a histamine Hi -receptor antagonist.
- Example 1(c) The compound of Example 1(c) (17.2 mmol) was dissolved in methylene chloride (20 ml) and stirred at 0°C under argon. Zinc iodide (1.87 mmol) was added, followed by the dropwise addition of trimethylsilyl cyanide (2.45 ml, 18.3 mmoles) dissolved in methylene chloride (30 ml). After 1 hour at 0°C the ice bath was removed and the mixture stirred for 1 hour at room temperature. The solvent was stripped and methanol (100 ml) was added after the residue was cooled in an ice bath. Excess hydrogen chloride was bubbled into the solution while the mixture was stirred at ice bath temperature.
- Example 1(d) The compound of Example 1(d) (12 mmol) was stirred under argon in an ice bath and thionyl chloride (20 ml) was added in a single portion. The ice bath was removed and the mixture was stirred under argon for 18 hours. The solvent was stripped and the residue was flash chromatographed on 200 grams of silica gel with 20% methylene chloride/carbon tetrachloride as eluant to give the product as a clear colorless liquid.
- Example 2(a) The compound of Example 2(a) (260 mg, 0.52 mmol) was dissolved in 4.2 ml of methanol and stirred under argon in an ice bath. A IN solution of sodium hydroxide (2.1 ml, 2.1 mmol) was added. The ice bath was removed, and the mixture stirred for 1 hour at ambient temperature during which time a white precipitate formed. The methanol was evaporated and an additional 4 ml of water added to give a slightly turbid mixture which was stirred overnight at ambient temperature. The mixture was acidified with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated.
- Example 3(a) The compound of Example 3(a) (411 mg, 0.82 mmol) was dissolved in 10 ml of methanol and stirred under argon in an ice bath. A 1 N solution of sodium hydroxide (3.2 ml, 3.2 mmol) was added dropwise, the ice bath removed and the mixture stirred overnight at ambient temperature. The solvent was stripped and the residue acidified with dilute hydrochloric acid at ice bath temperature. The crude product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated.
- sodium hydroxide 3.2 ml, 3.2 mmol
- 8-Phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride.
- a solution of 8-phenyloctanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 20°C for 4 hours to give 8- phenyloctanol.
- diborane in tetrahydrofuran (30 ml, 29.1 mmol
- Example 5(e) The compound of Example 5(e) (524 mg, 1 mmol) was dissolved in methanol (12 ml) and stirred under argon in an ice bath, A IN solution of sodium hydroxide (4 ml, 4 mmol) was added dropwise, the ice bath removed, and the mixture stirred overnight at room temperature. The solvent was stripped and the residue was cooled in an ice bath and acidified with dilute hydrochloric acid. The crude product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated.
- Example 5(f) The compound of Example 5(f) (495 mg, 0.97 mmol) was treated with a solution of potassium carbonate (415 mg, 3 mmol) in 10 ml of water under argon at ice-bath temperature. The ice bath was removed and the mixture allowed to stir for 15 minutes at room temperature. The solution was then chromatographed on a Ci column; elution was with water to remove the excess base and then with 1:1 (acetonitrile:water). Lyophilization gave the desired compound (524 mg, 92%) as a white hygroscopic solid. Analysis for C27H32N4O4S 2K H2O - Calculated: C,53,62; H,5.67; N,9.26. Found: C53.81; H,5.51 ; N,9.36.
- a 3 neck 100 ml round bottom flask equipped with a thermometer and stirring bar was cooled to -30°C using a dry ice- acetone bath followed by an ice-methanol bath.
- the flask was charged with trifluoroacetic acid (20 ml) followed by 5-mercapto-l- (3-carboxypropyl)tetrazole (0.00128 mol, 0.1923 g).
- the mixture was permitted to cool under argon for 10 minutes.
- the reaction was stirred for 2 hours at 15°C and was permitted to warm to ambient temperature.
- the trifluoroacetic acid was evaporated and the resulting oil was chromatographed on Ci 8 packing using 20% water in methanol with 1.0% formic acid to yield the desired product.
- a solution of diethylaluminum chloride (0.0082 moles, 8.2 ml) in hexane was added to a slurry of zinc dust (0.0111 mol; 0.7248 g) and a catalytic amount of copper (I) bromide (0.0004 mol; 0.0585 g) in anhydrous tetrahydrofuran (40 ml) while stirring under argon at 20°C.
- the resulting mixture was then cooled to -20°C in an ice- methanol bath.
- the trifluoroacetic acid was evarporated and azeotroped with methylene chloride.
- the resulting oil was chromatographed using 30% ethyl acetate in hexane with 0.5% formic acid to provide a 26% yield of desired product.
- reaction mixture was taken up in hexane (50 ml) and washed with 10 percent sodium hydroxide (2 x 50 ml) and saturated sodium chloride (50 ml).
- the organic phase was dried over anhydrous magnesium sulfate and charcoal. Evaporation of the volatiles yielded a colorless liquid which was purified by flash chromatography over silica gel with 2 percent ethyl acetate in hexane as eluant to afford the desired product as an oil.
- Example 9(a) is converted to the desired product.
- the following compounds are prepared according to the general methods described above from the appropriately substituted hydroxybenzaldehyde and the appropriate alkyl halide:
- 2-(2-Dodecylthiophenyl)-2-[(l -carboxymethyl-5- tetrazolyl)thio]acetic acid is prepared from 2-(dodecyl- thio)benzaldehyde.
- 2-(2-He ⁇ tylthio ⁇ henyl)-2-[(l -carboxymethyl-5- tetrazolyl)thio] acetic acid is prepared from 2-(heptylthio)benzaldehyde.
- Example 5(c) through 5(g) the compound of Example 10(a) is converted to the desired product.
- Example 12(b) To a solution of 10% sodium hydroxide (50 ml), methanol (12 ml) and ethylene glycol dimethyl ether is added the compound of Example 12(b) (93.9 mmol). The mixture is stirred for 24 hours at 25°C. The reaction mixture is then cooled in an ice-methanol bath to 0°C and is acidified with hydrochloric acid to pH 3.5, is extracted with diethyl ether, is dried over magnesium sulfate, filtered and evaporated. The resulting mixture of isomers is flash chromatographed on silica, and eluted with 30% ethyl acetate in hexane, to give the product.
- Example 7(a) The compound of Example 7(a) (2.94 g, 10 mmol) was dissolved in diethyl ether (25 ml) and the solution was stirred under argon at 0°C. Methyl chloroacetate (1.32 ml, 15 mmol) was added, followed by the addition of sodium methoxide (810 mg, 15 mmol). The mixture was stirred for 2.5 hours at ice bath temperature. A small quantity of water was added, the ether phase separated, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was flash chromatographed on 80 grams of silica gel eluted with 5-30% ethyl acetate/hexane to give the product. fc) Methyl 3-r2-f8-phenyloctyl)phenyll-3-rri -f3-carboxypropyl-5- tetrazolyll thiol -2-hydroxypropionate
- Example 13(c) The compound of Example 13(c) (549 mg, 1.5 mmol) was dissolved in methanol (6 ml) containing 2% triethylamine and the solution was stirred under argon at room temperature.
- the 5- mercapto-l -(3-carboxypropyl)tetrazole (282 mg, 1.5 mmol) and triethylamine (0.84 ml, 6 mmol) were dissolved in methanol (9 ml) and added dropwise to the reaction mixture which was then stirred for 5 days at room temperature.
- Example 14(a) The methyl 2,3-epoxy-3-[2-(8-phenyloctyl)-phenyl]propanoate (0.4g) of Example 14(a) was dissolved in 5 ml of methanol containing 2% triethylamine under an argon atmosphere. The reaction mixture was cooled using an ice/methanol bath. A solution of 0.205 g of 5- mercapto-1-carbethoxymethyltetrazole and 0.61 ml of triethylamine in 5 ml of methanol containing 2% triethylamine was added. The bath was removed and the reaction was permitted to warm to room temperature.
- Example 14(b) The methyl 2-hydroxy-3-[(l-carboxymethyl-5-tetrazolyl)thio]- propanoate (0.45 g) of Example 14(b) was dissolved in methanol (6.6 ml) and cooled with an ice and methanol bath to which was added 3.3 ml of a 4% solution of sodium hydroxide. The bath was removed and reaction permitted to warm to room temperature overnight. The methanol was then stripped, and the residue was diluted with dilute hydrochloric acid. Extraction with ethyl acetate was followed by drying over magnesium sulfate, filtration, and evaporation. The crude product was flash chromatographed on silica with 30-50% ethyl acetate/hexane. The column was washed with 100% methanol. 40 mg of desired product was recovered.
- Example 5(d) The compound of Example 5(d) (744 mg, 2 mmol) is dissolved in 25 ml of methylene chloride and stirred under argon at room temperature.
- Ethyl 5-mercapto-l,3,4-thiadiazole-2-carboxylate (380 mg. 2 mmol) and triethylamine (0.84 ml, 6 mmol) is dissolved in 25 ml of methylene chloride and added to the solution of the compound of Example 5(d). The mixture is stirred under argon for 48 hours. The solvent is evaporated, and the residue is flash chromatographed on silica gel eluted with ethyl acetate/hexane to give the product.
- Example 16(a) The compound of Example 16(a) (526 mg, 1 mmol) is dissolved in 10 ml of methanol and stirred under argon in an ice bath. A IN solution of sodium hydroxide (4 ml, 4 mmol) is added. The ice bath is removed and the mixture is stirred for 24 hours at room temperature. The solvent is evaporated, the residue cooled in an ice bath, acidified with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated to give the product.
- Example 17(a) The compound of Example 17(a) (494 mg, 1 mmol) is dissolved in 10 ml of methanol and stirred under argon in an ice bath. A IN solution of sodium hydroxide (4 ml, 4 mmol) is added. The ice bath is removed and the mixture is stirred for 24 hours at room temperature. The solvent is evaporated, the residue cooled in an ice bath, acidified with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated to give the product.
- EXAMPLE 18 Preparation of 3-r2-(6-thiophenoxyhexylthio)phenyll- 3-rri -f3-carboxypropyl)-5-tetrazolynthio1-2- hydroxypropanoic acid fa) Preparation of 2-f6-thiophenoxyhexylthio)benzoic acid Thiosalicylic acid (1.2 g, 0.008 mole) and 6-thio- phenoxyhexylbromide (2.5 g, 0.009 mole) are dissolved in dimethylformamide (50 ml) and the solution is stirred under argon. Potassium carbonate (1.5 g, 0.011 mole) is added carefully to the reaction.
- Example 18(c) The compound of Example 18(c) (10 mmol) is dissolved in diethyl ether (25 ml) and the solution is stirred under argon at 0°C. Methyl chloroacetate (15 mmol) is added followed by the addition of sodium methoxide (15 mmol). The mixture is stirred for 2.5 hours at ice bath temperature. A small quantity of water is added, the ether phase is separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue is flash chromatographed on 80 grams of silica gel eluted with 5-30% ethylacetate/hexane to give the product. fe) Methyl 3-r2-f6-thiophenoxyhexylthio)phenyl1-3-rri -f3- carboxypropyl-5-tetrazolvnthio1-2-hvdroxypropionate
- Example 18(d) The compound of Example 18(d) (1.5 mmol) is dissolved in methanol (6 ml) containing 2% triethylamine and the solution is stirred under argon at room temperature.
- 5-Mercapto-l-(3- carboxypropyl)tetrazole (1.5 mmol) and triethylamine (6 mmol) are dissolved in methanol (9 ml) and are added dropwise to the reaction mixture which is then stirred for 5 days at room temperature.
- the solvent is stripped and the residue is flash chromatographed on .50 grams of silica gel eluted with 70:30:1 (hexane: ethylacetate: formic acid) to give the desired product.
- EXAMPLE 22 As a specific embodiment of a composition of this invention, an active ingredient, such as the compound of Example 4, 13, or 14 is dissolved in isotonic saline at a concentration of 1 to 10 mg/ml and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired aerosolized weight of drug.
- EXAMPLE 23 As an additional embodiment of a composition of this invention 100 to 1000 mg of an active ingredient, such as the compound of
- Example 4 13, or 14 is combined with 4 mg of chlorpheniramine maleate with a suitable carrier or excipient.
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Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP91511751A JPH05507716A (en) | 1990-06-06 | 1991-06-04 | leukotriene antagonist |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US53398990A | 1990-06-06 | 1990-06-06 | |
US533,989 | 1990-06-06 |
Publications (1)
Publication Number | Publication Date |
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WO1991018889A1 true WO1991018889A1 (en) | 1991-12-12 |
Family
ID=24128254
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1991/003922 WO1991018889A1 (en) | 1990-06-06 | 1991-06-04 | Leukotriene antagonists |
Country Status (5)
Country | Link |
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EP (1) | EP0532674A4 (en) |
JP (1) | JPH05507716A (en) |
AU (1) | AU8208391A (en) |
CA (1) | CA2083610A1 (en) |
WO (1) | WO1991018889A1 (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4138410A (en) * | 1974-07-24 | 1979-02-06 | Firmenich & Cie | Flavoring agent |
US4174405A (en) * | 1974-02-25 | 1979-11-13 | Uniroyal, Inc. | Thiophenes useful in control of acarids |
US4536595A (en) * | 1981-09-21 | 1985-08-20 | Montedison S.P.A. | Process for the preparation of alpha-aryl-propionic acids and alkaline salts thereof |
US4609744A (en) * | 1983-04-21 | 1986-09-02 | Merck Frosst Canada Inc. | 4-oxo-benzopyran carboxylic acids |
US4833161A (en) * | 1987-01-13 | 1989-05-23 | Boehringer Mannheim Gmbh | Carboxylic acid derivatives and pharmaceutical compositions and uses |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1334200C (en) * | 1987-06-24 | 1995-01-31 | James Simpson Frazee | Leukotriene antagonists |
PT87616B (en) * | 1987-06-24 | 1992-09-30 | Smithkline Beecham Corp | PREPARATION PROCESS OF LEUCOTYREN ANTAGONISTS AND PHARMACEUTICAL COMPOSITIONS |
US4996214A (en) * | 1990-06-28 | 1991-02-26 | Smithkline Beecham Corporation | Quinolinyl substituted phenyl/thioalkanoic acid substituted propionic acids and leucotriene antagonist use thereof |
-
1991
- 1991-06-04 CA CA002083610A patent/CA2083610A1/en not_active Abandoned
- 1991-06-04 AU AU82083/91A patent/AU8208391A/en not_active Abandoned
- 1991-06-04 WO PCT/US1991/003922 patent/WO1991018889A1/en not_active Application Discontinuation
- 1991-06-04 JP JP91511751A patent/JPH05507716A/en active Pending
- 1991-06-04 EP EP19910912310 patent/EP0532674A4/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4174405A (en) * | 1974-02-25 | 1979-11-13 | Uniroyal, Inc. | Thiophenes useful in control of acarids |
US4138410A (en) * | 1974-07-24 | 1979-02-06 | Firmenich & Cie | Flavoring agent |
US4536595A (en) * | 1981-09-21 | 1985-08-20 | Montedison S.P.A. | Process for the preparation of alpha-aryl-propionic acids and alkaline salts thereof |
US4609744A (en) * | 1983-04-21 | 1986-09-02 | Merck Frosst Canada Inc. | 4-oxo-benzopyran carboxylic acids |
US4833161A (en) * | 1987-01-13 | 1989-05-23 | Boehringer Mannheim Gmbh | Carboxylic acid derivatives and pharmaceutical compositions and uses |
Non-Patent Citations (2)
Title |
---|
DERWENT PATENT ABSTRACT, 84-014267/03 of Japanese Patent Application 58206556A, published 01 December 1983. * |
See also references of EP0532674A4 * |
Also Published As
Publication number | Publication date |
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EP0532674A4 (en) | 1993-04-07 |
CA2083610A1 (en) | 1991-12-07 |
AU8208391A (en) | 1991-12-31 |
JPH05507716A (en) | 1993-11-04 |
EP0532674A1 (en) | 1993-03-24 |
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