WO1993003040A1 - Derive de thienopyrimidin-4-one - Google Patents
Derive de thienopyrimidin-4-one Download PDFInfo
- Publication number
- WO1993003040A1 WO1993003040A1 PCT/JP1992/000990 JP9200990W WO9303040A1 WO 1993003040 A1 WO1993003040 A1 WO 1993003040A1 JP 9200990 W JP9200990 W JP 9200990W WO 9303040 A1 WO9303040 A1 WO 9303040A1
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- WIPO (PCT)
- Prior art keywords
- compound
- nmr
- group
- methyl
- added
- Prior art date
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 125000004962 sulfoxyl group Chemical group 0.000 claims abstract description 4
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
- 229910052799 carbon Inorganic materials 0.000 claims abstract 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 172
- 150000001875 compounds Chemical class 0.000 abstract description 92
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 abstract description 13
- 206010019280 Heart failures Diseases 0.000 abstract description 4
- 206010020772 Hypertension Diseases 0.000 abstract description 4
- 102000008873 Angiotensin II receptor Human genes 0.000 abstract description 3
- 108050000824 Angiotensin II receptor Proteins 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- 239000003087 receptor blocking agent Substances 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract 1
- 229910052736 halogen Chemical group 0.000 abstract 1
- 150000002367 halogens Chemical group 0.000 abstract 1
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 59
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 53
- 239000013078 crystal Substances 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 39
- 239000000203 mixture Substances 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- 239000002904 solvent Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- -1 tetrazole-5-yl group Chemical group 0.000 description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 239000012156 elution solvent Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 150000003536 tetrazoles Chemical class 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000015427 Angiotensins Human genes 0.000 description 3
- 108010064733 Angiotensins Proteins 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- HZQLUIZFUXNFHK-UHFFFAOYSA-N 1-(bromomethyl)-4-phenylbenzene Chemical group C1=CC(CBr)=CC=C1C1=CC=CC=C1 HZQLUIZFUXNFHK-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000009739 binding Methods 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical group C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical class CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- LTJMHCGDSFTOHA-UHFFFAOYSA-N 2-carbamoylbenzenesulfonic acid Chemical compound NC(=O)C1=CC=CC=C1S(O)(=O)=O LTJMHCGDSFTOHA-UHFFFAOYSA-N 0.000 description 1
- FLKHCKPUJWBHCW-UHFFFAOYSA-N 3,6-dichlorophthalic acid Chemical compound OC(=O)C1=C(Cl)C=CC(Cl)=C1C(O)=O FLKHCKPUJWBHCW-UHFFFAOYSA-N 0.000 description 1
- OEYGTUAKNZFCDJ-UHFFFAOYSA-N 3-ethyloctane Chemical compound CCCCCC(CC)CC OEYGTUAKNZFCDJ-UHFFFAOYSA-N 0.000 description 1
- CYWHLOXWVAWMFO-UHFFFAOYSA-N 3-sulfanyl-1h-pyridine-2-thione Chemical class SC1=CC=CN=C1S CYWHLOXWVAWMFO-UHFFFAOYSA-N 0.000 description 1
- KXHZWUUTWSKONE-UHFFFAOYSA-N 4-[4-(4-carbamimidoylphenoxy)butoxy]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCOC1=CC=C(C(N)=N)C=C1 KXHZWUUTWSKONE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- OUUOFSFYEHYZBH-UHFFFAOYSA-N CCC(C)[Sn] Chemical compound CCC(C)[Sn] OUUOFSFYEHYZBH-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
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- 229920001393 Crofelemer Polymers 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
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- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
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- 108010071390 Serum Albumin Proteins 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
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- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- MOOAHMCRPCTRLV-UHFFFAOYSA-N boron sodium Chemical compound [B].[Na] MOOAHMCRPCTRLV-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical compound [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-M ethyl sulfate Chemical compound CCOS([O-])(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-M 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 210000004709 eyebrow Anatomy 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- TWEQNZZOOFKOER-UHFFFAOYSA-N methyl 3-aminothiophene-2-carboxylate Chemical compound COC(=O)C=1SC=CC=1N TWEQNZZOOFKOER-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- XREXPQGDOPQPAH-QKUPJAQQSA-K trisodium;[(z)-18-[1,3-bis[[(z)-12-sulfonatooxyoctadec-9-enoyl]oxy]propan-2-yloxy]-18-oxooctadec-9-en-7-yl] sulfate Chemical compound [Na+].[Na+].[Na+].CCCCCCC(OS([O-])(=O)=O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(CCCCCC)OS([O-])(=O)=O)COC(=O)CCCCCCC\C=C/CC(CCCCCC)OS([O-])(=O)=O XREXPQGDOPQPAH-QKUPJAQQSA-K 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to a thienovirimidine-141 derivative having angiotensin II receptor blocking activity.
- an angiotensin II antagonist having a pyrimidine skeleton Japanese Patent Application Laid-Open (JP-A) No. 3-115,711, European Patent Application Publication Nos. 407,342, and 419,048
- JP-A No. 4-45811 Japanese Patent Application Laid-Open (JP-A) No. 3-115,711
- European Patent Application Publication Nos. 407,342 European Patent Application Publication Nos. 407,342, and 419,048
- JP-A No. 4-45811 is known, but the compound having a chenovirimidine skeleton is not known.
- An object of the present invention is to provide a new compound having angiotensin ⁇ receptor blocker action of evening eve, which is useful for treating hypertension, heart failure and high intraocular pressure.
- the invention relates to the formula
- R 1 and R 2 are the same or different and each represent a hydrogen atom, an alkyl group having 1 to 7 carbon atoms or a furyl group, or R 1 and R 2 are adjacent to each other.
- R 1 and R 2 come together to represent an alkylene group having 3 to 5 carbon atoms.
- R 3 represents an alkyl group having 1 to 7 carbon atoms or an alkylthio group having 1 to 7 carbon atoms
- B represents a carbon-carbon single bond or a formula—NHCO—.
- R 4 represents a carboxyl group, a sulfoxyl group or a tetrazole-5-yl group, and X represents a hydrogen atom or a halogen atom.
- an alkyl group having 1 to 7 carbon atoms means a straight-chain or branched alkyl group such as a methyl group, a methyl group, a propyl group, an isopropyl group, a butyl group and an isobutyl group.
- the alkylthio group having 1 to 7 carbon atoms means a straight-chain or branched-chain alkylthio group such as methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, and isobutylthio group.
- Halogen atoms refer to fluorine, chlorine, bromine and iodine.
- the salt of the compound of the formula (I) means a metal salt such as a sodium salt and a potassium salt.
- the compound of the present invention can be produced, for example, by the following method. That is, a compound which is known or can be obtained by a conventional method from a known compound,
- R 5 represents a nitro group or a 2- (N-triphenylmethyl-tetrazol-1-yl) phenyl group
- X ⁇ represents a halogen atom
- R 3 and R 5 are as defined above.
- a chlorine atom, a bromine atom or an iodine atom can be used as the halogen atom.
- bases include metal hydrides such as sodium hydride, organic bases such as lithium lithium and lithium diisopropylamide, alcoholates such as sodium methoxide, and potassium hydroxide. Hydroxide or carbonate such as lime carbonate.
- organic solvent N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetate, and the like can be used.
- the reaction temperature is from 178 to the reflux temperature of the solvent.
- Hydrochloric acid, hydrochloric acid, p-toluenesulfonic acid and the like can be used as an acid in this reaction, and methanol, ethanol, tetrahydrofuran and the like can be used as a solvent.
- the reaction temperature is from room temperature to the reflux temperature of the solvent.
- the reducing agent iron Z drunk acid, tin dichloride Z hydrochloric acid, nickel chloride Z hydrogenation Sodium boron, palladium / carbon hydrogen, and the like can be used.
- the solvent an alcohol such as methanol, ethyl sulphate, water or the like can be used.
- the reaction temperature is from room temperature to the reflux temperature of the solvent.
- R 6 represents a carbonyl group or a sulfonyl group c) by reacting with an acid anhydride represented by the following formula (I):
- the compound of the present invention can be produced wherein NHC is 0 and R 4 is a carbonyl group or a sulfoxyl group.
- This reaction can be performed in the presence of a base or in the absence of a base.
- a base an organic base such as pyridine, triethylamine, diisobu ⁇ -viramine or the like can be used.
- the solvent chloroform, dichloromethane, N, N-dimethylformamide or the like can be used. The reaction temperature is from room temperature to the reflux temperature of the solvent.
- the compound of the present invention can be prepared orally or nonperiodically (for example, intravenously, rectally, or ocular mucosa) in the form of various dosage forms by conventional formulation techniques and administered.
- the dosage form of the microbial preparation solid preparations such as tablets, granules and capsules, or liquid preparations such as solutions, fat emulsions and ribosome preparations can be used.
- an aqueous or non-aqueous solution, an emulsifier, a suspension, or a solid preparation to be dissolved immediately before use can be used.
- Suppositories and the like can be used as the dosage form of the preparation for rectal administration.
- a solution, an emulsifier, a suspending agent, an ointment and the like can be used as the dosage form of the ophthalmic mucosal administration preparation.
- the dose of the compound of the present invention in these administration methods varies depending on the patient's condition, disease type, age, body weight, etc., but when administered for hypertension or heart failure, it is usually from l to 100 per 1 B. 0 mg, given once or several times a day.
- the compounds of the present invention have an excellent angiotensin II receptor blocking effect and can be useful for treating hypertension, heart failure and high intraocular pressure.
- the compound obtained here was dissolved in 210 ml of methanol, a solution of 9.2 g (1.3 equivalents) of hydroxide hydroxide in 50 ml of methanol was added, and the mixture was heated under reflux for 5 hours. After the solvent was distilled off, water was added, and the pH was adjusted to 5 to 6 with 10% hydrochloric acid. The precipitated crystals were washed with water and ethyl acetate to obtain 2-1.3 g of 2-butyl-5-methylthieno [2,3-d] pyrimidine-4 (3H) -crystal. The crystals were recrystallized from methanol to obtain colorless crystals.
- the mixture obtained here was dissolved in 70 ml of methanol, added with 1.19 ⁇ (1.2 equivalents) of a hydroxide, and stirred at room temperature at room temperature. After the reaction, add 10% hydrochloric acid The precipitated crystals were washed with water to obtain 2.79 g of crystals of 2-butylthieno [3,2-d] pyrimidine-14 (3H) -one. The crystals were recrystallized from methanol to obtain colorless crystals.
- Example 7 (1) Substantially the same as Example 7 (2) using 2-bromothiothieno [3,2-d] pyrimidin-14 (3H) one obtained in Example 1 2 (1). Thus, 2-propylthio-3- (4-nitrobenzyl) thieno [3,2-d] birimidine-14 (3H) -one was obtained.
- Example 15 (3) Using the compound obtained in Example 15 (2), the title compound was obtained in substantially the same manner as in Example 15 (3).
- the compound 2.Og obtained here was dissolved in 40 ml of methanol, 0.70 g (1.2 equivalents) of a hydrating power was added, and the mixture was heated and refluxed for 10 hours.
- % Hydrochloric acid was added to adjust the pH to 7-8, and the precipitated crystals were washed with water and crystallized with 2-butylethyleno [3,4-1C!] Birimidine-1 4 (3H) -one 1,71 g This crystal was meta- It was recrystallized from an aqueous solution of ethanol to obtain colorless crystals.
- the measurement of the angiotensin ⁇ receptor binding reaction of the compound of the present invention can be carried out by the method described in J. Pharmacoco 1. Ex. Ther., Pp. 247, pp. 1 (1988, PC ong et al.) in the following manner.
- the adrenal gland was removed and the cortex was separated. 50 times the adrenal cortex
- the filter was washed three times with 3 ml of 50 mM Tris-HCl buffer ( ⁇ ⁇ 7.5) The radioactivity on the filter was determined by liquid scintillation with 10 ml of Aquasol 2 scintillation overnight Non-specific binding was 100 nM.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
L'objet de la présente invention est la production d'un nouveau type de composé possédant une action de blocage du récepteur d'angiotensine II, ce qui contribue à la thérapie de l'hypertension et des insuffisances cardiaques. Ce composé est constitué d'un dérivé de thiénopyrimidin-4-one représenté par la formule générale (I) et d'un sel du dérivé. Dans la formule, (a) représente (b), (c) ou (d), où R1 et R2 représentent chacun hydrogène, alkyle ou phényle, ou alternativement lorsque R1 est adjacent à R?2, R1 et R2¿ sont combinés entre eux pour représenter alkylène; R3 représente alkyle ou alkylthio; B représente une liaison simple carbone-carbone ou -NHCO-; R4 représente carboxyle, sulfoxyle ou tétrazol-5-yle; et X représente hydrogène ou halogène.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3/284248 | 1991-08-05 | ||
| JP28424891 | 1991-08-05 | ||
| JP3/296106 | 1991-11-13 | ||
| JP29610691 | 1991-11-13 | ||
| JP135992 | 1992-01-08 | ||
| JP4/1359 | 1992-01-08 | ||
| JP4/12868 | 1992-01-28 | ||
| JP1286892 | 1992-01-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993003040A1 true WO1993003040A1 (fr) | 1993-02-18 |
Family
ID=27453386
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1992/000990 WO1993003040A1 (fr) | 1991-08-05 | 1992-08-04 | Derive de thienopyrimidin-4-one |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2390792A (fr) |
| WO (1) | WO1993003040A1 (fr) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001098290A2 (fr) * | 2000-06-19 | 2001-12-27 | Pharmacia Italia S.P.A. | Derives de thiophene actifs en tant qu'inhibiteurs de kinase, leur procede de preparation, et compositions pharmaceutiques les contenant |
| EP1925303A2 (fr) | 1999-08-27 | 2008-05-28 | Sanofi-Aventis Deutschland GmbH | Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale |
| WO2011069038A2 (fr) | 2009-12-03 | 2011-06-09 | Synergy Pharmaceuticals, Inc. | Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires |
| WO2013138352A1 (fr) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation |
| WO2014151200A2 (fr) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions utiles pour le traitement de troubles gastro-intestinaux |
| WO2014151206A1 (fr) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonistes de la guanylate cyclase et leurs utilisations |
| EP2810951A2 (fr) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles |
| WO2014197720A2 (fr) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation |
| EP2998314A1 (fr) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles |
| EP3241839A1 (fr) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres |
| US10588894B2 (en) | 2017-06-21 | 2020-03-17 | SHY Therapeutics LLC | Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
| US10870657B2 (en) | 2015-12-22 | 2020-12-22 | SHY Therapeutics LLC | Compounds for the treatment of cancer and inflammatory disease |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0344377A (ja) * | 1989-07-06 | 1991-02-26 | Ciba Geigy Ag | 新規ピリミジン誘導体 |
| JPH03115271A (ja) * | 1989-07-03 | 1991-05-16 | Merck & Co Inc | アンギオテンシン２拮抗薬としての置換キナゾリノン類 |
| EP0443568A1 (fr) * | 1990-02-22 | 1991-08-28 | Takeda Chemical Industries, Ltd. | Dérivés fusés de thiophène, leur préparation et leur application |
-
1992
- 1992-08-04 WO PCT/JP1992/000990 patent/WO1993003040A1/fr unknown
- 1992-08-04 AU AU23907/92A patent/AU2390792A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03115271A (ja) * | 1989-07-03 | 1991-05-16 | Merck & Co Inc | アンギオテンシン２拮抗薬としての置換キナゾリノン類 |
| JPH0344377A (ja) * | 1989-07-06 | 1991-02-26 | Ciba Geigy Ag | 新規ピリミジン誘導体 |
| EP0443568A1 (fr) * | 1990-02-22 | 1991-08-28 | Takeda Chemical Industries, Ltd. | Dérivés fusés de thiophène, leur préparation et leur application |
Cited By (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1925303A2 (fr) | 1999-08-27 | 2008-05-28 | Sanofi-Aventis Deutschland GmbH | Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale |
| EP2277519A2 (fr) | 1999-08-27 | 2011-01-26 | Sanofi-Aventis Deutschland GmbH | Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale |
| WO2001098290A3 (fr) * | 2000-06-19 | 2002-05-16 | Pharmacia Italia Spa | Derives de thiophene actifs en tant qu'inhibiteurs de kinase, leur procede de preparation, et compositions pharmaceutiques les contenant |
| US6414013B1 (en) | 2000-06-19 | 2002-07-02 | Pharmacia & Upjohn S.P.A. | Thiophene compounds, process for preparing the same, and pharmaceutical compositions containing the same background of the invention |
| AU2001285745B2 (en) * | 2000-06-19 | 2007-03-22 | Pharmacia Italia S.P.A. | Thiophene derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
| WO2001098290A2 (fr) * | 2000-06-19 | 2001-12-27 | Pharmacia Italia S.P.A. | Derives de thiophene actifs en tant qu'inhibiteurs de kinase, leur procede de preparation, et compositions pharmaceutiques les contenant |
| EP2998314A1 (fr) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles |
| EP2810951A2 (fr) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles |
| EP3241839A1 (fr) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres |
| EP2923706A1 (fr) | 2009-12-03 | 2015-09-30 | Synergy Pharmaceuticals Inc. | Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie |
| WO2011069038A2 (fr) | 2009-12-03 | 2011-06-09 | Synergy Pharmaceuticals, Inc. | Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires |
| WO2013138352A1 (fr) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation |
| EP3708179A1 (fr) | 2012-03-15 | 2020-09-16 | Bausch Health Ireland Limited | Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation |
| EP4309673A2 (fr) | 2012-03-15 | 2024-01-24 | Bausch Health Ireland Limited | Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation |
| WO2014151200A2 (fr) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions utiles pour le traitement de troubles gastro-intestinaux |
| WO2014151206A1 (fr) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonistes de la guanylate cyclase et leurs utilisations |
| WO2014197720A2 (fr) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation |
| EP4424697A2 (fr) | 2013-06-05 | 2024-09-04 | Bausch Health Ireland Limited | Agonistes ultra-purs de guanylate cyclase c, leur procédé de fabrication et d'utilisation |
| US11560390B2 (en) | 2015-12-22 | 2023-01-24 | SHY Therapeutics LLC | Compounds for the treatment of cancer and inflammatory disease |
| US10870657B2 (en) | 2015-12-22 | 2020-12-22 | SHY Therapeutics LLC | Compounds for the treatment of cancer and inflammatory disease |
| US10933054B2 (en) | 2017-06-21 | 2021-03-02 | SHY Therapeutics LLC | Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
| US11026930B1 (en) | 2017-06-21 | 2021-06-08 | SHY Therapeutics LLC | Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
| US11213515B1 (en) | 2017-06-21 | 2022-01-04 | SHY Therapeutics LLC | Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
| US11541041B1 (en) | 2017-06-21 | 2023-01-03 | SHY Therapeutics LLC | Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, Rasopathies, and fibrotic disease |
| US11000515B2 (en) | 2017-06-21 | 2021-05-11 | SHY Therapeutics LLC | Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
| US10940139B2 (en) | 2017-06-21 | 2021-03-09 | SHY Therapeutics LLC | Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
| US10588894B2 (en) | 2017-06-21 | 2020-03-17 | SHY Therapeutics LLC | Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2390792A (en) | 1993-03-02 |
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