DE69527072T2 - Endothelin antagoniste - Google Patents
Endothelin antagonisteInfo
- Publication number
- DE69527072T2 DE69527072T2 DE69527072T DE69527072T DE69527072T2 DE 69527072 T2 DE69527072 T2 DE 69527072T2 DE 69527072 T DE69527072 T DE 69527072T DE 69527072 T DE69527072 T DE 69527072T DE 69527072 T2 DE69527072 T2 DE 69527072T2
- Authority
- DE
- Germany
- Prior art keywords
- trans
- carboxylic acid
- methoxyphenyl
- pyrrolidine
- benzodioxol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 108050009340 Endothelin Proteins 0.000 title claims abstract description 23
- 102000002045 Endothelin Human genes 0.000 title claims abstract description 23
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 title claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims description 481
- -1 tetrahydroquinolyl Chemical group 0.000 claims description 275
- JAEIBKXSIXOLOL-UHFFFAOYSA-N pyrrolidin-1-ium-3-carboxylate Chemical compound OC(=O)C1CCNC1 JAEIBKXSIXOLOL-UHFFFAOYSA-N 0.000 claims description 181
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 129
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 65
- 125000002947 alkylene group Chemical group 0.000 claims description 59
- 125000003545 alkoxy group Chemical group 0.000 claims description 56
- 125000003118 aryl group Chemical group 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 125000000623 heterocyclic group Chemical group 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 44
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 42
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 32
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 31
- 125000005877 1,4-benzodioxanyl group Chemical group 0.000 claims description 30
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 30
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 29
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 28
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 27
- 125000003282 alkyl amino group Chemical group 0.000 claims description 21
- 125000001188 haloalkyl group Chemical group 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 18
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 15
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 15
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
- 125000005111 carboxyalkoxy group Chemical group 0.000 claims description 15
- 125000004212 difluorophenyl group Chemical group 0.000 claims description 15
- 125000005805 dimethoxy phenyl group Chemical group 0.000 claims description 15
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 14
- 150000003857 carboxamides Chemical class 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
- 125000002541 furyl group Chemical group 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 13
- MALIONKMKPITBV-UHFFFAOYSA-N 2-(3-chloro-4-hydroxyphenyl)-n-[2-(4-sulfamoylphenyl)ethyl]acetamide Chemical group C1=CC(S(=O)(=O)N)=CC=C1CCNC(=O)CC1=CC=C(O)C(Cl)=C1 MALIONKMKPITBV-UHFFFAOYSA-N 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 12
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 11
- 125000004450 alkenylene group Chemical group 0.000 claims description 10
- 125000004104 aryloxy group Chemical group 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 claims description 7
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 7
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 7
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000005493 quinolyl group Chemical group 0.000 claims description 7
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 6
- 230000003042 antagnostic effect Effects 0.000 claims description 6
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 5
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000005080 alkoxycarbonylalkenyl group Chemical group 0.000 claims description 5
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 5
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 5
- 125000005121 aminocarbonylalkoxy group Chemical group 0.000 claims description 5
- 125000005019 carboxyalkenyl group Chemical group 0.000 claims description 5
- 125000005159 cyanoalkoxy group Chemical group 0.000 claims description 5
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 5
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- 206010003162 Arterial injury Diseases 0.000 claims description 4
- 201000006474 Brain Ischemia Diseases 0.000 claims description 4
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 208000031481 Pathologic Constriction Diseases 0.000 claims description 4
- 101100311330 Schizosaccharomyces pombe (strain 972 / ATCC 24843) uap56 gene Proteins 0.000 claims description 4
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 4
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 4
- 206010008118 cerebral infarction Diseases 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 208000031225 myocardial ischemia Diseases 0.000 claims description 4
- 101150018444 sub2 gene Proteins 0.000 claims description 4
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 229910006069 SO3H Inorganic materials 0.000 claims description 3
- 125000005277 alkyl imino group Chemical group 0.000 claims description 3
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 3
- MOTJMGVDPWRKOC-QPVYNBJUSA-N atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 claims description 3
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 125000004069 aziridinyl group Chemical group 0.000 claims description 3
- 125000005507 decahydroisoquinolyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000005020 hydroxyalkenyl group Chemical group 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 3
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 3
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 3
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 claims description 3
- 125000003965 isoxazolidinyl group Chemical group 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 3
- 125000003566 oxetanyl group Chemical group 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 3
- 125000002755 pyrazolinyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 3
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 3
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
- WDFVWPLFSJGMFD-COHKGRJRSA-N (2r,3r,4r)-4-(1,3-benzodioxol-5-yl)-1-[(2r)-1-(dipropylamino)-1-oxopentan-2-yl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid Chemical compound C1([C@H]2[C@@H]([C@@H](CN2[C@H](CCC)C(=O)N(CCC)CCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 WDFVWPLFSJGMFD-COHKGRJRSA-N 0.000 claims description 2
- WDFVWPLFSJGMFD-KSZYUSJVSA-N (2s,3s,4s)-4-(1,3-benzodioxol-5-yl)-1-[(2r)-1-(dipropylamino)-1-oxopentan-2-yl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid Chemical compound C1([C@@H]2[C@H]([C@H](CN2[C@H](CCC)C(=O)N(CCC)CCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 WDFVWPLFSJGMFD-KSZYUSJVSA-N 0.000 claims description 2
- 229910018828 PO3H2 Inorganic materials 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 125000004689 alkyl amino carbonyl alkyl group Chemical group 0.000 claims description 2
- 125000005127 aryl alkoxy alkyl group Chemical group 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 5
- 150000002431 hydrogen Chemical group 0.000 claims 3
- 230000002490 cerebral effect Effects 0.000 claims 2
- 230000036262 stenosis Effects 0.000 claims 2
- 208000037804 stenosis Diseases 0.000 claims 2
- 239000013543 active substance Substances 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 claims 1
- 229940126214 compound 3 Drugs 0.000 claims 1
- 230000002526 effect on cardiovascular system Effects 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000000306 recurrent effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 291
- 239000000543 intermediate Substances 0.000 abstract description 19
- 230000008569 process Effects 0.000 abstract description 10
- 239000005557 antagonist Substances 0.000 abstract description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 338
- 238000005481 NMR spectroscopy Methods 0.000 description 219
- 239000000243 solution Substances 0.000 description 159
- 239000000203 mixture Substances 0.000 description 143
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 143
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 129
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 127
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 118
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 106
- 239000007787 solid Substances 0.000 description 104
- 229910001868 water Inorganic materials 0.000 description 100
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 96
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 95
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 88
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 61
- 239000000047 product Substances 0.000 description 59
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 58
- 235000019439 ethyl acetate Nutrition 0.000 description 53
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 51
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
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- 239000012267 brine Substances 0.000 description 24
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 24
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- 239000003921 oil Substances 0.000 description 22
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- 239000002904 solvent Substances 0.000 description 21
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- 238000003818 flash chromatography Methods 0.000 description 20
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 18
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- 125000004494 ethyl ester group Chemical group 0.000 description 18
- 239000010410 layer Substances 0.000 description 17
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 238000007792 addition Methods 0.000 description 14
- 125000006308 propyl amino group Chemical group 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
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- 235000011152 sodium sulphate Nutrition 0.000 description 14
- 229960000583 acetic acid Drugs 0.000 description 13
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 13
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- 230000007062 hydrolysis Effects 0.000 description 13
- 238000006460 hydrolysis reaction Methods 0.000 description 13
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- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
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- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
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- 150000003512 tertiary amines Chemical class 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- XOLBLPGZBRYERU-UHFFFAOYSA-N tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 description 1
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- JIVZKJJQOZQXQB-UHFFFAOYSA-N tolazoline Chemical compound C=1C=CC=CC=1CC1=NCCN1 JIVZKJJQOZQXQB-UHFFFAOYSA-N 0.000 description 1
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- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
-
- 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
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Steroid Compounds (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US29334994A | 1994-08-19 | 1994-08-19 | |
| US33471794A | 1994-11-04 | 1994-11-04 | |
| US08/442,575 US5767144A (en) | 1994-08-19 | 1995-05-30 | Endothelin antagonists |
| US49799895A | 1995-08-02 | 1995-08-02 | |
| PCT/US1995/009924 WO1996006095A1 (en) | 1994-08-19 | 1995-08-04 | Endothelin antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69527072D1 DE69527072D1 (de) | 2002-07-18 |
| DE69527072T2 true DE69527072T2 (de) | 2003-02-13 |
Family
ID=27501591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69527072T Expired - Lifetime DE69527072T2 (de) | 1994-08-19 | 1995-08-04 | Endothelin antagoniste |
Country Status (12)
| Country | Link |
|---|---|
| EP (2) | EP1186603A3 (enExample) |
| JP (1) | JP3741441B2 (enExample) |
| KR (2) | KR100447000B1 (enExample) |
| AT (1) | ATE219077T1 (enExample) |
| AU (1) | AU711832B2 (enExample) |
| CA (2) | CA2195677C (enExample) |
| DE (1) | DE69527072T2 (enExample) |
| DK (1) | DK0776324T3 (enExample) |
| ES (1) | ES2179881T3 (enExample) |
| IL (2) | IL134905A (enExample) |
| PT (1) | PT776324E (enExample) |
| WO (1) | WO1996006095A1 (enExample) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5852046A (en) * | 1993-08-03 | 1998-12-22 | Hoechst Aktiengesellschaft | Benzo-fused heterocyclic compounds having a 5-membered ring processes for their preparation their use as medicaments their use as diagnostic agents and medicaments containing them |
| US7208517B1 (en) | 1994-08-19 | 2007-04-24 | Abbott Labortories | Endothelin antagonists |
| US6162927A (en) | 1994-08-19 | 2000-12-19 | Abbott Laboratories | Endothelin antagonists |
| US5767144A (en) * | 1994-08-19 | 1998-06-16 | Abbott Laboratories | Endothelin antagonists |
| NZ330818A (en) * | 1996-02-13 | 2000-05-26 | Abbott Lab | Benzo-1, 3-dioxolyl- and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists |
| AU2763602A (en) * | 1996-02-13 | 2002-05-16 | Abbott Laboratories | Endothelin antagonists |
| ES2182029T3 (es) * | 1996-02-13 | 2003-03-01 | Abbott Lab | Derivados de acido 4-(benzo-1,3-dioxolil) pirrolidin-3-carboxilico como antagonistas de endotelina. |
| AU781355B2 (en) * | 1996-02-13 | 2005-05-19 | Abbott Laboratories | Novel benzo-1,3-dioxolyl-and benzofuranyl substituted pyrrolidine derivatives as endothelin antagonists |
| US5801250A (en) * | 1996-12-13 | 1998-09-01 | Abbott Laboratories | Process for the stereoselective production of nitro-enamine compounds |
| US6030975A (en) * | 1997-03-14 | 2000-02-29 | Basf Aktiengesellschaft | Carboxylic acid derivatives, their preparation and use in treating cancer |
| HUP0002681A3 (en) * | 1997-06-17 | 2001-09-28 | Abbott Lab | Pyrrolidine carboxylic acid derivatives as endothelin antagonists and pharmaceutical compositions containing the same |
| TR200101234T2 (tr) * | 1997-08-04 | 2002-06-21 | Abbott Laboratories | Endotelin antagonistleri. |
| US6339087B1 (en) | 1997-08-18 | 2002-01-15 | Syntex (U.S.A.) Llc | Cyclic amine derivatives-CCR-3 receptor antagonists |
| IL125658A0 (en) | 1997-08-18 | 1999-04-11 | Hoffmann La Roche | Ccr-3 receptor antagonists |
| DE19743681A1 (de) * | 1997-10-02 | 1999-04-08 | Knoll Ag | Methode zur Verhinderung der Transplantatabstoßung |
| US6410554B1 (en) | 1998-03-23 | 2002-06-25 | Merck & Co., Inc. | Combination therapy for the treatment of benign prostatic hyperplasia |
| AU5478799A (en) | 1998-09-14 | 2000-04-03 | Warner-Lambert Company | Branched alkyl pyrrolidine-3-carboxylic acids |
| EP1131290B1 (en) | 1998-11-20 | 2008-02-20 | F. Hoffmann-La Roche Ag | Piperidine ccr-3 receptor antagonists |
| WO2002017912A1 (en) * | 2000-08-31 | 2002-03-07 | Abbott Laboratories | Endothelin antagonists |
| US8168616B1 (en) | 2000-11-17 | 2012-05-01 | Novartis Ag | Combination comprising a renin inhibitor and an angiotensin receptor inhibitor for hypertension |
| GB0327839D0 (en) | 2003-12-01 | 2003-12-31 | Novartis Ag | Organic compounds |
| NZ586285A (en) | 2004-03-17 | 2011-12-22 | Novartis Ag | Use of aliskiren in monotherapy for treating diabetes and metabolic disorder (syndrome X) |
| CA2904447C (en) | 2007-08-22 | 2017-01-03 | Abbvie Deutschland Gmbh & Co Kg | Therapy for complications of diabetes |
| WO2011114103A1 (en) | 2010-03-18 | 2011-09-22 | Biolipox Ab | Pyrimidinones for use as medicaments |
| JO2998B1 (ar) | 2010-06-04 | 2016-09-05 | Amgen Inc | مشتقات بيبيريدينون كمثبطات mdm2 لعلاج السرطان |
| JP6093770B2 (ja) | 2011-09-27 | 2017-03-08 | アムジエン・インコーポレーテツド | 癌の治療のためのｍｄｍ２阻害剤としての複素環化合物 |
| US11407721B2 (en) | 2013-02-19 | 2022-08-09 | Amgen Inc. | CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer |
| AU2014223547B2 (en) | 2013-02-28 | 2017-11-16 | Amgen Inc. | A benzoic acid derivative MDM2 inhibitor for the treatment of cancer |
| JP6377123B2 (ja) | 2013-03-14 | 2018-08-22 | アムジエン・インコーポレーテツド | 癌の治療のためのｍｄｍ２阻害剤としてのヘテロアリール酸モルホリノン化合物 |
| JOP20200296A1 (ar) | 2013-06-10 | 2017-06-16 | Amgen Inc | عمليات صنع وأشكال بلورية من mdm2 مثبط |
| US8962675B1 (en) * | 2013-09-12 | 2015-02-24 | Abbvie Inc. | Atrasentan mandelate salts |
| KR102091932B1 (ko) | 2018-08-16 | 2020-03-20 | 장남순 | 안전하고 간편한 접첩구조를 갖는 접이식 트램펄린 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3342833A (en) * | 1964-08-07 | 1967-09-19 | Shell Oil Co | Pyrrolidine production from aziridines and olefins |
| ES2164054T3 (es) * | 1991-11-05 | 2002-02-16 | Smithkline Beecham Corp | Antagonistas de receptores de endotelina. |
| JPH07509465A (ja) * | 1992-07-17 | 1995-10-19 | スミスクライン・ビーチャム・コーポレイション | エンドセリン受容体アンタゴニスト |
-
1995
- 1995-08-04 DE DE69527072T patent/DE69527072T2/de not_active Expired - Lifetime
- 1995-08-04 EP EP01125462A patent/EP1186603A3/en not_active Withdrawn
- 1995-08-04 JP JP50810196A patent/JP3741441B2/ja not_active Expired - Lifetime
- 1995-08-04 PT PT95928323T patent/PT776324E/pt unknown
- 1995-08-04 DK DK95928323T patent/DK0776324T3/da active
- 1995-08-04 KR KR1019970701079A patent/KR100447000B1/ko not_active Expired - Lifetime
- 1995-08-04 WO PCT/US1995/009924 patent/WO1996006095A1/en not_active Ceased
- 1995-08-04 AT AT95928323T patent/ATE219077T1/de active
- 1995-08-04 AU AU32137/95A patent/AU711832B2/en not_active Expired
- 1995-08-04 CA CA002195677A patent/CA2195677C/en not_active Expired - Lifetime
- 1995-08-04 KR KR10-2004-7004682A patent/KR100483222B1/ko not_active Expired - Fee Related
- 1995-08-04 ES ES95928323T patent/ES2179881T3/es not_active Expired - Lifetime
- 1995-08-04 EP EP95928323A patent/EP0776324B1/en not_active Expired - Lifetime
- 1995-08-04 CA CA002517691A patent/CA2517691A1/en not_active Abandoned
- 1995-08-10 IL IL134905A patent/IL134905A/en not_active IP Right Cessation
- 1995-08-10 IL IL11489495A patent/IL114894A/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1186603A2 (en) | 2002-03-13 |
| DK0776324T3 (da) | 2002-10-07 |
| AU3213795A (en) | 1996-03-14 |
| DE69527072D1 (de) | 2002-07-18 |
| CA2195677C (en) | 2005-11-08 |
| EP1186603A3 (en) | 2003-07-09 |
| ATE219077T1 (de) | 2002-06-15 |
| PT776324E (pt) | 2002-11-29 |
| WO1996006095A1 (en) | 1996-02-29 |
| KR20040045036A (ko) | 2004-05-31 |
| IL134905A (en) | 2009-06-15 |
| KR100483222B1 (ko) | 2005-04-15 |
| EP0776324A1 (en) | 1997-06-04 |
| IL134905A0 (en) | 2001-05-20 |
| EP0776324B1 (en) | 2002-06-12 |
| HK1008328A1 (en) | 1999-05-07 |
| KR100447000B1 (ko) | 2004-12-10 |
| IL114894A (en) | 2003-04-10 |
| CA2195677A1 (en) | 1996-02-29 |
| JP3741441B2 (ja) | 2006-02-01 |
| CA2517691A1 (en) | 1996-02-29 |
| AU711832B2 (en) | 1999-10-21 |
| ES2179881T3 (es) | 2003-02-01 |
| KR970705561A (ko) | 1997-10-09 |
| IL114894A0 (en) | 1995-12-08 |
| JPH10504565A (ja) | 1998-05-06 |
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| 8364 | No opposition during term of opposition |