JPH0680630A - Heterocyclic carboxylic acid and ester - Google Patents
Heterocyclic carboxylic acid and esterInfo
- Publication number
- JPH0680630A JPH0680630A JP3037822A JP3782291A JPH0680630A JP H0680630 A JPH0680630 A JP H0680630A JP 3037822 A JP3037822 A JP 3037822A JP 3782291 A JP3782291 A JP 3782291A JP H0680630 A JPH0680630 A JP H0680630A
- Authority
- JP
- Japan
- Prior art keywords
- diphenyl
- methyl
- compound
- formula
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 Heterocyclic carboxylic acid Chemical class 0.000 title claims abstract description 46
- 150000002148 esters Chemical class 0.000 title description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 229910001413 alkali metal ion Inorganic materials 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims description 53
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 230000029936 alkylation Effects 0.000 claims description 9
- 238000005804 alkylation reaction Methods 0.000 claims description 9
- 230000003301 hydrolyzing effect Effects 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 5
- NWPUVGNLWQLUKD-UHFFFAOYSA-N methyl 9-(3-oxo-5,6-diphenyl-1,2,4-triazin-2-yl)nonanoate Chemical compound C=1C=CC=CC=1C1=NC(=O)N(CCCCCCCCC(=O)OC)N=C1C1=CC=CC=C1 NWPUVGNLWQLUKD-UHFFFAOYSA-N 0.000 claims description 4
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims description 4
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 claims description 4
- JTAFRNFLENEPEL-UHFFFAOYSA-N 2-[3-[2-(1,5-diphenylpyrazol-3-yl)ethyl]phenoxy]acetic acid Chemical compound OC(=O)COC1=CC=CC(CCC2=NN(C(C=3C=CC=CC=3)=C2)C=2C=CC=CC=2)=C1 JTAFRNFLENEPEL-UHFFFAOYSA-N 0.000 claims description 3
- VQDRTTRRUCUPAA-UHFFFAOYSA-N 2-[3-[2-(4,5-diphenylpyrazol-1-yl)ethyl]phenoxy]acetic acid Chemical compound OC(=O)COC1=CC=CC(CCN2C(=C(C=N2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 VQDRTTRRUCUPAA-UHFFFAOYSA-N 0.000 claims description 3
- 230000002152 alkylating effect Effects 0.000 claims description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- PKMYZACWHIHDII-UHFFFAOYSA-N 2-(6-oxo-3,4-diphenylpyridazin-1-yl)octanoic acid Chemical compound C=1C=CC=CC=1C1=CC(=O)N(C(C(O)=O)CCCCCC)N=C1C1=CC=CC=C1 PKMYZACWHIHDII-UHFFFAOYSA-N 0.000 claims description 2
- ACBOOXYWGJKRIY-UHFFFAOYSA-N 2-[3-[(4,5-diphenyl-1h-imidazol-2-yl)sulfanylmethyl]phenoxy]acetic acid Chemical compound OC(=O)COC1=CC=CC(CSC=2NC(=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 ACBOOXYWGJKRIY-UHFFFAOYSA-N 0.000 claims description 2
- BTFRTIRRPBIYAG-UHFFFAOYSA-N 2-[3-[2-(3,4-diphenylpyrazol-1-yl)ethyl]phenoxy]acetic acid Chemical compound OC(=O)COC1=CC=CC(CCN2N=C(C(=C2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 BTFRTIRRPBIYAG-UHFFFAOYSA-N 0.000 claims description 2
- GMTAWLUJHGIUPU-UHFFFAOYSA-N 4,5-diphenyl-1,3-dihydroimidazole-2-thione Chemical compound N1C(S)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 GMTAWLUJHGIUPU-UHFFFAOYSA-N 0.000 claims description 2
- JJFHTUZAYUEGQL-UHFFFAOYSA-N 9-(2,5-dioxo-3,4-diphenylimidazolidin-1-yl)nonanoic acid Chemical compound O=C1N(CCCCCCCCC(=O)O)C(=O)C(C=2C=CC=CC=2)N1C1=CC=CC=C1 JJFHTUZAYUEGQL-UHFFFAOYSA-N 0.000 claims description 2
- SNVVMDBDEZIAKH-UHFFFAOYSA-N 9-(3,4-diphenylpyrrol-1-yl)nonanoic acid Chemical compound C=1N(CCCCCCCCC(=O)O)C=C(C=2C=CC=CC=2)C=1C1=CC=CC=C1 SNVVMDBDEZIAKH-UHFFFAOYSA-N 0.000 claims description 2
- NTNDYCYJNIXYJP-UHFFFAOYSA-N 9-(5-benzhydryl-2,3-dihydrotetrazol-1-yl)nonanoic acid Chemical compound OC(=O)CCCCCCCCN1NNN=C1C(C=1C=CC=CC=1)C1=CC=CC=C1 NTNDYCYJNIXYJP-UHFFFAOYSA-N 0.000 claims description 2
- ZAPJIEOEJFTHQJ-UHFFFAOYSA-N 9-(6-oxo-3,4-diphenylpyridazin-1-yl)nonanoic acid Chemical compound C=1C=CC=CC=1C1=CC(=O)N(CCCCCCCCC(=O)O)N=C1C1=CC=CC=C1 ZAPJIEOEJFTHQJ-UHFFFAOYSA-N 0.000 claims description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims 3
- PKCRGGXGBNRQMW-UHFFFAOYSA-N 2-[3-[2-(6-oxo-3,4-diphenylpyridazin-1-yl)ethyl]phenoxy]acetic acid Chemical compound OC(=O)COC1=CC=CC(CCN2C(C=C(C(C=3C=CC=CC=3)=N2)C=2C=CC=CC=2)=O)=C1 PKCRGGXGBNRQMW-UHFFFAOYSA-N 0.000 claims 1
- NQCBLSGKNOFTMV-UHFFFAOYSA-N 9-(5-benzhydryltetrazol-2-yl)nonanoic acid Chemical compound OC(=O)CCCCCCCCN1N=NC(C(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 NQCBLSGKNOFTMV-UHFFFAOYSA-N 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 210000001772 blood platelet Anatomy 0.000 abstract description 13
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 abstract description 8
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 abstract description 8
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 8
- 230000002776 aggregation Effects 0.000 abstract description 7
- 238000004220 aggregation Methods 0.000 abstract description 6
- 102000008186 Collagen Human genes 0.000 abstract description 5
- 108010035532 Collagen Proteins 0.000 abstract description 5
- 229920001436 collagen Polymers 0.000 abstract description 5
- 239000003112 inhibitor Substances 0.000 abstract description 5
- 210000002966 serum Anatomy 0.000 abstract description 5
- IULRSOQGCBWJFQ-UHFFFAOYSA-N 2-[3-[2-(4,5-diphenyl-1,3-thiazol-2-yl)ethyl]phenoxy]acetic acid Chemical compound OC(=O)COC1=CC=CC(CCC=2SC(=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 IULRSOQGCBWJFQ-UHFFFAOYSA-N 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 120
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 88
- 239000000203 mixture Substances 0.000 description 88
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- 239000000243 solution Substances 0.000 description 49
- 238000004458 analytical method Methods 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 150000002009 diols Chemical class 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
- 239000003921 oil Substances 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- 239000002253 acid Substances 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 238000002844 melting Methods 0.000 description 23
- 230000008018 melting Effects 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 239000000284 extract Substances 0.000 description 21
- 229910052938 sodium sulfate Inorganic materials 0.000 description 21
- 235000011152 sodium sulphate Nutrition 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- 239000003480 eluent Substances 0.000 description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 10
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
- 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 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- 230000000202 analgesic effect Effects 0.000 description 9
- 239000012312 sodium hydride Substances 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- 150000003217 pyrazoles Chemical class 0.000 description 8
- 229910052783 alkali metal Inorganic materials 0.000 description 7
- 230000003110 anti-inflammatory effect Effects 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- WBDSXISQIHMTGL-UHFFFAOYSA-N 2-methyl-4,5-diphenyl-1h-imidazole Chemical compound N1C(C)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 WBDSXISQIHMTGL-UHFFFAOYSA-N 0.000 description 6
- 230000002785 anti-thrombosis Effects 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- ZFYWCVZNRMSXBT-UHFFFAOYSA-N 2-methyl-4,5-diphenyl-1,3-thiazole Chemical compound S1C(C)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 ZFYWCVZNRMSXBT-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 5
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 150000007979 thiazole derivatives Chemical class 0.000 description 4
- CVBUKMMMRLOKQR-UHFFFAOYSA-N 1-phenylbutane-1,3-dione Chemical compound CC(=O)CC(=O)C1=CC=CC=C1 CVBUKMMMRLOKQR-UHFFFAOYSA-N 0.000 description 3
- IXUSMEFHLXSTAV-UHFFFAOYSA-N 3,4-diphenyl-1h-pyridazin-6-one Chemical compound C=1C=CC=CC=1C1=NNC(=O)C=C1C1=CC=CC=C1 IXUSMEFHLXSTAV-UHFFFAOYSA-N 0.000 description 3
- VTLIICNKSDEWAY-UHFFFAOYSA-N 3-[2-(1,5-diphenylpyrazol-3-yl)ethyl]phenol Chemical compound OC1=CC=CC(CCC2=NN(C(C=3C=CC=CC=3)=C2)C=2C=CC=CC=2)=C1 VTLIICNKSDEWAY-UHFFFAOYSA-N 0.000 description 3
- DHCIDABYVHTUDK-UHFFFAOYSA-N 3-[2-(4,5-diphenyl-1,3-thiazol-2-yl)ethyl]phenol Chemical compound OC1=CC=CC(CCC=2SC(=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 DHCIDABYVHTUDK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000001754 anti-pyretic effect Effects 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- YOCZMPDLYNJAOQ-UHFFFAOYSA-N methyl 2-[3-[2-(1,5-diphenylpyrazol-3-yl)ethyl]phenoxy]acetate Chemical compound COC(=O)COC1=CC=CC(CCC2=NN(C(C=3C=CC=CC=3)=C2)C=2C=CC=CC=2)=C1 YOCZMPDLYNJAOQ-UHFFFAOYSA-N 0.000 description 3
- UEWKXXYDRZHKCR-UHFFFAOYSA-N methyl 9-bromononanoate Chemical compound COC(=O)CCCCCCCCBr UEWKXXYDRZHKCR-UHFFFAOYSA-N 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 3
- 229940067157 phenylhydrazine Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 150000003557 thiazoles Chemical class 0.000 description 3
- PXWJTOHJADWQQO-UHFFFAOYSA-N 2-(1h-pyrazol-4-yl)acetic acid Chemical compound OC(=O)CC=1C=NNC=1 PXWJTOHJADWQQO-UHFFFAOYSA-N 0.000 description 2
- GPURFBUGAZAPOV-UHFFFAOYSA-N 2-[3-[2-(3-oxo-5,6-diphenyl-1,2,4-triazin-2-yl)ethyl]phenoxy]acetic acid Chemical compound OC(=O)COC1=CC=CC(CCN2C(N=C(C(C=3C=CC=CC=3)=N2)C=2C=CC=CC=2)=O)=C1 GPURFBUGAZAPOV-UHFFFAOYSA-N 0.000 description 2
- WZVZDYPLNSASBJ-UHFFFAOYSA-N 3-[2-[1-(1-ethoxyethyl)-4,5-diphenylimidazol-2-yl]ethyl]phenol Chemical compound N=1C(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)N(C(C)OCC)C=1CCC1=CC=CC(O)=C1 WZVZDYPLNSASBJ-UHFFFAOYSA-N 0.000 description 2
- UIQOZVSFTPSBEC-UHFFFAOYSA-N 5,6-diphenyl-1h-pyrimidin-2-one Chemical compound C=1C=CC=CC=1C=1NC(=O)N=CC=1C1=CC=CC=C1 UIQOZVSFTPSBEC-UHFFFAOYSA-N 0.000 description 2
- OOFAFONRKNONDB-UHFFFAOYSA-N 5-[3-[tert-butyl(dimethyl)silyl]oxyphenyl]-1-phenylpentane-1,3-dione Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(CCC(=O)CC(=O)C=2C=CC=CC=2)=C1 OOFAFONRKNONDB-UHFFFAOYSA-N 0.000 description 2
- FTLSAYRDWMBGCQ-UHFFFAOYSA-N 5-benzhydryl-2h-tetrazole Chemical compound C1=CC=CC=C1C(C=1C=CC=CC=1)C1=NN=NN1 FTLSAYRDWMBGCQ-UHFFFAOYSA-N 0.000 description 2
- AQOVWACWKGWMMS-UHFFFAOYSA-N 9-(2-oxo-4,5-diphenylpyrimidin-1-yl)nonanoic acid Chemical compound C=1C=CC=CC=1C1=NC(=O)N(CCCCCCCCC(=O)O)C=C1C1=CC=CC=C1 AQOVWACWKGWMMS-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- UKWRSXOKBHFHTQ-UHFFFAOYSA-N [3-(bromomethyl)phenoxy]-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(CBr)=C1 UKWRSXOKBHFHTQ-UHFFFAOYSA-N 0.000 description 2
- 239000000538 analytical sample Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 125000005594 diketone group Chemical group 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 150000001469 hydantoins Chemical class 0.000 description 2
- 150000002461 imidazolidines Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000000749 insecticidal effect Effects 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BCFSCRYDGMJHBA-UHFFFAOYSA-N methyl 2-(6-oxo-3,4-diphenylpyridazin-1-yl)octanoate Chemical compound C=1C=CC=CC=1C1=CC(=O)N(C(C(=O)OC)CCCCCC)N=C1C1=CC=CC=C1 BCFSCRYDGMJHBA-UHFFFAOYSA-N 0.000 description 2
- QPAJJQWPOWUYPL-UHFFFAOYSA-N methyl 2-[3-(2-hydroxyethyl)phenoxy]acetate Chemical compound COC(=O)COC1=CC=CC(CCO)=C1 QPAJJQWPOWUYPL-UHFFFAOYSA-N 0.000 description 2
- QNKHEEFYAMXRIM-UHFFFAOYSA-N methyl 2-[3-[2-(4,5-diphenyl-1,3-thiazol-2-yl)ethyl]phenoxy]acetate Chemical compound COC(=O)COC1=CC=CC(CCC=2SC(=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 QNKHEEFYAMXRIM-UHFFFAOYSA-N 0.000 description 2
- SLQWKDZPVUEJSW-UHFFFAOYSA-N methyl 2-[3-[2-(4,5-diphenyl-1h-imidazol-2-yl)ethyl]phenoxy]acetate Chemical compound COC(=O)COC1=CC=CC(CCC=2NC(=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SLQWKDZPVUEJSW-UHFFFAOYSA-N 0.000 description 2
- IKVMLDFJXLSOQQ-UHFFFAOYSA-N methyl 2-[3-[2-(4,5-diphenylpyrazol-1-yl)ethyl]phenoxy]acetate Chemical compound COC(=O)COC1=CC=CC(CCN2C(=C(C=N2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 IKVMLDFJXLSOQQ-UHFFFAOYSA-N 0.000 description 2
- JPUVQCBPRXXSMF-UHFFFAOYSA-N methyl 2-[3-[2-(5-benzhydryltetrazol-2-yl)ethyl]phenoxy]acetate Chemical compound COC(=O)COC1=CC=CC(CCN2N=C(N=N2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 JPUVQCBPRXXSMF-UHFFFAOYSA-N 0.000 description 2
- IZIJRYNUYQXBPG-UHFFFAOYSA-N methyl 8-bromooctanoate Chemical compound COC(=O)CCCCCCCBr IZIJRYNUYQXBPG-UHFFFAOYSA-N 0.000 description 2
- PLAUBLRLPDFUAH-UHFFFAOYSA-N methyl 9-(2-oxo-4,5-diphenylpyrimidin-1-yl)nonanoate Chemical compound C=1C=CC=CC=1C1=NC(=O)N(CCCCCCCCC(=O)OC)C=C1C1=CC=CC=C1 PLAUBLRLPDFUAH-UHFFFAOYSA-N 0.000 description 2
- HWYCHLJLIFOYPO-UHFFFAOYSA-N methyl 9-(3,4-diphenylpyrrol-1-yl)nonanoate Chemical compound C=1N(CCCCCCCCC(=O)OC)C=C(C=2C=CC=CC=2)C=1C1=CC=CC=C1 HWYCHLJLIFOYPO-UHFFFAOYSA-N 0.000 description 2
- NOJYSKNVTXELNL-UHFFFAOYSA-N methyl 9-(6-oxo-3,4-diphenylpyridazin-1-yl)nonanoate Chemical compound C=1C=CC=CC=1C1=CC(=O)N(CCCCCCCCC(=O)OC)N=C1C1=CC=CC=C1 NOJYSKNVTXELNL-UHFFFAOYSA-N 0.000 description 2
- RIZOOQYPYGPBOC-UHFFFAOYSA-N methyl 9-hydroxynonanoate Chemical compound COC(=O)CCCCCCCCO RIZOOQYPYGPBOC-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000001732 thrombotic effect Effects 0.000 description 2
- BDGMEPAZTWBSPP-UHFFFAOYSA-N 1,5-diphenylimidazolidine-2,4-dione Chemical compound O=C1NC(=O)N(C=2C=CC=CC=2)C1C1=CC=CC=C1 BDGMEPAZTWBSPP-UHFFFAOYSA-N 0.000 description 1
- WMCLPCKMYDDDNA-UHFFFAOYSA-N 1-(1-ethoxyethyl)-2-methyl-4,5-diphenylimidazole Chemical compound CCOC(C)N1C(C)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 WMCLPCKMYDDDNA-UHFFFAOYSA-N 0.000 description 1
- KIOJMSCRODLEKL-UHFFFAOYSA-N 1-(1-ethoxyethyl)imidazole Chemical compound CCOC(C)N1C=CN=C1 KIOJMSCRODLEKL-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- CTVRFYFPNWXBDN-UHFFFAOYSA-N 1h-imidazole;prop-2-enal Chemical class C=CC=O.C1=CNC=N1 CTVRFYFPNWXBDN-UHFFFAOYSA-N 0.000 description 1
- KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical class OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 description 1
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 description 1
- GRWAIJBHBCCLGS-UHFFFAOYSA-N 2-(tetrazol-1-yl)acetic acid Chemical class OC(=O)CN1C=NN=N1 GRWAIJBHBCCLGS-UHFFFAOYSA-N 0.000 description 1
- BAURRIVAQPOGJL-UHFFFAOYSA-N 2-[2-(4-chlorophenyl)-1,3-thiazol-4-yl]propanoic acid Chemical compound OC(=O)C(C)C1=CSC(C=2C=CC(Cl)=CC=2)=N1 BAURRIVAQPOGJL-UHFFFAOYSA-N 0.000 description 1
- YVBKNRIVEUWTEA-UHFFFAOYSA-N 2-[3-(1h-pyrazol-5-yl)phenoxy]acetic acid Chemical class OC(=O)COC1=CC=CC(C=2NN=CC=2)=C1 YVBKNRIVEUWTEA-UHFFFAOYSA-N 0.000 description 1
- ZZEMCPSIAITLLC-UHFFFAOYSA-N 2-[3-[2-(4,5-diphenyl-1h-imidazol-2-yl)ethyl]phenoxy]acetic acid Chemical compound OC(=O)COC1=CC=CC(CCC=2NC(=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 ZZEMCPSIAITLLC-UHFFFAOYSA-N 0.000 description 1
- ZCBLTLSXWCDXBL-UHFFFAOYSA-N 2-[3-[2-(5-benzhydryltetrazol-2-yl)ethyl]phenoxy]acetic acid Chemical compound OC(=O)COC1=CC=CC(CCN2N=C(N=N2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 ZCBLTLSXWCDXBL-UHFFFAOYSA-N 0.000 description 1
- YWPLWDGXYMKCJR-UHFFFAOYSA-N 3,4-diphenyl-1h-pyrrole Chemical compound C=1NC=C(C=2C=CC=CC=2)C=1C1=CC=CC=C1 YWPLWDGXYMKCJR-UHFFFAOYSA-N 0.000 description 1
- DYASQUCCIHXBLN-UHFFFAOYSA-N 4,5-bis(4-methoxyphenyl)-2-(1h-pyrrol-2-yl)-1,3-thiazole Chemical class C1=CC(OC)=CC=C1C1=C(C=2C=CC(OC)=CC=2)SC(C=2NC=CC=2)=N1 DYASQUCCIHXBLN-UHFFFAOYSA-N 0.000 description 1
- YIBZNWWZBYIYDE-UHFFFAOYSA-N 4,5-diphenyl-1-sulfanylimidazole Chemical compound SN1C=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 YIBZNWWZBYIYDE-UHFFFAOYSA-N 0.000 description 1
- MQWYZELNDPRANJ-UHFFFAOYSA-N 4,5-diphenyl-1h-pyrazole Chemical compound C1=NNC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 MQWYZELNDPRANJ-UHFFFAOYSA-N 0.000 description 1
- FHDAQQSVIKNISU-UHFFFAOYSA-N 4,5-diphenyl-1h-pyridazin-6-one Chemical class C=1C=CC=CC=1C=1C(=O)NN=CC=1C1=CC=CC=C1 FHDAQQSVIKNISU-UHFFFAOYSA-N 0.000 description 1
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 1
- XEGRKZRPTBNSMN-UHFFFAOYSA-N 9-bromononanoic acid Chemical compound OC(=O)CCCCCCCCBr XEGRKZRPTBNSMN-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- GCSVCUMDOQKEMT-UHFFFAOYSA-N butan-1-amine;hydrofluoride Chemical compound [H+].[F-].CCCCN GCSVCUMDOQKEMT-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- TZMFJUDUGYTVRY-UHFFFAOYSA-N ethyl methyl diketone Natural products CCC(=O)C(C)=O TZMFJUDUGYTVRY-UHFFFAOYSA-N 0.000 description 1
- JXMLAPZRDDWRRV-UHFFFAOYSA-N ethyl n-(ethoxycarbonylamino)carbamate Chemical compound CCOC(=O)NNC(=O)OCC JXMLAPZRDDWRRV-UHFFFAOYSA-N 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- PRJKNHOMHKJCEJ-UHFFFAOYSA-N imidazol-4-ylacetic acid Chemical class OC(=O)CC1=CN=CN1 PRJKNHOMHKJCEJ-UHFFFAOYSA-N 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- YNMXTFAHOHLKLI-UHFFFAOYSA-N methyl 2-[3-(chloromethyl)phenoxy]acetate Chemical compound COC(=O)COC1=CC=CC(CCl)=C1 YNMXTFAHOHLKLI-UHFFFAOYSA-N 0.000 description 1
- OUNFNXYODFMBFW-UHFFFAOYSA-N methyl 8-(2-oxo-4,5-diphenylpyrimidin-1-yl)octanoate Chemical compound C=1C=CC=CC=1C1=NC(=O)N(CCCCCCCC(=O)OC)C=C1C1=CC=CC=C1 OUNFNXYODFMBFW-UHFFFAOYSA-N 0.000 description 1
- XAOLNBXXUITDBK-UHFFFAOYSA-N methyl 9-(2,5-dioxo-3,4-diphenylimidazolidin-1-yl)nonanoate Chemical compound O=C1N(CCCCCCCCC(=O)OC)C(=O)C(C=2C=CC=CC=2)N1C1=CC=CC=C1 XAOLNBXXUITDBK-UHFFFAOYSA-N 0.000 description 1
- MUGHPLKZNAQBJR-UHFFFAOYSA-N methyl 9-(5-benzhydryl-2,3-dihydrotetrazol-1-yl)nonanoate Chemical compound COC(=O)CCCCCCCCN1NNN=C1C(C=1C=CC=CC=1)C1=CC=CC=C1 MUGHPLKZNAQBJR-UHFFFAOYSA-N 0.000 description 1
- PIFHIWCCPZIDSS-UHFFFAOYSA-N methyl 9-(5-benzhydryltetrazol-2-yl)nonanoate Chemical compound COC(=O)CCCCCCCCN1N=NC(C(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 PIFHIWCCPZIDSS-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003205 muscle Anatomy 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
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【産業上の利用分野】本発明は一般的にいって薬品およ
びバイオ感染性をもつ複素環炭素化合物およびその製造
法に関する。特に本発明は血小板凝集の防止剤として特
徴のある種々の複素環誘導体に関する。FIELD OF THE INVENTION The present invention relates generally to heterocyclic carbon compounds having drug and bioinfectivity and processes for their preparation. Particularly, the present invention relates to various heterocyclic derivatives characterized as an inhibitor of platelet aggregation.
(1)ピロール化合物 米国特許第3,471,513号には下記の式16をも
つ抗菌性および潰瘍抑止性のカルボン酸が記載されてい
る。(1) Pyrrole Compound US Pat. No. 3,471,513 describes an antibacterial and ulcer-suppressing carboxylic acid having the following formula 16.
【式16】 米国特許第4,336,194号には下記の式17をも
つ殺虫性のカルボン酸エステルが記載されている。[Formula 16] U.S. Pat. No. 4,336,194 describes insecticidal carboxylic acid esters having the formula 17 below.
【式17】 米国特許第4,563,477号は下記の式18をもつ
抗血小板凝集性および鎮痛活性を有するα−(N−ピロ
リル)誘導体酸類が記載されている。[Formula 17] U.S. Pat. No. 4,563,477 describes α- (N-pyrrolyl) derivative acids having antiplatelet-aggregating and analgesic activity having the formula 18 below.
【式18】 米国特許第4,694,018号には下記の式19をも
つ5−リポオキシヂエナーゼ阻止性を有する置換1,5
−ジフェニル−2−ピロールプロピオン酸が記載されて
いる。[Formula 18] U.S. Pat. No. 4,694,018 has 5-lipooxydienase inhibitory substitution 1,5 having the following formula 19:
-Diphenyl-2-pyrrolepropionic acid is described.
【式19】 (2)ピリダジン化合物類 米国特許第2,712,542号には下記の式20をも
つ鎮痛、抗けいれん性、および鎮静活性を有する2−
(3−ピリダゾニル)酢酸が記載されている。[Formula 19] (2) Pyridazine Compounds US Pat. No. 2,712,542 has an analgesic, anticonvulsant, and sedative activity having the following formula 20:
(3-Pyridazonyl) acetic acid is described.
【式20】 米国特許第3,622,576号には向精神薬および鎮
痛活性を有する下記の式21をもつジフェニルピリダゾ
ン類が記載されている。[Formula 20] U.S. Pat. No. 3,622,576 describes diphenylpyridazones having the following formula 21 having psychotropic and analgesic activity.
【式21】 米国特許第4,162,317号には筋肉弛緩活性を有
する下記式22をもつ4,5−ジヒドロ−3−(2H)
−ピリジゾン類のコハク酸エステルが記載されている。[Formula 21] U.S. Pat. No. 4,162,317 discloses 4,5-dihydro-3- (2H) having the formula 22 having muscle relaxing activity.
-Succinates of the pyridizones have been described.
【式22】 (3)トリアジン化合物類 米国特許第4,167,566号には抗血栓性を有する
下記式23の2−プレニル−3−オキソ−5,6−ジア
リール−AS−トリアジン類が記載されている。[Formula 22] (3) Triazine Compounds US Pat. No. 4,167,566 describes 2-prenyl-3-oxo-5,6-diaryl-AS-triazines of the following formula 23 having antithrombotic properties.
【式23】 米国特許第4,318,911号には抗血栓活性をもつ
下記式24の5,6−ジアリール−1,2,4−トリア
ジン類が記載されている。[Formula 23] U.S. Pat. No. 4,318,911 describes 5,6-diaryl-1,2,4-triazines of formula 24 having antithrombotic activity.
【式24】 米国特許第4,511,566号には鎮痛活性を有する
下記式25の2−N−シクロアルキルメチル−3−オキ
ソ−5,6−ジアリール−アズ−トリアジン類が記載さ
れている。[Formula 24] U.S. Pat. No. 4,511,566 describes 2-N-cycloalkylmethyl-3-oxo-5,6-diaryl-az-triazines of formula 25 having analgesic activity.
【式25】 米国特許第4,677,105号には非炎症鎮痛活性を
有する下記式26の2−アルコキシカルボニルアルキル
−3−オキソ−5,6−ジアリール−アズ−トリアジン
類が記載されている。[Formula 25] U.S. Pat. No. 4,677,105 describes 2-alkoxycarbonylalkyl-3-oxo-5,6-diaryl-az-triazines of formula 26 below having non-inflammatory analgesic activity.
【式26】 米国特許第4,851,411号には抗不安または抗う
つ活性をもつ下記式28の5−モノアリール−アズ−ト
リアジン−3−オン類が記載されている。[Formula 26] US Pat. No. 4,851,411 describes 5-monoaryl-azu-triazin-3-ones of formula 28 having anxiolytic or antidepressant activity.
【式27】 (4)ピリミジン化合物類 米国特許第4,486,443号には抗血栓活性をもつ
下記式28のヒダントイン類が記載されている。[Formula 27] (4) Pyrimidine Compounds US Pat. No. 4,486,443 describes hydantoins of the following formula 28 having antithrombotic activity.
【式28】 (5)イミダゾリジン化合物類 米国特許第3,965,114号には抗コリン性および
抗けいれん性を有する下記式29のイミダゾリジン誘導
体が記載されている。[Formula 28] (5) Imidazolidine Compounds U.S. Pat. No. 3,965,114 describes imidazolidine derivatives of the following formula 29 having anticholinergic and anticonvulsant properties.
【式29】 米国特許第4,237,131号には気管支拡張活性を
もつ下記式30のヒダントイン類が記載されている。[Formula 29] U.S. Pat. No. 4,237,131 describes hydantoins of formula 30 having bronchodilator activity.
【式30】 米国特許第4,330,550号には抗血栓性および鎮
痛性をもつ下記式31のオメガ−(2−オキソ−4−イ
ミダゾリン−1−イル)アルカン酸およびエステルが記
載されている。[Formula 30] U.S. Pat. No. 4,330,550 describes omega- (2-oxo-4-imidazolin-1-yl) alkanoic acids and esters of formula 31 having antithrombotic and analgesic properties.
【式31】 米国特許第4,709,042号には下記式32の2−
(1−ヒドロキシアルキル)−5,5−ジフェニル−ヒ
ダントインの製造法が記載されている。[Formula 31] U.S. Pat. No. 4,709,042 describes 2-
A method for producing (1-hydroxyalkyl) -5,5-diphenyl-hydantoin is described.
【式32】 米国特許第4,797,493号には下記式33をもつ
紫外吸収性のイミダゾリン類が記載されている。[Formula 32] U.S. Pat. No. 4,797,493 describes UV absorbing imidazolines having the formula 33 below.
【式33】 (6)テトラゾール化合物類 米国特許第3,453,285号には抗炎症性をもつ下
記式34のテトラゾリルアルカン酸が記載されている。[Formula 33] (6) Tetrazole Compounds US Pat. No. 3,453,285 describes tetrazolyl alkanoic acids of the following formula 34 having anti-inflammatory properties.
【式34】 米国特許第3,962,272号にはセファロスポリン
およびペニシリン抗生物質の製造に有用な下記式35の
1H−テトラゾール−1−アセテートエステルおよび酸
が記載されている。[Formula 34] US Pat. No. 3,962,272 describes 1H-tetrazole-1-acetate esters of formula 35 and acids useful in the preparation of cephalosporins and penicillin antibiotics.
【式35】 米国特許第4,059,703号には殺菌活性をもつ下
記式36のテトラゾール化合物類が記載されている。[Formula 35] U.S. Pat. No. 4,059,703 describes tetrazole compounds of formula 36 below having bactericidal activity.
【式36】 米国特許第4,652,671号には下記式37のジク
ロロイソニトリロカルボン酸エステルの製造法が記載さ
れている。[Formula 36] U.S. Pat. No. 4,652,671 describes a method for producing a dichloroisonitrilolocarboxylic acid ester of formula 37 below.
【式37】 (7)チアゾール化合物類 米国特許第3,506,679号には抗炎症活性をもつ
下記式38をもつ2,5−および4,5−ジアリールチ
アゾリル低級脂肪酸が記載されている。ただし式中のR
3 は2〜6個の炭素原子をもつ直鎖または枝分かれ鎖の
脂肪酸基である。[Formula 37] (7) Thiazole Compounds US Pat. No. 3,506,679 describes 2,5- and 4,5-diaryl thiazolyl lower fatty acids having the following formula 38 having anti-inflammatory activity. However, R in the formula
3 is a straight or branched chain fatty acid radical having 2 to 6 carbon atoms.
【式38】 米国特許第3,538,107号には抗炎症、鎮痛およ
び解熱の活性を有する下記式39のアリール−チアゾリ
ル酢酸誘導体たとえばアルファ−〔2−(4−クロロフ
ェニル)チアゾール−4−イル〕プロピオン酸が記載さ
れている。[Formula 38] U.S. Pat. No. 3,538,107 discloses aryl-thiazolylacetic acid derivatives of formula 39 having anti-inflammatory, analgesic and antipyretic activity, such as alpha- [2- (4-chlorophenyl) thiazol-4-yl] propionic acid. Have been described.
【式39】 米国特許第3,661,920号には抗炎症、鎮痛およ
び解熱の活性をもつ下記式40のチアゾール誘導体が記
載されている。[Formula 39] U.S. Pat. No. 3,661,920 describes thiazole derivatives of formula 40 having anti-inflammatory, analgesic and antipyretic activity.
【式40】 米国特許第3,821,237号には腺維分解性、血小
板粘着減少性および抗潰腫性をもつ下記式41のチアゾ
リル安息香酸化合物類が記載されている。[Formula 40] U.S. Pat. No. 3,821,237 describes thiazolylbenzoic acid compounds of the following formula 41 having fibrinolytic properties, platelet adhesion-reducing properties and antiulcer properties.
【式41】 米国特許第3,840,548号には血栓溶解性をもつ
下記式42のチアゾリル安息香酸化合物類が記載されて
いる。[Formula 41] U.S. Pat. No. 3,840,548 describes thiazolylbenzoic acid compounds of the following formula 42 having thrombolytic properties.
【式42】 米国特許第4,168,315号には血小板の付着性を
減少させた且つ血小板の集塊を阻止する下記式43をも
つジアニシルチアゾール化合物類が記載されている。[Formula 42] U.S. Pat. No. 4,168,315 describes dianisyl thiazole compounds having the following formula 43 that reduce platelet adhesion and prevent platelet clumping.
【式43】 米国特許第4,659,726号には血小板集塊阻止性
をもつ下記式44の4,5−ビス(4−メトキシフェニ
ル)−2 (ピロール−2−イル)チアゾール類が記載さ
れている。[Formula 43] U.S. Pat. No. 4,659,726 describes 4,5-bis (4-methoxyphenyl) -2 (pyrrol-2-yl) thiazoles of the following formula 44 which have platelet aggregation inhibiting properties.
【式44】 米国特許第4,791,124号には殺虫性をもつ下記
式45のオキサゾールおよびチアゾール化合物類が記載
されている。[Formula 44] U.S. Pat. No. 4,791,124 describes oxazole and thiazole compounds of formula 45 having insecticidal properties.
【式45】 (8)イミダゾール化合物類。 米国特許第4,355,040号には昇圧性をもつ下記
式46のイミダゾール−5−酢酸誘導体が記載されてい
る。[Formula 45] (8) Imidazole compounds. U.S. Pat. No. 4,355,040 describes imidazole-5-acetic acid derivatives of the following formula 46 having pressor properties.
【式46】 米国特許第4,460,598号には抗血栓性をもつ下
記式47のトリフェニルイミダゾリルオキシアルカン酸
が記載されている。[Formula 46] U.S. Pat. No. 4,460,598 describes triphenylimidazolyloxyalkanoic acids of formula 47 below having antithrombotic properties.
【式47】 米国特許第4,668,794号には血中コレステロー
ル低下性をもつ下記式48のイミダゾールアクロレイン
類縁体が記載されている。[Formula 47] U.S. Pat. No. 4,668,794 describes imidazole acrolein analogs of formula 48 having blood cholesterol lowering properties.
【式48】 米国特許第4,686,231号には5−リポオキシジ
エナーゼ阻止性をもつ下記式49の4,5−ジアリール
−2 (置換)イミダゾール類が記載されている。[Formula 48] U.S. Pat. No. 4,686,231 describes 4,5-diaryl-2 (substituted) imidazoles of the following formula 49 having 5-lipooxydienase inhibitory properties.
【式49】 (9)ピラゾール化合物類 米国特許第3,704,241号には抗炎症性および鎮
痛性を有する下記式50の4−ピラゾール酢酸またはエ
ステルが記載されている。[Formula 49] (9) Pyrazole Compounds US Pat. No. 3,704,241 describes 4-pyrazole acetic acid or ester of the following formula 50 having anti-inflammatory and analgesic properties.
【式50】 米国特許第4,042,706号には抗炎症性をもつ下
記式51のピラゾール誘導体が記載されている。[Formula 50] U.S. Pat. No. 4,042,706 describes pyrazole derivatives of formula 51 below having anti-inflammatory properties.
【式51】 米国特許第4,146,721号には鎮痛性、抗炎症性
および解熱性を有する下記式52のピラゾール−4−酢
酸類が記載されている。[Formula 51] U.S. Pat. No. 4,146,721 describes pyrazole-4-acetic acids of formula 52 having analgesic, anti-inflammatory and antipyretic properties.
【式52】 米国特許第4,495,195号にはキサンチオキシダ
ーゼ阻止性をもつ下記式53の3 (5)−フェニル置換
−5 (3)−ピラゾール−カルボン酸が記載されてい
る。[Formula 52] U.S. Pat. No. 4,495,195 describes 3 (5) -phenyl-substituted-5 (3) -pyrazole-carboxylic acids of formula 53 having xanthioxidase inhibitory properties.
【式53】 米国特許第4,613,610号にはメバノロラクトン
のコレステロール−バイオ合成阻止性を有する下記式5
4のピラゾール類縁体が記載されている。[Formula 53] U.S. Pat. No. 4,613,610 discloses the following formula 5 which has cholesterol-biosynthesis inhibitory property of mevanololactone.
Four pyrazole analogs have been described.
【式54】 米国特許第4,826,868号にはシクロオキシジエ
ナーゼ酵素およびノポオキシジエナーゼ酵素の活性を阻
止する下記式55の1,5−ジアリール−3−置換ピラ
ゾール類が記載されている。[Formula 54] U.S. Pat. No. 4,826,868 describes 1,5-diaryl-3-substituted pyrazoles of formula 55 which block the activity of cyclooxydienase and nopooxydienase enzymes.
【式55】 米国特許第3,853,404号には利尿活性をもつ下
記式56の5−ピラゾリルフェノキシ酢酸類が記載され
ている。[Formula 55] US Pat. No. 3,853,404 describes 5-pyrazolylphenoxyacetic acids of the following formula 56 having diuretic activity.
【式56】 米国特許第4,870,095号には抗不整脈活性をも
つ下記式57の1H−ピラゾール−1−アルカナミド類
が記載されている。[Formula 56] U.S. Pat. No. 4,870,095 describes 1H-pyrazole-1-alkanamids of formula 57 having antiarrhythmic activity.
【式57】 [Formula 57]
【発明が解決しようとする課題】HET1 −(CH2 )
n CO2 Rおよび下記の式5で表わされる複素環カルボ
ン酸類およびエステル類を提供しようとするものであ
る。[Problems to be Solved by the Invention] HET 1- (CH 2 )
It is intended to provide n CO 2 R and heterocyclic carboxylic acids and esters represented by the following formula 5.
【式5】ただし上記式中、HET1 、HET2 、R、R
1 およびnは後に定義するものとする。これらの化合物
はアデノシン・ジホスフェートおよびコラーゲン誘起の
ヒト血小板富化血清集塊の阻止剤であり、哺乳動物血液
の血小板集塊の阻止剤として特に有用である。本発明の
別の態様は上記のHET1 −(CH2 )n CO2 R(た
だしRは水素である)および上記の式5(ただしR1 は
水素である)のカルボン酸のアルカリ金属塩にも関す
る。もう1つの態様は上記の化合物を医薬的に許容しう
る賦形薬と混合して成る医薬組成物に関する。更にもう
1つの態様はHET1 −(CH2)n CO2 Rの化合物
またはそのアルカリ金属塩(Rが水素である場合)ある
いは上記式5の化合物またはそのアルカリ金属塩(R1
が水素である場合)の治療有効量を治療の必要な哺乳動
物に投与することから成る哺乳動物の血液血小板集塊を
阻止する方法に関する。[Formula 5] In the above formula, HET 1 , HET 2 , R, R
1 and n shall be defined later. These compounds are inhibitors of adenosine diphosphate and collagen-induced human platelet-enriched serum clumping and are particularly useful as inhibitors of mammalian blood platelet clumping. Another aspect of the invention is the use of an HET 1- (CH 2 ) n CO 2 R (where R is hydrogen) as described above and an alkali metal salt of a carboxylic acid of formula 5 (where R 1 is hydrogen) as described above. It also concerns. Another aspect relates to a pharmaceutical composition comprising the above compound in admixture with a pharmaceutically acceptable excipient. Yet another embodiment is a compound of HET 1- (CH 2 ) n CO 2 R or an alkali metal salt thereof (when R is hydrogen) or a compound of the above formula 5 or an alkali metal salt thereof (R 1
Is a hydrogen), and the method comprises the step of administering to a mammal in need thereof a therapeutically effective amount of H).
【課題を解決するための手段】本発明はHET1 −(C
H2 )n CO2 Rを有する哺乳動物血液血小板集塊の阻
止剤に関する。ただしnは6〜9であり、Rは水素、低
級アルキルまたはアルカリ金属イオンであり、HET1
は下記の式1から成る群からえらばれた複素環基であ
る。The present invention relates to HET 1- (C
H 2) related inhibitors of mammalian blood platelet aggregates having n CO 2 R. However, n is 6 to 9, R is hydrogen, lower alkyl or an alkali metal ion, and HET 1
Is a heterocyclic group selected from the group consisting of formula 1 below.
【式1】更に本発明は下記の式5の化合物にも関する。## STR00001 ## The present invention also relates to a compound of formula 5 below.
【式5】ただしR1 は水素、低級アルキルまたはアルカ
リ金属イオンであり、基−OCH2 CO2 R1 は環の3
位または4位に結合しており、そしてHET2 は下記の
式6から成る群からえらばれた複素環基である。Wherein R 1 is hydrogen, lower alkyl or an alkali metal ion, and the group —OCH 2 CO 2 R 1 is a ring 3
HET 2 is a heterocyclic group selected from the group consisting of Formula 6 below.
【式6】「低級アルキル」とは1〜4個の炭素原子を含
む枝分かれした又は枝分かれしていない飽和炭化水素を
いう。特にメチル、エチル、n−プロピル、イソプロピ
ル、n−ブチル、第2級ブチル、および第3級ブチルが
あげられる。「低級アルカノール」とは低級アルキルで
定義した1〜4個の炭素原子をもつアルコールをいう。
「アルカリ金属イオン」とはアルカリ金属、最も好まし
くはナトリウムおよびカリウム、から誘導されるイオン
をいう。本発明によれば、前記HET1 −(CH2 )n
CO2 Rの化合物は次の(a),(b)または(c)の
方法によってえられる。(a)[Formula 6] "Lower alkyl" refers to a branched or unbranched saturated hydrocarbon containing 1-4 carbon atoms. In particular, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, and tertiary butyl are mentioned. "Lower alkanol" refers to an alcohol having 1 to 4 carbon atoms defined by lower alkyl.
"Alkali metal ion" refers to ions derived from alkali metals, most preferably sodium and potassium. According to the invention, said HET 1- (CH 2 ) n
The CO 2 R compound can be obtained by the following method (a), (b) or (c). (A)
【式2】の化合物を加水分解するか、(b)Hydrolyzing the compound of formula 2 or (b)
【式3】の化合物を低級アルカノールでエステル化する
か、またはEsterifying the compound of formula 3 with a lower alkanol, or
【式3】(c) HET1 −H(ただしHET1 は前記
定義のとおりである)を[Formula 3] (c) HET 1 -H (where HET 1 is as defined above)
【式4】の化合物でアルキル化する。下記の式58は前
記の方法を説明するものである。Alkylation with a compound of formula 4 Equation 58 below illustrates the above method.
【式58】 HET1 −(CH2 )n CO2 Rの化合物は式58に示
すようにHET1 −Hをオメガ−ハロゲンアルカン酸の
低級アルカノールでエステル化して中間アルキルエステ
ルHET1 −(CH2 )n CO2 Ra を製造することに
よって製造することができる。アルキル化は好適な溶媒
中の水素化ナトリウム、水素化カリウム、カリウム−t
−ブトキサイドを用いて行なうことができる。好適な溶
媒としてテトラヒドロフランおよびジメチルホルムアミ
ドがあげられる。条件は複素環(HET1 )の性質およ
び置換されるプロトンの酸性度に変じて変わる。好まし
いアルキル化条件は室温でのジメチルホルムアミド(D
MF)中の水素化ナトリウムまたは110℃でのDMF
中の炭酸カリウムを使用する。アルキル化が異性体混合
物をもたらす場合には、分離はシリカゲル上のクロマト
グラフによって容易に達成される。構造確認は 1Hおよ
び13CのNMRスペクトルの考察から行なわれる。出発
材料として使用するHET1 −Hは化学文献に報告され
ている方法によって、または当業者に容易なその変形に
よって合成される。エステル(Ia )すなわちHET1
−(CH2 )n CO2 Ra は複素環の感度に応じて水性
アルカリまたは水性酸のいずれかの影響下に対応する酸
(Ib )HET1 −(CH2 )n CO2 Rに転化され
る。あるいは逆に酸(Ib )は該酸をHCl、H2 SO
4 などの無機酸の存在下で低級アルカノール中で加熱す
ることによって対応するエステル(Ia )に好都合に軟
化される。HET1 −(CH2 )n CO2 Rのカルボン
酸のアルカリ金属塩(Rがアルカリ金属イオンである)
はメタノールのような好適な溶媒中でHET1 −(CH
2)n CO2 Rの酸をとかし、モル当量のアルカリ塩基
たとえばナトリウム−メトキシドの添加し、そして塩を
沈殿させるか、または溶媒を除去することによって製造
される。本発明によれば、前記式5の化合物は(a)[Formula 58] The compound of HET 1- (CH 2 ) n CO 2 R is an intermediate alkyl ester HET 1- (CH 2 ) n CO 2 which is obtained by esterifying HET 1 -H with a lower alkanol of omega-halogenalkanoic acid as shown in formula 58. It can be produced by producing R a . Alkylation is carried out with sodium hydride, potassium hydride, potassium-t in a suitable solvent.
-Can be done with butoxide. Suitable solvents include tetrahydrofuran and dimethylformamide. Conditions will vary depending on the nature of the heterocycle (HET 1 ) and the acidity of the substituted proton. Preferred alkylation conditions are dimethylformamide (D
Sodium hydride in MF) or DMF at 110 ° C
Use potassium carbonate in. If the alkylation results in a mixture of isomers, separation is easily achieved by chromatography on silica gel. Structural confirmation is made from consideration of 1 H and 13 C NMR spectra. The HET 1 -H used as starting material is synthesized by the methods reported in the chemical literature or by modifications thereof which are easy for the person skilled in the art. Ester (I a ) or HET 1
- (CH 2) n CO 2 R a is either the corresponding acid under the influence of aqueous alkaline or aqueous acid, depending on the sensitivity of the heterocyclic (I b) HET 1 - ( CH 2) converted to n CO 2 R To be done. Alternatively, on the contrary, the acid (I b ) is obtained by converting the acid into HCl, H 2 SO
It is conveniently softened to the corresponding ester (I a ) by heating in a lower alkanol in the presence of an inorganic acid such as 4 . HET 1- (CH 2 ) n CO 2 Alkali metal salt of carboxylic acid (R is an alkali metal ion)
(CH - HET 1 is in a suitable solvent such as methanol
2 ) prepared by dissolving the acid of n CO 2 R, adding a molar equivalent of an alkali base such as sodium methoxide, and precipitating the salt or removing the solvent. According to the present invention, the compound of formula 5 is (a)
【式7】の化合物を加水分解するか、(b)Hydrolyzing the compound of formula 7 or (b)
【式8】の化合物(HET2 は前記定義のとおりであ
る)をエステル化するか、(c)HET2 −H(HET
2 は前記定義のとおりである)をA compound of formula 8 (HET 2 is as defined above) is esterified or (c) HET 2 -H (HET 2
2 is as defined above)
【式9】の化合物でアルキル化するか、(d)Alkylation with a compound of formula 9 or (d)
【式10】の化合物をBrCH2 CO2 R1 a (R1 a
は低級アルキルである)でアルキル化するか、または
(e)The compound of formula 10 is converted to BrCH 2 CO 2 R 1 a (R 1 a
Is lower alkyl) or (e)
【式11】の化合物を加水分解する、ことから成ること
を特徴とする方法。式の式59〜式62は上記の方法を
更に具体的に説明するためのものである。Hydrolyzing the compound of formula 11). Expressions 59 to 62 are for explaining the above method more specifically.
【式59】 [Formula 59]
【式60】 [Formula 60]
【式61】 [Equation 61]
【式62】 式58はアリールオキシ酢酸部分を含む化合物の合成に
ついての数種の異なった試みを示すものである。複素環
(1)のブロマイド(2)による、またはアルコール
(5)からえられたトシレート(TS)(3)による直
接アルキル化は室温でのDMF中の水素化ナトリウムに
より、または110℃でのDMF中の炭酸カリウムによ
り達成されてエステル(6)を生じる。別法として、若
干の場合に、複素環(1)とジオール(4)からえたア
ルコール(5)との反応はジエチル・アゾジカルボキシ
レートとトリフェニルホスフィンの存在下で行なわれて
エステル(6)を生じる。この反応はMitsunob
u反応の特徴である温和な条件下で行なわれる。Syn
thesis 1,28 (1981)参照。カルボン酸
(7)はエステル(6)のアルカリ加水分解によってえ
られる。式60はアリールオキシ錯酸の側鎖が炭素に結
合しているチアゾール誘導体(12)および(13)の
合成を示すものである。n−ブチルリチウムによる2−
メチル−4,5−ジフェニルチアゾール(8)の金属化
を行ない、次いでブロマイド(9)による反応を行なっ
てシリルエーテル(10)を製造し、これをテトラ−n
−ブチルアンモニウムフルオライドによって脱プロトン
化してフェノール(11)を得る。フェノール(11)
をメチルブロモアセテートでアルキル化してエーテル
(12)をえて、これを水性アルカリ条件下で加水分解
して酸(13)を得る 式61はアリールオキシ酢酸側鎖が炭素に結合している
イミダゾール誘導体(19)および(20)の製造を示
すものである。合成は式60の場合と同様にして行なわ
れる。ただし2−メチル−4,5−ジフェニルイミダゾ
ール(14)中の活性水素の存在は金属化前の窒素原子
の1つに保護基を導入することを必要とする。当業者に
知られている種々の保護基を使用することができる。
T.S.ManoharanらのJ.Org.Che
m.,53,1107−1110 (1988)に記載の
エトキシエチル基は特に好ましい。それは安価であり導
入が容易であるからである。2−メチル−4,5−ジフ
ェニルイミダゾール(14)を過剰のエチルビニルエー
テルと共に密封容器中で加熱すると結晶N−(1−エト
キシエチル)イミダゾール(15)がえられる。このイ
ミダゾール(15)をn−ブチルリチウムで金属化し、
次いでブロマイド(9)と反応させてシリルエーテル
(16)を得る。シリル保護基の選択的除去はシリルエ
ーテル(16)をテトラ−n−ブチルアンモニウムフル
オライドに露出させることによって達成される。えられ
たフェノール(17)をメチルブロモアセテートでアル
キル化してエステル(18)を得て、これを濃硫酸の存
在下にメタノール中で加熱することによってイミダゾー
ル(19)に転化させる。これを水性アルカリ加水分解
して酸(20)を得る。式62はピラゾール(25)お
よび(26)の製造を示すものである。ブロマイド
(9)による1−ベンゾイルアセトン(21)のアルキ
ル化はジケトン(22)を与える。ジケトン(22)を
フェニルヒドラジンと反応させてピラゾール(23)を
得る。テトラ−n−ブチルアンモニウムフルオライドに
よるピラゾール(23)のシリル保護基の除去およびそ
の後のメチルブロモアセテートによるフェノール(2
4)のアルキル化によりエステル(25)を得る。エス
テル(25)の塩基誘発加水分解にかけて目的の酸(2
6)を得る。式5のカルボン酸のアルカリ金属塩(R1
はアルカリ金属イオンである)は式5の酸をメタノール
のような好適な溶媒にとかし、モル当量のアルカリ塩基
たとえばナトリウム・メトオキシドを加え、そして塩を
沈殿させるか又は溶媒を除去することによって製造され
る。 〔薬理効果〕以上のように、HET1 −(CH2 )n C
O2 Rおよび式5の化合物は血液血小板集塊剤として特
に有用な医薬的性質をもつ。血小板集塊は血管中の血栓
生物の複雑な生理学的機構の1つと考えられる。血栓生
成は血栓静脈、静脈血栓症、脳血栓、冠状動脈血栓症、
および網膜血栓症を包含する多数の哺乳動物疾患に包含
される。血小板集塊傾向の増大は出産、外科手術たとえ
ば冠状動脈バイパス手術、臓器移植、血管手術、心臓疾
患手術、動脈きょう膜、多重きょう膜、脳蓋内腫瘍、血
栓、および脂肪過多症に観察される。A.Poplaw
shi,et al.,J.Artheroscher
esis Research,8,721 (1968)
参照。抗血栓作用をもつ本発明の化合物は上記のような
血小板集塊および血栓を包含する症状の予防または治療
に有用である。本発明の化合物はまたその血小板凝集阻
止性のために有力な抗血栓剤と考えられる。本発明の化
合物の医学的性質は通常の試験管内試験および生体内バ
イオ試験によって実証することができる。 〔ヒト血小板凝集の試験管内阻止試験〕Borm,C.
V.R.,J.Physiol.,(London),
1962,162,67−68の凝集法をMustar
d,J.F.らのJ.Lab.Clin.Med.19
64,64,548−599により変性して使用して、
アデノシン・ジホスフェート(ADP)およびコラーゲ
ン誘発血小板凝集の阻止に関して種々の化合物の試験管
内活性を検査した。ボランティア提供者(ヒト)の腕を
70%エチルアルコールで清浄にする。滅菌した20ml
の注射器および注射針を使用して20mlの血液を抜き取
る。この血液を直ちに試験管(凝集防止のため3.8%
クエン酸ナトリウムを含む)に入れる。クエン酸ナトリ
ウム1部を血液9部に対して使用する。血小板に富む血
清(PKP)をクエン酸塩入り(3.8%)ヒト血液か
ら1000rpm (140×g)で10分間の遠心分離に
よって分離した。PRPの調製したすべてのガラスウェ
アはシリコーン処理した。0.5mcg /mlの最終濃度の
ADPまたはEvans,G.,et.al,J.Ex
p.Mad.,1968,128,877−894に記
載の方法により調製したコラーゲン懸濁液0.05mlを
使用して凝集を誘発させた。種々の試験化合物をジメチ
ルスルホキシド(DMSO)にとかし、5mcl を血小板
に富む血清に加えて所望の試験濃度をえた。賦形薬だけ
の対照試験を行ない、種々の濃度の試験化合物を含む血
小板に富む血清中で誘発される凝集と比較した。調剤応
答曲線を得て阻止濃度(IC50)値を計算した。この試
験において、臨床的に有用な抗血栓剤であるジピリダモ
ルのIC50値はADPに対して512mcg /mlであり、
コラーゲンに対して245mcg /mlである。ADP誘発
の凝集の50%阻止の結果を本発明の種々の化合物につ
いて得た。これらの結果を下記の表1および表2に示
す。[Formula 62] Formula 58 illustrates several different attempts at the synthesis of compounds containing an aryloxyacetic acid moiety. Direct alkylation of the heterocycle (1) with bromide (2) or with tosylate (TS) (3) derived from alcohol (5) can be performed with sodium hydride in DMF at room temperature or DMF at 110 ° C. Achieved with potassium carbonate in to yield ester (6). Alternatively, in some cases, the reaction of the heterocycle (1) with the alcohol (5) derived from the diol (4) is carried out in the presence of diethyl azodicarboxylate and triphenylphosphine to form the ester (6) Cause This reaction is Mitsunob
It is carried out under the mild conditions characteristic of the u reaction. Syn
See thesis 1, 28 (1981). The carboxylic acid (7) is obtained by alkaline hydrolysis of the ester (6). Formula 60 shows the synthesis of thiazole derivatives (12) and (13) in which the side chain of the aryloxy complex acid is carbon bonded. 2-by n-butyllithium
Metallization of methyl-4,5-diphenylthiazole (8) was carried out, followed by reaction with bromide (9) to produce silyl ether (10), which was prepared from tetra-n.
Deprotonated with butylammonium fluoride to give phenol (11). Phenol (11)
Is alkylated with methyl bromoacetate to give ether (12), which is hydrolyzed under aqueous alkaline conditions to give acid (13) Formula 61 is an imidazole derivative (wherein the aryloxyacetic acid side chain is bonded to carbon ( 19) and (20) are produced. The synthesis is performed in the same manner as in the case of Equation 60. However, the presence of active hydrogen in 2-methyl-4,5-diphenylimidazole (14) requires the introduction of a protecting group on one of the nitrogen atoms prior to metallation. Various protecting groups known to those skilled in the art can be used.
T. S. Manoharan et al. Org. Che
m. , 53, 1107-1110 (1988), the ethoxyethyl group being particularly preferred. It is cheap and easy to introduce. Heating 2-methyl-4,5-diphenylimidazole (14) with excess ethyl vinyl ether in a sealed vessel gives crystalline N- (1-ethoxyethyl) imidazole (15). Metallizing this imidazole (15) with n-butyllithium,
Then, it is reacted with bromide (9) to obtain silyl ether (16). Selective removal of the silyl protecting group is achieved by exposing the silyl ether (16) to tetra-n-butylammonium fluoride. The resulting phenol (17) is alkylated with methyl bromoacetate to give the ester (18), which is converted to the imidazole (19) by heating in methanol in the presence of concentrated sulfuric acid. This is hydrolyzed with aqueous alkali to obtain the acid (20). Formula 62 illustrates the preparation of pyrazoles (25) and (26). Alkylation of 1-benzoylacetone (21) with bromide (9) gives the diketone (22). The diketone (22) is reacted with phenylhydrazine to give the pyrazole (23). Removal of the silyl protecting group of pyrazole (23) with tetra-n-butylammonium fluoride followed by phenol (2
Alkylation of 4) gives the ester (25). Base-induced hydrolysis of the ester (25) gives the desired acid (2
6) is obtained. Alkali metal salt of carboxylic acid of formula 5 (R 1
Is an alkali metal ion) is prepared by dissolving the acid of formula 5 in a suitable solvent such as methanol, adding a molar equivalent of an alkali base such as sodium methoxide, and precipitating the salt or removing the solvent. It [Pharmacological effect] As described above, HET 1- (CH 2 ) n C
O 2 R and the compound of formula 5 have pharmaceutical properties that make them particularly useful as blood platelet agglomerates. Platelet clumping is considered to be one of the complex physiological mechanisms of thrombotic organisms in blood vessels. Thrombus formation is thrombotic vein, venous thrombosis, cerebral thrombosis, coronary thrombosis,
And a number of mammalian diseases including retinal thrombosis. Increased propensity for platelet aggregation is observed in childbirth, surgery such as coronary artery bypass surgery, organ transplantation, vascular surgery, heart disease surgery, arterial capsule, multiple capsule, intracranial tumor, thrombosis, and adiposity . A. Poplaw
shi, et al. J. Arteroscher
sis Research, 8, 721 (1968)
reference. The compound of the present invention having an antithrombotic effect is useful for preventing or treating the above-mentioned conditions including platelet aggregation and thrombosis. The compounds of the present invention are also considered to be potent antithrombotic agents due to their platelet aggregation inhibitory properties. The medical properties of the compounds of this invention may be demonstrated by routine in vitro and in vivo bioassays. [In vitro inhibition test for human platelet aggregation] Borm, C.I.
V. R. J. Physiol. , (London),
1962, 162, 67-68 agglomeration method Mustar
d, J. F. Et al. Lab. Clin. Med. 19
64, 64, 548-599 modified and used,
The in vitro activity of various compounds with respect to blocking adenosine diphosphate (ADP) and collagen-induced platelet aggregation was examined. The arm of a volunteer donor (human) is cleaned with 70% ethyl alcohol. 20 ml sterilized
20 ml of blood is withdrawn using a syringe and needle. Immediately transfer this blood to a test tube (3.8% to prevent aggregation)
(Including sodium citrate). 1 part sodium citrate is used for 9 parts blood. Platelet-rich serum (PKP) was separated from citrated (3.8%) human blood by centrifugation at 1000 rpm (140 xg) for 10 minutes. All prepared glassware of PRP was silicone treated. ADP or Evans, G., at a final concentration of 0.5 mcg / ml. , Et. al, J .; Ex
p. Mad. Aggregation was induced using 0.05 ml of a collagen suspension prepared by the method described in 1968, 128, 877-894. Various test compounds were dissolved in dimethyl sulfoxide (DMSO) and 5 mcl was added to platelet-rich serum to obtain the desired test concentration. A vehicle-only control study was performed and compared to aggregation induced in platelet-rich serum containing various concentrations of test compound. Dispensing response curves were obtained and inhibitory concentration (IC 50 ) values were calculated. In this test, the IC 50 value of dipyridamole, a clinically useful antithrombotic agent, was 512 mcg / ml against ADP,
245 mcg / ml for collagen. Results of 50% inhibition of ADP-induced aggregation were obtained for various compounds of the invention. The results are shown in Tables 1 and 2 below.
【表1】 [Table 1]
【表2】 1群としてみたとき、HET1 −(CH2 )n CO2 R
の化合物および式5すなわちHET2 −CH2 CH2 −
(C6 H4 )−OCH2 CO2 R1 の化合物はヒト血小
板のADP誘発凝集の特に有力な阻止形であることが明
らかである。エステルはもとの酸よりも一般に活性が低
いが、生体内前駆薬剤として有用である(エステルは生
体内で対応する酸に加水分解されるからである。本発明
の治療法に使用される調剤量は投与形体、えらばれた特
定の化合物、試験される課題、および所望の効果に応じ
て変化する。動物における好適な有効調剤量は経口投与
の場合には体重kg当り0.1〜50mg、そして非経口投
与(皮下、筋肉内、および静脈内の注射)の場合には体
重kg当り0.05〜10mgである。ヒト用の有効単位調
剤量は1〜100mgの範囲にあり、好ましくは1日に3
回、1〜20mgの投与を行なう。通常の臨床上の慣習に
よれば、有効調剤量は有効であると考えられる量より実
質的に少ない量を投与し、次いで調剤量を所望の効果が
えられるまで少しずつ増加させることによって決定され
る。本発明の治療法は実施する際に、前記のHET1 −
(CH2 )n CO2 Rの化合物または前記の式5の化合
物またはそれらのアルカリ金属塩を好ましくは医薬的に
許容しうる担体と一緒にして投与する。経口用に好適な
調剤形体は錠剤、分散性粉末、カプセル、シロップおよ
び薬液である。有力な形体の例は溶液、懸濁液、分散
液、乳化液、などである。経口投与に有用な組成物は1
種以上の通常の補薬たとえば甘味剤、芳香剤、着色剤、
および保存剤を含むことができる。錠剤は活性成分を通
常の医薬的に許容しうる賦形薬と混合して含んでいても
よい。このような賦形薬として希釈剤たとえば炭酸カル
シウム、炭酸ナトリウム、ラクトースおよびタルク;顆
粒化および崩壊用の試剤、たとえばデンプンおよびアル
ギン酸;バインダーたとえばデンプン、ゼラチンおよび
アカシア;および滑剤たとえばステアリン酸マグネシウ
ム、ステアリン酸、およびタルク;があげられる。錠剤
は被覆されていなくてもよく、あるいは長期間にわたっ
て持続作用を与えるために胃腸組織中での崩壊および吸
収をあくらせるよう周知技術によって被覆されたもので
あってもよい。同様に、懸濁液、シロップおよび薬液は
組成物の製造に使用した通常の賦形薬たとえば懸濁剤
(メチルセルロース、トラカガントおよびアルギン酸ナ
トリウム)、湿潤剤(レシチン、ポリエチレンステアレ
ート)、および保存剤(エチル−p−ヒドロキシベンゾ
エートなど)を活性成分と混合して含んでいてもよい。
カプセルは活性成分を単独で含んでいてもよく、または
活性成分を不活性固体希釈剤たとえば炭酸カルシウム、
リン酸カルシウム、カオリンなどと組合せて含んでいて
もよい。注射用組成物は当業技術において知られている
方法で処方することができ、上記と同じ又は類似の適切
な分散剤および懸濁剤を含むことができる。[Table 2] When viewed as one group, HET 1- (CH 2 ) n CO 2 R
And a compound of formula 5: HET 2 —CH 2 CH 2 —
(C 6 H 4) -OCH 2 CO 2 Compound of R 1 it is clear that a particularly potent blocking type ADP-induced aggregation of human platelets. Esters are generally less active than the original acid but are useful as in vivo precursors (because the ester is hydrolyzed in vivo to the corresponding acid. Formulations used in the therapeutic methods of the invention The amount will vary depending on the dosage form, the particular compound selected, the problem being tested, and the desired effect. Suitable effective dosages in animals are from 0.1 to 50 mg / kg body weight when orally administered, In the case of parenteral administration (subcutaneous, intramuscular, and intravenous injection), it is 0.05 to 10 mg / kg of body weight.The effective dose for humans is in the range of 1 to 100 mg, preferably 1 3 on a day
1 to 20 mg is administered once. According to normal clinical practice, the effective dosage is determined by administering substantially less than what is considered to be effective and then gradually increasing the dosage until the desired effect is achieved. It When the therapeutic method of the present invention is carried out, HET 1-
The compound of (CH 2 ) n CO 2 R or a compound of formula 5 above or an alkali metal salt thereof is administered, preferably in combination with a pharmaceutically acceptable carrier. Suitable dosage forms for oral use are tablets, dispersible powders, capsules, syrups and drug solutions. Examples of predominant forms are solutions, suspensions, dispersions, emulsions and the like. 1 useful composition for oral administration
One or more conventional auxiliaries such as sweeteners, fragrances, colorants,
And a preservative. Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients. Such excipients include diluents such as calcium carbonate, sodium carbonate, lactose and talc; agents for granulation and disintegration such as starch and alginic acid; binders such as starch, gelatin and acacia; and lubricants such as magnesium stearate, stearic acid. , And talc; The tablets may be uncoated or they may be coated by well known techniques to provide for disintegration and absorption in gastrointestinal tissue for prolonged action. Similarly, suspensions, syrups and solutions are conventional excipients used in the manufacture of compositions, such as suspending agents (methylcellulose, tracagant and sodium alginate), wetting agents (lecithin, polyethylene stearate), and preservatives ( Ethyl-p-hydroxybenzoate and the like) may be included in admixture with the active ingredient.
The capsules may contain the active ingredient alone, or the active ingredient may be an inert solid diluent such as calcium carbonate,
It may be contained in combination with calcium phosphate, kaolin and the like. Injectable compositions can be formulated in a manner known in the art and can include suitable dispersants and suspending agents that are the same as or similar to those described above.
【実施例】以下の実施例は本発明を更に具体的に説明す
るためのものであって、本発明を限定するものと解すべ
きではない。本発明の範囲内で多くの変化が可能だから
である。これらの実施例において、すべての温度は摂氏
℃で示されている。融点はThomas−Hoover
の毛管融点装置を使用して測定され、未補正で表示して
ある。プロトン磁気共鳴( 1H−NMR)スペクトルは
Bruher AM300,Bruker WM360
またはVarian Gemini 300の分光計に
記録されたものである。すべてのスペクトルは他に特別
の記載のない限りCDCl3 またはDMSO−d6 中で
測定されたものであり、そして化学シフトは内部標準テ
トラメチルシラン(TMS)からの下方分野のデルタ単
位で報告されたものであり、プロトン間のカップリング
常数はヘルツ(Hz)単位で報告されている。スプリッ
ト・パターンは次のように命名してある:s,シングレ
ット(単一子);d,タブレット(2重子);t,トリ
プレット(3重子);q,カルテット(4重子);m,
マルチプレット(多重子);br,ブロードピーク;お
よびdd,ダブレット・オブ・ダブレット。 実施例1 メチル3,4−ジフェニル−1Hピロール−
1−ノナノエートThe following examples are for the purpose of illustrating the present invention more specifically, and should not be construed as limiting the present invention. Many variations are possible within the scope of the invention. In these examples, all temperatures are given in degrees Celsius. Melting point is Thomas-Hoover
Capillary melting point apparatus, and is displayed uncorrected. Proton magnetic resonance ( 1 H-NMR) spectra are obtained by Bruher AM300, Bruker WM360.
Or recorded on a Varian Gemini 300 spectrometer. All spectra were measured in CDCl 3 or DMSO-d 6 unless otherwise noted, and chemical shifts are reported in Delta units in the lower field from the internal standard tetramethylsilane (TMS). The coupling constant between protons is reported in Hertz (Hz). The split patterns are named as follows: s, singlet (single child); d, tablet (doublet); t, triplet (triplet); q, quartet (quadruple); m,
Multiplet; br, broadpeak; and dd, doublet of doublet. Example 1 Methyl 3,4-diphenyl-1H pyrrole-
1-nonanoate
【式63】 水素化ナトリウム(鉱油中50%分散液789mg;16
ミリモル)をヘキサンで2回洗浄し、DMF(40ml)
で覆う。K.R.Kopecky et al.,Ca
n.J.Chem.,54,2645−2651 (19
76)により得た3,4−ジフェニルピロール(3g,
13ミリモル)を加え、混合物をガス発生が止むまで室
温で攪拌した。メチル−9−ブロモノナノエート(3.
61g,14ミリモル)を加え、室温で攪拌を続けた。
15分後に、混合物を1Nの塩酸溶液に注入し、ジエチ
ルエーテル(3×)で抽出した。合計の抽出物を水(3
×)で洗浄し、硫酸ナトリウム上で乾燥し、そして真空
濃縮して油状物を得た。これをシリカゲルのカラム上で
クロマトグラフ処理した。ヘキサンとジエチルエーテル
の(9:1)混合物により溶融して3,4−ジフェニル
−1H−ノナノエート(3.70g,69%)を油状物
としてえた。 分析:C26H31NO2 :計算値:C,80.17;H,
8.02;N,3.60。実測値:C,79.84;
H,8.02;N,3.36%。1 H−NMR(CDCl3 )delta:1.20 t
o 1.50(8H,m),1.60(2H,m),
1.82(2H,quintet,J=7Hz),2.
29(2H,t,J=8Hz),3.64(3H,
s),3.87(2H,t,J=7Hz),6.74
(2H,s),7.20 to 7.60(10H,
m)。 実施例2 3,4−ジフェニル−1H−ピロール−1−
ノナン酸[Equation 63] Sodium hydride (50% dispersion in mineral oil 789 mg; 16
Was washed twice with hexane and DMF (40 ml)
Cover with. K. R. Kopecky et al. , Ca
n. J. Chem. , 54, 2645-2651 (19
76) 3,4-diphenylpyrrole (3 g,
13 mmol) was added and the mixture was stirred at room temperature until gas evolution ceased. Methyl-9-bromononanoate (3.
61 g, 14 mmol) was added and stirring was continued at room temperature.
After 15 minutes, the mixture was poured into a 1N hydrochloric acid solution and extracted with diethyl ether (3x). Combine the total extract with water (3
X), dried over sodium sulfate and concentrated in vacuo to give an oil. This was chromatographed on a column of silica gel. Melting with a (9: 1) mixture of hexane and diethyl ether gave 3,4-diphenyl-1H-nonanoate (3.70 g, 69%) as an oil. Analysis: C 26 H 31 NO 2: Calculated: C, 80.17; H,
8.02; N, 3.60. Found: C, 79.84;
H, 8.02; N, 3.36%. 1 H-NMR (CDCl 3 ) delta: 1.20 t
o 1.50 (8H, m), 1.60 (2H, m),
1.82 (2H, quintet, J = 7Hz), 2.
29 (2H, t, J = 8Hz), 3.64 (3H,
s), 3.87 (2H, t, J = 7Hz), 6.74
(2H, s), 7.20 to 7.60 (10H,
m). Example 2 3,4-diphenyl-1H-pyrrole-1-
Nonanoic acid
【式64】 メチル3,4−ジフェニル−1H−ピロール−1−ノナ
ノエート(2.50g,6.4ミリモル),5N水酸化
ナトリウム溶液(3.86ml,19ミリモル)およびメ
タノール(50ml)の混合物を水蒸気浴上で加熱した。
30分後に、溶媒を蒸発させ、残渣を1N−HCl溶液
で希釈し、CH2 Cl2 で抽出した。全抽出物を硫酸ナ
トリウム上で乾燥し、真空濃縮し、そして残渣油をシリ
カゲルのカラム上でクロマトグラフ処理した。ジエチル
エーテルとヘキサン(3:2)の混合物で溶離して3,
4−ジフェニル−1Hピロール−1−ノナン酸(2.2
0g,91%)を油状物としてえた。 分析:C25H29NO2 ・0.7H2 O:計算値:C,7
7.37;H,7.90;N,3.61;H2 O,3.
25。実測値:C,77.23;H,7.52;N,
3.42;H2 O,0.43%。1 H−NMR(CDCl3 )delta:1.42(8
H,bs),1.72(2H,quintet,J=7
Hz),1.89(2H,quintet,J=7H
z),2.42(2H,t,J=7Hz),3.92
(2H,t,J=7Hz),6.83(2H,s),a
nd7.20 to 7.40(10H,m)。 実施例3 メチル 6−オキソ−3,4−ジフェニル−
1 (6H)ピリダジンノナノエート[Formula 64] A mixture of methyl 3,4-diphenyl-1H-pyrrole-1-nonanoate (2.50 g, 6.4 mmol), 5N sodium hydroxide solution (3.86 ml, 19 mmol) and methanol (50 ml) on a steam bath. Heated.
After 30 minutes, the solvent was evaporated, the residue diluted with 1N HCl solution and extracted with CH 2 Cl 2 . All extracts were dried over sodium sulphate, concentrated in vacuo and the residual oil chromatographed on a column of silica gel. Elute with a mixture of diethyl ether and hexane (3: 2) 3.
4-diphenyl-1H pyrrole-1-nonanoic acid (2.2
0 g, 91%) as an oil. Analysis: C 25 H 29 NO 2 .0.7H 2 O: Calculated value: C, 7
7.37; H, 7.90; N, 3.61; H 2 O, 3.
25. Found: C, 77.23; H, 7.52; N,
3.42; H 2 O, 0.43% . 1 H-NMR (CDCl 3 ) delta: 1.42 (8
H, bs), 1.72 (2H, quintet, J = 7)
Hz), 1.89 (2H, quintet, J = 7H
z), 2.42 (2H, t, J = 7Hz), 3.92
(2H, t, J = 7 Hz), 6.83 (2H, s), a
nd 7.20 to 7.40 (10H, m). Example 3 Methyl 6-oxo-3,4-diphenyl-
1 (6H) Pyridazine nonanoate
【式65】 水素化ナトリウム(840mgの油中60%分散液,20
ミリモル)をヘキサンで2回洗浄し、DMF(25ml)
で覆い、そしてP.Schmidt,et al.,H
elvetica Chim.Acta.,37,13
4−140 (1954)により製造した5,6−ジフェ
ニル−3 (2H)−ピリダジノン(4g,16ミリモ
ル)を加えた。ガス発生が止んだ後に、混合物を室温で
30分間攪拌し、その後に9−ブロモノナノエート
(4.45g,18ミリモル)を加えた。混合物を11
0℃に短時間加熱して溶液をえた。次いでこれを冷却し
てから室温で1時間攪拌した。混合物を水で希釈し、ジ
エチルエーテル(3×)で抽出した。合計抽出物を水で
洗浄し、硫酸ナトリウム上で乾燥し、濃縮して油状物を
えた。シリカゲルのカラム上でクロマトグラフ処理して
メチル6−オキソ−3,4−ジフェニル−1 (6H)−
ピリダジンノナノエート(6.44g,95%)を油状
物としてえた。 分析:C26H30N2 O3 :計算値:C,74.61;
H,7.22;N,6.69。実測値:C,74.8
9;H,7.38;N,7.23%。1 H−NMR(CDCl3 )delta:1.20 t
o 1.45(8H,m),1.56(2H,quin
tet,J=7Hz),1.85(2H,quinte
t,J=7Hz),2.23(2H,t,J=7.5H
z),3.59(3H,s),4.20(2H,t,J
=7Hz),6.88(1H,s)and 7.00
to 7.40(10H,m)。 実施例4 6−オキソ−3,4−ジフェニル−1 (6
H)−ピリダジンノナン酸[Formula 65] Sodium hydride (840 mg of a 60% dispersion in oil, 20
Was washed twice with hexane and DMF (25 ml)
Cover with P. Schmidt, et al. , H
elvetica Chim. Acta. , 37, 13
5,6-Diphenyl-3 (2H) -pyridazinone (4 g, 16 mmol) prepared by 4-140 (1954) was added. After gas evolution ceased, the mixture was stirred at room temperature for 30 minutes, after which 9-bromononanoate (4.45 g, 18 mmol) was added. Mix 11
A solution was obtained by heating at 0 ° C for a short time. It was then cooled and stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with diethyl ether (3x). The total extracts were washed with water, dried over sodium sulfate and concentrated to give an oil. Methyl 6-oxo-3,4-diphenyl-1 (6H)-was chromatographed on a column of silica gel.
Pyridazine nonanoate (6.44 g, 95%) was obtained as an oil. Analysis: C 26 H 30 N 2 O 3: Calculated: C, 74.61;
H, 7.22; N, 6.69. Found: C, 74.8.
9; H, 7.38; N, 7.23%. 1 H-NMR (CDCl 3 ) delta: 1.20 t
o 1.45 (8H, m), 1.56 (2H, quin
tet, J = 7 Hz), 1.85 (2H, quinte
t, J = 7 Hz), 2.23 (2H, t, J = 7.5H)
z), 3.59 (3H, s), 4.20 (2H, t, J
= 7 Hz), 6.88 (1H, s) and 7.00
to 7.40 (10H, m). Example 4 6-oxo-3,4-diphenyl-1 (6
H) -pyridazinenonanoic acid
【式66】 メチル 6−オキソ−3,4−ジフェニル−1 (6H)
−ピリダジンノナノエート(6g,14ミリモル),5
NのNaOH溶液(8.6ml,43ミリモル)およびメ
タノール(100ml)の混合物を水蒸気浴上で還流加熱
した。30分後に、混合物を濃縮し、水で希釈し、そし
て2N−HCl溶液でpH=1に酸性化した。この混合物
をCH2 Cl2 で抽出し、合計抽出物を硫酸ナトリウム
上で乾燥し、そして油状物をえた。これを放置して結晶
化させた。CH2 Cl2 とヘキサンの混合物から再結晶
させて6−オキソ−3,4−ジフェニル−1 (6H)−
ピリダジンノナン酸(3.92g,67%)をえた。融
点100〜103℃。 分析:C25H28N2 O3 :計算値:C,74.23;
H,6.98;N,6.93。実測値:C,74.2
5;H,7.13;N,7.11%。1 H−NMR(CDCl3 )delta:1.20 t
o 1.50(8H,m),1.59(2H,t),
1.87(2H,quintet,J=6.5Hz),
2.29(2H,t,J=7Hz),4.24(2H,
t,J=7Hz),6.98(1H,s),7.00
to 7.40(10H,m)and 9.83(1
H,bs)。 実施例5 メチル 6−オキソ−3,4−ジフェニル−
1 (6H)ピリダジニルオクタノエート[Formula 66] Methyl 6-oxo-3,4-diphenyl-1 (6H)
-Pyridazine nonanoate (6 g, 14 mmol), 5
A mixture of N NaOH solution (8.6 ml, 43 mmol) and methanol (100 ml) was heated to reflux on a steam bath. After 30 minutes, the mixture was concentrated, diluted with water and acidified to pH = 1 with a 2N HCl solution. The mixture was extracted with CH 2 Cl 2 , the total extracts were dried over sodium sulphate and gave an oil. This was left to crystallize. Recrystallization from a mixture of CH 2 Cl 2 and hexane gave 6-oxo-3,4-diphenyl-1 (6H)-.
Pyridazine nonanoic acid (3.92 g, 67%) was obtained. Melting point 100-103 [deg.] C. Analysis: C 25 H 28 N 2 O 3: Calculated: C, 74.23;
H, 6.98; N, 6.93. Found: C, 74.2.
5; H, 7.13; N, 7.11%. 1 H-NMR (CDCl 3 ) delta: 1.20 t
o 1.50 (8H, m), 1.59 (2H, t),
1.87 (2H, quintet, J = 6.5Hz),
2.29 (2H, t, J = 7Hz), 4.24 (2H,
t, J = 7 Hz), 6.98 (1H, s), 7.00
to 7.40 (10H, m) and 9.83 (1
H, bs). Example 5 Methyl 6-oxo-3,4-diphenyl-
1 (6H) Pyridazinyl octanoate
【式67】 5,6−ジフェニル−3 (2H)−ピリダゾンを実施例
3の方法によりメチルδ−ブロモオクタノエートと反応
させて表記化合物を油状物としてえた。 分析:C25H28N2 O3 :計算値:C,74.23;
H,6.98;N,6.93。実測値:C,74.2
3;H,7.27;N,7.34%。 実施例6 6−オキソ−3,4−ジフェニル−1 (6
H)−ピリダジニルオクタン酸[Formula 67] 5,6-Diphenyl-3 (2H) -pyridazone was reacted with methyl δ-bromooctanoate by the method of Example 3 to give the title compound as an oil. Analysis: C 25 H 28 N 2 O 3: Calculated: C, 74.23;
H, 6.98; N, 6.93. Found: C, 74.2.
3; H, 7.27; N, 7.34%. Example 6 6-oxo-3,4-diphenyl-1 (6
H) -Pyridazinyl octanoic acid
【式68】 メチル 6−オキソ−3,4−ジフェニル−1 (6H)
−ピリダジニルオクタノエートを実施例4の方法により
加水分解して表記化合物をえた。融点108〜110
℃。 分析:C24H26N2 O3 ・0.2H2 O:計算値:C,
73.15;H,6.76;N,7.11;H2 O,
0.91。実測値:C,73.20;H,6.69;
N,7.13;H2 O,1.16。 実施例7 メチル 3−オキソ−5,6−ジフェニル−
1,2,4−トリアジン−2 (3H)−ノナノエート[Formula 68] Methyl 6-oxo-3,4-diphenyl-1 (6H)
-Pyridazinyl octanoate was hydrolyzed by the method of Example 4 to give the title compound. Melting point 108-110
° C. Analysis: C 24 H 26 N 2 O 3 .0.2H 2 O: Calculated value: C,
73.15; H, 6.76; N, 7.11; H 2 O,
0.91. Found: C, 73.20; H, 6.69;
N, 7.13; H 2 O, 1.16. Example 7 Methyl 3-oxo-5,6-diphenyl-
1,2,4-triazine-2 (3H) -nonanoate
【式69】 水素化ナトリウム(577mg)の油中60%分散液(1
4ミリモル)をヘキサンで2回洗浄し、DMF(40m
l)で覆った。M.Friedman,J.Org.C
hem.30 859−863(1965)により製造
した5,6−ジフェニル−1,2,4−トリアゾール−
3 (2H)−オン(3g,12ミリモル)を加えた。ガ
ス発生が止んだ後に、混合物を室温で15分間攪拌し、
その後に水中に注入し、ジエチルエーテル(3×)で抽
出した。合計の抽出物を水(3×)で洗浄し、硫酸ナト
リウム上で乾燥し、濃縮して油状物をえた。これをシリ
カゲルのカラムでクロマトグラフ処理した。ジエチルエ
ーテルとヘキサン(3:2)の混合物を溶離してメチル
3−オキソ−5,6−ジフェニル−1,2,4−トリア
ジン−2 (3H)−ノナノエート(3.09g,61
%)をえた。 分析:C25H29N3 O3 :計算値:C,71.58;
H,6.97;N,10.02。実測値:C,71.5
9;H,7.13;N,10.06%。1 H−NMR(CDCl3 )delta:1.20 t
o 1.45(8H,m),1.58(2H,quin
tet,J=6Hz),1.90(2H,quinte
t,J=6Hz),2.26(2H,t,J=6H
z),3.63(3H,s),4.21(2H,t,J
=6Hz)and 7.20 to 7.55(10
H,m)。 実施例8 3−オキソ−5,6−ジフェニル−1,2,
4−トリアジン−2 (3H)−ノナン酸[Formula 69] 60% dispersion of sodium hydride (577 mg) in oil (1
4 mmol) was washed twice with hexane, and DMF (40 m
l) covered. M. Friedman, J .; Org. C
hem. 30 5,859-863 (1965) 5,6-diphenyl-1,2,4-triazole-
3 (2H) -one (3 g, 12 mmol) was added. After the gas evolution ceased, the mixture was stirred at room temperature for 15 minutes,
It was then poured into water and extracted with diethyl ether (3x). The combined extracts were washed with water (3x), dried over sodium sulphate and concentrated to give an oil. This was chromatographed on a column of silica gel. Methyl 3-oxo-5,6-diphenyl-1,2,4-triazine-2 (3H) -nonanoate (3.09 g, 61) was eluted by eluting with a mixture of diethyl ether and hexane (3: 2).
%). Analysis: C 25 H 29 N 3 O 3: Calculated: C, 71.58;
H, 6.97; N, 10.02. Found: C, 71.5
9; H, 7.13; N, 10.06%. 1 H-NMR (CDCl 3 ) delta: 1.20 t
o 1.45 (8H, m), 1.58 (2H, quin
tet, J = 6 Hz), 1.90 (2H, quinte
t, J = 6 Hz), 2.26 (2H, t, J = 6H)
z), 3.63 (3H, s), 4.21 (2H, t, J
= 6 Hz) and 7.20 to 7.55 (10
H, m). Example 8 3-oxo-5,6-diphenyl-1,2,
4-triazine-2 (3H) -nonanoic acid
【式70】 メチル 3−オキソ−5,6−ジフェニル−1,2,4
−トリアジン−2(3H)−ノナノエート(1.90
g,4.5ミリモル)、5NのNaOH溶液(2.72
ml,13ミリモル)およびメタノール(130ml)の混
合物を水蒸気浴上で30分間加熱した。揮発物を真空除
去し、残渣を水で希釈し、pH=1まで希HCl溶液を加
えた。混合物をCH2 Cl2 で抽出し、抽出物の硫酸ナ
トリウム上で乾燥し、濃縮して油状物をえた。溶離液と
してジエチルエーテルを使用し、シリカゲルのカラム上
でクロマトグラフ処理して3−オキソ−5,6−ジフェ
ニル−1,2,4−トリアジン−2 (1H)−ノナン酸
(1.50g,81%)を得た。これを放置して結晶化
させた。融点97〜100℃。 分析:C24H27N3 O3 :計算値:C,71.09;
H,6.71;N,10.36。実測値:C,71.2
9;H,6.97;N,10.21%。1 H−NMR(CDCl3 )delta:1.20 t
o 1.50(8H,m),1.57(2H,t,J=
7Hz),1.88(2H,quintet,J=7H
z),2.27(2H,t,J=7.5Hz),4.1
9(2H,t,J=7Hz),7.20 to 7.6
0(10H,m)and10.89(1H,bs)。 実施例9 メチル 3−オキソ−5,6−ジフェニル−
1,2,4−トリアジン2(3H)−オクタノエート[Formula 70] Methyl 3-oxo-5,6-diphenyl-1,2,4
-Triazine-2 (3H) -nonanoate (1.90)
g, 4.5 mmol), 5N NaOH solution (2.72)
ml, 13 mmol) and methanol (130 ml) was heated on a steam bath for 30 minutes. The volatiles were removed in vacuo, the residue was diluted with water and dilute HCl solution was added until pH = 1. The mixture was extracted with CH 2 Cl 2 , the extract was dried over sodium sulfate and concentrated to give an oil. Chromatograph on a column of silica gel using diethyl ether as eluent to give 3-oxo-5,6-diphenyl-1,2,4-triazine-2 (1H) -nonanoic acid (1.50 g, 81 %) Was obtained. This was left to crystallize. Melting point 97-100 [deg.] C. Analysis: C 24 H 27 N 3 O 3: Calculated: C, 71.09;
H, 6.71; N, 10.36. Found: C, 71.2
9; H, 6.97; N, 10.21%. 1 H-NMR (CDCl 3 ) delta: 1.20 t
o 1.50 (8H, m), 1.57 (2H, t, J =
7Hz), 1.88 (2H, quintet, J = 7H
z), 2.27 (2H, t, J = 7.5 Hz), 4.1
9 (2H, t, J = 7Hz), 7.20 to 7.6
0 (10H, m) and 10.89 (1H, bs). Example 9 Methyl 3-oxo-5,6-diphenyl-
1,2,4-triazine 2 (3H) -octanoate
【式71】 5,6−ジフェニル−1,2,4−トリアゾール−3
(2H)オンとメチル8−ブロモオクタノエートと実施
例7の方法により反応させて表記化合物を油状物として
えた。 分析:C24H27N3 O3 :計算値:C,71.09;
H,6.71;N,10.36。実測値:C,71.0
5;H,6.87;N,10.41。 実施例10 3−オキソ−5,6−ジフェニル−1,
2,4−トリアジン−2(3H)−オクタン酸[Formula 71] 5,6-diphenyl-1,2,4-triazole-3
(2H) one was reacted with methyl 8-bromooctanoate by the method of Example 7 to obtain the title compound as an oily substance. Analysis: C 24 H 27 N 3 O 3: Calculated: C, 71.09;
H, 6.71; N, 10.36. Found: C, 71.0
5; H, 6.87; N, 10.41. Example 10 3-oxo-5,6-diphenyl-1,
2,4-triazine-2 (3H) -octanoic acid
【式72】 メチル 3−オキソ−5,6−ジフェニル−1,2,4
−トリアジン−2(3H)−オクタノエートを実施例8
の方法により加水分解して表記化合物をえた。 融点111〜113℃ 分析:C23H25N3 O3 :計算値:C,70.57;
H,6.44;N,10.73。実測値:C,70.3
5;H,6.72;N,10.33。 実施例11 メチル 2−オキソ−4,5−ジフェニル
−1(2H)−ピリミジンノナノエート[Formula 72] Methyl 3-oxo-5,6-diphenyl-1,2,4
-Triazine-2 (3H) -octanoate was used in Example 8
The title compound was obtained by hydrolysis according to the above method. Mp 111 to 113 ° C. Analysis: C 23 H 25 N 3 O 3: Calculated: C, 70.57;
H, 6.44; N, 10.73. Found: C, 70.3
5; H, 6.72; N, 10.33. Example 11 Methyl 2-oxo-4,5-diphenyl-1 (2H) -pyrimidine nonanoate
【式73】 G.M.CoppolaらのJ.Het.Chem.,
16,545,554により製造した4,5−ジフェニ
ル−2(1H)−ピリミジノン(6.00g,24ミリ
モル)、メチル9−ブロモノナノエート(6.37g,
25ミリモル)、炭酸カリウム(4.00g,29ミリ
モル)、沃化カリウム(触媒量)、およびDMF(12
0ml)から成る混合物を窒素雰囲気に110℃で攪拌し
た。30分後に、混合物を冷却し、水で希釈してエチル
エーテルにより3回抽出した。合計の抽出物を水(3
×)で洗浄し、硫酸ナトリウム上で乾燥し、そして溶媒
を蒸発させた。残渣油をジエチルエーテルを使用してシ
リカゲルのカラム上でクロマトグラフ処理し、油状物と
してメチル 9−〔4,5−ジフェニル−2−ピリミジ
ニル)オキシ〕ノナノエート(3.27g,32%)を
えた。次いで更に溶離してメチル2−オキソ−4,5−
ジフェニル−1 (2H)−ピリミジンノナノエート
(6.00g,59%)を油状物としてえた。 分析:C26H30N2 O3 :計算値:C,74.61;
H,7.22;N,6.69。実測値:C,74.9
4;H,7.38;N,6.89%。1 H−NMR(CDCl3 )delta:1.20 t
o 1.45(8H,m),1.56(2H,quin
tet,J=7Hz),1.81(2H,quinte
t,J=7Hz),2.24(2H,t,J=7H
z),3.60(3H,s),3.94(2H,t,J
=7Hz),6.95 to 7.45(10H,m)
and 7.61(1H,s)。 実施例12 2−オキソ−4,5−ジフェニル−1(2
H)−ピリミジンノナン酸[Formula 73] G. M. J. Coppola et al. Het. Chem. ,
4,5-Diphenyl-2 (1H) -pyrimidinone (6.00 g, 24 mmol) prepared by 16,545,554, methyl 9-bromononanoate (6.37 g,
25 mmol), potassium carbonate (4.00 g, 29 mmol), potassium iodide (catalytic amount), and DMF (12
0 ml) was stirred at 110 ° C. under a nitrogen atmosphere. After 30 minutes, the mixture was cooled, diluted with water and extracted 3 times with ethyl ether. Combine the total extract with water (3
X) washed, dried over sodium sulphate and the solvent evaporated. The residual oil was chromatographed on a column of silica gel with diethyl ether to give methyl 9- [4,5-diphenyl-2-pyrimidinyl) oxy] nonanoate (3.27 g, 32%) as an oil. Then elute further and methyl 2-oxo-4,5-
Diphenyl-1 (2H) -pyrimidine nonanoate (6.00 g, 59%) was obtained as an oil. Analysis: C 26 H 30 N 2 O 3: Calculated: C, 74.61;
H, 7.22; N, 6.69. Found: C, 74.9.
4; H, 7.38; N, 6.89%. 1 H-NMR (CDCl 3 ) delta: 1.20 t
o 1.45 (8H, m), 1.56 (2H, quin
tet, J = 7 Hz), 1.81 (2H, quinte
t, J = 7 Hz), 2.24 (2H, t, J = 7H)
z), 3.60 (3H, s), 3.94 (2H, t, J
= 7 Hz), 6.95 to 7.45 (10 H, m)
and 7.61 (1H, s). Example 12 2-oxo-4,5-diphenyl-1 (2
H) -pyrimidine nonanoic acid
【式74】 メチル 2−オキソ−4,5−ジフェニル−1(2H)
−ピリミジンノナノエート(4.70g,11ミリモ
ル)、5NのNaOH溶液(7.40ml,36ミリモ
ル)およびメタノール(80ml)の混合物を室温で75
分間攪拌し、次いで還流温度で75分間攪拌してから、
冷却し濃縮した。残渣を水で希釈し、2NのHClを加
えてpH2にした。混合物をCH2 Cl2 で抽出し、抽出
物を集めて硫酸ナトリウム上で乾燥し、溶媒を除去して
油状物(結晶化する)を得た。ジエチルエーテルとCH
2 Cl2 の混合物から再結晶させて2−オキソ−4,5
−ジフェニル−1(2H)−ピリミジンノナン酸(3.
35g,73%)をえた。融点120〜123℃。 分析:C25H28N2 O3 :計算値:C,74.23;
H,6.98;N,6.93。実測値:C,74.2
2;H,7.08;N,6.61%。1 H−NMR(CDCl3 )delta:1.20 t
o 1.50(8H,m),1.56(2H,bt),
1.80(2H,bt),2.27(2H,t,J=7
Hz),3.94(2H,t,J=7Hz),6.95
to 7.55(10H,m);7.65(1H)a
nd 10.56(1H,bs)。 実施例13 メチル 2−オキソ−4,5−ジフェニル
−1 (2H)−ピリミジンオクタノエート[Formula 74] Methyl 2-oxo-4,5-diphenyl-1 (2H)
A mixture of pyrimidine nonanoate (4.70 g, 11 mmol), 5N NaOH solution (7.40 ml, 36 mmol) and methanol (80 ml) at room temperature 75
Stir for 1 minute, then at reflux for 75 minutes, then
Cooled and concentrated. The residue was diluted with water and 2N HCl was added to pH2. The mixture was extracted with CH 2 Cl 2 , the extracts were combined, dried over sodium sulfate and the solvent removed to give an oil (crystallized). Diethyl ether and CH
Recrystallization from a mixture of 2 Cl 2 yielded 2-oxo-4,5
-Diphenyl-1 (2H) -pyrimidinenonanoic acid (3.
35 g, 73%). Melting point 120-123 ° C. Analysis: C 25 H 28 N 2 O 3: Calculated: C, 74.23;
H, 6.98; N, 6.93. Found: C, 74.2.
2; H, 7.08; N, 6.61%. 1 H-NMR (CDCl 3 ) delta: 1.20 t
o 1.50 (8H, m), 1.56 (2H, bt),
1.80 (2H, bt), 2.27 (2H, t, J = 7
Hz), 3.94 (2H, t, J = 7Hz), 6.95
to 7.55 (10H, m); 7.65 (1H) a
nd 10.56 (1H, bs). Example 13 Methyl 2-oxo-4,5-diphenyl-1 (2H) -pyrimidine octanoate
【式75】 実施例11の方法により4,5−ジフェニル−2(1
H)−ピリミジノンとメチル8−ブロモオクタノエート
を反応させて表記化合物をえた。融点80〜83℃。 分析:C25H28N2 O3 :計算値:C,74.23;
H,6.98;N,6.93。実測値:C,74.6
4;H,7.21;N,7.00。 実施例14 2−オキソ−4,5−ジフェニル−1 (2
H)ピリミジンオクタン酸[Formula 75] By the method of Example 11, 4,5-diphenyl-2 (1
H) -pyrimidinone was reacted with methyl 8-bromooctanoate to give the title compound. Melting point 80-83 [deg.] C. Analysis: C 25 H 28 N 2 O 3: Calculated: C, 74.23;
H, 6.98; N, 6.93. Found: C, 74.6.
4; H, 7.21; N, 7.00. Example 14 2-oxo-4,5-diphenyl-1 (2
H) Pyrimidine octanoic acid
【式76】 メチル 2−オキソ−4,5−ジフェニル−2 (1H)
−ピリミジニルオクタノエートを実施例12の方法によ
り加水分解して表記化合物をえた。融点121〜123
℃ 分析:C24H26N2 O3 :計算値:C,73.82;
H,6.71;N,7.17。実測値:C,73.4
3;H,6.83;N,7.28。 実施例15 メチル 2,3−ジオキソ−3,4−ジフ
ェニル−1−イミダゾリジンノナノエート[Formula 76] Methyl 2-oxo-4,5-diphenyl-2 (1H)
Hydrolysis of -pyrimidinyl octanoate by the method of Example 12 gave the title compound. Melting point 121-123
℃ Analysis: C 24 H 26 N 2 O 3: Calculated: C, 73.82;
H, 6.71; N, 7.17. Found: C, 73.4.
3; H, 6.83; N, 7.28. Example 15 Methyl 2,3-dioxo-3,4-diphenyl-1-imidazolidine nonanoate
【式77】 THF(5ml)中のジエチルアゾジカルボキシレート
(1.39g,8ミリモル)を、メチル9−ヒドロキシ
ノナノエート(1.50g,8ミリモル)、K.C.J
oshi,et al.,J.Het.Chem.1
8,1651〜1653 (1981)により製造した
3,4−ジフェニルイミダゾリジン−2,5−ジオン
(2.02g,8ミリモル)およびTHF(35ml)中
のトリフェニルホスフィン(2.10,8ミリモル)か
ら成る攪拌溶液に、滴下状に添加した。この混合物を室
温で72時間攪拌し、THFを除去し、残渣をヘキサン
とジエチルエーテルの混合物ですりつぶし、溶離剤とし
てヘキサンとエチルアセテート(3:2)の混合物を使
用してシリカゲルのカラム上でクロマトグラフ処理し
た。溶離によりメチル2,5−ジオキソ−3,4−ジフ
ェニル−1−イミダゾリジンノナノエート(2.78
g,82%)をえた。融点69〜70℃。 分析:C25H30N2 O4 :計算値:C,71.07;
H,7.16;N,6.65。実測値:C,71.1
3;H,7.19;N,6.66%。1 H−NMR(CDCl3 )delta:1.20 t
o 1.40(8H,m),1.50 to 1.70
(4H,m),2.25(2H,t,J=6Hz),
3.55(2H,t,J=6Hz),3.61(3H,
s),5.41(1H,s),7.03(1H,t,J
=6.5Hz),7.10 to 7.40(7H,
m)and 7.45(2H,d,J=6.5Hz)。 実施例16 2,5−ジオキソ−3,4−ジフェニル−
1−イミダゾリジンノナン酸[Formula 77] Diethylazodicarboxylate (1.39 g, 8 mmol) in THF (5 ml) was treated with methyl 9-hydroxynonanoate (1.50 g, 8 mmol), K.I. C. J
oshi, et al. J. Het. Chem. 1
3,165-1653 (1981) 3,4-diphenylimidazolidine-2,5-dione (2.02 g, 8 mmol) and triphenylphosphine (2.10,8 mmol) in THF (35 ml). Was added dropwise to a stirred solution consisting of. The mixture was stirred at room temperature for 72 hours, the THF was removed, the residue was triturated with a mixture of hexane and diethyl ether and chromatographed on a column of silica gel using a mixture of hexane and ethyl acetate (3: 2) as eluent. Graphed. Elution with methyl 2,5-dioxo-3,4-diphenyl-1-imidazolidine nonanoate (2.78)
g, 82%). Melting point 69-70 [deg.] C. Analysis: C 25 H 30 N 2 O 4: Calculated: C, 71.07;
H, 7.16; N, 6.65. Found: C, 71.1
3; H, 7.19; N, 6.66%. 1 H-NMR (CDCl 3 ) delta: 1.20 t
o 1.40 (8H, m), 1.50 to 1.70
(4H, m), 2.25 (2H, t, J = 6Hz),
3.55 (2H, t, J = 6Hz), 3.61 (3H,
s), 5.41 (1H, s), 7.03 (1H, t, J
= 6.5 Hz), 7.10 to 7.40 (7H,
m) and 7.45 (2H, d, J = 6.5 Hz). Example 16 2,5-Dioxo-3,4-diphenyl-
1-imidazolidine nonanoic acid
【式78】 メチル 2,5−ジオキソ−3,4−ジフェニル−1−
イミダゾリジンノナノエート(3.00g,7ミリモ
ル)と6NのHCl溶液(30ml)との混合物を還流温
度で22時間加熱した。混合物を冷却し、CH2 Cl2
で抽出し、抽出物を水で洗浄し、飽和塩化ナトリウムで
2回洗浄した。硫酸ナトリウム上で乾燥した後、溶媒を
蒸発させ、残渣を溶離液としてヘキサンとエチルアセテ
ート(2:1)の混合物を使用してシリカゲルのカラム
上でクロマトグラフ処理した。溶離液はヘキサンとジエ
チルエーテルとCH2 Cl2 (6:2:2)の混合物か
ら再結晶させると、2,3−ジオキソ−3,4−ジフェ
ニル−1−イミダゾリジンナノン酸(1.06g,36
%)を与えた。融点111.5〜112.5℃ 分析:C24H28N2 O4 :計算値:C,70.57;
H,6.91;N,6.86。実測値:C,70.4
5;H,7.05;N,6.75%。1 H−NMR(CDCl3 )delta:1.20 t
o 1.40(6H,m),1.50 to 1.80
(4H,m),2.14(2H,t,J=6Hz),
3.61(2H,t,J=6Hz),5.42(1H,
s),7.09(1H,t,J=6Hz)and 7.
15 to 7.60(9H,m)。 実施例17 メチル 5−(ジフェニルメチル)−2H
−テトラゾール−2−ノナノエート[Formula 78] Methyl 2,5-dioxo-3,4-diphenyl-1-
A mixture of imidazolidine nonanoate (3.00 g, 7 mmol) and 6N HCl solution (30 ml) was heated at reflux temperature for 22 hours. The mixture is cooled and CH 2 Cl 2
The extract was washed with water and twice with saturated sodium chloride. After drying over sodium sulfate, the solvent was evaporated and the residue was chromatographed on a column of silica gel using a mixture of hexane and ethyl acetate (2: 1) as eluent. The eluent was recrystallized from a mixture of hexane, diethyl ether and CH 2 Cl 2 (6: 2: 2) to give 2,3-dioxo-3,4-diphenyl-1-imidazolidinenanonic acid (1.06 g, 36
%) Was given. Mp 111.5-112.5 ° C. Analysis: C 24 H 28 N 2 O 4: Calculated: C, 70.57;
H, 6.91; N, 6.86. Found: C, 70.4
5; H, 7.05; N, 6.75%. 1 H-NMR (CDCl 3 ) delta: 1.20 t
o 1.40 (6H, m), 1.50 to 1.80
(4H, m), 2.14 (2H, t, J = 6Hz),
3.61 (2H, t, J = 6Hz), 5.42 (1H,
s), 7.09 (1H, t, J = 6Hz) and 7.
15 to 7.60 (9H, m). Example 17 Methyl 5- (diphenylmethyl) -2H
-Tetrazole-2-nonanoate
【式79】 米国特許第3,155,666号の方法により製造した
5−(ジフェニルメチル)−1H−テトラゾール(5
g,21ミリモル)、メチル 9−ブロモノナノエート
(5.84g,23ミリモル)、炭酸カリウム(3.5
g,25ミリモル)、沃化カリウム(触媒量)およびD
MF(75ml)から成る混合物を110℃で15分間攪
拌した。この混合物を冷却し、水で希釈してジエチルエ
ーテルで3回抽出した。合計抽出物を水で3回洗浄し、
硫酸ナトリウム上で乾燥し、そして真空濃縮して油状物
をえた。ヘキサンとジエチルエーテル(1:1)の混合
物を溶離液として使用したシリカゲルのカラム上でクロ
マトグラフ処理してメチル5−(ジフェニルメチル)−
2H−テトラゾール−2−ノナノエート(6.50g,
75%)をえた。 分析:C24H30N4 O2 :計算値:C,70.91;
H,7.44;N,13.78。実測値:C,71.0
0;H,7.57;N,14.24%。1 H−NMR(CDCl3 )delta:1.20 t
o 1.40(8H,m),1.59(2H,quin
tet,J=7Hz),1.96(2H,quinte
t,J=7Hz),2.28(2H,t,J=7.5H
z),3.64(3H,s),4.53(2H,t,J
=7Hz),5.81(1H,s)and 7.10
to 7.50(10H,m)。 実施例18 5−(ジフェニルメチル)−2H−テトラ
ゾール−1−ノナン酸[Formula 79] 5- (diphenylmethyl) -1H-tetrazole (5 produced by the method of US Pat. No. 3,155,666)
g, 21 mmol), methyl 9-bromononanoate (5.84 g, 23 mmol), potassium carbonate (3.5
g, 25 mmol), potassium iodide (catalytic amount) and D
The mixture consisting of MF (75 ml) was stirred at 110 ° C. for 15 minutes. The mixture was cooled, diluted with water and extracted 3 times with diethyl ether. Wash the total extract 3 times with water,
Dry over sodium sulfate and concentrate in vacuo to give an oil. Chromatograph on a column of silica gel using a mixture of hexane and diethyl ether (1: 1) as eluent to give methyl 5- (diphenylmethyl)-.
2H-tetrazole-2-nonanoate (6.50 g,
75%). Analysis: C 24 H 30 N 4 O 2: Calculated: C, 70.91;
H, 7.44; N, 13.78. Found: C, 71.0
0; H, 7.57; N, 14.24%. 1 H-NMR (CDCl 3 ) delta: 1.20 t
o 1.40 (8H, m), 1.59 (2H, quin
tet, J = 7 Hz), 1.96 (2H, quinte
t, J = 7 Hz), 2.28 (2H, t, J = 7.5H)
z), 3.64 (3H, s), 4.53 (2H, t, J
= 7 Hz), 5.81 (1H, s) and 7.10
to 7.50 (10H, m). Example 18 5- (Diphenylmethyl) -2H-tetrazole-1-nonanoic acid
【式80】 メチル 5−(ジフェニルメチル)−2H−テトラゾー
ル−1−ノナノエート(5.00g,12ミリモル)、
5NのNaOH溶液(7.40ml,36ミリモル)およ
びメタノール(100ml)の混合物を水蒸気浴上で還流
温度に加熱した。20分後に、混合物を濃縮し、水およ
び2NのHCl溶液で希釈し、濾過して白色固体を収集
した。CH2 Cl2 とヘキサンの混合物から再結晶させ
て5−(ジフェニルメチル)−2H−テトラゾール−1
−ノナン酸(4.40g,90%)をえた。融点68〜
70℃。 分析:C23H28N4 O2 :計算値:C,70.38;
H,7.19;N,14.27。実測値:C,70.3
7;H,7.24;N,14.35%。1 H−NMR(CDCl3 )delta:1.28(8
H,bs),1.58(2H,quintet,J=
6.5Hz),1.97(2H,quintet,J=
6.5Hz),2.29(2H,t,J=7.5H
z),4.55(2H,t,J=7Hz),5.81
(1H,s),7.15 to 7.40(10H,
m)and10.52(1H,bs)。 実施例19 メチル(3−〔2−(4,5−ジフェニル
−2−チアゾリル)エチル〕フェノキシ)アセテート[Formula 80] Methyl 5- (diphenylmethyl) -2H-tetrazole-1-nonanoate (5.00 g, 12 mmol),
A mixture of 5N NaOH solution (7.40 ml, 36 mmol) and methanol (100 ml) was heated to reflux temperature on a steam bath. After 20 minutes, the mixture was concentrated, diluted with water and 2N HCl solution and filtered to collect a white solid. Recrystallized from a mixture of CH 2 Cl 2 and hexane to give 5- (diphenylmethyl) -2H-tetrazole-1.
-Nonanoic acid (4.40 g, 90%) was obtained. Melting point 68-
70 ° C. Analysis: C 23 H 28 N 4 O 2: Calculated: C, 70.38;
H, 7.19; N, 14.27. Found: C, 70.3
7; H, 7.24; N, 14.35%. 1 H-NMR (CDCl 3 ) delta: 1.28 (8
H, bs), 1.58 (2H, quintet, J =
6.5 Hz), 1.97 (2H, quintet, J =
6.5 Hz), 2.29 (2H, t, J = 7.5H
z), 4.55 (2H, t, J = 7Hz), 5.81
(1H, s), 7.15 to 7.40 (10H,
m) and 10.52 (1H, bs). Example 19 Methyl (3- [2- (4,5-diphenyl-2-thiazolyl) ethyl] phenoxy) acetate
【式81】 3−〔2−(4,5−ジフェニル−2−チアゾリル)−
エチル〕フェノール(3.65g,10ミリモル)、メ
チルブロモアセテート(1.72g,1.06ml,11
ミリモル)、炭酸カリウム(1.69g,12ミリモ
ル)およびアセトニトリル(60ml)から成る混合物を
還流温度で90分間加熱した。混合物を濾過し、濃縮し
て油状物をえた。これをシリカゲルのカラム上でクロマ
トグラフ処理した。ヘキサンとジエチルエーテル(2:
1)の混合物で溶離してメチル〔3−〔2−(4,5−
ジフェニル−2−チアゾリル)−エチル〕フェノキシ〕
アセテート(3.63g,82%)を油状物としてえ
た。 分析:C26H23NO3 S:計算値:C,72.70;
H,5.40;N,3.26。実測値:C,73.1
3;H,5.50;N,3.26%。1 H−NMR(CDCl3 )delta:3.10 t
o 3.20(2H,m),3.30 to 3.40
(2H,m),3.78(3H,s),4.62(2
H,s),6.76(1H,dd,J=8Hz,J′=
2.5Hz),6.16(1H,d,J=2.5H
z),6.92(1H,d,J=8Hz),7.15
to 7.40(9H,m)and 7.50 to
7.60(2H,m)。 実施例20 〔3−〔2−(4,5−ジフェニル−2チ
アゾリル)エチル〕フェノキシ〕酢酸[Formula 81] 3- [2- (4,5-diphenyl-2-thiazolyl)-
Ethyl] phenol (3.65 g, 10 mmol), methyl bromoacetate (1.72 g, 1.06 ml, 11
Mmol), potassium carbonate (1.69 g, 12 mmol) and acetonitrile (60 ml) were heated at reflux temperature for 90 minutes. The mixture was filtered and concentrated to give an oil. This was chromatographed on a column of silica gel. Hexane and diethyl ether (2:
Elution with a mixture of 1) methyl [3- [2- (4,5-
Diphenyl-2-thiazolyl) -ethyl] phenoxy]
Acetate (3.63 g, 82%) was obtained as an oil. Analysis: C 26 H 23 NO 3 S : Calculated: C, 72.70;
H, 5.40; N, 3.26. Found: C, 73.1.
3; H, 5.50; N, 3.26%. 1 H-NMR (CDCl 3 ) delta: 3.10 t
o 3.20 (2H, m), 3.30 to 3.40
(2H, m), 3.78 (3H, s), 4.62 (2
H, s), 6.76 (1H, dd, J = 8Hz, J '=
2.5Hz), 6.16 (1H, d, J = 2.5H
z), 6.92 (1H, d, J = 8Hz), 7.15
to 7.40 (9H, m) and 7.50 to
7.60 (2H, m). Example 20 [3- [2- (4,5-Diphenyl-2thiazolyl) ethyl] phenoxy] acetic acid
【式82】 メチル〔3−〔2−(4,5−ジフェニル−2−チアゾ
リル)エチル〕フェノキシアセテート(2.7g,6ミ
リモル)、5NのNaOH溶液(3.77ml,18ミリ
モル)およびメタノール(40ml)を水蒸気浴上で加熱
還流させた。20分後に、混合物を冷却し、メタノール
で除去して残渣を水および2N−HCl溶液で希釈し
た。沈殿物を濾過し、水で洗浄して空気中で乾燥した。
CH2 Cl2 とヘキサンの混合物からの再結晶により
〔3−〔2−(4,5−ジフェニル−2−チアゾリル)
エチル〕フェノキシ〕酢酸(1.97g,75%)をえ
た。融点118〜120℃。 分析:C25H21NO3 S・0.1H2 O:計算値:C,
71.96;H,5.13;N,3.36;H2 O,
0.43。実測値:C,71.69;H,5.10;
N,3.06;H2 O 0.30%。1 H−NMR(DMSO−d6 )delta:3.06
(2H,t,J=8Hz),3.31(2H,t,J=
8Hz),4.62(2H,s),6.73(1H,
d,J=8Hz),6.90(2H,bs),7.19
(1H,t,J=8Hz)and 7.25 to
7.60(10H,m)。 実施例21 メチル〔3−〔2−(4,5−ジフェニル
−1H−イミダゾール−2−イル)エチル〕フェノキ
シ〕アセテート[Formula 82] Methyl [3- [2- (4,5-diphenyl-2-thiazolyl) ethyl] phenoxyacetate (2.7 g, 6 mmol), 5N NaOH solution (3.77 ml, 18 mmol) and methanol (40 ml) were steamed. Heated to reflux on the bath. After 20 minutes, the mixture was cooled, removed with methanol and the residue diluted with water and 2N HCl solution. The precipitate was filtered, washed with water and dried in air.
By recrystallization from a mixture of CH 2 Cl 2 and hexane [3- [2- (4,5-diphenyl-2-thiazolyl)]
Ethyl] phenoxy] acetic acid (1.97 g, 75%) was obtained. Melting point 118-120 [deg.] C. Analysis: C 25 H 21 NO 3 S · 0.1H 2 O: Calculated: C,
71.96; H, 5.13; N, 3.36; H 2 O,
0.43. Found: C, 71.69; H, 5.10;
N, 3.06; H 2 O 0.30 %. 1 H-NMR (DMSO-d 6 ) delta: 3.06
(2H, t, J = 8Hz), 3.31 (2H, t, J =
8Hz), 4.62 (2H, s), 6.73 (1H,
d, J = 8 Hz), 6.90 (2H, bs), 7.19
(1H, t, J = 8Hz) and 7.25 to
7.60 (10H, m). Example 21 Methyl [3- [2- (4,5-diphenyl-1H-imidazol-2-yl) ethyl] phenoxy] acetate
【式83】 3−〔2−〔1−(1−エトキシエチル)−4,5−ジ
フェニル−1H−イミダゾ−2−イル〕エチル〕フェノ
ール(6.60g,16ミリモル)、メチルブロモアセ
テート(2.69g,1.66ml,18ミリモル)、炭
酸カリウム(2.65g,19ミリモル)、沃化カリウ
ム(触媒量)およびアセトニトリル(100ml)からな
る混合物を還流温度で2.5時間攪拌した。混合物を濾
過し、濃縮し、そして残渣油をメタノール(120ml)
にとかした。濃硫酸(6滴)を添加し、混合物を還流温
度に加熱した。75分後に、濃硫酸(3滴)を加え、混
合物を更に3.75時間還流させた。メタノールを蒸発
させ、残渣を水および飽和炭酸ナトリウム溶液で希釈
し、そして混合物をCH2 Cl2 で抽出した。合計抽出
物を硫酸ナトリウム上で乾燥し、溶媒を除去して油状物
を残し、これを40時間放置して結晶化させた。ジエチ
ルエーテルですりつぶしてメチル〔3−〔2−(4,5
−ジフェニル−1H−イミダゾール−2イル〕エチル〕
フェノキシ〕アセテート(5.15g,78%)をえ
た。試料をCH2 Cl2 、ジエチルエーテルおよびヘキ
サンの混合物から2回再結晶させて分析試料を製造し
た。融点123〜125℃。 分析:C26H24N2 O3 ・0.8H2 O:計算値:C,
73.16;H,6.05;N,6.57;H2 O,
3.38。実測値:C,73.00;H,5.78;
N,6.56;H2 O 3.92%。1 H−NMR(CDCl3 )delta:2.80(4
H,bs),3.71(3H,s),4.52(2H,
s),6.50 to 6.70(3H,m),6.9
4(1H,t,J=7.5Hz),7.15 to
7.35(8H,m),7.40 to 7.45(2
H,m)and 10.13(1H,bs)。 実施例22 〔3−〔2−(4,5−ジフェニル−1H
−イミダゾール−2−イル)エチル〕フェノキシ酢酸[Formula 83] 3- [2- [1- (1-ethoxyethyl) -4,5-diphenyl-1H-imidazo-2-yl] ethyl] phenol (6.60 g, 16 mmol), methyl bromoacetate (2.69 g, 1) .66 ml, 18 mmol), potassium carbonate (2.65 g, 19 mmol), potassium iodide (catalytic amount) and acetonitrile (100 ml) were stirred at reflux temperature for 2.5 hours. The mixture is filtered, concentrated and the residual oil is methanol (120 ml).
I have been Concentrated sulfuric acid (6 drops) was added and the mixture was heated to reflux temperature. After 75 minutes concentrated sulfuric acid (3 drops) was added and the mixture was refluxed for an additional 3.75 hours. The methanol was evaporated, the residue diluted with water and saturated sodium carbonate solution and the mixture extracted with CH 2 Cl 2 . The combined extracts were dried over sodium sulphate and the solvent removed to leave an oil which left to crystallize for 40 hours. Triturate with diethyl ether and methyl [3- [2- (4,5
-Diphenyl-1H-imidazol-2yl] ethyl]
Phenoxy] acetate (5.15 g, 78%) was obtained. An analytical sample was prepared by recrystallizing the sample twice from a mixture of CH 2 Cl 2 , diethyl ether and hexane. Melting point 123-125 [deg.] C. Analysis: C 26 H 24 N 2 O 3 · 0.8H 2 O: Calculated: C,
73.16; H, 6.05; N, 6.57; H 2 O,
3.38. Found: C, 73.00; H, 5.78;
N, 6.56; H 2 O 3.92 %. 1 H-NMR (CDCl 3 ) delta: 2.80 (4
H, bs), 3.71 (3H, s), 4.52 (2H,
s), 6.50 to 6.70 (3H, m), 6.9.
4 (1H, t, J = 7.5 Hz), 7.15 to
7.35 (8H, m), 7.40 to 7.45 (2
H, m) and 10.13 (1H, bs). Example 22 [3- [2- (4,5-diphenyl-1H
-Imidazol-2-yl) ethyl] phenoxyacetic acid
【式84】 〔3−〔2−(4,5−ジフェニル−1H−イミダゾー
ル−2−イル)エチル〕フェノキシ〕アセテート(1.
20g,3ミリモル)、5NのNaOH溶液(1.74
ml,9ミリモル)およびメタノール(30ml)から成る
混合物を水蒸気浴上で20分間加熱して還流させた。溶
媒を除去し、残渣を水で希釈して2NのHCl溶液でpH
=1に酸性化した。黄色固体を濾過し、クロロホルムと
メタノール(9:1)の混合物を溶離液として使用して
シリカゲルのカラム上でクロマトグラフ処理し、〔3−
〔2−(4,5−ジフェニル−1H−イミダゾール−2
−イル)エチル〕フェノキシ〕酢酸(0.42g,36
%)をえた。融点244〜246℃。 分析:C25H22N2 O3 ・H2 O:計算値:C,72.
10;H,5.81;N,6.36;H2 O,4.3
3。実測値:C,72.01;H,5.72;N,6.
36;H2 O 1.07%。1 H−NMR(DMSO−d6 )delta:3.03
(4H,bs),4.63(2H,s),6.73(1
H,d,J=8Hz),6.80 to 6.90(2
H,m),7.20(1H,t,J=8Hz)and
7.25 to7.60(10H,m)。 実施例23 メチル〔3−〔2−(3,4−ジフェニル
−1H−ピラゾール−1−イル)エチル〕フェノキシ〕
アセテートおよびメチル〔3−〔2−(4,5−ジフェ
ニル−1H−ピラゾール−1−イル)エチル〕フェノキ
シ〕アセテート[Formula 84] [3- [2- (4,5-diphenyl-1H-imidazol-2-yl) ethyl] phenoxy] acetate (1.
20 g, 3 mmol), 5N NaOH solution (1.74)
ml, 9 mmol) and methanol (30 ml) were heated to reflux on a steam bath for 20 minutes. Remove the solvent, dilute the residue with water and adjust the pH with 2N HCl solution.
Acidified to = 1. The yellow solid was filtered and chromatographed on a column of silica gel using a mixture of chloroform and methanol (9: 1) as eluent, [3-
[2- (4,5-diphenyl-1H-imidazole-2
-Yl) ethyl] phenoxy] acetic acid (0.42 g, 36
%). Melting point 244-246 [deg.] C. Analysis: C 25 H 22 N 2 O 3 .H 2 O: Calculated value: C, 72.
10; H, 5.81; N, 6.36; H 2 O, 4.3
3. Found: C, 72.01; H, 5.72; N, 6.
36; H 2 O 1.07%. 1 H-NMR (DMSO-d 6 ) delta: 3.03
(4H, bs), 4.63 (2H, s), 6.73 (1
H, d, J = 8 Hz), 6.80 to 6.90 (2
H, m), 7.20 (1H, t, J = 8 Hz) and
7.25 to 7.60 (10H, m). Example 23 Methyl [3- [2- (3,4-diphenyl-1H-pyrazol-1-yl) ethyl] phenoxy]
Acetate and methyl [3- [2- (4,5-diphenyl-1H-pyrazol-1-yl) ethyl] phenoxy] acetate
【式85】 [Formula 85]
【式86】 水素化ナトリウム(鉱油中50%分散液0.72g,1
5ミリモル)をヘキサンで2回洗浄し、DMF(10m
l)で覆い、3,4−ジフェニル−1H−ピラゾール
(2.99g,13ミリモル)を加えた。ガス発生が止
んだ後に、混合物を110℃で1時間攪拌し、室温に冷
却し、そしてDMF(20ml)中の〔3−〔2−
〔〔(4−メチルフェニル)スルホニル〕オキシ〕エチ
ル〕フェノキシ〕アセテート(4.95g,12ミリモ
ル)を加えた。室温で15時間攪拌後に、混合物を水に
注入し、エチルアセテートで抽出した。合計抽出物を水
で3回洗浄し、飽和塩化ナトリウムで1回洗浄し、硫酸
ナトリウム上で乾燥し、そして溶媒を蒸発させた。残渣
油をヘキサンとエチルアセテート(4:1)の混合物を
溶離液として使用してシリカゲル上でくりかえしクロマ
トグラフ処理した。極性の小さい物質をメチル〔3−
〔2−(3,4−ジフェニル)−1H−ピラゾール−1
−イル〕エチル〕フェノキシ〕アセテート(1.71
%,30%)と確認した。 分析:C26H24N2 O3 ・0.3H2 O:計算値:C,
74.73;H,5.94;N,6.71;H2 O,
1.29。実測値:C,74.42;H,6.07;
N,6.55;H2 O 0.65%。1 H−NMR(CDCl3 )delta:3.21(2
H,t,J=7Hz),3.75(3H,s),4.3
6(2H,t,J=7Hz),4.56(2H,s),
6.60 to 6.80(3H,m),7.10 t
o 7.40(10H,m)and 7.45 to
7.55(2H,m)。 The more polar material w
as identified as methyl〔3
−〔2−(4,5−diphenyl−1H−pyra
zol−1−yl)ethyl〕phenoxy〕ac
etate(0.66g,11%)。 分析:C26H24N2 O3 :計算値:C,75.71;
H,5.87;N,6.80。実測値:C,75.8
4;H,5.90;N,6.71%。1 H−NMR(CDCl3 )delta:3.06(2
H,t,J=7Hz),3.75(3H,s),4.1
6(2H,t,J=7Hz),4.48(2H,s),
6.39(1H,d,J=1.5Hz),6.56(1
H,d,J=7.5Hz),6.72(1H,dd,J
=7.5Hz,J′=1.5Hz),6.85 to
7.40(11H,m)and 7.81(1H,
s)。 実施例24 〔3−〔2−(3,4−ジフェニル−1H
−ピラゾール−1−イル)エチル〕フェノキシ〕酢酸[Formula 86] Sodium hydride (50% dispersion in mineral oil 0.72 g, 1
(5 mmol) was washed twice with hexane, and DMF (10 m
Cover with l) and add 3,4-diphenyl-1H-pyrazole (2.99 g, 13 mmol). After the evolution of gas ceased, the mixture was stirred at 110 ° C. for 1 hour, cooled to room temperature and [3- [2-
[[(4-Methylphenyl) sulfonyl] oxy] ethyl] phenoxy] acetate (4.95 g, 12 mmol) was added. After stirring for 15 hours at room temperature, the mixture was poured into water and extracted with ethyl acetate. The total extracts were washed 3 times with water, once with saturated sodium chloride, dried over sodium sulphate and the solvent was evaporated. The residual oil was repeatedly chromatographed on silica gel using a mixture of hexane and ethyl acetate (4: 1) as eluent. Methyl [3-
[2- (3,4-diphenyl) -1H-pyrazole-1
-Yl] ethyl] phenoxy] acetate (1.71)
%, 30%). Analysis: C 26 H 24 N 2 O 3 .0.3H 2 O: Calculated value: C,
74.73; H, 5.94; N, 6.71; H 2 O,
1.29. Found: C, 74.42; H, 6.07;
N, 6.55; H 2 O 0.65 %. 1 H-NMR (CDCl 3 ) delta: 3.21 (2
H, t, J = 7 Hz), 3.75 (3H, s), 4.3
6 (2H, t, J = 7Hz), 4.56 (2H, s),
6.60 to 6.80 (3H, m), 7.10 t
o 7.40 (10H, m) and 7.45 to
7.55 (2H, m). The more polar material w
as identified as methyl [3
-[2- (4,5-diphenyl-1 H- pyra
zol-1-yl) ethyl] phenoxy] ac
etate (0.66 g, 11%). Analysis: C 26 H 24 N 2 O 3: Calculated: C, 75.71;
H, 5.87; N, 6.80. Found: C, 75.8.
4; H, 5.90; N, 6.71%. 1 H-NMR (CDCl 3 ) delta: 3.06 (2
H, t, J = 7 Hz), 3.75 (3H, s), 4.1
6 (2H, t, J = 7Hz), 4.48 (2H, s),
6.39 (1H, d, J = 1.5Hz), 6.56 (1
H, d, J = 7.5 Hz), 6.72 (1H, dd, J
= 7.5 Hz, J '= 1.5 Hz), 6.85 to
7.40 (11H, m) and 7.81 (1H,
s). Example 24 [3- [2- (3,4-diphenyl-1H
-Pyrazol-1-yl) ethyl] phenoxy] acetic acid
【式87】 メチル〔3−〔2−(3,4−ジフェニル−1H−ピラ
ゾール−1−イル)エチル〕フェノキシ〕アセテート
(1.70g,4ミリモル)、3NのNaOH溶液
(2.42ml,12ミリモル)およびメタノール(60
ml)から成る混合物を水蒸気浴上で10分間加熱した。
混合物を濃縮し、水で希釈し、希HCl溶液でpH=1と
なし、CH2 Cl2 で抽出した。合計抽出物を飽和塩化
ナトリウム溶液で洗浄し、硫酸ナトリウム上で乾燥し、
溶媒を蒸発させた。残渣をCH2 Cl2にとかし、ヘキ
サンで希釈して〔3−〔2−(3,4−ジフェニル)−
1H−ピラゾール−1−イル〕エチル〕フェノキシ酢酸
(1.27g,77%)をえた。 融点147.5〜149℃。 分析:C25H22N2 O3 ・0.15H2 O:計算値:
C,74.86;H,5.61;N,6.98;H
2 O,0.67。実測値:C,74.55;H,5.5
7;N,6.96;H2 O,0.43%。1 H−NMR(CDCl3 )delta:3.18(2
H,t,J=7.5Hz),4.39(2H,t,J=
7.5Hz),4.57(2H,s),6.70 to
6.90(3H,m),7.10 to 7.40
(10H,m),7.45 to 7.50(2H,
m)and 7.60(1H,bs)。 実施例25 〔3−〔2−(4,5−ジフェニル−1H
−ピラゾール−1−イル)エチル〕フェノキシ〕酢酸[Formula 87] Methyl [3- [2- (3,4-diphenyl-1H-pyrazol-1-yl) ethyl] phenoxy] acetate (1.70 g, 4 mmol), 3N NaOH solution (2.42 ml, 12 mmol) and methanol. (60
ml) was heated on a steam bath for 10 minutes.
The mixture was concentrated, diluted with water, brought to pH = 1 with dilute HCl solution and extracted with CH 2 Cl 2 . The total extract was washed with saturated sodium chloride solution, dried over sodium sulfate,
The solvent was evaporated. The residue was dissolved in CH 2 Cl 2, and diluted with hexane [3- [2- (3,4-diphenyl) -
1H-pyrazol-1-yl] ethyl] phenoxyacetic acid (1.27 g, 77%) was obtained. Melting point 147.5-149 [deg.] C. Analysis: C 25 H 22 N 2 O 3 .0.15H 2 O: Calculated value:
C, 74.86; H, 5.61; N, 6.98; H
2 O, 0.67. Found: C, 74.55; H, 5.5.
7; N, 6.96; H 2 O, 0.43%. 1 H-NMR (CDCl 3 ) delta: 3.18 (2
H, t, J = 7.5 Hz), 4.39 (2H, t, J =
7.5 Hz), 4.57 (2H, s), 6.70 to
6.90 (3H, m), 7.10 to 7.40
(10H, m), 7.45 to 7.50 (2H,
m) and 7.60 (1H, bs). Example 25 [3- [2- (4,5-diphenyl-1H
-Pyrazol-1-yl) ethyl] phenoxy] acetic acid
【式88】 メチル〔3−〔2−(4,5−ジフェニル−1H−ピラ
ゾール−1−イル)エチル〕フェノキシ〕アセテート
(0.42g,1ミリモル)、3NのNaOH溶液
(1.0ml,3ミリモル)およびメタノール(30ml)
から成る混合物を水蒸気浴上で15分間加熱し、その後
に真空蒸発した。残渣を水で希釈し、1NのHCl溶液
でpH=1まで加え、混合物をCH2 Cl2 で抽出した。
合計有機相を飽和塩化ナトリウム溶液で洗浄し、硫酸ナ
トリウム上で乾燥し、そして真空蒸発した。残渣をCH
2 Cl2 にとかし、ヘキサンで希釈して〔3−〔2−
(4,5−ジフェニル−1H−ピラゾール−1−イル)
エチル〕フェノキシ〕酢酸(0.28g,58%)をえ
た。融点133〜138℃ 分析:C25H22N2 O3 :計算値:C,75.36;
H,5.57;N,7.04。実測値:C,75.2
1;H,5.48;N,7.09%。1 H−NMR(CDCl3 )delta:2.99(2
H,t,J=7Hz),4.21(2H,t,J=7H
z),4.57(2H,s),6.51(1H,d,J
=7.5Hz),6.57(1H,s),6.78(1
H,dd,J=7.5Hz,J′=2Hz),6.95
to 7.45(11H,m)and7.85(1
H,s)。 実施例26 メチル〔3−〔2−(1,5−ジフェニル
−1H−ピラゾール−3−イル)エチル〕フェノキシ〕
アセテート[Formula 88] Methyl [3- [2- (4,5-diphenyl-1H-pyrazol-1-yl) ethyl] phenoxy] acetate (0.42 g, 1 mmol), 3N NaOH solution (1.0 ml, 3 mmol) and methanol. (30 ml)
The mixture consisting of was heated on a steam bath for 15 minutes and then evaporated in vacuo. The residue was diluted with water, added with 1N HCl solution until pH = 1 and the mixture was extracted with CH 2 Cl 2 .
The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. CH the residue
It was dissolved in 2 Cl 2 , diluted with hexane, and then [3- [2-
(4,5-Diphenyl-1H-pyrazol-1-yl)
Ethyl] phenoxy] acetic acid (0.28 g, 58%) was obtained. Mp one hundred thirty-three to one hundred and thirty-eight ° C. Analysis: C 25 H 22 N 2 O 3: Calculated: C, 75.36;
H, 5.57; N, 7.04. Found: C, 75.2.
1; H, 5.48; N, 7.09%. 1 H-NMR (CDCl 3 ) delta: 2.99 (2
H, t, J = 7Hz), 4.21 (2H, t, J = 7H)
z), 4.57 (2H, s), 6.51 (1H, d, J
= 7.5 Hz), 6.57 (1 H, s), 6.78 (1
H, dd, J = 7.5 Hz, J ′ = 2 Hz), 6.95
to 7.45 (11H, m) and 7.85 (1
H, s). Example 26 Methyl [3- [2- (1,5-diphenyl-1H-pyrazol-3-yl) ethyl] phenoxy]
acetate
【式89】 〔3−〔2−(1,5−ジフェニル−1H−ピラゾール
−3−イル)エチル〕フェノール(4.50g,13ミ
リモル)、メチルブロモアセテート(2.23g,1.
375ml,14.5ミリモル)、炭酸カリウム(2.1
9g,16ミリモル)、沃化カリウム(触媒量)、およ
びアセトニトリル(80ml)から成る混合物を還流温度
で3時間攪拌した。混合物を濾過し、濃縮して残渣をヘ
キサンとジエチルエーテル(9:1)の混合物中で調製
したシリカゲルのカラムでクロマトグラフ処理した。次
いでヘキサンとジエチルエーテル(1:1)の混合物で
溶離してメチル〔3−〔2−(1,5−ジフェニル−1
H−ピラゾール−3−イル)エチル〕フェノキシ〕アセ
テート(4.83g,85%)を油状物としてえた。 分析:C26H24N2 O3 :計算値:C,75.71;
H,5.86;N,6.79。実測値:C,75.4
6;H,6.13;N,7.12%。1 H−NMR(CDCl3 )delta:3.04(4
H,s),3.77(3H,s),4.51(2H,
s),6.30(1H,s),6.75(1H,d,J
=7Hz),6.86(1H,s),6.93(1H,
d,J=7Hz),and 7.10 to 7.40
(11H,m)。 実施例27 〔3−〔2−(1,5−ジフェニル−1H
−ピラゾール−3−イル)エチル〕フェノキシ〕酢酸[Formula 89] [3- [2- (1,5-diphenyl-1H-pyrazol-3-yl) ethyl] phenol (4.50 g, 13 mmol), methyl bromoacetate (2.23 g, 1.
375 ml, 14.5 mmol), potassium carbonate (2.1
A mixture of 9 g, 16 mmol), potassium iodide (catalytic amount), and acetonitrile (80 ml) was stirred at reflux temperature for 3 hours. The mixture was filtered, concentrated and the residue chromatographed on a column of silica gel prepared in a mixture of hexane and diethyl ether (9: 1). Then elute with a mixture of hexane and diethyl ether (1: 1) to obtain methyl [3- [2- (1,5-diphenyl-1
H-pyrazol-3-yl) ethyl] phenoxy] acetate (4.83 g, 85%) was obtained as an oil. Analysis: C 26 H 24 N 2 O 3: Calculated: C, 75.71;
H, 5.86; N, 6.79. Found: C, 75.4.
6; H, 6.13; N, 7.12%. 1 H-NMR (CDCl 3 ) delta: 3.04 (4
H, s), 3.77 (3H, s), 4.51 (2H,
s), 6.30 (1H, s), 6.75 (1H, d, J
= 7 Hz), 6.86 (1H, s), 6.93 (1H,
d, J = 7 Hz), and 7.10 to 7.40.
(11H, m). Example 27 [3- [2- (1,5-diphenyl-1H
-Pyrazol-3-yl) ethyl] phenoxy] acetic acid
【式90】 メチル〔3−〔2−(1,5−ジフェニル−1H−ピラ
ゾール−3−イル)エチル〕フェノキシ〕アセテート
(3.50g,8.5ミリモル)、5NのNaOH溶液
(5ml,25ミリモル)およびメタノール(70ml)か
ら成る混合物を水蒸気浴上で還流温度に15分間加熱し
た。溶媒を蒸発させ、残渣を水で希釈し、2NのHCl
でpH=1に酸性化した。白色固体を濾過し、ヘキサンと
CH2 Cl2 の混合物から再結晶させて〔3−〔2−
(1,5−ジフェニル−1H−ピラゾール−3−イル)
エチル〕フェノキシ〕酢酸(2.85g,84%)をえ
た。融点125〜127℃。 分析C25H22N2 O3 ・0.2H2 O:計算値:C,7
4.69;H,5.62;N,6.97;H2 O,0.
90。実測値:C,74.68;H,6.08;N,
6.87;H2 O,0.05%。1 H−NMR(DMSO−d6 )delta:2.95
(4H,m),4.65(2H,s),6.51(1
H,s),6.73(1H,d,J=7Hz),6.8
5 to 6.95(2H,m),7.15 to
7.25(5H,m),7.25 to 7.40(6
H,m)and 12.65(1H,bs)。 実施例28 メチル〔3−〔2−(1,6−ジヒドロ−
6−オキソ−3,4−ジフェニル−1−ピペラジニル)
エチル〕フェノキシ〕アセテート[Formula 90] Methyl [3- [2- (1,5-diphenyl-1H-pyrazol-3-yl) ethyl] phenoxy] acetate (3.50 g, 8.5 mmol), 5N NaOH solution (5 ml, 25 mmol) and methanol. A mixture of (70 ml) was heated to reflux temperature on a steam bath for 15 minutes. The solvent was evaporated, the residue diluted with water and 2N HCl
Acidified to pH = 1. The white solid was filtered and recrystallized from a mixture of hexane and CH 2 Cl 2 [3- [2-
(1,5-diphenyl-1H-pyrazol-3-yl)
Ethyl] phenoxy] acetic acid (2.85 g, 84%) was obtained. Melting point 125-127 [deg.] C. Analysis C 25 H 22 N 2 O 3 .0.2H 2 O: Calculated value: C, 7
4.69; H, 5.62; N, 6.97; H 2 O, 0.
90. Found: C, 74.68; H, 6.08; N,
6.87; H 2 O, 0.05% . 1 H-NMR (DMSO-d 6 ) delta: 2.95.
(4H, m), 4.65 (2H, s), 6.51 (1
H, s), 6.73 (1H, d, J = 7 Hz), 6.8
5 to 6.95 (2H, m), 7.15 to
7.25 (5H, m), 7.25 to 7.40 (6
H, m) and 12.65 (1H, bs). Example 28 Methyl [3- [2- (1,6-dihydro-
6-oxo-3,4-diphenyl-1-piperazinyl)
Ethyl] phenoxy] acetate
【式91】 ジエチルアゾジカルボキシレート(2.73g,2.5
0ml,16ミリモル)を、0℃の乾燥THF(75ml)
中の5,6−ジフェニル−3 (2H)−ピリダジノン
(3.00g,12ミリモル)、メチル〔3−(2−ヒ
ドロキシエチル)−フェノキシ〕アセテート(2.80
g,13ミリモル)およびトリフェニルホスフィン
(4.12g,16ミリモル)から成る攪拌溶液に加え
た。氷浴を除き、混合物を室温で1.75時間攪拌し、
その後に溶媒を除去した。残渣を、ジエチルエーテルと
ヘキサン(7:3)の混合物を使用してシリカゲルのカ
ラム上で2回クロマトグラフ処理してメチル〔3−〔2
−(1,6−ジヒドロ−6−オキソ−3,4−ジフェニ
ル−1−ピリダジニル)エチル〕フェノキシアセテート
(5.12g,98%)を0.6当量の1,2−ジカル
ボエトキシヒドラジンを夾雑させた白色泡状物としてえ
た。 分析C27H24N2 O4 ・0.3H2 O・0.6C6 H12
N2 O4 :計算値:C,66.64;H,5.82;
N,8.13;H2 O,0.98。実測値:C,66.
45;H,5.60;N,7.73;H2 O,0.42
%。1 H−NMR(CDCl3 )delta:1.24(3
H,t,J=7Hz),4.49(2H,t,J=8H
z),4.59(1H,s),6.77(1H,dd,
J=8Hz,J′=2.5Hz),8.83(1H,
d,J=2.5Hz),6.93(1H,s),6.9
3(1H,m),7.00 to 7.10(4H,
m)and 7.15 to 7.40(8H,m)。 実施例29 〔3−〔2−(1,6−ジヒドロ−6−オ
キソ−3,4−ジフェニル−1−ピリダジニル)エチ
ル〕フェノキシ酢酸[Formula 91] Diethylazodicarboxylate (2.73 g, 2.5
0 ml, 16 mmol) was added to dry THF (75 ml) at 0 ° C.
5,6-diphenyl-3 (2H) -pyridazinone (3.00 g, 12 mmol), methyl [3- (2-hydroxyethyl) -phenoxy] acetate (2.80).
g, 13 mmol) and triphenylphosphine (4.12 g, 16 mmol) were added to a stirred solution. Remove the ice bath, stir the mixture at room temperature for 1.75 h,
Then the solvent was removed. The residue was chromatographed twice on a column of silica gel with a mixture of diethyl ether and hexane (7: 3) to give methyl [3- [2
-(1,6-Dihydro-6-oxo-3,4-diphenyl-1-pyridazinyl) ethyl] phenoxyacetate (5.12 g, 98%) was contaminated with 0.6 equivalents of 1,2-dicarboethoxyhydrazine. As a white foam. Analysis C 27 H 24 N 2 O 4 · 0.3H 2 O · 0.6C 6 H 12
N 2 O 4: Calculated: C, 66.64; H, 5.82 ;
N, 8.13; H 2 O, 0.98. Found: C, 66.
45; H, 5.60; N, 7.73; H 2 O, 0.42
%. 1 H-NMR (CDCl 3 ) delta: 1.24 (3
H, t, J = 7Hz), 4.49 (2H, t, J = 8H
z), 4.59 (1H, s), 6.77 (1H, dd,
J = 8Hz, J '= 2.5Hz), 8.83 (1H,
d, J = 2.5 Hz), 6.93 (1H, s), 6.9
3 (1H, m), 7.00 to 7.10 (4H,
m) and 7.15 to 7.40 (8H, m). Example 29 [3- [2- (1,6-dihydro-6-oxo-3,4-diphenyl-1-pyridazinyl) ethyl] phenoxyacetic acid
【式92】 メチル〔3−〔2−(1,6−ジヒドロ−6−オキソ−
3,4−ジフェニル−1−ピリダジニル)エチル〕フェ
ノキシアセテート(4.60g,11ミリモル)、5N
のNaOH溶液(3.20ml,32ミリモル)およびメ
タノール(90ml)から成る混合物を水蒸気浴上で還流
温度に加熱した。25分後にメタノールを蒸発させ、残
渣を水で希釈し、2NのHCl溶液でpH=1に酸性化し
た。白色固体を濾過し、CH2 Cl2 にとかした。ジエ
チルエーテルを加えて〔3−〔2−(1,6−ジヒドロ
−6−オキソ−3,4−ジフェニル)−1−ピリダジニ
ル)エチル〕フェノキシ〕酢酸水和ジクロロメタン溶媒
和物(2.60g,58%)をえた。融点165〜16
7℃。 分析:C26H22N2 O4 ・0.1H2 O・CH2 C
l2 :計算値:C,63.20;H,4.76;N,
5.46;H2 O,0.35。実測値:C,63.4
1;H,4.69;N,5.44;H2 O,0.14
%。1 H−NMR(DMSO−d6 )delta:3.06
(2H,t,J=7.5Hz),4.37(2H,t,
J=7.5Hz),4.62(1H,s),5.74
(2H,s),6.65 to 6.90(3H,
m),6.94(1H,s),7.00 to 7.4
5(11H,m)and 12.96(1H,bs)。 実施例30 メチル〔3−〔2−(2,3−ジヒドロ−
3−オキソ−5,6−ジフェニル−1,2,4−トリア
ジン−2−イル)エチル〕フェノキシ〕アセテート[Formula 92] Methyl [3- [2- (1,6-dihydro-6-oxo-
3,4-Diphenyl-1-pyridazinyl) ethyl] phenoxyacetate (4.60 g, 11 mmol), 5N
A mixture of the above NaOH solution (3.20 ml, 32 mmol) and methanol (90 ml) was heated to reflux temperature on a steam bath. After 25 minutes the methanol was evaporated, the residue diluted with water and acidified to pH = 1 with 2N HCl solution. The white solid was filtered and dissolved in CH 2 Cl 2 . Diethyl ether was added to add [3- [2- (1,6-dihydro-6-oxo-3,4-diphenyl) -1-pyridazinyl) ethyl] phenoxy] acetic acid hydrated dichloromethane solvate (2.60 g, 58). %). Melting point 165-16
7 ° C. Analysis: C 26 H 22 N 2 O 4 · 0.1H 2 O · CH 2 C
l 2 : calculated: C, 63.20; H, 4.76; N,
5.46; H 2 O, 0.35. Found: C, 63.4.
1; H, 4.69; N, 5.44; H 2 O, 0.14
%. 1 H-NMR (DMSO-d 6 ) delta: 3.06
(2H, t, J = 7.5 Hz), 4.37 (2H, t,
J = 7.5 Hz), 4.62 (1H, s), 5.74
(2H, s), 6.65 to 6.90 (3H,
m), 6.94 (1H, s), 7.00 to 7.4
5 (11H, m) and 12.96 (1H, bs). Example 30 Methyl [3- [2- (2,3-dihydro-
3-oxo-5,6-diphenyl-1,2,4-triazin-2-yl) ethyl] phenoxy] acetate
【式93】 ジエチルアゾジカルボキシレート(2.72g,2.5
0ml,16ミリモル)を、0℃の乾燥THF(75ml)
中の5,6−ジフェニル−1,2,4−トリアゾール−
3(2H)−オン(3.00g,12ミリモル)、トリ
フェニルホスフィン(4.11g,16ミリモル)およ
びメチル〔3−(2−ヒドロキシエチル)フェノキシ〕
アセテート(2.78g,13ミリモル)から成る攪拌
溶液に加えた。氷浴を除き、混合物を室温で3時間攪拌
した。溶媒を蒸発し、残渣をジエチルエーテルとヘキサ
ン(7:3)の混合物を溶離液として使用してシリカゲ
ルのカラム上で2回クロマトグラフ処理してメチル〔3
−〔2−(2,3−ジヒドロ−3−オキソ−5,6−ジ
フェニル−1,2,4−トリアジン−2−イル)エチ
ル〕フェノキシ〕アセテート(6.40g,90%)を
黄色泡状物としてえた。 分析:C26H23N3 O4 ・0.5H2 O:計算値:C,
69.33;H,5.38;N,9.33;H2 O,
1.99。実測値:C,69.23;H,5.19;
N,9.56;H2 O,0.15%。1 H−NMR(CDCl3 )delta:3.19(2
H,t,J=7.5Hz),3.72(3H,s),
4.45(2H,t,J=7.5Hz),4.56(1
H,s),6.70 to 6.80(2H,m),
6.88(1H,d,J=7.5Hz),7.10 t
o 7.50(11H,m)。 実施例31 〔3−〔2−(2,3−ジヒドロ−3−オ
キソ−5,6−ジフェニル−1,2,4−トリアジン−
2−イル)エチル〕フェノキシ〕酢酸[Formula 93] Diethylazodicarboxylate (2.72 g, 2.5
0 ml, 16 mmol) was added to dry THF (75 ml) at 0 ° C.
5,6-diphenyl-1,2,4-triazole-in
3 (2H) -one (3.00 g, 12 mmol), triphenylphosphine (4.11 g, 16 mmol) and methyl [3- (2-hydroxyethyl) phenoxy].
Add to a stirred solution of acetate (2.78 g, 13 mmol). The ice bath was removed and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue was chromatographed twice on a column of silica gel using a mixture of diethyl ether and hexane (7: 3) as eluent to give methyl [3
-[2- (2,3-Dihydro-3-oxo-5,6-diphenyl-1,2,4-triazin-2-yl) ethyl] phenoxy] acetate (6.40 g, 90%) as a yellow foam I got it as a thing. Analysis: C 26 H 23 N 3 O 4 · 0.5H 2 O: Calculated: C,
69.33; H, 5.38; N, 9.33; H 2 O,
1.99. Found: C, 69.23; H, 5.19;
N, 9.56; H 2 O, 0.15%. 1 H-NMR (CDCl 3 ) delta: 3.19 (2
H, t, J = 7.5 Hz), 3.72 (3H, s),
4.45 (2H, t, J = 7.5Hz), 4.56 (1
H, s), 6.70 to 6.80 (2H, m),
6.88 (1H, d, J = 7.5 Hz), 7.10 t
o 7.50 (11H, m). Example 31 [3- [2- (2,3-dihydro-3-oxo-5,6-diphenyl-1,2,4-triazine-
2-yl) ethyl] phenoxy] acetic acid
【式94】 メチル〔3−〔2−(2,3−ジヒドロ−3−オキソ−
5,6−ジフェニル−1,2,4−トリアジン−2−イ
ル)エチル〕フェノキシ〕アセテート(4.00g,9
ミリモル)、5NのNaOH(3.70ml,18ミリモ
ル)およびメタノール(60ml)から成る混合物を水蒸
気浴上で還流温度に加熱した。20分後に、メタノール
を蒸発し、残渣を水で希釈し、2NのHCl溶液で酸性
化した。黄色固体を濾過し、ヘキサンとCH2 Cl2 の
混合物から再結晶させて〔3−〔2−(2,3−ジヒド
ロ−3−オキソ−5,6−ジフェニル−1,2,4−ト
リアジン−2−イル)エチル〕フェノキシ〕酢酸(2.
79g,72%)をえた。 融点179〜182℃。 分析:C25H21N3 O4 ・0.5H2 O:計算値:C,
68.80;H,5.09;N,9.63;H2 O,
2.06。実測値:C,68.81;H,4.79;
N,8.64;H2 O,0.51%。1 H−NMR(DMSO−d6 )delta:3.10
(2H,t,J=7.5Hz),4.36(2H,t,
J=7.5Hz),4.62(2H,s),6.70
to 6.95(3H,m),7.10 to 7.6
0(11H,m)and 12.97(1H,bs)。 実施例32 メチル〔3−〔2−〔5−(ジフェニルメ
チル)−2H−テトラゾール−2−イル)エチル〕フェ
ノキシ〕アセテート[Formula 94] Methyl [3- [2- (2,3-dihydro-3-oxo-
5,6-Diphenyl-1,2,4-triazin-2-yl) ethyl] phenoxy] acetate (4.00 g, 9
Mmol), 5N NaOH (3.70 ml, 18 mmol) and methanol (60 ml) were heated to reflux temperature on a steam bath. After 20 minutes the methanol was evaporated, the residue diluted with water and acidified with 2N HCl solution. The yellow solid was filtered and recrystallized from a mixture of hexane and CH 2 Cl 2 to give [3- [2- (2,3-dihydro-3-oxo-5,6-diphenyl-1,2,4-triazine- 2-yl) ethyl] phenoxy] acetic acid (2.
79 g, 72%). Melting point 179-182 [deg.] C. Analysis: C 25 H 21 N 3 O 4 .0.5H 2 O: Calculated value: C,
68.80; H, 5.09; N, 9.63; H 2 O,
2.06. Found: C, 68.81; H, 4.79;
N, 8.64; H 2 O, 0.51%. 1 H-NMR (DMSO-d 6 ) delta: 3.10
(2H, t, J = 7.5 Hz), 4.36 (2H, t,
J = 7.5 Hz), 4.62 (2H, s), 6.70
to 6.95 (3H, m), 7.10 to 7.6
0 (11H, m) and 12.97 (1H, bs). Example 32 Methyl [3- [2- [5- (diphenylmethyl) -2H-tetrazol-2-yl) ethyl] phenoxy] acetate
【式95】 ジエチルアゾジカルボキシレート(0.96g,5.5
ミリモル)を、氷冷中0℃に冷却した乾燥THF(17
ml)中の5−(ジフェニルメチル)−2H−テトラゾー
ル(1.00g,4.2ミリモル)、メチル〔3−(2
−ヒドロキシエチル)−フェノキシ〕アセテート(0.
98g,4.6ミリモル)およびトリフェニルホスフィ
ン(1.44g,5.5ミリモル)から成る攪拌溶液に
加えた。氷浴を除き、混合物を室温で1時間攪拌してか
ら溶媒を蒸発した。残渣をヘキサンとエチルアセテート
の混合物を使用してシリカゲルのカラム上でクロマトグ
ラフ処理して、メチル〔3−〔2−〔5−(ジフェニル
メチル)−2H−テトラゾール−2−イル〕フェノキ
シ〕アセテート(1.06g,58%)を無色油状物と
してえた。 分析:C25H24N4 O3 :計算値:C,70.08;
H,5.65;N,13.08。実測値:C,70.0
3;H,5.73;N,12.66%。1 H−NMR(CDCl3 )delta:3.26(2
H,t,J=7.5Hz),3.78(3H,s),
4.53(2H,s),4.79(2H,t,J=7.
5Hz),5.77(1H,s),6.65 to
6.80(3H,m)and 7.10 to 7.4
0(11H,m)。 実施例33 〔3−〔2−〔5−ジフェニルメチル)−
2H−テトラゾール−2−イル〕エチル〕フェノキシ〕
酢酸[Formula 95] Diethylazodicarboxylate (0.96g, 5.5
Mmol) in dry THF (17
5- (diphenylmethyl) -2H-tetrazole (1.00 g, 4.2 mmol), methyl [3- (2
-Hydroxyethyl) -phenoxy] acetate (0.
98 g, 4.6 mmol) and triphenylphosphine (1.44 g, 5.5 mmol) were added to a stirred solution. The ice bath was removed, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated. The residue was chromatographed on a column of silica gel using a mixture of hexane and ethyl acetate to give methyl [3- [2- [5- (diphenylmethyl) -2H-tetrazol-2-yl] phenoxy] acetate ( 1.06 g, 58%) was obtained as a colorless oil. Analysis: C 25 H 24 N 4 O 3: Calculated: C, 70.08;
H, 5.65; N, 13.08. Found: C, 70.0
3; H, 5.73; N, 12.66%. 1 H-NMR (CDCl 3 ) delta: 3.26 (2
H, t, J = 7.5 Hz), 3.78 (3H, s),
4.53 (2H, s), 4.79 (2H, t, J = 7.
5 Hz), 5.77 (1 H, s), 6.65 to
6.80 (3H, m) and 7.10 to 7.4
0 (11H, m). Example 33 [3- [2- [5-diphenylmethyl)-
2H-tetrazol-2-yl] ethyl] phenoxy]
Acetic acid
【式96】 メチル〔3−〔2−〔5−(ジフェニルメチル)−2H
−テトラゾール−2−イル〕エチル〕フェノキシ〕アセ
テート(0.84g,2ミリモル)、3NのNaOH溶
液(2.00ml,6ミリモル)およびメタノール(35
ml)を水蒸気浴上で10分間加熱した。メタノールを蒸
発し、残渣を水で希釈し、1NのHCl溶液でpH=1に
酸性化した。混合物をCH2 Cl2 で3回抽出し、合計
抽出物を飽和塩化ナトリウム溶液で洗浄し、硫酸ナトリ
ウム上で乾燥した。溶媒蒸発後に残った油状物をクロロ
ホルムとメタノール(93:7)の混合物を溶離液とし
て使用してシリカゲルのカラム上でクロマトグラフ処理
して、〔3−〔2−〔5−(ジフェニルメチル)−2H
−テトラゾール−2−イル〕エチル〕フェノキシ〕酢酸
(0.50g,61%)を無色油状物としてえた。 分析:C24H22N4 O3 ・0.2H2 O:計算値:C,
68.96;H,5.41;N,13.41;H2 O,
0.86。実測値:C,68.58;H,5.42;
N,13.05;H2 O,0.54%。1 H−NMR(CDCl3 )delta:3.25(2
H,t,J=7.5Hz),4.54(2H,s),
4.78(2H,t,J=7.5Hz),5.80(1
H,s),6.60 to 6.85(3H,m),
7.20 to 7.40(11H,m)and 9.
62(1H,bs)。 実施例34 中間体の製造 (34−1) 3−〔2−(4,5−ジフェニル−2−
チアゾリル)エチル〕フェノール[Formula 96] Methyl [3- [2- [5- (diphenylmethyl) -2H
-Tetrazol-2-yl] ethyl] phenoxy] acetate (0.84 g, 2 mmol), 3N NaOH solution (2.00 ml, 6 mmol) and methanol (35
ml) was heated on a steam bath for 10 minutes. The methanol was evaporated, the residue diluted with water and acidified to pH = 1 with 1N HCl solution. The mixture was extracted 3 times with CH 2 Cl 2 and the combined extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The oil remaining after evaporation of the solvent was chromatographed on a column of silica gel using a mixture of chloroform and methanol (93: 7) as eluent, [3- [2- [5- (diphenylmethyl)- 2H
-Tetrazol-2-yl] ethyl] phenoxy] acetic acid (0.50 g, 61%) was obtained as a colorless oil. Analysis: C 24 H 22 N 4 O 3 .0.2H 2 O: Calculated value: C,
68.96; H, 5.41; N, 13.41; H 2 O,
0.86. Found: C, 68.58; H, 5.42;
N, 13.05; H 2 O, 0.54%. 1 H-NMR (CDCl 3 ) delta: 3.25 (2
H, t, J = 7.5 Hz), 4.54 (2H, s),
4.78 (2H, t, J = 7.5Hz), 5.80 (1
H, s), 6.60 to 6.85 (3H, m),
7.20 to 7.40 (11H, m) and 9.
62 (1H, bs). Example 34 Production of intermediate (34-1) 3- [2- (4,5-diphenyl-2-
Thiazolyl) ethyl] phenol
【式97】 ヘキサン(9.5ml)中のn−ブチルリチウム(1.5
3g,24ミリモル)を、窒素雰囲気下−78℃に保っ
た乾燥THF(150ml)中の2−メチル−4,5−ジ
フェニルチアゾール(5g,20ミリモル)の攪拌溶液
に滴下状に加えた。25分後に、THF(10ml)中の
〔3−(ブロモメチル)フェノキシ〕ジメチル(1,1
−ジメチルエチル)シラン(0.60g,22ミリモ
ル)の溶液を滴下状に加え、混合物を−78℃で10分
間攪拌し、次いで室温にまで加温した。反応混合物を飽
和塩化アンモニウム溶液に注入し、CH2 Cl2 で抽出
し、抽出物を集めて硫酸ナトリウム上で乾燥し、真空濃
縮して油状物をえた。これをTHF(25ml)中にとか
した。THF(25.86ml)中のテトラ−n−ブチル
アンモニウムフルオライド(6.77g,26ミリモ
ル)の溶液を加え、混合物を室温で30分間攪拌してか
ら1NのHCl溶液(100ml)で希釈した。混合物を
CH2 Cl2 で抽出し、全抽出物を硫酸ナトリウム上で
乾燥し、濃縮して油状物をえた。ヘキサンとジエチルエ
ーテル(2:1)の混合物を溶離液として使用してシリ
カゲルのカラム上でクロマトグラフ処理して3−〔2−
(4,5−ジフェニル−2−チアゾリル)−エチル〕フ
ェノール(4.13g,58%)を、ヘキサンとCH2
Cl2 の混合物からの再結晶化後にえた。融点166〜
168℃。 分析:C23H19NOS:計算値:C,77.28;H,
5.36;N,3.92。実測値:C,77.22;
H,5.46;N,3.71%。1 H−NMR(CDCl3 )delta:3.04 t
o 3.14(2H,m),3.20 to 3.40
(2H,m),5.89(1H,s),6.60 to
6.75(2H,m),6.80 to 6.90
(1H,m),7.13(1H,t,J=8Hz),
7.20 to 7.45(8H,m)and 7.5
0 to 8.00(2H,m)。 (34−2) 1−(1−エトキシエチル)−2−メチ
ル−4,5−ジフェニル−1H−イミダゾール[Formula 97] N-Butyllithium (1.5 ml) in hexane (9.5 ml)
3 g, 24 mmol) was added dropwise to a stirred solution of 2-methyl-4,5-diphenylthiazole (5 g, 20 mmol) in dry THF (150 ml) kept at -78 ° C under a nitrogen atmosphere. After 25 minutes, [3- (bromomethyl) phenoxy] dimethyl (1,1) in THF (10 ml).
A solution of -dimethylethyl) silane (0.60 g, 22 mmol) was added dropwise and the mixture was stirred at -78 ° C for 10 minutes then warmed to room temperature. The reaction mixture was poured into saturated ammonium chloride solution and extracted with CH 2 Cl 2 , the extracts were combined, dried over sodium sulfate and concentrated in vacuo to give an oil. It was dissolved in THF (25 ml). A solution of tetra-n-butylammonium fluoride (6.77 g, 26 mmol) in THF (25.86 ml) was added, the mixture was stirred at room temperature for 30 minutes and then diluted with 1N HCl solution (100 ml). The mixture was extracted with CH 2 Cl 2 and all extracts were dried over sodium sulfate and concentrated to give an oil. Chromatograph on a column of silica gel using a mixture of hexane and diethyl ether (2: 1) as eluent 3- [2-
(4,5-Diphenyl-2-thiazolyl) -ethyl] phenol (4.13 g, 58%) was added to hexane and CH 2.
Obtained after recrystallization from a mixture of Cl 2 . Melting point 166 ~
168 ° C. Analysis: C 23 H 19 NOS: Calculated: C, 77.28; H,
5.36; N, 3.92. Found: C, 77.22;
H, 5.46; N, 3.71%. 1 H-NMR (CDCl 3 ) delta: 3.04 t
o 3.14 (2H, m), 3.20 to 3.40
(2H, m), 5.89 (1H, s), 6.60 to
6.75 (2H, m), 6.80 to 6.90
(1H, m), 7.13 (1H, t, J = 8Hz),
7.20 to 7.45 (8H, m) and 7.5
0 to 8.00 (2H, m). (34-2) 1- (1-Ethoxyethyl) -2-methyl-4,5-diphenyl-1H-imidazole
【式98】 2−メチル−4,5−ジフェニルイミダゾール(3.0
0g,13ミリモル)、エチルビニルエーテル(9.2
3g,12.30ml,130ミリモル)およびハイドロ
キノン(0.14g,1.2ミリモル)から成る混合物
を密封容器中180℃で17時間加熱した。過剰のエチ
ルビニルエーテルを除去し、残渣をジエチルエーテルと
ヘキサン(3:2)の混合物を溶離液として使用してシ
リカゲルのカラム上でクロマトグラフ処理した。溶離に
より1−(1−エトキシエチル)−2−メチル−4,5
−ジフェニル−1H−イミダゾール(2.68g,68
%)をえた。融点87〜89℃。 分析:C20H22N2 O:計算値:C,78.40;H,
7.24;N,9.14。実測値:C,78.64;
H,7.31;N,9.56%。1 H−NMR(CDCl3 )delta:1.09(3
H,t,J=7Hz),1.55 (3H,d,J=6H
z),2.62(3H,s),3.20 and 3.
35(2H,m),5.07(1H,q,J=6Hz)
and 7.00 to 7.50(10H,m)。 (34−3) 3−〔2−〔1−(1−エトキシエチ
ル)4,5−ジフェニル−1H−イミダゾール−2−イ
ル〕エチル〕フェノール[Formula 98] 2-Methyl-4,5-diphenylimidazole (3.0
0 g, 13 mmol), ethyl vinyl ether (9.2
A mixture of 3 g, 12.30 ml, 130 mmol) and hydroquinone (0.14 g, 1.2 mmol) was heated in a sealed vessel at 180 ° C for 17 hours. Excess ethyl vinyl ether was removed and the residue was chromatographed on a column of silica gel using a mixture of diethyl ether and hexane (3: 2) as eluent. 1- (1-ethoxyethyl) -2-methyl-4,5 by elution
-Diphenyl-1H-imidazole (2.68 g, 68
%). Melting point 87-89 [deg.] C. Analysis: C 20 H 22 N 2 O : Calculated: C, 78.40; H,
7.24; N, 9.14. Found: C, 78.64.
H, 7.31; N, 9.56%. 1 H-NMR (CDCl 3 ) delta: 1.09 (3
H, t, J = 7Hz), 1.55 (3H, d, J = 6H
z), 2.62 (3H, s), 3.20 and 3.
35 (2H, m), 5.07 (1H, q, J = 6Hz)
and 7.00 to 7.50 (10H, m). (34-3) 3- [2- [1- (1-ethoxyethyl) 4,5-diphenyl-1H-imidazol-2-yl] ethyl] phenol
【式99】 ヘキサン(24.31ml)中のn−ブチルリチウム
(3.89g,61ミリモル)を、窒素雰囲気下に−7
8℃に保った乾燥THF(300ml)中の1−(1−エ
トキシエチル)−2−メチル−4,5−ジフェニル−1
H−イミダゾール(15.50g,51ミリモル)の攪
拌溶液に、滴下状に加えた。混合物を45分間攪拌し、
〔3−(ブロモメチル)−フェノキシ〕ジメチル(1,
1−ジメチルエチル)シラン(16.77g,50ミリ
モル)を滴下状に加えた。10分後に、混合物を水に注
入し、CH2 Cl2 に抽出し、抽出物を集め、硫酸ナト
リウム上で乾燥した。溶媒を蒸発して油状物を残し、こ
れをTHF(75ml)にとかして、THF(65ml)中
のテトラ−n−ブチルアンモニウムフルオライド(1
7.22g,66ミリモル)を加えた。溶液を室温で3
0分間攪拌し、溶媒を蒸発して残渣を水で希釈した。2
NのHCl溶液(薬20ml)を加えてpH=5とし、混合
物をCH2 Cl2 で抽出した。合計抽出物を硫酸ナトリ
ウム上で乾燥し、真空濃縮して残渣をシリカゲルのカラ
ム上でクロマトグラフ処理した。ジエチルエーテルとヘ
キサン(1:1)の混合物で溶離して3−〔2−〔1−
(1−エトキシエチル)−4,5−ジフェニル−1H−
イミダゾール−2−イル〕エチル〕−フェノール(8.
18g,39%)をCH2 Cl2 とヘキサンの混合物か
らの再結晶後にえた。融点165.5〜167℃ 分析:C27H28N2 O2 ・0.4H2 O:計算値:C,
77.27;H,6.92;N,6.68;H2 O,
1.72。実測値:C,77.31;H,6.93;
N,6.29;H2 O,1.75%。1 H−NMR(CDCl3 )delta:0.99(3
H,t,J=7Hz),1.45 (3H,d,J=6H
z),3.00 to 3.40(6H,m),5.0
5(1H,q,J=6Hz),6.60(1H,dd,
J=7Hz,J′=1.5Hz),6.74(2H,
m),7.00 to 7.30(4H,m),7.3
0 to 7.45(4H,m),7.45 to
7.60(3H,m)and 9.30(1H,s)。 (34−4) 5−〔3−〔ジメチル(1,1−ジメチ
ルエチル)−シロキシ〕フェニル〕−1−フェニル−
1,3−ペンタンジオン[Formula 99] N-Butyllithium (3.89 g, 61 mmol) in hexane (24.31 ml) was added under nitrogen atmosphere to -7.
1- (1-ethoxyethyl) -2-methyl-4,5-diphenyl-1 in dry THF (300 ml) kept at 8 ° C.
H-imidazole (15.50 g, 51 mmol) was added dropwise to a stirred solution. The mixture is stirred for 45 minutes,
[3- (bromomethyl) -phenoxy] dimethyl (1,
1-Dimethylethyl) silane (16.77 g, 50 mmol) was added dropwise. After 10 minutes, the mixture was poured into water, extracted into CH 2 Cl 2 , the extracts were combined and dried over sodium sulfate. Evaporation of the solvent left an oil which was dissolved in THF (75 ml) to give tetra-n-butylammonium fluoride (1 ml in THF (65 ml).
7.22 g, 66 mmol) was added. Solution at room temperature 3
Stirred for 0 minutes, evaporated the solvent and diluted the residue with water. Two
N HCl solution (20 ml drug) was added to pH = 5 and the mixture was extracted with CH 2 Cl 2 . The combined extracts were dried over sodium sulfate, concentrated in vacuo and the residue chromatographed on a column of silica gel. Elution with a mixture of diethyl ether and hexane (1: 1) 3- [2- [1-
(1-Ethoxyethyl) -4,5-diphenyl-1H-
Imidazol-2-yl] ethyl] -phenol (8.
18 g, 39%) was obtained after recrystallization from a mixture of CH 2 Cl 2 and hexane. Mp 165.5 to 167 ° C. Analysis: C 27 H 28 N 2 O 2 · 0.4H 2 O: Calculated: C,
77.27; H, 6.92; N, 6.68; H 2 O,
1.72. Found: C, 77.31; H, 6.93;
N, 6.29; H 2 O, 1.75%. 1 H-NMR (CDCl 3 ) delta: 0.99 (3
H, t, J = 7Hz), 1.45 (3H, d, J = 6H
z), 3.00 to 3.40 (6H, m), 5.0
5 (1H, q, J = 6Hz), 6.60 (1H, dd,
J = 7Hz, J '= 1.5Hz), 6.74 (2H,
m), 7.00 to 7.30 (4H, m), 7.3
0 to 7.45 (4H, m), 7.45 to
7.60 (3H, m) and 9.30 (1H, s). (34-4) 5- [3- [Dimethyl (1,1-dimethylethyl) -siloxy] phenyl] -1-phenyl-
1,3-pentanedione
【式100】 水素化ナトリウム(鉱油中の50%分散液2.13g,
44ミリモル)をヘキサンで2回洗浄し、乾燥THF
(150ml)で覆い、1−ベンゾイルアセトン(6.0
0g,37ミリモル)を小分けして加えた。混合物を窒
素雰囲気下に室温で10分間攪拌してスラリを得て、こ
れを−20℃に冷却した。ヘキサン(163.ml)中の
n−ブチルリチウム(2.60g,40ミリモル)を滴
下状に加えて溶液を得た。この溶液を20分間攪拌して
から〔3−(ブロモメチル)フェノキシ〕ジメチル
(1,1−ジメチルエチル)シラン(11.17g,3
7ミリモル)を滴下状に加えた。15分後に、混合物を
飽和塩化アンモニウムに注入し、CH2 Cl2 で抽出し
た。全抽出物を硫酸ナトリウム上で乾燥し、真空濃縮し
て残渣油をシリカゲルのカラム上でクロマトグラフ処理
した。ヘキサンとジエチルエーテル(9:1)の混合物
で溶離して5−〔3−〔ジメチル(1,1−ジメチルエ
チル)シロキシ〕フェニル〕−1−フェニル−1,3−
ペンタンジオン(9.00g,63%)をえた。 (34−5) 3−〔2−(1,5−ジフェニル−1H
−ピラゾール−3−イル)エチル〕フェノール[Formula 100] Sodium hydride (2.13 g of 50% dispersion in mineral oil,
(44 mmol) was washed twice with hexane and dried with THF.
Cover with (150 ml) and 1-benzoylacetone (6.0
0 g, 37 mmol) was added in small portions. The mixture was stirred under a nitrogen atmosphere at room temperature for 10 minutes to obtain a slurry, which was cooled to -20 ° C. N-Butyllithium (2.60 g, 40 mmol) in hexane (163.ml) was added dropwise to give a solution. The solution was stirred for 20 minutes and then [3- (bromomethyl) phenoxy] dimethyl (1,1-dimethylethyl) silane (11.17 g, 3
7 mmol) was added dropwise. After 15 minutes, the mixture was poured into saturated ammonium chloride and extracted with CH 2 Cl 2 . All extracts were dried over sodium sulfate, concentrated in vacuo and the residual oil chromatographed on a column of silica gel. 5- [3- [Dimethyl (1,1-dimethylethyl) siloxy] phenyl] -1-phenyl-1,3-eluting with a mixture of hexane and diethyl ether (9: 1).
Pentanedione (9.00 g, 63%) was obtained. (34-5) 3- [2- (1,5-diphenyl-1H
-Pyrazol-3-yl) ethyl] phenol
【式101】 5−〔3−〔ジメチル(1,1−ジメチルエチル)シロ
キシ〕フェニル〕−1−フェニル−1,3−ペンタンジ
オン(8.80g,23ミリモル)、フェニルヒドラジ
ン(2.73g,2.50ml,25ml)、ピリジン(3
ml)およびメタノール(70ml)から成る混合物を室温
で攪拌した。20分後に、フェニルヒドラジン(0.3
ml)を加え、更に7時間攪拌を続けた。溶媒を蒸発し、
残渣をヘキサンとジエチルエーテル(9:1)の混合物
を溶離液として使用してシリカゲルのカラムでクロマト
グラフ処理して、3−〔2−〔3−ジメチル(1,1−
ジメチルエチル)−シロキシ〕フェニル〕−1−(ジフ
ェニルメチル)−5−フェニル−1H−ピラゾール(1
0.27g,98%)をえた。その一部(9.20g,
20ミリモル)をTHF(180ml)にとかした。テト
ラ−n−ブチルアンモニウムフルオライド(6.89
g,26ミリモル)をTHF(26.34ml)にとかし
たものを加え、混合物を室温で30分間攪拌した。溶媒
を蒸発し、CH2 Cl2 で抽出した。全抽出部を硫酸ナ
トリウム上で乾燥し、濃縮して白色固体をえた。これを
ジエチルエーテルですりつぶして濾過し、3−〔2−
(1,5−ジフェニル−1H−ピラゾール−3−イル)
エチル〕フェノール(5.31g,77%)をえた。エ
タノールから再結晶させた分析試料は融点211〜21
2℃をもっていた。 分析:C23H20N2 O:計算値:C,81.15;H,
5.92;N,8.23;。実測値:C,80.90;
H,6.24;N,8.22%。1 H−NMR(DMSO−d6 )delta:2.87
(4H,bs),3.35(1H,s),6.49(1
H,s),6.58(1H,dd,J=7Hz,J′=
1.5Hz),6.67 to 6.70(2H,
m),7.07(1H,t,J=7Hz),7.10
to 7.30(4H,m),and 7.30 to
7.50(6H,m)。 HET2 が4,5−ジフェニル−1H−イミダゾール−
2−イルの複素環基である本発明の化合物は化12によ
って表わされる。[Formula 101] 5- [3- [dimethyl (1,1-dimethylethyl) siloxy] phenyl] -1-phenyl-1,3-pentanedione (8.80 g, 23 mmol), phenylhydrazine (2.73 g, 2.50 ml, 25 ml), pyridine (3
ml) and methanol (70 ml) was stirred at room temperature. After 20 minutes, phenylhydrazine (0.3
ml) was added and stirring was continued for another 7 hours. Evaporate the solvent,
The residue was chromatographed on a column of silica gel using a mixture of hexane and diethyl ether (9: 1) as eluent to give 3- [2- [3-dimethyl (1,1-
Dimethylethyl) -siloxy] phenyl] -1- (diphenylmethyl) -5-phenyl-1H-pyrazole (1
0.27 g, 98%) was obtained. Part of it (9.20g,
20 mmol) was dissolved in THF (180 ml). Tetra-n-butylammonium fluoride (6.89
g, 26 mmol) in THF (26.34 ml) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and extracted with CH 2 Cl 2 . All extracts were dried over sodium sulfate and concentrated to give a white solid. Triturate this with diethyl ether, filter, and then 3- [2-
(1,5-diphenyl-1H-pyrazol-3-yl)
Ethyl] phenol (5.31 g, 77%) was obtained. The analytical sample recrystallized from ethanol has a melting point of 211-21.
Had 2 ° C. Analysis: C 23 H 20 N 2 O : Calculated: C, 81.15; H,
5.92; N, 8.23 ;. Found: C, 80.90;
H, 6.24; N, 8.22%. 1 H-NMR (DMSO-d 6 ) delta: 2.87.
(4H, bs), 3.35 (1H, s), 6.49 (1
H, s), 6.58 (1H, dd, J = 7Hz, J '=
1.5 Hz), 6.67 to 6.70 (2H,
m), 7.07 (1H, t, J = 7Hz), 7.10
to 7.30 (4H, m), and 7.30 to
7.50 (6H, m). HET 2 is 4,5-diphenyl-1H-imidazole-
The compound of the present invention, which is a 2-yl heterocyclic group, is represented by Chemical formula 12.
【式12】ただしR1 は水素、低級アルキルまたはアル
カリ金属イオンであり、基−OCH2 CO2 には3位ま
たは4位に結合している。上記式12の化合物は、
(a)Wherein R 1 is hydrogen, lower alkyl or an alkali metal ion and is bonded to the group —OCH 2 CO 2 at the 3- or 4-position. The compound of formula 12 above is
(A)
【式13】の化合物を加水分解するか、(b)Hydrolyzing the compound of formula 13 or (b)
【式14】の化合物をエステル化するか、または(c)
4,5−ジフェニル−2−イミダゾールチオールをEsterifying a compound of formula 14 or (c)
4,5-diphenyl-2-imidazole thiol
【式15】の化合物でアルキル化することから成る方法
によってえられる。上記の式12の化合物は前記のHE
T1 −(CH2 )n CO2 Rおよび前記の式5と同様の
医薬的性質をもつ。式12の化合物の例である実施例3
5および36の化合物の試験管内のヒト血小板凝集阻止
試験結果を表3に示す。Obtained by a process which comprises alkylating with a compound of formula 15. The compound of formula 12 above is the above HE
T 1 - (CH 2) having the same pharmaceutical properties as the n CO 2 R, and the Equation 5. Example 3 which is an example of a compound of formula 12
In vitro human platelet aggregation inhibition test results for compounds 5 and 36 are shown in Table 3.
【表3】 実施例35 メチル〔3−〔(4,5−ジフェニル−1
H−イミダゾール−2−イル)チオ〕メチル〕フェノキ
シ〕アセテート[Table 3] Example 35 Methyl [3-[(4,5-diphenyl-1
H-imidazol-2-yl) thio] methyl] phenoxy] acetate
【式102】 水素化ナトリウム(50%分散液684mg、14ミリモ
ル)をヘキサンで3回洗浄し、DMF(60ml)で覆っ
た。4,5−ジフェニル−1−イミダゾールチオール
(3g,12ミリモル)を加えて、水素発生が止んだ後
に黄色溶液をえた。メチル(3−クロロメチルフェノキ
シ)アセテート(2.68g,12.5ミリモル)を加
え、混合物を室温で1.5時間攪拌してから100℃で
0.5時間攪拌した。冷却後、混合物を水で希釈し、ジ
エチルエーテルで(3回)洗浄した。合計抽出物を水で
(3回)洗浄し、乾燥して真空濃縮した。残渣固体をヘ
キサンとCH2 Cl2 の混合物から再結晶させて〔3−
〔4,5−ジフェニル−1H−イミダゾール−2−イ
ル)チオ〕メチル〕フェノキシ〕−アセテート(3.0
0g,58%)をえた。融点 不明確。 分析:C25H22N2 O3 S:計算値:C,69.75;
H,5.15;N,6.51;。実測値:C,69.7
9;H,5.23;N,6.24。1 H−NMR(CDCl3 )delta:3.72(3
H,s),4.13(2H,s),4.56(2H,
s),6.75 to 6.80(3H,m),and
7.10 to 7.50(12H,m)。 実施例36 〔3−〔〔(4,5−ジフェニル−1H−
イミダゾール−2−イル)チオ〕メチル〕フェノキシ〕
酢酸[Formula 102] Sodium hydride (50% dispersion 684 mg, 14 mmol) was washed 3 times with hexane and covered with DMF (60 ml). 4,5-Diphenyl-1-imidazolethiol (3 g, 12 mmol) was added to give a yellow solution after hydrogen evolution ceased. Methyl (3-chloromethylphenoxy) acetate (2.68 g, 12.5 mmol) was added and the mixture was stirred at room temperature for 1.5 hours and then at 100 ° C for 0.5 hours. After cooling, the mixture was diluted with water and washed with diethyl ether (3 times). The total extract was washed with water (3 times), dried and concentrated in vacuo. The residual solid was recrystallized from a mixture of hexane and CH 2 Cl 2 [3-
[4,5-Diphenyl-1H-imidazol-2-yl) thio] methyl] phenoxy] -acetate (3.0
0 g, 58%). Melting point unclear. Analysis: C 25 H 22 N 2 O 3 S: Calculated: C, 69.75;
H, 5.15; N, 6.51 ;. Found: C, 69.7.
9; H, 5.23; N, 6.24. 1 H-NMR (CDCl 3 ) delta: 3.72 (3
H, s), 4.13 (2H, s), 4.56 (2H,
s), 6.75 to 6.80 (3H, m), and
7.10 to 7.50 (12H, m). Example 36 [3-[[(4,5-diphenyl-1H-
Imidazol-2-yl) thio] methyl] phenoxy]
Acetic acid
【式103】 メチル〔3−〔〔4,5−ジフェニル−1H−イミダゾ
ール−2−イル)チオ〕メチル〕フェノキシ〕アセテー
ト(2.00g,4.6ミリモル)、水酸化リチウム−
水和物(586mg,14ミリモル)、メタノール(35
ml)および水(10ml)から成る混合物を室温で2時間
攪拌した。溶媒を蒸発し、残渣を水で希釈し、2NのH
Cl溶液を加えてpH=7にした。白色固体を濾過し、水
性DMFから再結晶させて〔3−〔(4,5−ジフェニ
ル−1H−イミダゾール−2−イル)チオ〕メチル〕フ
ェノキシ〕酢酸(1.33g,69%)をえた。融点2
33〜235℃。 分析:C24H20N2 O3 S:計算値:C,69.21;
H,4.84;N,6.73;。実測値:C,69.4
3;H,4.92;N,6.92。1 H−NMR(DMSO−d6 )delta:4.34
(2H,s),4.60(2H,s),6.77(1
H,dd,J=8Hz,J′=2Hz),6.90 t
o 7.00(2H,m),7.05 to 7.60
(12H)and12.40 to 13.00(1
H,bs)。 [Formula 103] Methyl [3-[[4,5-diphenyl-1H-imidazol-2-yl) thio] methyl] phenoxy] acetate (2.00 g, 4.6 mmol), lithium hydroxide-
Hydrate (586 mg, 14 mmol), methanol (35
(ml) and water (10 ml) was stirred at room temperature for 2 hours. The solvent was evaporated, the residue diluted with water and 2N H 2
A Cl solution was added to bring the pH to 7. The white solid was filtered and recrystallized from aqueous DMF to give [3-[(4,5-diphenyl-1H-imidazol-2-yl) thio] methyl] phenoxy] acetic acid (1.33g, 69%). Melting point 2
33-235 ° C. Analysis: C 24 H 20 N 2 O 3 S: Calculated: C, 69.21;
H, 4.84; N, 6.73 ;. Found: C, 69.4.
3; H, 4.92; N, 6.92. 1 H-NMR (DMSO-d 6 ) delta: 4.34
(2H, s), 4.60 (2H, s), 6.77 (1
H, dd, J = 8 Hz, J '= 2 Hz), 6.90 t
o 7.00 (2H, m), 7.05 to 7.60
(12H) and 12.40 to 13.00 (1
H, bs).
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 FI 技術表示箇所 A61K 31/50 9360−4C 31/505 9360−4C 31/53 9360−4C C07D 233/64 101 106 233/74 233/84 237/14 239/36 8615−4C 253/06 257/04 7433−4C 277/30 (31)優先権主張番号 479561 (32)優先日 1990年2月13日 (33)優先権主張国 米国(US) (31)優先権主張番号 479464 (32)優先日 1990年2月13日 (33)優先権主張国 米国(US) (31)優先権主張番号 479559 (32)優先日 1990年2月13日 (33)優先権主張国 米国(US) (31)優先権主張番号 479560 (32)優先日 1990年2月13日 (33)優先権主張国 米国(US) (31)優先権主張番号 479506 (32)優先日 1990年2月13日 (33)優先権主張国 米国(US) (31)優先権主張番号 540988 (32)優先日 1990年6月20日 (33)優先権主張国 米国(US) (31)優先権主張番号 479505 (32)優先日 1990年2月13日 (33)優先権主張国 米国(US)─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Internal reference number FI Technical display area A61K 31/50 9360-4C 31/505 9360-4C 31/53 9360-4C C07D 233/64 101 106 233/74 233/84 237/14 239/36 8615-4C 253/06 257/04 7433-4C 277/30 (31) Priority claim number 479561 (32) Priority date February 13, 1990 (33) Priority Claiming country United States (US) (31) Priority claim number 479464 (32) Priority date February 13, 1990 (33) Priority claiming country United States (US) (31) Priority claim number 479559 (32) Priority date February 13, 1990 (33) Priority claiming United States (US) (31) Priority claiming number 479560 (32) Priority date February 13, 1990 (33) Priority claiming United States (US) (31) Priority claim number 479506 (32) Priority date February 13, 1990 (33) Priority claiming United States (US) (31) Priority claiming number 540988 (32) Priority date June 20, 1990 (33) Priority claiming United States (US) (31) Priority claiming number 479505 ( 32) Priority date February 13, 1990 (33) Priority claiming countries United States (US)
Claims (39)
はアルカリ金属イオンであり;そしてHET1 は 【式1】から成る群からえらばれた複素環基である)の
化合物の製造法であって、(a) 【式2】 の化合物を加水分解するか、(b) 【式3】 の化合物を低級アルカノールでエステル化するか、また
は(c)HET1 −H(HET1 は前記定義のとおりで
ある)を 【式4】 の化合物でアルキル化する、ことから成ることを特徴と
する方法。1. The formula 1 HET 1- (CH 2 ) n CO 2 R (n is 6-9; R is hydrogen or lower alkyl or an alkali metal ion; and HET 1 is a heterocycle selected from the group consisting of A compound of group (a), which comprises (a) By hydrolyzing the compound of (b) Esterified with a lower alkanol, or (c) HET 1 -H (HET 1 is as defined above) Alkylating with a compound of
ンであり、基−OCH2CO2 R1 は環の3位または4
位に結合してあり、そしてHET2 は 【式6】 から成る群からえらばれた複素環基である)の化合物の
製造法であって、(a) 【式7】 の化合物を加水分解するか、(b) 【式8】 の化合物(HET2 は前記定義のとおりである)をエス
テル化するか、(c)HET2 −H(HET2 は前記定
義のとおりである)を 【式9】 の化合物でアルキル化するか、(d) 【式10】 の化合物をBrCH2 CO2 R1 a (R1 a は低級アル
キルである)でアルキル化するか、または(e) 【式11】 の化合物を加水分解する、ことから成ることを特徴とす
る方法。2. The formula 5. (R 1 is hydrogen, lower alkyl, or an alkali metal ion, and the group —OCH 2 CO 2 R 1 is 3 or 4 of the ring.
Is bound to position HET 2 is A heterocyclic group selected from the group consisting of: By hydrolyzing the compound of (b) (HET 2 is as defined above) or (c) HET 2 -H (HET 2 is as defined above) Alkylation with a compound of formula (d) Is alkylated with BrCH 2 CO 2 R 1 a, where R 1 a is lower alkyl, or (e) Hydrolyzing the compound of claim 1.
ンであり、基−OCH2CO2 R1 は環の3位または4
位に結合している)の化合物の製造法であって、(a) 【式13】 の化合物を加水分解するか、(b) 【式14】 の化合物をエステル化するか、または(c)4,5−ジ
フェニル−2−イミダゾールチオールを 【式15】 の化合物でアルキル化する、ことから成ることを特徴と
する方法。3. The equation 12 (R 1 is hydrogen, lower alkyl, or an alkali metal ion, and the group —OCH 2 CO 2 R 1 is 3 or 4 of the ring.
A compound of formula (13), which is By hydrolyzing the compound of (b) Esterified compound of (c) or (c) 4,5-diphenyl-2-imidazole thiol Alkylating with a compound of
あるメチル3,4−ジフェニル−1H−ピロール−1−
ノナノエート。4. Methyl 3,4-diphenyl-1H-pyrrole-1-, which is a compound produced by the method of claim 1.
Nonanoate.
ある3,4−ジフェニル−1H−ピロール−1−ノナン
酸。5. A compound produced by the method of claim 1, 3,4-diphenyl-1H-pyrrole-1-nonanoic acid.
あるメチル6−オキソ−3,4−ジフェニル−1 (6
H)−ピリダジンノナノエート。6. A compound produced by the method of claim 1, methyl 6-oxo-3,4-diphenyl-1 (6).
H) -Pyridazine nonanoate.
あるオキソ−3,4−ジフェニル−1 (6H)−ピリダ
ジンノナン酸。7. Oxo-3,4-diphenyl-1 (6H) -pyridazinenonanoic acid, which is a compound produced by the method of claim 1.
あるメチル6−オキソ−3,4−ジフェニル−1 (6
H)−ピリダジニルオクタノエート。8. A compound prepared by the method of claim 1, methyl 6-oxo-3,4-diphenyl-1 (6).
H) -Pyridazinyl octanoate.
ある6−オキソ−3,4−ジフェニル−1 (6H)−ピ
リダジニルオクタン酸。9. 6-oxo-3,4-diphenyl-1 (6H) -pyridazinyloctanoic acid, which is a compound produced by the method of claim 1.
であるメチル3−オキソ−5,6−ジフェニル−1,
2,4−トリアジン−2 (3H)−ノナノエート。10. A compound produced by the method of claim 1, methyl 3-oxo-5,6-diphenyl-1,
2,4-triazine-2 (3H) -nonanoate.
である3−オキソ−5,6−ジフェニル−1,2,4−
トリアジン−2 (3H)−ノナン酸。11. A compound produced by the method of claim 1, which is 3-oxo-5,6-diphenyl-1,2,4-.
Triazine-2 (3H) -nonanoic acid.
であるメチル−3−オキソ−5,6−ジフェニル−1,
2,4−トリアジン−2 (3H)−オクタノエート。12. A compound produced by the method of claim 1, methyl-3-oxo-5,6-diphenyl-1,
2,4-triazine-2 (3H) -octanoate.
である3−オキソ−5,6−ジフェニル−1,2,4−
トリアジン−2 (3H)−オクタン酸。13. A compound prepared by the method of claim 1, 3-oxo-5,6-diphenyl-1,2,4-.
Triazine-2 (3H) -octanoic acid.
であるメチル2−オキソ−4,5−ジフェニル−1 (2
H)−ピリミジンオクタノエート。14. Methyl 2-oxo-4,5-diphenyl-1 (2) which is a compound produced by the method of claim 1.
H) -Pyrimidine octanoate.
である2−オキソ−4,5−ジフェニル−1(2H)−
ピリミジンオクタン酸。15. A compound prepared by the method of claim 1, 2-oxo-4,5-diphenyl-1 (2H)-.
Pyrimidine octanoic acid.
であるメチル2−オキソ−4,5−ジフェニル−1(2
H)−ピリミジンオクタノエート。16. A compound produced by the method of claim 1, methyl 2-oxo-4,5-diphenyl-1 (2).
H) -Pyrimidine octanoate.
である2−オキソ−4,5−ジフェニル−1(2H)−
ピリミジンオクタン酸。17. A compound produced by the method of claim 1, 2-oxo-4,5-diphenyl-1 (2H)-.
Pyrimidine octanoic acid.
であるメチル2,5−ジオキソ−3,4−ジフェニル−
1−イミダゾリジンオクタノエート。18. A compound, methyl 2,5-dioxo-3,4-diphenyl-, produced by the method of claim 1.
1-Imidazolidine octanoate.
である2,5−ジオキソ−3,4−ジフェニル−1−イ
ミダゾリジンノナン酸。19. 2,5-Dioxo-3,4-diphenyl-1-imidazolidinenonanoic acid, which is a compound produced by the method of claim 1.
である5−(ジフェニルメチル)−2H−テトラゾール
−2−ノナノエート。20. 5- (Diphenylmethyl) -2H-tetrazole-2-nonanoate, which is a compound produced by the method of claim 1.
である5−(ジフェニルメチル)−2H−テトラゾール
−1−ノナン酸。21. 5- (Diphenylmethyl) -2H-tetrazole-1-nonanoic acid, which is a compound produced by the method of claim 1.
であるメチル(3−〔2−(4,5−ジフェニル−2−
チアゾリル)−エチル〕フェノキシ)アセテート。22. Methyl (3- [2- (4,5-diphenyl-2-, which is a compound produced by the method of claim 2.
Thiazolyl) -ethyl] phenoxy) acetate.
である〔3−〔2−4,5−ジフェニル−2−チアゾリ
ル)エチル〕フェノキシ酢酸。23. [3- [2-4,5-Diphenyl-2-thiazolyl) ethyl] phenoxyacetic acid, which is a compound produced by the method of claim 2.
であるメチル〔3−〔2−(4,5−ジフェニル−1H
−イミダゾール2−イル)エチル〕フェノキシ〕アセテ
ート。24. Methyl [3- [2- (4,5-diphenyl-1H) which is a compound produced by the method of claim 2.
-Imidazol 2-yl) ethyl] phenoxy] acetate.
である〔3−〔2−(4,5−ジフェニル−1H−イミ
ダゾール−2−イル)−エチル〕フェノキシ酢酸。25. [3- [2- (4,5-Diphenyl-1H-imidazol-2-yl) -ethyl] phenoxyacetic acid, which is a compound produced by the method of claim 2.
であるメチル〔3−〔2−(3,4−ジフェニル−1H
−ピラゾール−1−イル)エチル〕フェノキシ〕アセテ
ート。26. Methyl [3- [2- (3,4-diphenyl-1H) which is a compound produced by the method of claim 2.
-Pyrazol-1-yl) ethyl] phenoxy] acetate.
であるメチル〔3−〔2−(4,5−ジフェニル−1H
−ピラゾール−1−イル)エチル〕フェノキシ〕アセテ
ート。27. Methyl [3- [2- (4,5-diphenyl-1H) which is a compound produced by the method of claim 2.
-Pyrazol-1-yl) ethyl] phenoxy] acetate.
である〔3−〔2−(3,4−ジフェニル−1H−ピラ
ゾール−1−イル)エチル〕フェノキシ〕酢酸。28. [3- [2- (3,4-Diphenyl-1H-pyrazol-1-yl) ethyl] phenoxy] acetic acid, which is a compound produced by the method of claim 2.
である〔3−〔2−(4,5−ジフェニル−1H−ピラ
ゾール−1−イル)−エチル〕フェノキシ〕酢酸。29. [3- [2- (4,5-Diphenyl-1H-pyrazol-1-yl) -ethyl] phenoxy] acetic acid, which is a compound produced by the method of claim 2.
であるメチル〔3−〔2−(1,5−ジフェニル−1H
−ピラゾール−3−イル)エチル〕フェノキシ〕アセテ
ート。30. Methyl [3- [2- (1,5-diphenyl-1H) which is a compound produced by the method of claim 2.
-Pyrazol-3-yl) ethyl] phenoxy] acetate.
である〔3−〔2−(1,5−ジフェニル−1H−ピラ
ゾール−3−イル)−エチル〕フェノキシ〕酢酸。31. [3- [2- (1,5-Diphenyl-1H-pyrazol-3-yl) -ethyl] phenoxy] acetic acid, which is a compound produced by the method of claim 2.
であるメチル〔3−〔2−(1,6−ジヒドロ−6−オ
キソ−3,4−ジフェニル−1−ピリダジニル)エチ
ル〕フェノキシ〕アセテート。32. Methyl [3- [2- (1,6-dihydro-6-oxo-3,4-diphenyl-1-pyridazinyl) ethyl] phenoxy] acetate which is a compound produced by the method of claim 2.
である〔3−〔2−(1,6−ジヒドロ−6−オキソ−
3,4−ジフェニル−1−ピリダジニル)エチル〕フェ
ノキシ〕酢酸。33. A compound produced by the method of claim 2 [3- [2- (1,6-dihydro-6-oxo-
3,4-diphenyl-1-pyridazinyl) ethyl] phenoxy] acetic acid.
であるメチル〔3−〔2−(2,3−ジヒドロ−3−オ
キソ−5,6−ジフェニル−1,2,4−トリアジン−
2−イル)エチル〕フェノキシ〕アセテート。34. Methyl [3- [2- (2,3-dihydro-3-oxo-5,6-diphenyl-1,2,4-triazine- which is a compound produced by the method of claim 2.
2-yl) ethyl] phenoxy] acetate.
である〔3−〔2−(2,3−ジヒドロ−3−オキソ−
5,6−ジフェニル−1,2,4−トリアジン−2−イ
ル)エチル〕フェニル〕酢酸。35. A compound produced by the method of claim 2 [3- [2- (2,3-dihydro-3-oxo-
5,6-Diphenyl-1,2,4-triazin-2-yl) ethyl] phenyl] acetic acid.
であるメチル〔3−〔2−〔5−(ジフェニルメチル)
−2H−テトラゾール−2−イル〕エチル〕フェノキ
シ〕アセテート。36. Methyl [3- [2- [5- (diphenylmethyl)) which is a compound produced by the method of claim 2.
-2H-tetrazol-2-yl] ethyl] phenoxy] acetate.
である〔3−〔2−〔5−(ジフェニルメチル)−2H
−テトラゾール−2−イル〕エチル〕フェノキシ〕酢
酸。37. A compound produced by the method of claim 2, which is [3- [2- [5- (diphenylmethyl) -2H].
-Tetrazol-2-yl] ethyl] phenoxy] acetic acid.
であるメチル〔3−〔(4,5−ジフェニル−1H−イ
ミダゾール−2−イル)チオ〕メチル〕フェノキシ〕ア
セテート。38. Methyl [3-[(4,5-diphenyl-1H-imidazol-2-yl) thio] methyl] phenoxy] acetate which is a compound produced by the method of claim 3.
である〔3−〔〔(4,5−ジフェニル−1H−イミダ
ゾール−2−イル)−チオ〕メチル〕フェノキシ〕酢
酸。39. [3-[[(4,5-Diphenyl-1H-imidazol-2-yl) -thio] methyl] phenoxy] acetic acid, which is a compound produced by the method of claim 3.
Applications Claiming Priority (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US479464 | 1983-03-28 | ||
US47950690A | 1990-02-13 | 1990-02-13 | |
US07/479,508 US4992439A (en) | 1990-02-13 | 1990-02-13 | Pyridazine carboxylic acids and esters |
US07/479,560 US5077305A (en) | 1990-02-13 | 1990-02-13 | Thiazole carboxylic acids and esters |
US479508 | 1990-02-13 | ||
US479561 | 1990-02-13 | ||
US07/479,561 US4983610A (en) | 1990-02-13 | 1990-02-13 | Pyrimidine carboxylic acids and esters |
US07/479,505 US4956379A (en) | 1990-02-13 | 1990-02-13 | Pyrazole carboxylic acids and esters and inhibition of blood platelet aggregation therewith |
US07/479,559 US4956376A (en) | 1990-02-13 | 1990-02-13 | Tetrazole carboxylic acids and esters and inhibition of blood platelet aggregation therewith |
US07/479,563 US5021415A (en) | 1990-02-13 | 1990-02-13 | Triazine carboxylic acids and esters |
US479563 | 1990-02-13 | ||
US479505 | 1990-02-13 | ||
US479560 | 1990-02-13 | ||
US479506 | 1990-02-13 | ||
US07/479,464 US5018030A (en) | 1989-02-18 | 1990-02-13 | Cassette loading mechanism of a magnetic recording and reproducing apparatus |
US540988 | 1990-06-20 | ||
US07/540,988 US5011851A (en) | 1990-02-13 | 1990-06-20 | Imidazole carboxylic acids and esters and inhibition of blood platelet aggregation therewith |
US479559 | 2000-01-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0680630A true JPH0680630A (en) | 1994-03-22 |
Family
ID=27578849
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP3037822A Pending JPH0680630A (en) | 1990-02-13 | 1991-02-08 | Heterocyclic carboxylic acid and ester |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0680630A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004277397A (en) * | 2002-05-24 | 2004-10-07 | Takeda Chem Ind Ltd | 1, 2-azole derivative |
WO2006090920A1 (en) * | 2005-02-28 | 2006-08-31 | Nippon Chemiphar Co., Ltd. | ACTIVATOR FOR PEROXISOME PROLIFERATOR ACTIVATING RECEPTOR δ |
-
1991
- 1991-02-08 JP JP3037822A patent/JPH0680630A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004277397A (en) * | 2002-05-24 | 2004-10-07 | Takeda Chem Ind Ltd | 1, 2-azole derivative |
WO2006090920A1 (en) * | 2005-02-28 | 2006-08-31 | Nippon Chemiphar Co., Ltd. | ACTIVATOR FOR PEROXISOME PROLIFERATOR ACTIVATING RECEPTOR δ |
JPWO2006090920A1 (en) * | 2005-02-28 | 2008-07-24 | 日本ケミファ株式会社 | Activator of peroxisome proliferator activated receptor δ |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4353905A (en) | Substituted 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and 6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones | |
JP3593031B2 (en) | Heterocyclic vinyl ethers for neurological disorders | |
KR20020062277A (en) | N-Heterocyclic Derivatives as NOS Inhibitors | |
JPH05117239A (en) | Phenylpyrazolidinone for bronchodilator and anti- inflammatory | |
EP0442448A2 (en) | Heterocyclic carboxylic acids and esters | |
EP0430709A2 (en) | Benzthiophen derivatives | |
JP2003513961A (en) | 5-aryl-1H-1,2,4-triazole compounds which are inhibitors of cyclooxygenase-2 and pharmaceutical compositions containing the same | |
KR19990063989A (en) | 1,3,5-trisubstituted pyrazole compounds for the treatment of inflammation | |
JP2002518377A (en) | Arylalkanoylpyridazine | |
JPH05507079A (en) | 1H-substituted-1,2,4-triazole compounds for the treatment of cardiovascular disorders | |
US5011851A (en) | Imidazole carboxylic acids and esters and inhibition of blood platelet aggregation therewith | |
US4946842A (en) | Novel guanidino pyridazinones as cardiac stimulants | |
US4740513A (en) | Methyl substituted imidazol-1-yl quinolones | |
US4992439A (en) | Pyridazine carboxylic acids and esters | |
US5532234A (en) | Use of 1-[4-[4-aryl (or heteroaryl)-1-piperazinyl]-butyl)-1H-azole derivatives for the preparation of medicaments intended for the treatment of disorders of gastric secretion | |
EP0201988B1 (en) | Dihydropyridazinone derivatives | |
US5605901A (en) | Indane derivatives, processes for preparing the same and synthetic intermediate of the same | |
EP0434034A1 (en) | Oxazole derivatives | |
HU201015B (en) | Process for producing pyridine derivatives | |
US4956379A (en) | Pyrazole carboxylic acids and esters and inhibition of blood platelet aggregation therewith | |
US5082943A (en) | Novel imidazole derivatives | |
JPH0680630A (en) | Heterocyclic carboxylic acid and ester | |
US4503061A (en) | Substituted phenyl-pyridinones as cardiotonic agents | |
EP0199465A2 (en) | Cyanoalkanimidamido compounds | |
JPH0971534A (en) | Pharmaceutical composition |