LU84803A1 - Bicyclische verbindungen - Google Patents
Bicyclische verbindungen Download PDFInfo
- Publication number
- LU84803A1 LU84803A1 LU84803A LU84803A LU84803A1 LU 84803 A1 LU84803 A1 LU 84803A1 LU 84803 A LU84803 A LU 84803A LU 84803 A LU84803 A LU 84803A LU 84803 A1 LU84803 A1 LU 84803A1
- Authority
- LU
- Luxembourg
- Prior art keywords
- octahydro
- dioxo
- diazepine
- pyridazo
- carboxylate
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 177
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 97
- -1 monoalkylaminoalkyl Chemical group 0.000 claims description 86
- MSBJCEKFIIGEOW-UHFFFAOYSA-N 1h-pyridazine-2-carboxylic acid Chemical compound OC(=O)N1NC=CC=C1 MSBJCEKFIIGEOW-UHFFFAOYSA-N 0.000 claims description 82
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 78
- 239000000203 mixture Substances 0.000 claims description 75
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 48
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 42
- QRKPPWPLSQRGSU-UHFFFAOYSA-N diazepine-1-carboxylic acid Chemical compound OC(=O)N1C=CC=CC=N1 QRKPPWPLSQRGSU-UHFFFAOYSA-N 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 37
- 239000002253 acid Substances 0.000 claims description 32
- 125000004894 pentylamino group Chemical group C(CCCC)N* 0.000 claims description 28
- 229920006395 saturated elastomer Polymers 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 150000007942 carboxylates Chemical class 0.000 claims description 13
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 12
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 11
- 239000005977 Ethylene Substances 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 10
- 125000004945 acylaminoalkyl group Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 150000002431 hydrogen Chemical group 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- 125000006308 propyl amino group Chemical group 0.000 claims description 9
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 7
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 241000251730 Chondrichthyes Species 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- OJUAMMUUNWSYLW-UHFFFAOYSA-N 3,9-dihydropyrazolo[1,2-a]diazepine-3-carboxylic acid Chemical compound C1C=CC=CN2C(C(=O)O)C=CN21 OJUAMMUUNWSYLW-UHFFFAOYSA-N 0.000 claims description 4
- 150000001540 azides Chemical class 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 3
- JUSIWJONLKBPDU-UHFFFAOYSA-N pyridazine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NN=C1 JUSIWJONLKBPDU-UHFFFAOYSA-N 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000005154 alkyl sulfonyl amino alkyl group Chemical group 0.000 claims description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims 21
- 239000008186 active pharmaceutical agent Substances 0.000 claims 15
- 125000005128 aryl amino alkyl group Chemical group 0.000 claims 7
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 4
- 230000003276 anti-hypertensive effect Effects 0.000 claims 3
- AWGBKZRMLNVLAF-UHFFFAOYSA-N 3,5-dibromo-n,2-dihydroxybenzamide Chemical compound ONC(=O)C1=CC(Br)=CC(Br)=C1O AWGBKZRMLNVLAF-UHFFFAOYSA-N 0.000 claims 1
- QXKAIJAYHKCRRA-JJYYJPOSSA-N D-arabinonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(O)=O QXKAIJAYHKCRRA-JJYYJPOSSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- VNWKTOKETHGBQD-YPZZEJLDSA-N carbane Chemical compound [10CH4] VNWKTOKETHGBQD-YPZZEJLDSA-N 0.000 claims 1
- 230000006806 disease prevention Effects 0.000 claims 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 1
- 229920002554 vinyl polymer Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 191
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 156
- 239000000243 solution Substances 0.000 description 137
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 108
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 93
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 77
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 70
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 69
- 239000007787 solid Substances 0.000 description 66
- 230000008018 melting Effects 0.000 description 59
- 238000002844 melting Methods 0.000 description 59
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 43
- 239000003921 oil Substances 0.000 description 43
- 235000019198 oils Nutrition 0.000 description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- 239000000741 silica gel Substances 0.000 description 37
- 229910002027 silica gel Inorganic materials 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 26
- 238000010828 elution Methods 0.000 description 25
- 229960000583 acetic acid Drugs 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 23
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 23
- 235000017557 sodium bicarbonate Nutrition 0.000 description 23
- 239000007858 starting material Substances 0.000 description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 21
- 235000019341 magnesium sulphate Nutrition 0.000 description 21
- 239000003480 eluent Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 19
- 239000003456 ion exchange resin Substances 0.000 description 19
- 229920003303 ion-exchange polymer Polymers 0.000 description 19
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 18
- 239000003054 catalyst Substances 0.000 description 17
- 239000013078 crystal Substances 0.000 description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 15
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 14
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 12
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 12
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 11
- 239000000155 melt Substances 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 8
- STPXIOGYOLJXMZ-UHFFFAOYSA-N ethyl 2-oxo-4-phenylbutanoate Chemical compound CCOC(=O)C(=O)CCC1=CC=CC=C1 STPXIOGYOLJXMZ-UHFFFAOYSA-N 0.000 description 8
- 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 8
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 7
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 7
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- PPKAIMDMNWBOKN-UHFFFAOYSA-N 2-Oxo-4-phenylbutyric acid Chemical compound OC(=O)C(=O)CCC1=CC=CC=C1 PPKAIMDMNWBOKN-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- JKEXRGAYWPIPJS-UHFFFAOYSA-N 2-amino-3-oxo-1,2,5,6,7,8-hexahydropyrazolo[1,2-a]pyridazine-5-carboxylic acid Chemical compound C1CCC(C(O)=O)N2C(=O)C(N)CN21 JKEXRGAYWPIPJS-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 5
- 229920001971 elastomer Polymers 0.000 description 5
- 150000004820 halides Chemical class 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- OJUAMMUUNWSYLW-QMMMGPOBSA-N (3s)-3,9-dihydropyrazolo[1,2-a]diazepine-3-carboxylic acid Chemical compound C1C=CC=CN2[C@H](C(=O)O)C=CN21 OJUAMMUUNWSYLW-QMMMGPOBSA-N 0.000 description 4
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 4
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- 229910000510 noble metal Inorganic materials 0.000 description 4
- 150000007530 organic bases Chemical group 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- 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 3
- 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 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- CRGRWBQSZSQVIE-UHFFFAOYSA-N diazomethylbenzene Chemical compound [N-]=[N+]=CC1=CC=CC=C1 CRGRWBQSZSQVIE-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
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- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 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
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- UDJNHUAEPSYCRU-LLVKDONJSA-N ethyl (2r)-4-phenyl-2-(trifluoromethylsulfonyloxy)butanoate Chemical compound CCOC(=O)[C@H](OS(=O)(=O)C(F)(F)F)CCC1=CC=CC=C1 UDJNHUAEPSYCRU-LLVKDONJSA-N 0.000 description 1
- WFLQXECQLHZKMV-UHFFFAOYSA-N ethyl 2-amino-4-phenylbutanoate Chemical compound CCOC(=O)C(N)CCC1=CC=CC=C1 WFLQXECQLHZKMV-UHFFFAOYSA-N 0.000 description 1
- ZLZXSWNRZFMSSS-UHFFFAOYSA-N ethyl 2-bromo-4-phenylbutanoate Chemical compound CCOC(=O)C(Br)CCC1=CC=CC=C1 ZLZXSWNRZFMSSS-UHFFFAOYSA-N 0.000 description 1
- SXZHDULBCLKRAE-UHFFFAOYSA-N ethyl 2-bromo-5-methylhexanoate Chemical compound CCOC(=O)C(Br)CCC(C)C SXZHDULBCLKRAE-UHFFFAOYSA-N 0.000 description 1
- WFNOGYJCUILODY-UHFFFAOYSA-N ethyl 2-bromo-6-(phenylmethoxycarbonylamino)hexanoate Chemical compound CCOC(=O)C(Br)CCCCNC(=O)OCC1=CC=CC=C1 WFNOGYJCUILODY-UHFFFAOYSA-N 0.000 description 1
- RNKJLNWXMDLRLO-UHFFFAOYSA-N ethyl 2-oxo-4-(2-phenylphenyl)butanoate Chemical compound CCOC(=O)C(=O)CCC1=CC=CC=C1C1=CC=CC=C1 RNKJLNWXMDLRLO-UHFFFAOYSA-N 0.000 description 1
- VUMFPMBWHQNWKS-UHFFFAOYSA-N ethyl 4-(4-chlorophenyl)-2-oxobutanoate Chemical compound CCOC(=O)C(=O)CCC1=CC=C(Cl)C=C1 VUMFPMBWHQNWKS-UHFFFAOYSA-N 0.000 description 1
- YBQMIWIQGUAOTP-UHFFFAOYSA-N ethyl 4-(4-methoxyphenyl)-2-oxobutanoate Chemical compound CCOC(=O)C(=O)CCC1=CC=C(OC)C=C1 YBQMIWIQGUAOTP-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000001530 fumaric acid Substances 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
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-M lysinate Chemical compound NCCCCC(N)C([O-])=O KDXKERNSBIXSRK-UHFFFAOYSA-M 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- LJDLNNZTQJVBNJ-SNAWJCMRSA-N methyl (2e)-penta-2,4-dienoate Chemical compound COC(=O)\C=C\C=C LJDLNNZTQJVBNJ-SNAWJCMRSA-N 0.000 description 1
- YEPNFOMBMXWUOG-UHFFFAOYSA-N methyl 2-amino-4-phenylbutanoate Chemical compound COC(=O)C(N)CCC1=CC=CC=C1 YEPNFOMBMXWUOG-UHFFFAOYSA-N 0.000 description 1
- ZCUUVQGLXPIZRL-UHFFFAOYSA-N methyl 2-amino-5-methylhexanoate Chemical compound COC(=O)C(N)CCC(C)C ZCUUVQGLXPIZRL-UHFFFAOYSA-N 0.000 description 1
- XUHINRSSRAMEHK-UHFFFAOYSA-N methyl 2-amino-5-phenylpentanoate Chemical compound COC(=O)C(N)CCCC1=CC=CC=C1 XUHINRSSRAMEHK-UHFFFAOYSA-N 0.000 description 1
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral 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
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000006247 phenyl propyl amino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 235000015277 pork Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- MQGYVGKMCRDEAF-UHFFFAOYSA-M sodium;2-oxo-3-phenylpropanoate Chemical compound [Na+].[O-]C(=O)C(=O)CC1=CC=CC=C1 MQGYVGKMCRDEAF-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- MDUKXPOXPIYBLH-LSDHHAIUSA-N tert-butyl (3r,6s)-6-(1,3-dioxoisoindol-2-yl)-5,9-dioxo-1,2,3,6,7,8-hexahydropyrazolo[1,2-a]diazepine-3-carboxylate Chemical compound C([C@@H]1C(=O)OC(C)(C)C)CN(C(CC2)=O)N1C(=O)[C@H]2N1C(=O)C2=CC=CC=C2C1=O MDUKXPOXPIYBLH-LSDHHAIUSA-N 0.000 description 1
- MDUKXPOXPIYBLH-GJZGRUSLSA-N tert-butyl (3s,6s)-6-(1,3-dioxoisoindol-2-yl)-5,9-dioxo-1,2,3,6,7,8-hexahydropyrazolo[1,2-a]diazepine-3-carboxylate Chemical compound C([C@H]1C(=O)OC(C)(C)C)CN(C(CC2)=O)N1C(=O)[C@H]2N1C(=O)C2=CC=CC=C2C1=O MDUKXPOXPIYBLH-GJZGRUSLSA-N 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/04—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3886—Acids containing the structure -C(=X)-P(=X)(XH)2 or NC-P(=X)(XH)2, (X = O, S, Se)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/409—Compounds containing the structure P(=X)-X-acyl, P(=X) -X-heteroatom, P(=X)-X-CN (X = O, S, Se)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650905—Six-membered rings having the nitrogen atoms in the positions 1 and 2
- C07F9/650947—Six-membered rings having the nitrogen atoms in the positions 1 and 2 condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8213850 | 1982-05-12 | ||
| GB8213850 | 1982-05-12 | ||
| GB08305505A GB2128984B (en) | 1982-05-12 | 1983-02-28 | Diaza-bicyclic compounds |
| GB8305505 | 1983-02-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| LU84803A1 true LU84803A1 (fr) | 1985-03-21 |
Family
ID=26282820
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LU84803A LU84803A1 (fr) | 1982-05-12 | 1983-05-11 | Bicyclische verbindungen |
| LU88299C LU88299I2 (fr) | 1982-05-12 | 1993-06-09 | Cilazapril (Vascace / Inhibace) |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LU88299C LU88299I2 (fr) | 1982-05-12 | 1993-06-09 | Cilazapril (Vascace / Inhibace) |
Country Status (32)
| Country | Link |
|---|---|
| US (3) | US4512924A (enExample) |
| EP (1) | EP0094095B1 (enExample) |
| KR (1) | KR890002106B1 (enExample) |
| AR (1) | AR240940A1 (enExample) |
| AU (1) | AU567873B2 (enExample) |
| BG (1) | BG61123B2 (enExample) |
| CA (1) | CA1234568A (enExample) |
| CS (2) | CS249128B2 (enExample) |
| CU (1) | CU21532A3 (enExample) |
| DE (2) | DE3381884D1 (enExample) |
| DK (1) | DK160612C (enExample) |
| DO (1) | DOP1983004163A (enExample) |
| DZ (1) | DZ540A1 (enExample) |
| ES (6) | ES8407049A1 (enExample) |
| FI (1) | FI77244C (enExample) |
| FR (1) | FR2531956B1 (enExample) |
| GB (1) | GB2128984B (enExample) |
| GR (1) | GR77462B (enExample) |
| HK (1) | HK91692A (enExample) |
| HU (3) | HU199842B (enExample) |
| IE (1) | IE56480B1 (enExample) |
| IL (1) | IL68620A (enExample) |
| IT (1) | IT1212738B (enExample) |
| LU (2) | LU84803A1 (enExample) |
| MC (1) | MC1515A1 (enExample) |
| MY (1) | MY102889A (enExample) |
| NL (2) | NL8301640A (enExample) |
| NO (1) | NO160368C (enExample) |
| PT (1) | PT76681B (enExample) |
| SE (1) | SE461792B (enExample) |
| SG (1) | SG81192G (enExample) |
| ZW (1) | ZW9883A1 (enExample) |
Families Citing this family (102)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA833214B (en) * | 1982-05-12 | 1983-12-28 | Hoffmann La Roche | Bicyclic compounds |
| GB2128984B (en) * | 1982-05-12 | 1985-05-22 | Hoffmann La Roche | Diaza-bicyclic compounds |
| DE3315464A1 (de) * | 1983-04-28 | 1984-10-31 | Hoechst Ag, 6230 Frankfurt | Verfahren zur herstellung von n-alkylierten dipeptiden und deren estern |
| US4801721A (en) * | 1984-08-16 | 1989-01-31 | Ryan James W | Stereospecific synthesis of carboxyalkyl peptides |
| US4692438A (en) * | 1984-08-24 | 1987-09-08 | Hoffmann-La Roche Inc. | Pyridazo-diazepines, diazocines, and -triazepines having anti-hypertensive activity |
| US4826992A (en) * | 1985-04-30 | 1989-05-02 | Eli Lilly And Company | 2,3-(Dihydro) bicyclic pyrazolidinones |
| US4902707A (en) * | 1985-04-30 | 1990-02-20 | Eli Lilly And Company | Bicyclic pyrazolidinones, compositions and use |
| US4940718A (en) * | 1985-04-30 | 1990-07-10 | Eli Lilly And Company | 7-substituted bicyclic pyrazolidinones, pharmaceutical compositions and use |
| CA1274832A (en) * | 1985-04-30 | 1990-10-02 | Richard Elmer Holmes | 7-substituted bicyclic pyrazolidinones |
| ZW11586A1 (en) * | 1985-07-01 | 1987-12-30 | Hoffmann La Roche | Bicyclic compounds |
| US4832763A (en) * | 1985-10-15 | 1989-05-23 | Westinghouse Electric Corp. | Method of stress-relief annealing a magnetic core containing amorphous material |
| DE3542794A1 (de) * | 1985-12-04 | 1987-06-11 | Bayer Ag | Antihypertensives kombinationspraeparat |
| EP0566157A1 (en) | 1986-06-20 | 1993-10-20 | Schering Corporation | Neutral metalloendopeptidase inhibitors in the treatment of hypertension |
| EP0254032A3 (en) | 1986-06-20 | 1990-09-05 | Schering Corporation | Neutral metalloendopeptidase inhibitors in the treatment of hypertension |
| GB8629875D0 (en) * | 1986-12-15 | 1987-01-28 | Hoffmann La Roche | Pyridazodiazepine derivatives |
| US5262436A (en) * | 1987-03-27 | 1993-11-16 | Schering Corporation | Acylamino acid antihypertensives in the treatment of congestive heart failure |
| US4956490A (en) * | 1989-03-09 | 1990-09-11 | Merck & Co., Inc. | Process for preparing benzylpyruvic acids and esters |
| ZA902661B (en) * | 1989-04-10 | 1991-01-30 | Schering Corp | Mercapto-acyl amino acids |
| DE3917255A1 (de) * | 1989-05-26 | 1990-11-29 | Schopf Masch | Verfahren und vorrichtung zum aufnehmen eines flugzeugbugfahrwerks durch einen flugzeugschlepper |
| US5011938A (en) * | 1989-10-02 | 1991-04-30 | Eli Lilly And Company | 7-substituted bicyclic pyrazolidinones |
| AU6880291A (en) * | 1989-11-21 | 1991-06-13 | Schering Corporation | Carboxyalkylcarbonyl aminoacid endopeptidase inhibitors |
| WO1991009840A1 (en) * | 1989-12-22 | 1991-07-11 | Schering Corporation | Mercaptocycloacyl aminoacid endopeptidase inhibitors |
| US5075302A (en) * | 1990-03-09 | 1991-12-24 | Schering Corporation | Mercaptoacyl aminolactam endopeptidase inhibitors |
| US5173506A (en) * | 1990-08-16 | 1992-12-22 | Schering Corporation | N-(mercaptoalkyl)ureas and carbamates |
| DE59107840D1 (de) * | 1990-11-21 | 1996-06-27 | Ciba Geigy Ag | Silylierte Acylphosphinoxide |
| US5208230A (en) * | 1990-12-21 | 1993-05-04 | Merrell Dow Pharmaceuticals | Amino and nitro containing tricyclic compounds useful as inhibitors of ACE |
| US5506193A (en) * | 1991-03-19 | 1996-04-09 | Ciba-Geigy Corporation | Herbicidally, acaricidally and insecticidally active pyrazolidine compounds |
| TW216770B (enExample) * | 1991-07-23 | 1993-12-01 | Hoffmann La Roche | |
| US5457196A (en) * | 1991-09-27 | 1995-10-10 | Merrell Dow Pharmaceuticals Inc. | 2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE |
| US5455242A (en) * | 1991-09-27 | 1995-10-03 | Merrell Dow Pharmaceuticals Inc. | Carboxyalkyl tricyclic derivatives useful as inhibitors of enkephalinase and ace |
| CA2078759C (en) * | 1991-09-27 | 2003-09-16 | Alan M. Warshawsky | Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ace |
| US5442062A (en) * | 1991-10-24 | 1995-08-15 | The Upjohn Company | Imidazole derivatives and pharmaceutical compositions containing the same |
| JPH06107661A (ja) * | 1991-10-24 | 1994-04-19 | Upjohn Co:The | イミダゾール誘導体およびこれを有効成分とする医薬組成物 |
| US5972990A (en) * | 1992-04-10 | 1999-10-26 | Brigham And Women's Hospital, Inc. | Methods for reducing risk of repeat myocardial infarction and increasing survival in heart attack victims |
| US5977160A (en) * | 1992-04-10 | 1999-11-02 | Brigham And Women's Hospital, Inc. | Methods for reducing risk of repeat myocardial infarction and increasing survival in heart attack victims |
| US5552397A (en) * | 1992-05-18 | 1996-09-03 | E. R. Squibb & Sons, Inc. | Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase |
| KR100281450B1 (ko) * | 1992-05-15 | 2001-02-01 | 슈테펜 엘. 네스비트 | 엔케팔리나제 및 안지오텐신 전환 효소의 억제제로서 유용한 신규 메르캅토아세틸아미도 피리다조[1,2]피리다진, 피라졸로[1,2]피리다진, 피리다조[1,2-a][1,2]디아제핀 및 피라졸로[1,2-a][1,2]디아제핀 유도체 |
| ATE203242T1 (de) * | 1992-05-18 | 2001-08-15 | Hoffmann La Roche | Asymmetrische hydrierung |
| US5238932A (en) * | 1992-05-20 | 1993-08-24 | Merrell Dow Pharmaceuticals Inc. | Mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase |
| NZ256589A (en) * | 1992-10-30 | 1996-05-28 | Merrell Dow Pharma | Condensed azepine analogues and medicaments (where a is c, o or s and b is o or s) |
| JPH072859A (ja) * | 1993-01-28 | 1995-01-06 | Upjohn Co:The | ピラゾール誘導体およびこれを有効成分とする医薬組成物 |
| US5476395A (en) * | 1993-03-01 | 1995-12-19 | Methode Electronics, Inc. | Planar fuse panel |
| US5654294A (en) * | 1993-05-13 | 1997-08-05 | Bristol-Myers Squibb | Spiro lactam dual action inhibitors |
| EP0634175B1 (de) * | 1993-07-15 | 2001-01-10 | F. Hoffmann-La Roche Ag | Pharmazeutische Kombination, die einen Hemmer des Renin-Angiotensin-Systems und einen Endothelin-Antagonisten enthält |
| NZ279397A (en) * | 1994-02-14 | 1997-08-22 | Merrell Pharma Inc | Mercaptoacetylamido 1,3,4,5-tetrahydro-benzo[c]azepin-3-one disulfide derivatives and pharmaceutucal compositions |
| JP3561753B2 (ja) * | 1994-02-14 | 2004-09-02 | メレル ファーマスーティカルズ インコーポレーテッド | エンケファリナーゼ及びａｃｅの阻害剤として有用な、新規な２−置換インダン−２−メルカプトアセチルアミドジスルフィド誘導体類 |
| US5530013A (en) * | 1994-02-14 | 1996-06-25 | American Home Products Corporation | Venlafaxine in the inducement of cognition enhancement |
| EP0745081B1 (en) * | 1994-02-14 | 2001-11-21 | Merrell Pharmaceuticals Inc. | indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase |
| US5750521A (en) * | 1994-02-14 | 1998-05-12 | Hoechst Marion Roussel Inc. | Mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase and ACE |
| US5484783A (en) * | 1994-03-24 | 1996-01-16 | Merrell Dow Pharmaceuticals Inc. | Hypocholesterolemic, antiatherosclerotic and hypotriglyceridemic mercaptoacetylamide and benzazapine derivatives |
| HUP9774624A2 (en) * | 1994-03-24 | 1997-01-28 | Merrell Pharma Inc | Hypocholesterolemic, antiatheroclerotic and hypotriglyceridemic condensed benzazepine mercaptoacetylamide disulfide derivatives |
| PT751783E (pt) * | 1994-03-24 | 2000-05-31 | Merrell Pharma Inc | Derivados aminoacetilmercapto hipocolesterolemicos antiateroscleroticos e hipotrigliceridemicos |
| US5756466A (en) | 1994-06-17 | 1998-05-26 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1β converting enzyme |
| US5587375A (en) * | 1995-02-17 | 1996-12-24 | Bristol-Myers Squibb Company | Azepinone compounds useful in the inhibition of ACE and NEP |
| US5877313A (en) * | 1995-05-17 | 1999-03-02 | Bristol-Myers Squibb | Benzo-fused azepinone and piperidinone compounds useful in the inhibition of ACE and NEP |
| US5650408A (en) * | 1995-06-07 | 1997-07-22 | Karanewsky; Donald S. | Thiazolo benzazepine containing dual action inhibitors |
| US5635504A (en) * | 1995-06-07 | 1997-06-03 | Bristol-Myers Squibb Co. | Diazepine containing dual action inhibitors |
| FR2777889B1 (fr) * | 1998-04-27 | 2004-07-09 | Hoechst Marion Roussel Inc | Nouveaux derives de l'acide octahydro-6,10-dioxo-6h- pyridazino[1,2-a][1,2]diazepine-1-carboxylique, leur procede de preparation et leur application a la preparation de composes therapeutiquement actifs |
| AU2003200034B2 (en) * | 1998-04-27 | 2006-07-20 | Aventis Pharma S.A. | New derivatives of octahydro-6, 10-dioxo-6H-pyridazino [1,2-A][1,2]diazepine-1-carboxylic acid, their preparation process and their use in the preparation of therapeutically active compounds |
| FR2777888B1 (fr) * | 1998-04-27 | 2004-07-16 | Hoechst Marion Roussel Inc | Nouveaux derives de l'acide (3,4,7,8,9,10-hexahydro-6,10- dioxo-6h-pyridazino[1,2-a][1,2]diazepine-1-carboxylique, leur procede de preparation et leur application a la preparation de medicaments |
| US6703500B2 (en) | 1998-08-19 | 2004-03-09 | Vertex Pharmaceuticals, Incorporated | Method of preparing bicyclic intermediates from piperazic acid or an ester thereof useful in the manufacture of caspase inhibitors |
| US6559304B1 (en) | 1998-08-19 | 2003-05-06 | Vertex Pharmaceuticals Incorporated | Method for synthesizing caspase inhibitors |
| US6177565B1 (en) * | 1998-08-19 | 2001-01-23 | Vertex Pharmaceuticals Inc. | Process for synthesizing piperazic acid |
| FR2788276B1 (fr) * | 1999-01-12 | 2001-02-16 | Hoechst Marion Roussel Inc | NOUVEAU PROCEDE DE PREPARATION DE COMPOSES BICYCLIQUES ET L'APPLICATION DE CE PROCEDE COMME ETAPE INTERMEDIAIRE POUR LA PREPARATION D'UN COMPOSE INHIBITEUR DE L'ENZYME DE CONVERSION DE L'INTERLEUKINE 1-BETA (ice) |
| US6376242B1 (en) * | 1999-09-21 | 2002-04-23 | Emory University | Methods and compositions for treating platelet-related disorders using MPL pathway inhibitory agents |
| US20030113330A1 (en) * | 1999-11-08 | 2003-06-19 | Uhal Bruce D. | Methods for treating pulmonary fibrosis |
| AU2002230848B2 (en) | 2000-12-14 | 2008-01-24 | The Brigham And Women's Hospital, Inc. | Inflammatory markers for detection and prevention of diabetes mellitus |
| GB0119305D0 (en) | 2001-04-12 | 2001-10-03 | Aventis Pharma Gmbh | Mercaptoacetylamide derivatives,a process for their preparation and their use |
| WO2003094856A2 (en) | 2002-05-09 | 2003-11-20 | The Brigham And Women's Hospital, Inc. | 1l1rl-1 as a cardiovascular disease marker and therapeutic target |
| US20040110241A1 (en) * | 2002-12-06 | 2004-06-10 | Segal Mark S. | Materials and methods for monitoring vascular endothelial function |
| JP2006523613A (ja) * | 2002-12-20 | 2006-10-19 | エスティ．ジェイムス アソシエイト エルエルシー／フェイバー リサーチ シリーズ | 徐放性医薬投与のための被覆粒子 |
| US20060293517A1 (en) * | 2003-03-06 | 2006-12-28 | Yatendra Kumar | Enantiomerically pure cilazapril, process for preparation |
| WO2005003134A1 (en) * | 2003-07-07 | 2005-01-13 | Hetero Drugs Limited | A novel process for the preparation of cilazapril |
| AU2004315596B2 (en) | 2003-08-29 | 2011-11-24 | President And Fellows Of Harvard College | Inhibitors of cellular necrosis |
| US7781219B2 (en) | 2003-12-05 | 2010-08-24 | The Cleveland Clinic Foundation | Risk markers for cardiovascular disease |
| US7803838B2 (en) * | 2004-06-04 | 2010-09-28 | Forest Laboratories Holdings Limited | Compositions comprising nebivolol |
| WO2005122682A2 (en) | 2004-06-18 | 2005-12-29 | Ranbaxy Laboratories Limited | Process for the preparation of esters of piperazic acid |
| EP2927693A1 (en) | 2004-10-06 | 2015-10-07 | The Brigham and Women's Hospital | Relevance of achieved levels of markers of systemic inflammation following treatment |
| EP1846380A4 (en) * | 2005-01-21 | 2010-02-17 | Nicox Sa | HETEROCYCLIC NITROGEN MONOXIDE DONOR COMPOSITIONS CONTAINING CARDIOVASCULAR COMPOUNDS, AND METHODS OF USING THE SAME |
| AP2764A (en) * | 2005-01-31 | 2013-09-30 | Mylan Lab Inc | Hydroxylated nebivolol metabolites |
| CA2610694A1 (en) | 2005-05-31 | 2006-12-07 | Mylan Laboratories, Inc. | Compositions comrising nebivolol |
| US8119358B2 (en) | 2005-10-11 | 2012-02-21 | Tethys Bioscience, Inc. | Diabetes-related biomarkers and methods of use thereof |
| US20070281000A1 (en) * | 2006-06-02 | 2007-12-06 | Michael Fox | Stable formulation comprising moisture sensitive drug/s and manufacturing procedure thereof |
| DE602006000402T8 (de) | 2006-06-02 | 2009-04-09 | Teva Pharmaceutical Industries Ltd. | Stabile Zubereitung enthaltend eine feuchtigkeitsempfindliche aktive Substanz und Verfahren zur Herstellung der Zubereitung. |
| EP2302395B1 (en) | 2006-06-07 | 2015-04-15 | Health Diagnostic Laboratory, Inc. | Markers associated with arteriovascular events and methods of use thereof |
| US20080008751A1 (en) * | 2006-07-10 | 2008-01-10 | Michael Fox | Stable formulation comprising a combination of a moisture sensitive drug and a second drug and manufacturing procedure thereof |
| EP2891885A3 (en) | 2007-04-18 | 2015-10-14 | Health Diagnostic Laboratory, Inc. | Diabetes-related biomarkers and methods of use thereof |
| US7828840B2 (en) * | 2007-11-15 | 2010-11-09 | Med Institute, Inc. | Medical devices and methods for local delivery of angiotensin II type 2 receptor antagonists |
| GB2460915B (en) * | 2008-06-16 | 2011-05-25 | Biovascular Inc | Controlled release compositions of agents that reduce circulating levels of platelets and methods therefor |
| EP2221299A3 (en) | 2009-02-11 | 2010-11-03 | Dr. Reddy's Laboratories Ltd. | Preparation of cilazapril intermediates |
| KR20120139723A (ko) | 2010-02-01 | 2012-12-27 | 더 호스피탈 포 식 칠드런 | 재발협착증의 치료 및 예방을 위한 원격 허혈 처치 |
| CN102939054A (zh) | 2010-03-31 | 2013-02-20 | 儿童医院 | 远端缺血处理改进心肌梗死之后的结果的用途 |
| KR20130040878A (ko) | 2010-04-08 | 2013-04-24 | 더 호스피탈 포 식 칠드런 | 외상성 손상을 위한 원격 허혈 처치의 사용 |
| WO2012049646A1 (en) | 2010-10-12 | 2012-04-19 | Ranbaxy Laboratories Limited | Process for the preparation of an intermediate of cilazapril |
| EP2537534B1 (en) | 2011-06-22 | 2014-12-17 | Hexal AG | Esters of (1S,9S)-9-[[(1S)-1-carboxy-3-phenylpropyl]amino]octahydro-10-oxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid and their therapeutic use. |
| EP2734222B1 (en) | 2011-07-18 | 2016-10-19 | Critical Care Diagnostics, Inc. | Methods of treating cardiovascular diseases and predicting the efficacy of exercise therapy |
| NZ728724A (en) | 2012-05-11 | 2018-03-23 | Reset Therapeutics Inc | Carbazole-containing sulfonamides as cryptochrome modulators |
| AU2013296803B2 (en) | 2012-08-01 | 2018-03-08 | Eric Ostertag | Free flowing, frozen compositions comprising a therapeutic agent |
| WO2014145022A1 (en) | 2013-03-15 | 2014-09-18 | President And Fellows Of Harvard College | Hybrid necroptosis inhibitors |
| WO2014153541A1 (en) | 2013-03-21 | 2014-09-25 | Eupraxia Pharmaceuticals USA LLC | Injectable sustained release composition and method of using the same for treating inflammation in joints and pain associated therewith |
| TWI690521B (zh) | 2014-04-07 | 2020-04-11 | 美商同步製藥公司 | 作為隱花色素調節劑之含有咔唑之醯胺類、胺基甲酸酯類及脲類 |
| RU2018119121A (ru) | 2015-10-27 | 2019-11-28 | Юпраксия Фармасьютикалз Инк. | Лекарственные формы местных анастетиков с замедленным высвобождением |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL58849A (en) * | 1978-12-11 | 1983-03-31 | Merck & Co Inc | Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them |
| IL60617A0 (en) * | 1979-07-23 | 1980-09-16 | Sparamedica Ag | Triazolopyridazine derivative,their preparation and pharmaceutical compositions containing them |
| DE3062972D1 (en) * | 1979-09-19 | 1983-06-09 | Hoffmann La Roche | Pyridazopyridazine derivatives, processes for their preparation and pharmaceutical compositions containing these pyridazopyridazine derivatives |
| EP0042100A1 (de) * | 1980-06-13 | 1981-12-23 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Pyrazolopyridazin-Derivate, Zwischenprodukte und Verfahren zu deren Herstellung, sowie diese enthaltende Arzneimittel |
| EP0047620B1 (en) * | 1980-09-10 | 1985-03-13 | Beecham Group Plc | Aryl diazabicyclyl amides, a process for their preparation and use |
| GB2128984B (en) * | 1982-05-12 | 1985-05-22 | Hoffmann La Roche | Diaza-bicyclic compounds |
-
1983
- 1983-02-28 GB GB08305505A patent/GB2128984B/en not_active Expired
- 1983-04-29 ZW ZW98/83A patent/ZW9883A1/xx unknown
- 1983-04-29 CA CA000427095A patent/CA1234568A/en not_active Expired
- 1983-05-02 DK DK194783A patent/DK160612C/da not_active IP Right Cessation
- 1983-05-06 IL IL68620A patent/IL68620A/xx not_active IP Right Cessation
- 1983-05-09 HU HU875409A patent/HU199842B/hu not_active IP Right Cessation
- 1983-05-09 CU CU8335899A patent/CU21532A3/xx unknown
- 1983-05-09 AU AU14364/83A patent/AU567873B2/en not_active Expired
- 1983-05-09 IT IT8321000A patent/IT1212738B/it active
- 1983-05-09 NL NL8301640A patent/NL8301640A/nl not_active Application Discontinuation
- 1983-05-09 HU HU875410A patent/HU198935B/hu unknown
- 1983-05-09 HU HU831589A patent/HU195965B/hu unknown
- 1983-05-10 FR FR8307785A patent/FR2531956B1/fr not_active Expired
- 1983-05-10 MC MC821633A patent/MC1515A1/fr unknown
- 1983-05-10 DZ DZ836846A patent/DZ540A1/fr active
- 1983-05-11 IE IE1084/83A patent/IE56480B1/en not_active IP Right Cessation
- 1983-05-11 CS CS833303A patent/CS249128B2/cs unknown
- 1983-05-11 DE DE8383104668T patent/DE3381884D1/de not_active Expired - Lifetime
- 1983-05-11 EP EP83104668A patent/EP0094095B1/de not_active Expired - Lifetime
- 1983-05-11 AR AR292991A patent/AR240940A1/es active
- 1983-05-11 SE SE8302716A patent/SE461792B/sv not_active IP Right Cessation
- 1983-05-11 NO NO831675A patent/NO160368C/no not_active IP Right Cessation
- 1983-05-11 ES ES522291A patent/ES8407049A1/es not_active Expired
- 1983-05-11 DE DE19833317290 patent/DE3317290A1/de not_active Ceased
- 1983-05-11 KR KR1019830002033A patent/KR890002106B1/ko not_active Expired
- 1983-05-11 LU LU84803A patent/LU84803A1/de unknown
- 1983-05-12 GR GR71331A patent/GR77462B/el unknown
- 1983-05-12 FI FI831661A patent/FI77244C/fi not_active IP Right Cessation
- 1983-05-12 DO DO1983004163A patent/DOP1983004163A/es unknown
- 1983-05-12 US US06/493,876 patent/US4512924A/en not_active Expired - Lifetime
- 1983-05-12 PT PT76681A patent/PT76681B/pt unknown
-
1984
- 1984-01-02 ES ES528625A patent/ES528625A0/es active Granted
- 1984-01-02 ES ES528628A patent/ES8706672A1/es not_active Expired
- 1984-01-02 ES ES528630A patent/ES8607970A1/es not_active Expired
- 1984-01-02 ES ES528627A patent/ES528627A0/es active Granted
-
1985
- 1985-02-01 US US06/697,559 patent/US4658024A/en not_active Expired - Lifetime
-
1986
- 1986-05-14 ES ES554935A patent/ES8800170A1/es not_active Expired
- 1986-11-28 US US06/936,003 patent/US4772701A/en not_active Expired - Lifetime
-
1987
- 1987-09-08 MY MYPI87001597A patent/MY102889A/en unknown
-
1991
- 1991-12-23 CS CS914021A patent/CS402191A3/cs unknown
-
1992
- 1992-08-12 SG SG811/92A patent/SG81192G/en unknown
- 1992-11-19 HK HK916/92A patent/HK91692A/xx not_active IP Right Cessation
-
1993
- 1993-06-09 LU LU88299C patent/LU88299I2/fr unknown
- 1993-06-11 NL NL930055C patent/NL930055I2/nl unknown
-
1994
- 1994-02-21 BG BG098502A patent/BG61123B2/bg unknown
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