WO2011053948A1 - Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals - Google Patents
Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals Download PDFInfo
- Publication number
- WO2011053948A1 WO2011053948A1 PCT/US2010/055035 US2010055035W WO2011053948A1 WO 2011053948 A1 WO2011053948 A1 WO 2011053948A1 US 2010055035 W US2010055035 W US 2010055035W WO 2011053948 A1 WO2011053948 A1 WO 2011053948A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- series consisting
- chosen
- ring
- group
- Prior art date
Links
- -1 cyclic carboxylic acid derivatives Chemical class 0.000 title claims description 297
- 239000003814 drug Substances 0.000 title claims description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 629
- 238000000034 method Methods 0.000 claims abstract description 134
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 31
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 206010019280 Heart failures Diseases 0.000 claims abstract description 9
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 172
- 239000001257 hydrogen Substances 0.000 claims description 159
- 229910052739 hydrogen Inorganic materials 0.000 claims description 159
- 125000001424 substituent group Chemical group 0.000 claims description 145
- 125000005842 heteroatom Chemical group 0.000 claims description 143
- 229910052799 carbon Inorganic materials 0.000 claims description 120
- 229910052757 nitrogen Inorganic materials 0.000 claims description 115
- 229910052736 halogen Inorganic materials 0.000 claims description 107
- 150000002367 halogens Chemical class 0.000 claims description 106
- 229910052717 sulfur Inorganic materials 0.000 claims description 82
- 150000002431 hydrogen Chemical class 0.000 claims description 80
- 229910052760 oxygen Inorganic materials 0.000 claims description 76
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 75
- 229910020008 S(O) Inorganic materials 0.000 claims description 72
- 150000003839 salts Chemical class 0.000 claims description 68
- 239000011737 fluorine Substances 0.000 claims description 64
- 229910052731 fluorine Inorganic materials 0.000 claims description 64
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 61
- 125000004432 carbon atom Chemical group C* 0.000 claims description 48
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 125000001153 fluoro group Chemical group F* 0.000 claims description 42
- 229920006395 saturated elastomer Polymers 0.000 claims description 42
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
- 125000002950 monocyclic group Chemical group 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 28
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 125000003566 oxetanyl group Chemical group 0.000 claims description 23
- 125000002619 bicyclic group Chemical group 0.000 claims description 22
- 239000002243 precursor Substances 0.000 claims description 20
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 18
- 125000000524 functional group Chemical group 0.000 claims description 18
- 229910052740 iodine Inorganic materials 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 206010016654 Fibrosis Diseases 0.000 claims description 11
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
- 230000004761 fibrosis Effects 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- 230000002792 vascular Effects 0.000 claims description 9
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 7
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 5
- 230000009787 cardiac fibrosis Effects 0.000 claims description 5
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 5
- 230000003176 fibrotic effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 201000002793 renal fibrosis Diseases 0.000 claims description 5
- MVQUSWQILIXADZ-UHFFFAOYSA-N 1-[[2-chloro-4-(2-chlorophenyl)benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound C=1C=C(C=2C(=CC=CC=2)Cl)C=C(Cl)C=1C(=O)NC1(C(=O)O)CCCCCC1 MVQUSWQILIXADZ-UHFFFAOYSA-N 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 230000002107 myocardial effect Effects 0.000 claims description 4
- 238000007634 remodeling Methods 0.000 claims description 4
- DALPSIAWBFTYGE-UHFFFAOYSA-N 1-[(4-phenylbenzoyl)amino]cyclohexane-1-carboxylic acid Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1C(=O)NC1(C(=O)O)CCCCC1 DALPSIAWBFTYGE-UHFFFAOYSA-N 0.000 claims description 3
- SUNJMRQLZZINTH-UHFFFAOYSA-N 1-[[2-chloro-4-[(3-hydroxyphenyl)methylcarbamoyl]benzoyl]amino]cyclopropane-1-carboxylic acid Chemical compound C=1C=C(C(=O)NCC=2C=C(O)C=CC=2)C=C(Cl)C=1C(=O)NC1(C(=O)O)CC1 SUNJMRQLZZINTH-UHFFFAOYSA-N 0.000 claims description 3
- CBTRHRDBYLKFPX-UHFFFAOYSA-N 1-[[4-(2-oxopyrrolidin-1-yl)benzoyl]amino]cyclohexane-1-carboxylic acid Chemical compound C=1C=C(N2C(CCC2)=O)C=CC=1C(=O)NC1(C(=O)O)CCCCC1 CBTRHRDBYLKFPX-UHFFFAOYSA-N 0.000 claims description 3
- FXJJTMIMJZEUGF-UHFFFAOYSA-N 1-[[4-(2-oxopyrrolidin-1-yl)furan-2-carbonyl]amino]cyclohexane-1-carboxylic acid Chemical compound C=1C(N2C(CCC2)=O)=COC=1C(=O)NC1(C(=O)O)CCCCC1 FXJJTMIMJZEUGF-UHFFFAOYSA-N 0.000 claims description 3
- NGKPSILRDYEKHA-UHFFFAOYSA-N 1-[[4-(2-piperidin-1-ylethoxy)benzoyl]amino]cyclohexane-1-carboxylic acid Chemical compound C=1C=C(OCCN2CCCCC2)C=CC=1C(=O)NC1(C(=O)O)CCCCC1 NGKPSILRDYEKHA-UHFFFAOYSA-N 0.000 claims description 3
- ZFYORNJUWZZILC-UHFFFAOYSA-N 1-[[4-(2-pyrrolidin-1-ylethoxy)benzoyl]amino]cyclohexane-1-carboxylic acid Chemical compound C=1C=C(OCCN2CCCC2)C=CC=1C(=O)NC1(C(=O)O)CCCCC1 ZFYORNJUWZZILC-UHFFFAOYSA-N 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 208000002193 Pain Diseases 0.000 claims description 3
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 3
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 3
- 230000005961 cardioprotection Effects 0.000 claims description 3
- IFUCEQSXGGNYQC-UHFFFAOYSA-N ethyl 1-[[4-(4,6-dimethylpyrimidin-2-yl)sulfanylbenzoyl]amino]cyclopentane-1-carboxylate Chemical compound C=1C=C(SC=2N=C(C)C=C(C)N=2)C=CC=1C(=O)NC1(C(=O)OCC)CCCC1 IFUCEQSXGGNYQC-UHFFFAOYSA-N 0.000 claims description 3
- 208000017169 kidney disease Diseases 0.000 claims description 3
- 201000006370 kidney failure Diseases 0.000 claims description 3
- 230000009401 metastasis Effects 0.000 claims description 3
- ZRPRMIFLQPEDCD-UHFFFAOYSA-N methyl 1-[[4-(4-oxopiperidin-1-yl)benzoyl]amino]cyclopropane-1-carboxylate Chemical compound C=1C=C(N2CCC(=O)CC2)C=CC=1C(=O)NC1(C(=O)OC)CC1 ZRPRMIFLQPEDCD-UHFFFAOYSA-N 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- AEBWATHAIVJLTA-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropentalene Chemical compound C1CCC2CCCC21 AEBWATHAIVJLTA-UHFFFAOYSA-N 0.000 claims description 2
- ODJQFZXHKPCJMD-UHFFFAOYSA-N 1,2,3,3a,4,5,6,7,8,8a-decahydroazulene Chemical group C1CCCCC2CCCC21 ODJQFZXHKPCJMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 2
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 206010020850 Hyperthyroidism Diseases 0.000 claims description 2
- 208000019693 Lung disease Diseases 0.000 claims description 2
- 208000003251 Pruritus Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 206010038491 Renal papillary necrosis Diseases 0.000 claims description 2
- 206010063837 Reperfusion injury Diseases 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 claims description 2
- 208000032594 Vascular Remodeling Diseases 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- JAPMJSVZDUYFKL-UHFFFAOYSA-N bicyclo[3.1.0]hexane Chemical compound C1CCC2CC21 JAPMJSVZDUYFKL-UHFFFAOYSA-N 0.000 claims description 2
- AWYMFBJJKFTCFO-UHFFFAOYSA-N bicyclo[3.2.0]heptane Chemical group C1CCC2CCC21 AWYMFBJJKFTCFO-UHFFFAOYSA-N 0.000 claims description 2
- 230000002490 cerebral effect Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- BNRNAKTVFSZAFA-UHFFFAOYSA-N hydrindane Chemical compound C1CCCC2CCCC21 BNRNAKTVFSZAFA-UHFFFAOYSA-N 0.000 claims description 2
- 208000026278 immune system disease Diseases 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 208000030159 metabolic disease Diseases 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 210000005036 nerve Anatomy 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims description 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 2
- 208000020016 psychiatric disease Diseases 0.000 claims description 2
- 230000000241 respiratory effect Effects 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 208000032253 retinal ischemia Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 230000037390 scarring Effects 0.000 claims description 2
- 230000004614 tumor growth Effects 0.000 claims description 2
- 230000008728 vascular permeability Effects 0.000 claims description 2
- 230000035876 healing Effects 0.000 claims 1
- 208000002780 macular degeneration Diseases 0.000 claims 1
- 102000004137 Lysophosphatidic Acid Receptors Human genes 0.000 abstract description 45
- 108090000642 Lysophosphatidic Acid Receptors Proteins 0.000 abstract description 45
- WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 abstract description 42
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 abstract description 41
- 239000003112 inhibitor Substances 0.000 abstract description 18
- 101000966782 Homo sapiens Lysophosphatidic acid receptor 1 Proteins 0.000 abstract description 9
- 102100040607 Lysophosphatidic acid receptor 1 Human genes 0.000 abstract description 9
- 102000036530 EDG receptors Human genes 0.000 abstract description 6
- 108091007263 EDG receptors Proteins 0.000 abstract description 6
- 102000005962 receptors Human genes 0.000 abstract description 6
- 108020003175 receptors Proteins 0.000 abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 98
- 150000001721 carbon Chemical group 0.000 description 89
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 75
- 238000006243 chemical reaction Methods 0.000 description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 68
- 235000002639 sodium chloride Nutrition 0.000 description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 61
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 60
- 238000005160 1H NMR spectroscopy Methods 0.000 description 58
- 239000000243 solution Substances 0.000 description 56
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 229910052796 boron Inorganic materials 0.000 description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 125000004043 oxo group Chemical group O=* 0.000 description 34
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 31
- 125000003118 aryl group Chemical group 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 125000004433 nitrogen atom Chemical group N* 0.000 description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 28
- 229910052938 sodium sulfate Inorganic materials 0.000 description 28
- 235000011152 sodium sulphate Nutrition 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 235000001014 amino acid Nutrition 0.000 description 27
- 239000008346 aqueous phase Substances 0.000 description 27
- 239000003480 eluent Substances 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 24
- 239000000543 intermediate Substances 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 21
- 239000002253 acid Substances 0.000 description 21
- 230000007062 hydrolysis Effects 0.000 description 21
- 238000006460 hydrolysis reaction Methods 0.000 description 21
- 238000005859 coupling reaction Methods 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- DUVCCEMTDGDVRL-UHFFFAOYSA-N methyl 1-aminocycloheptane-1-carboxylate;hydrochloride Chemical compound Cl.COC(=O)C1(N)CCCCCC1 DUVCCEMTDGDVRL-UHFFFAOYSA-N 0.000 description 19
- 238000004007 reversed phase HPLC Methods 0.000 description 19
- VZFUCHSFHOYXIS-UHFFFAOYSA-N Cycloheptanecarboxylic acid Chemical compound OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 18
- 150000001408 amides Chemical class 0.000 description 18
- 239000002585 base Substances 0.000 description 18
- 230000008878 coupling Effects 0.000 description 18
- 238000010168 coupling process Methods 0.000 description 18
- 238000001819 mass spectrum Methods 0.000 description 17
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
- 150000001413 amino acids Chemical class 0.000 description 16
- 150000002148 esters Chemical class 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000000752 ionisation method Methods 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 description 15
- 235000011181 potassium carbonates Nutrition 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 14
- 125000002843 carboxylic acid group Chemical group 0.000 description 14
- 239000012442 inert solvent Substances 0.000 description 14
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- 235000019341 magnesium sulphate Nutrition 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 229910052801 chlorine Inorganic materials 0.000 description 13
- 229960004132 diethyl ether Drugs 0.000 description 13
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- WCFOCJIEESXGJX-UHFFFAOYSA-N 4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OCCC1=CC=CC(C)=C1 WCFOCJIEESXGJX-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000000132 electrospray ionisation Methods 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- 150000002576 ketones Chemical class 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 125000003277 amino group Chemical group 0.000 description 11
- 125000004185 ester group Chemical group 0.000 description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 239000003039 volatile agent Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 125000001624 naphthyl group Chemical group 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 230000011664 signaling Effects 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 125000001544 thienyl group Chemical group 0.000 description 10
- 229910052727 yttrium Inorganic materials 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 9
- 238000006266 etherification reaction Methods 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 150000004702 methyl esters Chemical class 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 8
- 238000006150 Bucherer-Bergs reaction Methods 0.000 description 8
- NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Natural products OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 8
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 239000012279 sodium borohydride Substances 0.000 description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 7
- 125000006164 6-membered heteroaryl group Chemical group 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- 238000011065 in-situ storage Methods 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 125000004430 oxygen atom Chemical group O* 0.000 description 7
- 230000000144 pharmacologic effect Effects 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 6
- ZOIQMOPABGFDGI-UHFFFAOYSA-N 3-acetyloxy-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC(C)=O ZOIQMOPABGFDGI-UHFFFAOYSA-N 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- QXOXUEFXRSIYSW-UHFFFAOYSA-N methyl 3-hydroxy-4-methoxybenzoate Chemical compound COC(=O)C1=CC=C(OC)C(O)=C1 QXOXUEFXRSIYSW-UHFFFAOYSA-N 0.000 description 6
- 150000002825 nitriles Chemical class 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 5
- KWHVBVJDKLSOTB-UHFFFAOYSA-N 2-(3-methylphenyl)ethanol Chemical compound CC1=CC=CC(CCO)=C1 KWHVBVJDKLSOTB-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 description 5
- 150000008064 anhydrides Chemical class 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 5
- 150000001602 bicycloalkyls Chemical group 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 5
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 5
- 229940091173 hydantoin Drugs 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- ZQRWVDWWKSVCIK-UHFFFAOYSA-N methyl 4-oxo-1-(phenylmethoxycarbonylamino)cycloheptane-1-carboxylate Chemical compound C=1C=CC=CC=1COC(=O)NC1(C(=O)OC)CCCC(=O)CC1 ZQRWVDWWKSVCIK-UHFFFAOYSA-N 0.000 description 5
- ZQWPRMPSCMSAJU-UHFFFAOYSA-N methyl cyclohexanecarboxylate Chemical compound COC(=O)C1CCCCC1 ZQWPRMPSCMSAJU-UHFFFAOYSA-N 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 5
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 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
- BVUFCTJBJVGJGJ-UHFFFAOYSA-N 1-azaniumyl-4-ethylcyclohexane-1-carboxylate Chemical compound CCC1CCC(N)(C(O)=O)CC1 BVUFCTJBJVGJGJ-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 4
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 4
- VGVHNLRUAMRIEW-UHFFFAOYSA-N 4-methylcyclohexan-1-one Chemical compound CC1CCC(=O)CC1 VGVHNLRUAMRIEW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 4
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 4
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-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
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 4
- 150000004703 alkoxides Chemical class 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 150000001540 azides Chemical class 0.000 description 4
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 150000001934 cyclohexanes Chemical group 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 4
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- 230000001747 exhibiting effect Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000004678 hydrides Chemical class 0.000 description 4
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- SBYAYPHPGUVGOU-UHFFFAOYSA-N methyl 8-(phenylmethoxycarbonylamino)-1,4-dioxaspiro[4.6]undecane-8-carboxylate Chemical compound C1CC(C(=O)OC)(NC(=O)OCC=2C=CC=CC=2)CCCC21OCCO2 SBYAYPHPGUVGOU-UHFFFAOYSA-N 0.000 description 4
- 208000004296 neuralgia Diseases 0.000 description 4
- 208000021722 neuropathic pain Diseases 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- DIXXBDCBUHBJMK-UTSGNWPNSA-N (1r,3r,4s)-3-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid Chemical compound N([C@]1([C@]2([H])CC[C@@](O2)(C1)[H])C(O)=O)C(=O)C(C=1)=CC=C(OC)C=1OCCC1=CC=CC(C)=C1 DIXXBDCBUHBJMK-UTSGNWPNSA-N 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 3
- STQJFINZGUXVEX-UHFFFAOYSA-N 1-(2-bromoethyl)-3-methylbenzene Chemical compound CC1=CC=CC(CCBr)=C1 STQJFINZGUXVEX-UHFFFAOYSA-N 0.000 description 3
- GPYYQZNDIKGFSB-UHFFFAOYSA-N 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-2-phenylmethoxycyclopentane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(C(CCC2)OCC=2C=CC=CC=2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 GPYYQZNDIKGFSB-UHFFFAOYSA-N 0.000 description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 3
- JJJCAJWXGQKFCI-UHFFFAOYSA-N 2-(2,5-dimethylphenyl)ethanol Chemical compound CC1=CC=C(C)C(CCO)=C1 JJJCAJWXGQKFCI-UHFFFAOYSA-N 0.000 description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
- 101100515517 Arabidopsis thaliana XI-I gene Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 3
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 3
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 3
- 206010020880 Hypertrophy Diseases 0.000 description 3
- 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
- 206010061218 Inflammation Diseases 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 108010081690 Pertussis Toxin Proteins 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 3
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 3
- 238000007239 Wittig reaction Methods 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 206010000891 acute myocardial infarction Diseases 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000005907 alkyl ester group Chemical group 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000005219 aminonitrile group Chemical group 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 235000012501 ammonium carbonate Nutrition 0.000 description 3
- 239000011260 aqueous acid Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 150000001793 charged compounds Chemical class 0.000 description 3
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 3
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- GOBGVVAHHOUMDK-UHFFFAOYSA-N fluorocyclohexane Chemical group FC1CCCCC1 GOBGVVAHHOUMDK-UHFFFAOYSA-N 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000012948 isocyanate Substances 0.000 description 3
- 150000002513 isocyanates Chemical class 0.000 description 3
- 238000011813 knockout mouse model Methods 0.000 description 3
- 229910000000 metal hydroxide Inorganic materials 0.000 description 3
- 150000004692 metal hydroxides Chemical class 0.000 description 3
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 3
- HFBONNYHELEHCI-UHFFFAOYSA-N methyl 1-aminocyclooctane-1-carboxylate;hydrochloride Chemical compound Cl.COC(=O)C1(N)CCCCCCC1 HFBONNYHELEHCI-UHFFFAOYSA-N 0.000 description 3
- OTSODGMSRREDQO-UHFFFAOYSA-N methyl 2-fluoro-3-hydroxy-4-methoxybenzoate Chemical compound COC(=O)C1=CC=C(OC)C(O)=C1F OTSODGMSRREDQO-UHFFFAOYSA-N 0.000 description 3
- UNMSFZXTTMKBRY-UHFFFAOYSA-N methyl 3-fluoro-5-hydroxy-4-methoxybenzoate Chemical compound COC(=O)C1=CC(O)=C(OC)C(F)=C1 UNMSFZXTTMKBRY-UHFFFAOYSA-N 0.000 description 3
- 150000002902 organometallic compounds Chemical class 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000010118 platelet activation Effects 0.000 description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 3
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 230000010410 reperfusion Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 230000029663 wound healing Effects 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- XDBHWPLGGBLUHH-UHFFFAOYSA-N (3-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(C#N)=C1 XDBHWPLGGBLUHH-UHFFFAOYSA-N 0.000 description 2
- WDJHJCFUJVLBCM-UHFFFAOYSA-N (5-carbonochloridoyl-2-methoxyphenyl) acetate Chemical compound COC1=CC=C(C(Cl)=O)C=C1OC(C)=O WDJHJCFUJVLBCM-UHFFFAOYSA-N 0.000 description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 2
- 125000006709 (C5-C7) cycloalkenyl group Chemical group 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- AMPMQYWLGNLUQN-UHFFFAOYSA-N 1,4-dioxaspiro[4.6]undecane Chemical compound O1CCOC11CCCCCC1 AMPMQYWLGNLUQN-UHFFFAOYSA-N 0.000 description 2
- DAFOLBFSRCKLOZ-UHFFFAOYSA-N 1-[[2-fluoro-4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound FC1=C(OCCC=2C=C(C)C=CC=2)C(OC)=CC=C1C(=O)NC1(C(O)=O)CCCCCC1 DAFOLBFSRCKLOZ-UHFFFAOYSA-N 0.000 description 2
- GIXLMNSTJLCIIZ-UHFFFAOYSA-N 1-[[3-(2,2-difluoro-2-phenylethoxy)-4-methoxybenzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCC(F)(F)C1=CC=CC=C1 GIXLMNSTJLCIIZ-UHFFFAOYSA-N 0.000 description 2
- JAFHEMMGQAFASO-UHFFFAOYSA-N 1-[[3-[2-(5-chloro-2-fluorophenyl)ethoxy]-4-methoxybenzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC(Cl)=CC=C1F JAFHEMMGQAFASO-UHFFFAOYSA-N 0.000 description 2
- RNMYZPMTFHOVHU-UHFFFAOYSA-N 1-[[3-[2-[3-(2-hydroxyethyl)phenyl]ethoxy]-4-methoxybenzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(CCO)=C1 RNMYZPMTFHOVHU-UHFFFAOYSA-N 0.000 description 2
- YYRIDRHOMZNGNY-UHFFFAOYSA-N 1-[[3-[2-hydroxy-2-(3-methylphenyl)ethoxy]-4-methoxybenzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCC(O)C1=CC=CC(C)=C1 YYRIDRHOMZNGNY-UHFFFAOYSA-N 0.000 description 2
- KTDQNJBNZKYNJL-UHFFFAOYSA-N 1-[[4-acetyl-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound CC(=O)C1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 KTDQNJBNZKYNJL-UHFFFAOYSA-N 0.000 description 2
- IHAUDGVRFIGDKE-UHFFFAOYSA-N 1-[[4-chloro-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound CC1=CC=CC(CCOC=2C(=CC=C(C=2)C(=O)NC2(CCCCCC2)C(O)=O)Cl)=C1 IHAUDGVRFIGDKE-UHFFFAOYSA-N 0.000 description 2
- XGNOLFABYMLZBZ-UHFFFAOYSA-N 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-3-methylcyclobutane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CC(C)C2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 XGNOLFABYMLZBZ-UHFFFAOYSA-N 0.000 description 2
- WGVPUNHFZNUENH-UHFFFAOYSA-N 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-4-methylidenecyclohexane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCC(=C)CC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 WGVPUNHFZNUENH-UHFFFAOYSA-N 0.000 description 2
- CAECUZMMWIZOFU-UHFFFAOYSA-N 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 CAECUZMMWIZOFU-UHFFFAOYSA-N 0.000 description 2
- CKYANZDPJCMXOV-UHFFFAOYSA-N 1-[[4-methoxy-3-[3-(3-methylphenyl)propyl]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1CCCC1=CC=CC(C)=C1 CKYANZDPJCMXOV-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- NDWAVJKRSASRPH-UHFFFAOYSA-N 2-(3-chlorophenyl)ethanol Chemical compound OCCC1=CC=CC(Cl)=C1 NDWAVJKRSASRPH-UHFFFAOYSA-N 0.000 description 2
- BBRCCHXSWPEMER-UHFFFAOYSA-N 2-(3-methylphenyl)ethyl 7-[2-(3-methylphenyl)ethoxy]-1,3-benzodioxole-5-carboxylate Chemical compound CC1=CC=CC(CCOC(=O)C=2C=C(OCCC=3C=C(C)C=CC=3)C=3OCOC=3C=2)=C1 BBRCCHXSWPEMER-UHFFFAOYSA-N 0.000 description 2
- RJMZFHCIPUEWEB-UHFFFAOYSA-N 2-(5-chloro-2-fluorophenyl)ethanol Chemical compound OCCC1=CC(Cl)=CC=C1F RJMZFHCIPUEWEB-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- QCYAJCGCGWQKJT-UHFFFAOYSA-N 2-[3-(2-hydroxyethyl)phenyl]ethanol Chemical compound OCCC1=CC=CC(CCO)=C1 QCYAJCGCGWQKJT-UHFFFAOYSA-N 0.000 description 2
- QGGOFLISMFDJCJ-UHFFFAOYSA-N 2-[3-(oxetan-3-yl)phenyl]ethanol Chemical compound OCCC1=CC=CC(C2COC2)=C1 QGGOFLISMFDJCJ-UHFFFAOYSA-N 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- FHRFIIMTGNGBSI-UHFFFAOYSA-N 3-[2-(3-methylphenyl)ethoxy]-4-(oxetan-3-yl)benzoic acid Chemical compound CC1=CC=CC(CCOC=2C(=CC=C(C=2)C(O)=O)C2COC2)=C1 FHRFIIMTGNGBSI-UHFFFAOYSA-N 0.000 description 2
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 2
- GDIHCYVROCTJEJ-UHFFFAOYSA-N 3-amino-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid Chemical compound C1CC2C(N)(C(O)=O)CC1O2 GDIHCYVROCTJEJ-UHFFFAOYSA-N 0.000 description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- LBKFGYZQBSGRHY-UHFFFAOYSA-N 3-hydroxy-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1O LBKFGYZQBSGRHY-UHFFFAOYSA-N 0.000 description 2
- KBEIFKMKVCDETC-UHFFFAOYSA-N 3-iodooxetane Chemical compound IC1COC1 KBEIFKMKVCDETC-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- PMFZVYATOSUBAL-UHFFFAOYSA-N 4-(hydroxymethyl)-1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cyclohexane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCC(CO)CC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 PMFZVYATOSUBAL-UHFFFAOYSA-N 0.000 description 2
- FRBKOXMMSUPRLM-UHFFFAOYSA-N 4-hydroxy-1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCC(O)CCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 FRBKOXMMSUPRLM-UHFFFAOYSA-N 0.000 description 2
- CRHLEIFYKJGQTK-UHFFFAOYSA-N 4-oxo-1-(phenylmethoxycarbonylamino)cycloheptane-1-carboxylic acid Chemical compound C=1C=CC=CC=1COC(=O)NC1(C(=O)O)CCCC(=O)CC1 CRHLEIFYKJGQTK-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- DYSLRNROALTKNA-UHFFFAOYSA-N 5-bromo-6-methoxypyridine-3-carboxylic acid Chemical compound COC1=NC=C(C(O)=O)C=C1Br DYSLRNROALTKNA-UHFFFAOYSA-N 0.000 description 2
- DVUFBHCQMMGTTP-UHFFFAOYSA-N 7-[2-(3-methylphenyl)ethoxy]-1,3-benzodioxole-5-carboxylic acid Chemical compound CC1=CC=CC(CCOC=2C=3OCOC=3C=C(C=2)C(O)=O)=C1 DVUFBHCQMMGTTP-UHFFFAOYSA-N 0.000 description 2
- GBCNJRZVAXOSKV-UHFFFAOYSA-N 8-(phenylmethoxycarbonylamino)-1,4-dioxaspiro[4.6]undecane-8-carboxylic acid Chemical compound C1CC(C(=O)O)(NC(=O)OCC=2C=CC=CC=2)CCCC21OCCO2 GBCNJRZVAXOSKV-UHFFFAOYSA-N 0.000 description 2
- CJFUYCXFUUOOSV-UHFFFAOYSA-N 8-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-1,4-dioxaspiro[4.6]undecane-8-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCC3(CCC2)OCCO3)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 CJFUYCXFUUOOSV-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 2
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 2
- 102000005927 Cysteine Proteases Human genes 0.000 description 2
- 108010005843 Cysteine Proteases Proteins 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 108010074864 Factor XI Proteins 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 2
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000006751 Mitsunobu reaction Methods 0.000 description 2
- FFKZOUIEAHOBHW-UHFFFAOYSA-N N,4-dimethyl-N-nitrosobenzenesulfonamide Chemical compound O=NN(C)S(=O)(=O)C1=CC=C(C)C=C1 FFKZOUIEAHOBHW-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102000003729 Neprilysin Human genes 0.000 description 2
- 108090000028 Neprilysin Proteins 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- 102100038831 Peroxisome proliferator-activated receptor alpha Human genes 0.000 description 2
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 2
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 206010061481 Renal injury Diseases 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- NJLPYJKKKSBCSK-MJPIYRIWSA-N [(2r)-2-[[(z)-octadec-9-enoyl]amino]-3-(4-phenylmethoxyphenyl)propyl] dihydrogen phosphate Chemical compound C1=CC(C[C@H](COP(O)(O)=O)NC(=O)CCCCCCC\C=C/CCCCCCCC)=CC=C1OCC1=CC=CC=C1 NJLPYJKKKSBCSK-MJPIYRIWSA-N 0.000 description 2
- QDVYNSDLTZYUIQ-UHFFFAOYSA-N [3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]phenyl]boronic acid Chemical compound CC(C)(C)[Si](C)(C)OCCC1=CC=CC(B(O)O)=C1 QDVYNSDLTZYUIQ-UHFFFAOYSA-N 0.000 description 2
- YUPVHUSUZGGXML-UHFFFAOYSA-N [4-methoxycarbonyl-2-[2-(3-methylphenyl)ethoxy]phenyl]boronic acid Chemical compound COC(=O)C1=CC=C(B(O)O)C(OCCC=2C=C(C)C=CC=2)=C1 YUPVHUSUZGGXML-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000007675 cardiac surgery Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 150000003997 cyclic ketones Chemical class 0.000 description 2
- 150000001932 cycloheptanes Chemical group 0.000 description 2
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 2
- 150000001942 cyclopropanes Chemical group 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- UYKSYRMKGNNMMU-UHFFFAOYSA-L dipotassium;n-carboxylatoiminocarbamate Chemical compound [K+].[K+].[O-]C(=O)N=NC([O-])=O UYKSYRMKGNNMMU-UHFFFAOYSA-L 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 150000002168 ethanoic acid esters Chemical class 0.000 description 2
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000030279 gene silencing Effects 0.000 description 2
- 150000002366 halogen compounds Chemical class 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 2
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 2
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 150000002632 lipids Chemical group 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 230000007257 malfunction Effects 0.000 description 2
- 150000002690 malonic acid derivatives Chemical class 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- KCTOTTPIEMSTEN-UHFFFAOYSA-N methyl 1-[(3-hydroxy-4-methoxybenzoyl)amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(OC)C(O)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 KCTOTTPIEMSTEN-UHFFFAOYSA-N 0.000 description 2
- ZYNWTCJQAOTMEI-UHFFFAOYSA-N methyl 3-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-7-oxabicyclo[2.2.1]heptane-3-carboxylate Chemical compound C1C(O2)CCC2C1(C(=O)OC)NC(=O)C(C=1)=CC=C(OC)C=1OCCC1=CC=CC(C)=C1 ZYNWTCJQAOTMEI-UHFFFAOYSA-N 0.000 description 2
- WTNQSIUJCFXQTQ-UHFFFAOYSA-N methyl 3-amino-7-oxabicyclo[2.2.1]heptane-3-carboxylate Chemical compound C1CC2C(C(=O)OC)(N)CC1O2 WTNQSIUJCFXQTQ-UHFFFAOYSA-N 0.000 description 2
- RLHNCRFEGUYTPO-UHFFFAOYSA-N methyl 5-hydroxy-6-methoxypyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(OC)C(O)=C1 RLHNCRFEGUYTPO-UHFFFAOYSA-N 0.000 description 2
- MQWCXKGKQLNYQG-UHFFFAOYSA-N methyl cyclohexan-4-ol Natural products CC1CCC(O)CC1 MQWCXKGKQLNYQG-UHFFFAOYSA-N 0.000 description 2
- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 description 2
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-UHFFFAOYSA-L 0.000 description 2
- 125000002560 nitrile group Chemical group 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTLGXFASUHKSGN-UHFFFAOYSA-N oxepan-4-one Chemical compound O=C1CCCOCC1 CTLGXFASUHKSGN-UHFFFAOYSA-N 0.000 description 2
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 description 2
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 2
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 150000002941 palladium compounds Chemical class 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 230000035778 pathophysiological process Effects 0.000 description 2
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 2
- 238000011458 pharmacological treatment Methods 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- HDFUBEWCLXNARX-UHFFFAOYSA-N propan-2-yl 3-[2-(3-methylphenyl)ethoxy]-4-(oxetan-3-yl)benzoate Chemical compound C=1C=CC(C)=CC=1CCOC1=CC(C(=O)OC(C)C)=CC=C1C1COC1 HDFUBEWCLXNARX-UHFFFAOYSA-N 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 229910052705 radium Inorganic materials 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 102000000568 rho-Associated Kinases Human genes 0.000 description 2
- 108010041788 rho-Associated Kinases Proteins 0.000 description 2
- 238000006049 ring expansion reaction Methods 0.000 description 2
- 229910052701 rubidium Inorganic materials 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- DVDJICIUXXAIKJ-UHFFFAOYSA-N spiro[2.6]nonane Chemical compound C1CC11CCCCCC1 DVDJICIUXXAIKJ-UHFFFAOYSA-N 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- XSWYIMXJZYBCAT-UHFFFAOYSA-N tert-butyl-dimethyl-[2-[3-(oxetan-3-yl)phenyl]ethoxy]silane Chemical compound CC(C)(C)[Si](C)(C)OCCC1=CC=CC(C2COC2)=C1 XSWYIMXJZYBCAT-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- NNLBRYQGMOYARS-UHFFFAOYSA-N thiane 1-oxide Chemical compound O=S1CCCCC1 NNLBRYQGMOYARS-UHFFFAOYSA-N 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical compound C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 2
- CFRVORMUGQWQNZ-UHFFFAOYSA-N thiepane 1,1-dioxide Chemical compound O=S1(=O)CCCCCC1 CFRVORMUGQWQNZ-UHFFFAOYSA-N 0.000 description 2
- LBMZLLXZMSMJPJ-UHFFFAOYSA-N thiepane 1-oxide Chemical compound O=S1CCCCCC1 LBMZLLXZMSMJPJ-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 230000017105 transposition Effects 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- 208000037999 tubulointerstitial fibrosis Diseases 0.000 description 2
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 description 1
- PQMCFTMVQORYJC-PHDIDXHHSA-N (1r,2r)-2-aminocyclohexan-1-ol Chemical compound N[C@@H]1CCCC[C@H]1O PQMCFTMVQORYJC-PHDIDXHHSA-N 0.000 description 1
- KPTSPGHYXDYSTC-UHFFFAOYSA-N (2,2-difluoro-2-phenylethyl) trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OCC(F)(F)C1=CC=CC=C1 KPTSPGHYXDYSTC-UHFFFAOYSA-N 0.000 description 1
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- VUTJHOWRPUPHIG-UHFFFAOYSA-N (3-chloro-4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1Cl VUTJHOWRPUPHIG-UHFFFAOYSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 description 1
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 description 1
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- FKTXDTWDCPTPHK-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical group FC(F)(F)[C](F)C(F)(F)F FKTXDTWDCPTPHK-UHFFFAOYSA-N 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 description 1
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 description 1
- NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 description 1
- POTIYWUALSJREP-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline Chemical compound N1CCCC2CCCCC21 POTIYWUALSJREP-UHFFFAOYSA-N 0.000 description 1
- QACMXJJLQXUOPQ-UHFFFAOYSA-N 1,2-dichloroethane;3-(ethyliminomethylideneamino)-n,n-dimethylpropan-1-amine Chemical compound ClCCCl.CCN=C=NCCCN(C)C QACMXJJLQXUOPQ-UHFFFAOYSA-N 0.000 description 1
- MBDSUZSCJLRKPC-QGZVFWFLSA-N 1,2-dioctanoyl-sn-glycerol 3-diphosphate Chemical compound CCCCCCCC(=O)OC[C@H](COP(O)(=O)OP(O)(O)=O)OC(=O)CCCCCCC MBDSUZSCJLRKPC-QGZVFWFLSA-N 0.000 description 1
- FCDRINPELRTVHD-UHFFFAOYSA-N 1,2-oxazole Chemical compound C=1C=NOC=1.C=1C=NOC=1 FCDRINPELRTVHD-UHFFFAOYSA-N 0.000 description 1
- UGBLVKBJELNFPS-UHFFFAOYSA-N 1,2-thiazole Chemical compound C=1C=NSC=1.C=1C=NSC=1 UGBLVKBJELNFPS-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- GCBNIIKPVIHBGR-UHFFFAOYSA-N 1,3-oxazole Chemical compound C1=COC=N1.C1=COC=N1 GCBNIIKPVIHBGR-UHFFFAOYSA-N 0.000 description 1
- IJDXSTIWUARVEK-UHFFFAOYSA-N 1,4-dioxaspiro[4.4]nonane Chemical compound C1CCCC21OCCO2 IJDXSTIWUARVEK-UHFFFAOYSA-N 0.000 description 1
- GZGPRZYZKBQPBQ-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decane Chemical compound O1CCOC11CCCCC1 GZGPRZYZKBQPBQ-UHFFFAOYSA-N 0.000 description 1
- IZELAGGXOUSOTJ-UHFFFAOYSA-N 1,4-dioxaspiro[4.6]undecan-8-one Chemical compound C1CC(=O)CCCC21OCCO2 IZELAGGXOUSOTJ-UHFFFAOYSA-N 0.000 description 1
- ZQGDSZPGKPJABN-UHFFFAOYSA-N 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane Chemical compound C1C[N+]2(CCl)CC[N+]1(F)CC2 ZQGDSZPGKPJABN-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- FTACIHVCPNVPHC-UHFFFAOYSA-N 1-[[3-(3-cyanophenyl)-4-methoxybenzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1C1=CC=CC(C#N)=C1 FTACIHVCPNVPHC-UHFFFAOYSA-N 0.000 description 1
- VYVZUKGPZCWKQP-UHFFFAOYSA-N 1-[[3-[2-(2-fluoro-5-methylphenyl)ethoxy]-4-methoxybenzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC(C)=CC=C1F VYVZUKGPZCWKQP-UHFFFAOYSA-N 0.000 description 1
- SKNHJSXRGRDYBO-UHFFFAOYSA-N 1-[[3-[2-(2-fluoro-5-methylphenyl)ethoxy]-4-methoxybenzoyl]amino]cyclooctane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCCC2)C(O)=O)C=C1OCCC1=CC(C)=CC=C1F SKNHJSXRGRDYBO-UHFFFAOYSA-N 0.000 description 1
- UHVWIZDHRDDBOU-UHFFFAOYSA-N 1-[[3-[2-(3-chlorophenyl)ethoxy]-4-(2-hydroxyethoxy)benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound OCCOC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(Cl)=C1 UHVWIZDHRDDBOU-UHFFFAOYSA-N 0.000 description 1
- PGESCJUYHOZBPJ-UHFFFAOYSA-N 1-[[3-[2-(3-chlorophenyl)ethoxy]-4-(2-methoxyethoxy)benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COCCOC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(Cl)=C1 PGESCJUYHOZBPJ-UHFFFAOYSA-N 0.000 description 1
- SIWGVFRDUWXLHW-UHFFFAOYSA-N 1-[[3-[2-[3-(2-hydroxyethyl)phenyl]ethoxy]-4-methoxybenzoyl]amino]cyclooctane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(CCO)=C1 SIWGVFRDUWXLHW-UHFFFAOYSA-N 0.000 description 1
- YJOKYXSMXZVRDB-UHFFFAOYSA-N 1-[[3-chloro-4-(2-chlorophenyl)benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound C=1C=C(C=2C(=CC=CC=2)Cl)C(Cl)=CC=1C(=O)NC1(C(=O)O)CCCCCC1 YJOKYXSMXZVRDB-UHFFFAOYSA-N 0.000 description 1
- CBOHTDQWUNIMTE-UHFFFAOYSA-N 1-[[3-fluoro-4-methoxy-5-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=C(F)C=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 CBOHTDQWUNIMTE-UHFFFAOYSA-N 0.000 description 1
- AIDNGOBQUPAGES-UHFFFAOYSA-N 1-[[4-(1-fluoroethyl)-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound CC(F)C1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 AIDNGOBQUPAGES-UHFFFAOYSA-N 0.000 description 1
- UUDRSVOKRIFFLT-UHFFFAOYSA-N 1-[[4-(1-hydroxyethyl)-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound CC(O)C1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 UUDRSVOKRIFFLT-UHFFFAOYSA-N 0.000 description 1
- FPCAECNSJZQCEB-UHFFFAOYSA-N 1-[[4-(2-hydroxyethoxy)-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound CC1=CC=CC(CCOC=2C(=CC=C(C=2)C(=O)NC2(CCCCCC2)C(O)=O)OCCO)=C1 FPCAECNSJZQCEB-UHFFFAOYSA-N 0.000 description 1
- VWTZPOCRXAMDOL-UHFFFAOYSA-N 1-[[4-(2-methoxyethoxy)-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COCCOC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 VWTZPOCRXAMDOL-UHFFFAOYSA-N 0.000 description 1
- RQQFFNHPPUWFSK-UHFFFAOYSA-N 1-[[4-bromo-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound CC1=CC=CC(CCOC=2C(=CC=C(C=2)C(=O)NC2(CCCCCC2)C(O)=O)Br)=C1 RQQFFNHPPUWFSK-UHFFFAOYSA-N 0.000 description 1
- KABQWOPVLVBPJZ-UHFFFAOYSA-N 1-[[4-ethyl-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound CCC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 KABQWOPVLVBPJZ-UHFFFAOYSA-N 0.000 description 1
- XLHIXIFAUKGJAH-UHFFFAOYSA-N 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-4-oxocycloheptane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCC(=O)CCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 XLHIXIFAUKGJAH-UHFFFAOYSA-N 0.000 description 1
- BQNODSSDHUNLTF-UHFFFAOYSA-N 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-4-oxocyclohexane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCC(=O)CC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 BQNODSSDHUNLTF-UHFFFAOYSA-N 0.000 description 1
- GSNSNPJXIPSIKD-UHFFFAOYSA-N 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cyclohept-4-ene-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCC=CCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 GSNSNPJXIPSIKD-UHFFFAOYSA-N 0.000 description 1
- CLKSVIRJKYOSIH-UHFFFAOYSA-N 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cyclooctane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 CLKSVIRJKYOSIH-UHFFFAOYSA-N 0.000 description 1
- AXLVZZJXBZBZQM-UHFFFAOYSA-N 1-[[4-methoxy-3-[2-[3-(oxetan-3-yl)phenyl]ethoxy]benzoyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC(C=1)=CC=CC=1C1COC1 AXLVZZJXBZBZQM-UHFFFAOYSA-N 0.000 description 1
- AXKKUKZBALLXCG-UHFFFAOYSA-N 1-[[5-(3-cyanophenyl)-6-methoxypyridine-3-carbonyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=NC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1C1=CC=CC(C#N)=C1 AXKKUKZBALLXCG-UHFFFAOYSA-N 0.000 description 1
- LQOMTNLUXMULSM-UHFFFAOYSA-N 1-[[5-[2-(2,5-dimethylphenyl)ethoxy]-6-methoxypyridine-3-carbonyl]amino]cycloheptane-1-carboxylic acid Chemical compound COC1=NC=C(C(=O)NC2(CCCCCC2)C(O)=O)C=C1OCCC1=CC(C)=CC=C1C LQOMTNLUXMULSM-UHFFFAOYSA-N 0.000 description 1
- NMJJIXCSEOOOAA-UHFFFAOYSA-N 1-[[7-[2-(3-methylphenyl)ethoxy]-1,3-benzodioxole-5-carbonyl]amino]cycloheptane-1-carboxylic acid Chemical compound CC1=CC=CC(CCOC=2C=3OCOC=3C=C(C=2)C(=O)NC2(CCCCCC2)C(O)=O)=C1 NMJJIXCSEOOOAA-UHFFFAOYSA-N 0.000 description 1
- BHWDRHYQCMQTQO-UHFFFAOYSA-N 1-amino-2-phenylmethoxycyclopentane-1-carbonitrile Chemical compound N#CC1(N)CCCC1OCC1=CC=CC=C1 BHWDRHYQCMQTQO-UHFFFAOYSA-N 0.000 description 1
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 1
- AETRUHZNQVWNDQ-UHFFFAOYSA-N 1-ethoxycarbonyl-3-methylcyclobutane-1-carboxylic acid ethyl 1-amino-3-methylcyclobutane-1-carboxylate hydrochloride Chemical compound C(C)OC(=O)C1(CC(C1)C)C(=O)O.Cl.C(C)OC(=O)C1(CC(C1)C)N AETRUHZNQVWNDQ-UHFFFAOYSA-N 0.000 description 1
- 125000006420 1-fluorocyclopropyl group Chemical group [H]C1([H])C([H])([H])C1(F)* 0.000 description 1
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- 125000005987 1-oxo-thiomorpholinyl group Chemical group 0.000 description 1
- CBUHYYSHSILDSD-UHFFFAOYSA-N 1-phenylpiperidin-3-one Chemical class C1C(=O)CCCN1C1=CC=CC=C1 CBUHYYSHSILDSD-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- MGHNDJJPPOAIHK-UHFFFAOYSA-N 1H-inden-1-yl Chemical group C1=CC=C2[CH]C=CC2=C1 MGHNDJJPPOAIHK-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- XKGODUKBPIRBOF-UHFFFAOYSA-N 2,2-difluoro-2-phenylethanol Chemical compound OCC(F)(F)C1=CC=CC=C1 XKGODUKBPIRBOF-UHFFFAOYSA-N 0.000 description 1
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 1
- DECMAHBZGLEVJI-UHFFFAOYSA-N 2-(2-fluoro-5-methylphenyl)ethanol;methyl 3-[2-(2-fluoro-5-methylphenyl)ethoxy]-4-methoxybenzoate Chemical compound CC1=CC=C(F)C(CCO)=C1.COC(=O)C1=CC=C(OC)C(OCCC=2C(=CC=C(C)C=2)F)=C1 DECMAHBZGLEVJI-UHFFFAOYSA-N 0.000 description 1
- HRFLXGYDQUBZCO-UHFFFAOYSA-N 2-(3-bromophenyl)ethoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCC1=CC=CC(Br)=C1 HRFLXGYDQUBZCO-UHFFFAOYSA-N 0.000 description 1
- 125000000301 2-(3-chlorophenyl)ethyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- GTEXIOINCJRBIO-UHFFFAOYSA-N 2-[2-(dimethylamino)ethoxy]-n,n-dimethylethanamine Chemical compound CN(C)CCOCCN(C)C GTEXIOINCJRBIO-UHFFFAOYSA-N 0.000 description 1
- KXJLIBAPJXKTBU-UHFFFAOYSA-N 2-[2-fluoro-5-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC(OC(F)(F)F)=CC=C1F KXJLIBAPJXKTBU-UHFFFAOYSA-N 0.000 description 1
- BANFRNTVKCHZDE-UHFFFAOYSA-N 2-bromo-1-(3-methylphenyl)ethanone Chemical compound CC1=CC=CC(C(=O)CBr)=C1 BANFRNTVKCHZDE-UHFFFAOYSA-N 0.000 description 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- MURVZYSXRRPIMU-UHFFFAOYSA-N 2-hydroxy-1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cyclopentane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(C(CCC2)O)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 MURVZYSXRRPIMU-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- ACWPHUPLGQELAV-UHFFFAOYSA-N 2-methoxy-1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cyclopentane-1-carboxylic acid Chemical compound COC1CCCC1(C(O)=O)NC(=O)C1=CC=C(OC)C(OCCC=2C=C(C)C=CC=2)=C1 ACWPHUPLGQELAV-UHFFFAOYSA-N 0.000 description 1
- OLNNYNLMEOFPET-UHFFFAOYSA-N 2-methoxycyclopentan-1-one Chemical compound COC1CCCC1=O OLNNYNLMEOFPET-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 1
- 125000003890 2-phenylbutyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- WYNUTNLIODWGDR-UHFFFAOYSA-N 2-phenylmethoxycyclopentan-1-one Chemical compound O=C1CCCC1OCC1=CC=CC=C1 WYNUTNLIODWGDR-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- 125000004361 3,4,5-trifluorophenyl group Chemical group [H]C1=C(F)C(F)=C(F)C([H])=C1* 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- WHNQTHDJEZTVHS-UHFFFAOYSA-N 3-(1,3-benzothiazol-2-yl)propanoic acid Chemical compound C1=CC=C2SC(CCC(=O)O)=NC2=C1 WHNQTHDJEZTVHS-UHFFFAOYSA-N 0.000 description 1
- NMBMCOAJKMBDOS-UHFFFAOYSA-N 3-(3-chloro-4-methoxyphenyl)-4-(trifluoromethyl)benzoic acid Chemical compound C1=C(Cl)C(OC)=CC=C1C1=CC(C(O)=O)=CC=C1C(F)(F)F NMBMCOAJKMBDOS-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- LHFSHQJEMCMLPM-UHFFFAOYSA-N 3-[2-(2-fluoro-5-methylphenyl)ethoxy]-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OCCC1=CC(C)=CC=C1F LHFSHQJEMCMLPM-UHFFFAOYSA-N 0.000 description 1
- KIJAJWSRJVBBKO-UHFFFAOYSA-N 3-[2-(3-chlorophenyl)ethoxy]-4-phenylmethoxybenzoic acid Chemical compound C=1C=CC(Cl)=CC=1CCOC1=CC(C(=O)O)=CC=C1OCC1=CC=CC=C1 KIJAJWSRJVBBKO-UHFFFAOYSA-N 0.000 description 1
- MFGBNOYZJLRTJL-UHFFFAOYSA-N 3-[2-[3-(2-hydroxyethyl)phenyl]ethoxy]-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OCCC1=CC=CC(CCO)=C1 MFGBNOYZJLRTJL-UHFFFAOYSA-N 0.000 description 1
- DIXXBDCBUHBJMK-UHFFFAOYSA-N 3-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(C3CCC(O3)C2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 DIXXBDCBUHBJMK-UHFFFAOYSA-N 0.000 description 1
- IISBBMWHPMZHRS-UHFFFAOYSA-N 3-acetyloxy-4-chlorobenzoic acid Chemical compound CC(=O)OC1=CC(C(O)=O)=CC=C1Cl IISBBMWHPMZHRS-UHFFFAOYSA-N 0.000 description 1
- OWNPWXHFRGDHMC-UHFFFAOYSA-N 3-bromo-4-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C(Br)=C1 OWNPWXHFRGDHMC-UHFFFAOYSA-N 0.000 description 1
- BBPZABXVRBFWGD-UHFFFAOYSA-N 3-bromo-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1Br BBPZABXVRBFWGD-UHFFFAOYSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- XKQMOXMZXFZQSB-UHFFFAOYSA-N 4-(fluoromethyl)-1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cyclohexane-1-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCC(CF)CC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 XKQMOXMZXFZQSB-UHFFFAOYSA-N 0.000 description 1
- MFIWGLLVNIOCBZ-UHFFFAOYSA-N 4-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]oxepane-4-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCOCCC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 MFIWGLLVNIOCBZ-UHFFFAOYSA-N 0.000 description 1
- DCMSMWSVNONFKR-UHFFFAOYSA-N 4-[[4-methyl-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]bicyclo[5.1.0]octane-4-carboxylic acid Chemical compound CC1=CC=CC(CCOC=2C(=CC=C(C=2)C(=O)NC2(CCC3CC3CC2)C(O)=O)C)=C1 DCMSMWSVNONFKR-UHFFFAOYSA-N 0.000 description 1
- MKTAASUBWXZBNB-UHFFFAOYSA-N 4-acetyl-3-hydroxybenzoic acid Chemical compound CC(=O)C1=CC=C(C(O)=O)C=C1O MKTAASUBWXZBNB-UHFFFAOYSA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- PAJSESFUWIYFNF-UHFFFAOYSA-N 4-bromo-3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C(O)=C1 PAJSESFUWIYFNF-UHFFFAOYSA-N 0.000 description 1
- SCPUNJAMWFAYED-UHFFFAOYSA-N 4-chloro-3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C(O)=C1 SCPUNJAMWFAYED-UHFFFAOYSA-N 0.000 description 1
- QTDXSEZXAPHVBI-UHFFFAOYSA-N 4-methylcyclohexane-1-carboxylic acid Chemical compound CC1CCC(C(O)=O)CC1 QTDXSEZXAPHVBI-UHFFFAOYSA-N 0.000 description 1
- HTMGQIXFZMZZKD-UHFFFAOYSA-N 5,6,7,8-tetrahydroisoquinoline Chemical compound N1=CC=C2CCCCC2=C1 HTMGQIXFZMZZKD-UHFFFAOYSA-N 0.000 description 1
- YQDGQEKUTLYWJU-UHFFFAOYSA-N 5,6,7,8-tetrahydroquinoline Chemical compound C1=CC=C2CCCCC2=N1 YQDGQEKUTLYWJU-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- SRLJIOCRHFUUHK-UHFFFAOYSA-N 6-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]spiro[2.5]octane-6-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCC3(CC3)CC2)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 SRLJIOCRHFUUHK-UHFFFAOYSA-N 0.000 description 1
- SQGGNLFYTASSGX-UHFFFAOYSA-N 7-hydroxy-1,3-benzodioxole-5-carboxylic acid Chemical compound OC1=CC(C(=O)O)=CC2=C1OCO2 SQGGNLFYTASSGX-UHFFFAOYSA-N 0.000 description 1
- WXPQJUYTXIJMPB-UHFFFAOYSA-N 7-oxabicyclo[2.2.1]heptan-3-one Chemical compound C1CC2C(=O)CC1O2 WXPQJUYTXIJMPB-UHFFFAOYSA-N 0.000 description 1
- YPWFNLSXQIGJCK-UHFFFAOYSA-N 7-oxabicyclo[2.2.1]heptane Chemical compound C1CC2CCC1O2 YPWFNLSXQIGJCK-UHFFFAOYSA-N 0.000 description 1
- BZSKJNYPGFMGKN-UHFFFAOYSA-N 7-oxaspiro[4.6]undecane Chemical compound C1CCCC11COCCCC1 BZSKJNYPGFMGKN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BNRODGXINHWIPI-UHFFFAOYSA-N 8-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-1,4-dioxaspiro[4.5]decane-8-carboxylic acid Chemical compound COC1=CC=C(C(=O)NC2(CCC3(CC2)OCCO3)C(O)=O)C=C1OCCC1=CC=CC(C)=C1 BNRODGXINHWIPI-UHFFFAOYSA-N 0.000 description 1
- MHZQYURAVYGEHW-UHFFFAOYSA-N 8-amino-1,4-dioxaspiro[4.6]undecane-8-carboxylic acid Chemical compound C1CC(N)(C(O)=O)CCCC21OCCO2 MHZQYURAVYGEHW-UHFFFAOYSA-N 0.000 description 1
- HIIFALCQUKTUHB-UHFFFAOYSA-N 8-azaniumyl-1,4-dioxaspiro[4.5]decane-8-carboxylate Chemical compound C1CC(N)(C(O)=O)CCC21OCCO2 HIIFALCQUKTUHB-UHFFFAOYSA-N 0.000 description 1
- DBTMQODRSDEGRZ-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-(2-oxoethyl)carbamate Chemical compound C1=CC=C2C(COC(=O)NCC=O)C3=CC=CC=C3C2=C1 DBTMQODRSDEGRZ-UHFFFAOYSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical group NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- MTUIGMLMTASPQM-UHFFFAOYSA-N C(C)OC(C1=CC(=C(C=C1)O)O)=O.C(C)OC(C1=CC(=C(C=C1)O)OC(C)=O)=O Chemical compound C(C)OC(C1=CC(=C(C=C1)O)O)=O.C(C)OC(C1=CC(=C(C=C1)O)OC(C)=O)=O MTUIGMLMTASPQM-UHFFFAOYSA-N 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- IZUBFIJKLQFBQJ-UHFFFAOYSA-N CC1=CC=CC(CCO)=C1.CC1=CC=CC(CCO)=C1 Chemical compound CC1=CC=CC(CCO)=C1.CC1=CC=CC(CCO)=C1 IZUBFIJKLQFBQJ-UHFFFAOYSA-N 0.000 description 1
- DZIZENXFFANJKG-UHFFFAOYSA-N COC(C1=CC(=C(C=C1)OC)O)=O.COC(C1=CC(=C(C=C1)OC)OCC(C=1C=C(C=CC1)C)=O)=O Chemical compound COC(C1=CC(=C(C=C1)OC)O)=O.COC(C1=CC(=C(C=C1)OC)OCC(C=1C=C(C=CC1)C)=O)=O DZIZENXFFANJKG-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102000000018 Chemokine CCL2 Human genes 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102100022641 Coagulation factor IX Human genes 0.000 description 1
- 208000027932 Collagen disease Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000003037 Diastolic Heart Failure Diseases 0.000 description 1
- 201000003066 Diffuse Scleroderma Diseases 0.000 description 1
- 240000001879 Digitalis lutea Species 0.000 description 1
- 208000001708 Dupuytren contracture Diseases 0.000 description 1
- 108010024212 E-Selectin Proteins 0.000 description 1
- 102100023471 E-selectin Human genes 0.000 description 1
- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 description 1
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 229940102550 Estrogen receptor antagonist Drugs 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 108010048049 Factor IXa Proteins 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108090001064 Gelsolin Proteins 0.000 description 1
- 102000004878 Gelsolin Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101001038006 Homo sapiens Lysophosphatidic acid receptor 3 Proteins 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 101710149643 Integrin alpha-IIb Proteins 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 206010024119 Left ventricular failure Diseases 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- 102000016994 Lysolipids receptors Human genes 0.000 description 1
- 102100040388 Lysophosphatidic acid receptor 3 Human genes 0.000 description 1
- 108010027749 Lysophospholipid Receptors Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 1
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ZRKWMRDKSOPRRS-UHFFFAOYSA-N N-Methyl-N-nitrosourea Chemical compound O=NN(C)C(N)=O ZRKWMRDKSOPRRS-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 208000034827 Neointima Diseases 0.000 description 1
- 208000003510 Nephrogenic Fibrosing Dermopathy Diseases 0.000 description 1
- 206010067467 Nephrogenic systemic fibrosis Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000010886 Peripheral nerve injury Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 108010064785 Phospholipases Proteins 0.000 description 1
- 102000015439 Phospholipases Human genes 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229940124090 Platelet-derived growth factor (PDGF) receptor antagonist Drugs 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 206010063897 Renal ischaemia Diseases 0.000 description 1
- 108091006647 SLC9A1 Proteins 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 102000052126 Sodium-Hydrogen Exchangers Human genes 0.000 description 1
- 102100030980 Sodium/hydrogen exchanger 1 Human genes 0.000 description 1
- 108091006672 Sodium–hydrogen antiporter Proteins 0.000 description 1
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 description 1
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 208000008253 Systolic Heart Failure Diseases 0.000 description 1
- 206010042957 Systolic hypertension Diseases 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 208000004608 Ureteral Obstruction Diseases 0.000 description 1
- 229940116211 Vasopressin antagonist Drugs 0.000 description 1
- 208000033774 Ventricular Remodeling Diseases 0.000 description 1
- WWGJEDDFWJBVPW-UHFFFAOYSA-N [[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium Chemical compound CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C WWGJEDDFWJBVPW-UHFFFAOYSA-N 0.000 description 1
- WXIONIWNXBAHRU-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Chemical compound C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 WXIONIWNXBAHRU-UHFFFAOYSA-N 0.000 description 1
- 229960000446 abciximab Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000006668 aldol addition reaction Methods 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001339 alkali metal compounds Chemical class 0.000 description 1
- 150000001341 alkaline earth metal compounds Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 108010022198 alkylglycerophosphoethanolamine phosphodiesterase Proteins 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940082988 antihypertensives serotonin antagonists Drugs 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 150000003976 azacycloalkanes Chemical class 0.000 description 1
- 125000004320 azepan-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- ZUDYPQRUOYEARG-UHFFFAOYSA-L barium(2+);dihydroxide;octahydrate Chemical compound O.O.O.O.O.O.O.O.[OH-].[OH-].[Ba+2] ZUDYPQRUOYEARG-UHFFFAOYSA-L 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical group NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 1
- SHOMMGQAMRXRRK-UHFFFAOYSA-N bicyclo[3.1.1]heptane Chemical compound C1C2CC1CCC2 SHOMMGQAMRXRRK-UHFFFAOYSA-N 0.000 description 1
- LPCWKMYWISGVSK-UHFFFAOYSA-N bicyclo[3.2.1]octane Chemical compound C1C2CCC1CCC2 LPCWKMYWISGVSK-UHFFFAOYSA-N 0.000 description 1
- AKHMHYGTZRJYBS-UHFFFAOYSA-N bicyclo[5.1.0]octane Chemical compound C1CCCCC2CC21 AKHMHYGTZRJYBS-UHFFFAOYSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 229960003065 bosentan Drugs 0.000 description 1
- SXTRWVVIEPWAKM-UHFFFAOYSA-N bosentan hydrate Chemical compound O.COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 SXTRWVVIEPWAKM-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 125000003262 carboxylic acid ester group Chemical group [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000001054 cardiac fibroblast Anatomy 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- 238000011208 chromatographic data Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003601 chymase inhibitor Substances 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 125000000332 coumarinyl group Chemical class O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- GPTJTTCOVDDHER-UHFFFAOYSA-N cyclononane Chemical compound C1CCCCCCCC1 GPTJTTCOVDDHER-UHFFFAOYSA-N 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- 150000001940 cyclopentanes Chemical group 0.000 description 1
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 125000005508 decahydronaphthalenyl group Chemical group 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- PBGGNZZGJIKBMJ-UHFFFAOYSA-N di(propan-2-yl)azanide Chemical compound CC(C)[N-]C(C)C PBGGNZZGJIKBMJ-UHFFFAOYSA-N 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- ZQTNQVWKHCQYLQ-UHFFFAOYSA-N dronedarone Chemical compound C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)C1=C(CCCC)OC2=CC=C(NS(C)(=O)=O)C=C12 ZQTNQVWKHCQYLQ-UHFFFAOYSA-N 0.000 description 1
- 229960002084 dronedarone Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003602 elastase inhibitor Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 1
- 229960001208 eplerenone Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- GJJASJCGLOUWAC-UHFFFAOYSA-N ethoxycyclohexane Chemical compound CCOC1CCCCC1 GJJASJCGLOUWAC-UHFFFAOYSA-N 0.000 description 1
- ZGIYMVCSKRMIPB-UHFFFAOYSA-N ethyl 1-[[4-methoxy-3-[2-(3-methylphenyl)-2-oxoethoxy]benzoyl]amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(OC)C(OCC(=O)C=2C=C(C)C=CC=2)=CC=1C(=O)NC1(C(=O)OCC)CCCCCC1 ZGIYMVCSKRMIPB-UHFFFAOYSA-N 0.000 description 1
- CHAJAQRVAZTEPG-UHFFFAOYSA-N ethyl 1-amino-2-ethylcyclopropane-1-carboxylate Chemical compound CCOC(=O)C1(N)CC1CC CHAJAQRVAZTEPG-UHFFFAOYSA-N 0.000 description 1
- XHAOHFNBBUINOT-UHFFFAOYSA-N ethyl 1-aminocycloheptane-1-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1(N)CCCCCC1 XHAOHFNBBUINOT-UHFFFAOYSA-N 0.000 description 1
- MUWAMLYKLZSGPE-UHFFFAOYSA-N ethyl 2-ethenyl-1-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopropane-1-carboxylate Chemical compound CC(C)(C)OC(=O)NC1(C(=O)OCC)CC1C=C MUWAMLYKLZSGPE-UHFFFAOYSA-N 0.000 description 1
- BUCSFMMWCFKKCF-UHFFFAOYSA-N ethyl 3-[2-(3-chlorophenyl)ethoxy]-4-phenylmethoxybenzoate Chemical compound C=1C=CC(Cl)=CC=1CCOC1=CC(C(=O)OCC)=CC=C1OCC1=CC=CC=C1 BUCSFMMWCFKKCF-UHFFFAOYSA-N 0.000 description 1
- ZEJVYQQBJKMABH-UHFFFAOYSA-N ethyl 3-acetyloxy-4-phenylmethoxybenzoate Chemical compound CC(=O)OC1=CC(C(=O)OCC)=CC=C1OCC1=CC=CC=C1 ZEJVYQQBJKMABH-UHFFFAOYSA-N 0.000 description 1
- FAENFNUEKOZHCS-UHFFFAOYSA-N ethyl 3-hydroxy-4-phenylmethoxybenzoate Chemical compound OC1=CC(C(=O)OCC)=CC=C1OCC1=CC=CC=C1 FAENFNUEKOZHCS-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 208000038003 heart failure with preserved ejection fraction Diseases 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000002363 herbicidal 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
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 150000004324 hydroxyarenes Chemical class 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- YVKJMACNGRYTAY-UHFFFAOYSA-N imidazo[4,5-b]azepine Chemical class C1=CC=NC2=NC=NC2=C1 YVKJMACNGRYTAY-UHFFFAOYSA-N 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 1
- 125000004282 imidazolidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])N([H])C1([H])* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- HEBMCVBCEDMUOF-UHFFFAOYSA-N isochromane Chemical compound C1=CC=C2COCCC2=C1 HEBMCVBCEDMUOF-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004254 isoquinolin-1-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C([H])C([H])=C2C(*)=N1 0.000 description 1
- 125000004551 isoquinolin-3-yl group Chemical group C1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 125000004552 isoquinolin-4-yl group Chemical group C1=NC=C(C2=CC=CC=C12)* 0.000 description 1
- 208000011379 keloid formation Diseases 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- OVWYEQOVUDKZNU-UHFFFAOYSA-N m-tolualdehyde Chemical compound CC1=CC=CC(C=O)=C1 OVWYEQOVUDKZNU-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000003584 mesangial cell Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- GHDIHPNJQVDFBL-UHFFFAOYSA-N methoxycyclohexane Chemical compound COC1CCCCC1 GHDIHPNJQVDFBL-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- LTLVEKZXGKBTER-UHFFFAOYSA-N methyl 1-[(3-acetyloxy-4-chlorobenzoyl)amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(Cl)C(OC(C)=O)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 LTLVEKZXGKBTER-UHFFFAOYSA-N 0.000 description 1
- MHVJIJLGLDDSTI-UHFFFAOYSA-N methyl 1-[(3-acetyloxy-4-methoxybenzoyl)amino]-4-ethylcyclohexane-1-carboxylate Chemical compound C1CC(CC)CCC1(C(=O)OC)NC(=O)C1=CC=C(OC)C(OC(C)=O)=C1 MHVJIJLGLDDSTI-UHFFFAOYSA-N 0.000 description 1
- LZROLJRUAQXDOW-UHFFFAOYSA-N methyl 1-[(3-bromo-4-methoxybenzoyl)amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(OC)C(Br)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 LZROLJRUAQXDOW-UHFFFAOYSA-N 0.000 description 1
- CPWKLTNANOJFOZ-UHFFFAOYSA-N methyl 1-[(4-acetyl-3-hydroxybenzoyl)amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(C(C)=O)C(O)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 CPWKLTNANOJFOZ-UHFFFAOYSA-N 0.000 description 1
- YFCHBCHJMYOMKZ-UHFFFAOYSA-N methyl 1-[(4-chloro-3-hydroxybenzoyl)amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(Cl)C(O)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 YFCHBCHJMYOMKZ-UHFFFAOYSA-N 0.000 description 1
- RIOVIUZRRYKOMP-UHFFFAOYSA-N methyl 1-[(5-bromo-6-methoxypyridine-3-carbonyl)amino]cycloheptane-1-carboxylate Chemical compound C=1N=C(OC)C(Br)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 RIOVIUZRRYKOMP-UHFFFAOYSA-N 0.000 description 1
- GBLMUVNVOFCCPY-UHFFFAOYSA-N methyl 1-[[3-(2,2-difluoro-2-phenylethoxy)-4-methoxybenzoyl]amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(OC)C(OCC(F)(F)C=2C=CC=CC=2)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 GBLMUVNVOFCCPY-UHFFFAOYSA-N 0.000 description 1
- JALAEMNNIVCGGM-UHFFFAOYSA-N methyl 1-[[3-[1,3-dihydroxy-3-(3-methylphenyl)propyl]-4-methoxybenzoyl]amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(OC)C(C(O)CC(O)C=2C=C(C)C=CC=2)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 JALAEMNNIVCGGM-UHFFFAOYSA-N 0.000 description 1
- URKBYNAHMJYIMR-UHFFFAOYSA-N methyl 1-[[3-[2-(2-fluoro-5-methylphenyl)ethoxy]-4-methoxybenzoyl]amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(OC)C(OCCC=2C(=CC=C(C)C=2)F)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 URKBYNAHMJYIMR-UHFFFAOYSA-N 0.000 description 1
- GPBNZPPVVGLACI-UHFFFAOYSA-N methyl 1-[[3-[2-(5-chloro-2-fluorophenyl)ethoxy]-4-methoxybenzoyl]amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(OC)C(OCCC=2C(=CC=C(Cl)C=2)F)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 GPBNZPPVVGLACI-UHFFFAOYSA-N 0.000 description 1
- DNPJCSPCFCQPAA-UHFFFAOYSA-N methyl 1-[[3-[2-[3-(2-hydroxyethyl)phenyl]ethoxy]-4-methoxybenzoyl]amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(OC)C(OCCC=2C=C(CCO)C=CC=2)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 DNPJCSPCFCQPAA-UHFFFAOYSA-N 0.000 description 1
- KSVNTTAZKVCOHN-UHFFFAOYSA-N methyl 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-4-methylidenecyclohexane-1-carboxylate Chemical compound C=1C=C(OC)C(OCCC=2C=C(C)C=CC=2)=CC=1C(=O)NC1(C(=O)OC)CCC(=C)CC1 KSVNTTAZKVCOHN-UHFFFAOYSA-N 0.000 description 1
- UYBWJVQGRCNBNC-UHFFFAOYSA-N methyl 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-4-oxocycloheptane-1-carboxylate Chemical compound C=1C=C(OC)C(OCCC=2C=C(C)C=CC=2)=CC=1C(=O)NC1(C(=O)OC)CCCC(=O)CC1 UYBWJVQGRCNBNC-UHFFFAOYSA-N 0.000 description 1
- ZUMLZZCCKZPBFH-UHFFFAOYSA-N methyl 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-4-oxocyclohexane-1-carboxylate Chemical compound C=1C=C(OC)C(OCCC=2C=C(C)C=CC=2)=CC=1C(=O)NC1(C(=O)OC)CCC(=O)CC1 ZUMLZZCCKZPBFH-UHFFFAOYSA-N 0.000 description 1
- RCLCGOVSXLVNBJ-UHFFFAOYSA-N methyl 1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cyclohept-4-ene-1-carboxylate Chemical compound C=1C=C(OC)C(OCCC=2C=C(C)C=CC=2)=CC=1C(=O)NC1(C(=O)OC)CCC=CCC1 RCLCGOVSXLVNBJ-UHFFFAOYSA-N 0.000 description 1
- CYTGJMXELHFIBS-UHFFFAOYSA-N methyl 1-[[5-(3-cyanophenyl)-6-methoxypyridine-3-carbonyl]amino]cycloheptane-1-carboxylate Chemical compound C=1N=C(OC)C(C=2C=C(C=CC=2)C#N)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 CYTGJMXELHFIBS-UHFFFAOYSA-N 0.000 description 1
- VAZOHNZRAOCIRF-UHFFFAOYSA-N methyl 1-[[7-[2-(3-methylphenyl)ethoxy]-1,3-benzodioxole-5-carbonyl]amino]cycloheptane-1-carboxylate Chemical compound C=1C=2OCOC=2C(OCCC=2C=C(C)C=CC=2)=CC=1C(=O)NC1(C(=O)OC)CCCCCC1 VAZOHNZRAOCIRF-UHFFFAOYSA-N 0.000 description 1
- DQNFTVRKJDPGOJ-UHFFFAOYSA-N methyl 1-amino-4-ethylcyclohexane-1-carboxylate Chemical compound CCC1CCC(N)(C(=O)OC)CC1 DQNFTVRKJDPGOJ-UHFFFAOYSA-N 0.000 description 1
- HBZZFTZZPFNPKT-UHFFFAOYSA-N methyl 1-aminocyclohept-4-ene-1-carboxylate Chemical compound COC(=O)C1(N)CCC=CCC1 HBZZFTZZPFNPKT-UHFFFAOYSA-N 0.000 description 1
- PPOCOUMSZRPEKV-UHFFFAOYSA-N methyl 3-acetyl-4-methoxybenzoate Chemical compound COC(=O)C1=CC=C(OC)C(C(C)=O)=C1 PPOCOUMSZRPEKV-UHFFFAOYSA-N 0.000 description 1
- OCDPTCACMBMJMX-UHFFFAOYSA-N methyl 3-acetyloxy-4-methoxybenzoate Chemical compound COC(=O)C1=CC=C(OC)C(OC(C)=O)=C1 OCDPTCACMBMJMX-UHFFFAOYSA-N 0.000 description 1
- LXCQVWRESZDFGW-UHFFFAOYSA-N methyl 3-hydroxy-4-iodobenzoate Chemical compound COC(=O)C1=CC=C(I)C(O)=C1 LXCQVWRESZDFGW-UHFFFAOYSA-N 0.000 description 1
- SFDXNRIUDJAYHF-UHFFFAOYSA-N methyl 4-aminooxepane-4-carboxylate;hydrochloride Chemical compound Cl.COC(=O)C1(N)CCCOCC1 SFDXNRIUDJAYHF-UHFFFAOYSA-N 0.000 description 1
- IFENLBJFSAHIIX-UHFFFAOYSA-N methyl 4-ethyl-1-[(3-hydroxy-4-methoxybenzoyl)amino]cyclohexane-1-carboxylate Chemical compound C1CC(CC)CCC1(C(=O)OC)NC(=O)C1=CC=C(OC)C(O)=C1 IFENLBJFSAHIIX-UHFFFAOYSA-N 0.000 description 1
- YFTRAYAHPBUMMK-UHFFFAOYSA-N methyl 4-ethyl-1-[[4-methoxy-3-[2-[3-(oxetan-3-yl)phenyl]ethoxy]benzoyl]amino]cyclohexane-1-carboxylate Chemical compound C1CC(CC)CCC1(C(=O)OC)NC(=O)C1=CC=C(OC)C(OCCC=2C=C(C=CC=2)C2COC2)=C1 YFTRAYAHPBUMMK-UHFFFAOYSA-N 0.000 description 1
- DSJHEFVZTTWTQS-UHFFFAOYSA-N methyl 4-hydroxy-1-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]cycloheptane-1-carboxylate Chemical compound C=1C=C(OC)C(OCCC=2C=C(C)C=CC=2)=CC=1C(=O)NC1(C(=O)OC)CCCC(O)CC1 DSJHEFVZTTWTQS-UHFFFAOYSA-N 0.000 description 1
- BGKPLXDLHCARAX-UHFFFAOYSA-N methyl 4-iodo-3-[2-(3-methylphenyl)ethoxy]benzoate Chemical compound COC(=O)C1=CC=C(I)C(OCCC=2C=C(C)C=CC=2)=C1 BGKPLXDLHCARAX-UHFFFAOYSA-N 0.000 description 1
- CYUVAYRBQAGWLJ-UHFFFAOYSA-N methyl 4-methoxy-3-[3-(3-methylphenyl)propyl]benzoate Chemical compound COC(=O)C1=CC=C(OC)C(CCCC=2C=C(C)C=CC=2)=C1 CYUVAYRBQAGWLJ-UHFFFAOYSA-N 0.000 description 1
- UCOBYBCUAQNLBK-UHFFFAOYSA-N methyl 5-bromo-6-methoxypyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(OC)C(Br)=C1 UCOBYBCUAQNLBK-UHFFFAOYSA-N 0.000 description 1
- BRPREIDVQXJOJH-UHFFFAOYSA-N methyl 6-chloro-5-nitropyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(Cl)C([N+]([O-])=O)=C1 BRPREIDVQXJOJH-UHFFFAOYSA-N 0.000 description 1
- JWPVMTMRKJBYMJ-UHFFFAOYSA-N methyl 8-[[4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzoyl]amino]-1,4-dioxaspiro[4.5]decane-8-carboxylate Chemical compound C1CC(C(=O)OC)(NC(=O)C=2C=C(OCCC=3C=C(C)C=CC=3)C(OC)=CC=2)CCC21OCCO2 JWPVMTMRKJBYMJ-UHFFFAOYSA-N 0.000 description 1
- CNEFBUKEZWNRFI-UHFFFAOYSA-N methyl 8-amino-1,4-dioxaspiro[4.6]undecane-8-carboxylate Chemical compound C1CC(C(=O)OC)(N)CCCC21OCCO2 CNEFBUKEZWNRFI-UHFFFAOYSA-N 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229940124303 multikinase inhibitor Drugs 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- RZSCFTDHFNHMOR-UHFFFAOYSA-N n-(2,4-difluorophenyl)-2-[3-(trifluoromethyl)phenoxy]pyridine-3-carboxamide;1,1-dimethyl-3-(4-propan-2-ylphenyl)urea Chemical compound CC(C)C1=CC=C(NC(=O)N(C)C)C=C1.FC1=CC(F)=CC=C1NC(=O)C1=CC=CN=C1OC1=CC=CC(C(F)(F)F)=C1 RZSCFTDHFNHMOR-UHFFFAOYSA-N 0.000 description 1
- SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000005054 naphthyridines Chemical class 0.000 description 1
- 230000008692 neointimal formation Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- JFNLZVQOOSMTJK-UHFFFAOYSA-N norbornene Chemical compound C1C2CCC1C=C2 JFNLZVQOOSMTJK-UHFFFAOYSA-N 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- UZGLIIJVICEWHF-UHFFFAOYSA-N octogen Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)CN([N+]([O-])=O)C1 UZGLIIJVICEWHF-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000004027 organic amino compounds Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 150000002900 organolithium compounds Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 108091008880 orphan GPCRs Proteins 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
- 125000004322 oxepan-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- QJPQVXSHYBGQGM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 230000009038 pharmacological inhibition Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 125000005499 phosphonyl group Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 1
- 229960003073 pirfenidone Drugs 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 230000004983 pleiotropic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 208000007232 portal hypertension Diseases 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 230000007112 pro inflammatory response Effects 0.000 description 1
- 230000000019 pro-fibrinolytic effect Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000009696 proliferative response Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DEDZSLCZHWTGOR-UHFFFAOYSA-N propylcyclohexane Chemical compound CCCC1CCCCC1 DEDZSLCZHWTGOR-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- CTVOZUFKICZROL-UHFFFAOYSA-N pyrrolo[3,2-b]azepine Chemical class C1=CC=CC2=NC=CC2=N1 CTVOZUFKICZROL-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 1
- 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 description 1
- 125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 description 1
- 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 102000009929 raf Kinases Human genes 0.000 description 1
- 108010077182 raf Kinases Proteins 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 210000001567 regular cardiac muscle cell of ventricle Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000005084 renal tissue Anatomy 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 239000003590 rho kinase inhibitor Substances 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 102000035025 signaling receptors Human genes 0.000 description 1
- 108091005475 signaling receptors Proteins 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-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
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- HEMCGZPSGYRIOL-UHFFFAOYSA-N spiro[2.4]heptane Chemical compound C1CC11CCCC1 HEMCGZPSGYRIOL-UHFFFAOYSA-N 0.000 description 1
- FOEYMRPOKBCNCR-UHFFFAOYSA-N spiro[2.5]octane Chemical compound C1CC11CCCCC1 FOEYMRPOKBCNCR-UHFFFAOYSA-N 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 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
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical compound O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 125000004569 thiomorpholin-2-yl group Chemical group N1CC(SCC1)* 0.000 description 1
- 125000004570 thiomorpholin-3-yl group Chemical group N1C(CSCC1)* 0.000 description 1
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-O tritert-butylphosphanium Chemical compound CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-O 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 239000003038 vasopressin antagonist Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/54—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- 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
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/10—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- 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
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms 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
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D305/06—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings 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 atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings 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
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/04—Seven-membered rings not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/02—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2
- C07D317/06—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2 condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
- C07D335/12—Thioxanthenes
- C07D335/14—Thioxanthenes 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 in position 9
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
- C07D335/12—Thioxanthenes
- C07D335/14—Thioxanthenes 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 in position 9
- C07D335/18—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/22—All rings being cycloaliphatic the ring system containing eight carbon atoms, e.g. pentalene
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/50—Spiro compounds
Definitions
- the present invention relates to compounds of the formula I,
- A, Y, Z, R to R and R have the meanings indicated below, which are valuable pharmaceutical active compounds. Specifically, they are inhibitors of the endothelial differentiation gene receptor 2 (Edg-2, EDG2), which is activated by lysophosphatidic acid (LPA) and is also termed as LPAi receptor, and are useful for the treatment of diseases such as atherosclerosis, myocardial infarction and heart failure, for example.
- EDG2 endothelial differentiation gene receptor 2
- LPAi receptor lysophosphatidic acid
- the invention furthermore relates to processes for the
- LPA is a group of endogenous lysophospholipid derivatives including 1 -oleoyl-sn- glycerol 3-phosphate, for example.
- LPA activates G-protein-coupled receptors (GPCR's) from the endothelial differentiation gene receptor family which belong to the lysophospholipid receptors.
- GPCR's G-protein-coupled receptors
- LPA signaling exerts a variety of pleiotropic biological responses on many different cell types which interfere with processes such as cell proliferation, cell growth, cell hypertrophy, re-differentiation, cell retraction, cell contraction, cell migration, cell survival or inflammation.
- the Edg receptor family originally identified as a family of orphan GPCR's, currently comprises eight different members which were recently termed according to their respective ligand as LPA receptors or S1 P receptors (sphingosine-1 -phosphate receptors). According to the nomenclature of the International Union of Basic and Clinical Pharmacology (IUPHAR), LPA receptors Edg-2, Edg-4 and Edg-7 are now also termed as LPAi , LPA 2 and LPA 3 receptor (cf. I. Ishii et al., Annu. Rev. Biochem. 73 (2004), 321 -354).
- LPA is generated mainly in the extracellular compartment by different pathways predominantly by the cancer cell motility factor autotaxin which was recently found to be identical with lysophospholipase D.
- LPA can also be generated by alternative routes involving phospholipase hydrolysis (PLAi and PLA 2 ) or other mechanisms such as de novo phospholipid synthesis.
- PPAi and PLA 2 alternative routes involving phospholipase hydrolysis
- LPA in contrast to other phospholipids, is highly soluble in water, in plasma it is carried by different binding proteins such as albumin and gelsolin which display a high affinity to LPA and from which it can be released. Under pathophysiological conditions, levels of LPA can be elevated to an undesirable amount and thus increase LPA-mediated signaling and lead to detrimental processes such as abnormal cell proliferation, for example.
- Blocking LPA signaling for example by Edg-2 inhibitors, allows to prevent such processes.
- LPA serum levels were significantly raised in humans to about 6-fold higher concentrations, and LPA was regarded to be involved in the pathophysiological processes in the
- LPA low density lipoprotein
- LPA was identified as an important bioactive component of moxLDL (mildly oxidized low density lipoprotein) leading to platelet activation, and it was shown that the effects of LPA, moxLDL or lipid core extracts from human atherosclerotic plaques on platelet activation could be abrogated by the Edg-2/Edg-7 receptor inhibitor
- dioctanoylglycerol pyrophosphate DGPP(8:0) implicating a causative role of LPA- mediated Edg receptor signaling in platelet aggregation and usefulness of such LPA receptor inhibitors in the treatment of cardiovascular diseases (E. Rother et al., Circulation 108 (2003), 741 -747).
- LPA leads to pertussis toxin-sensitive, NFKB (nuclear factor kappa B)-mediated pro-inflammatory responses of endothelial cells including upregulation of chemokines like monocyte chemoattractant protein-1 (MCP-1 ) and interleukin-8 (IL8) (A. Palmetshofer et al., Thromb. Haemost. 82 (1999), 1532-1537) and exposure of endothelial cell adhesion molecules like E-selectin or intercellular adhesion molecule-1 (ICAM-1 ) (H. Lee et al., Am. J. Physiol. 287 (2004), C1657- C1666).
- chemokines like monocyte chemoattractant protein-1 (MCP-1 ) and interleukin-8 (IL8)
- MCP-1 monocyte chemoattractant protein-1
- IL8 interleukin-8
- IAM-1 intercellular adhesion molecule-1
- Edg-2 receptors Direct evidence for the involvement of Edg-2 receptors arises from recent studies which demonstrate that LPA induces oxidative stress in vascular smooth muscle cells and endothelial cells which was attenuated by pharmacological inhibition by DGPP(8:0) or THG1603, a specific Edg-2 receptor antagonist (U.
- LPA leads to pertussis toxin-sensitive Ca 2+ release from internal stores, to activation of 42 kDa mitogen-activated protein kinase (p42MAPK) and to cell proliferation (S. Seewald et al., Atherosclerosis 130 (1997), 121 -131 ). Intravascular injection of LPA was shown to induce neointima formation in vivo (K.
- LPA furthermore attenuates the force of contraction in human myocardial ventricular and atrial preparations and impairs isoprenaline-induced fractional shortening of isolated adult rat ventricular myocytes. The latter effects were reverted after pre-incubation with pertussis toxin indicating the relevance of a GPCR-mediated and G a i/o-mediated pathway (B. Cremers et al., J. Mol. Cell. Cardiol. 35 (2003), 71 -80). LPA was also found to lead to enhanced matrix generation and proliferation of cardiac fibroblasts (J. Chen et al., FEBS Letters 580 (2006), 4737-4745).
- Edg-2 receptors Direct involvement of Edg-2 receptors was recently demonstrated for the progression of bone metastasis in vivo. Progression was reduced under pharmacological treatment with the Edg-2/Edg-7 receptor inhibitor Ki16425 as well as after specific silencing of the Edg-2 receptors in the same order of magnitude (A. Boucharaba et al., Proc. Natl. Acad. Sci. 103 (2006), 9643-9648). The relevance of Edg-2 receptors was also shown in vitro with respect to prostate cancer cell proliferation and metastatic potential of human colon carcinoma cells (R. Guo et al., Endocrinology 147 (2006), 4883-4892; D. Shida et al., Cancer Res. 63 (2003), 1706-171 1 ). The relevance of LPA-mediated Edg-2 receptor signaling was also demonstrated in an in vivo model of neuropathic pain. Intrathecal injection of LPA mimicked
- LPA receptor antagonistic azole compounds which are characterized by a carbamate group in the 4-position of the azole ring, are described in EP 1258484.
- the use of azole compounds, further heterocycles and other compounds for modulating the Edg-2, Edg-3, Edg-4 and Edg-7 receptor is described in WO 03/062392.
- the compound of the formula I in which the ring A is an unsubstituted cycloheptane ring, R is hydrogen, R is hydroxy and the ring comprising Y and Z and carrying R 21 and R 22 is 2',3-dichloro-biphen-4-yl ( 2', 3- dichloro-biphenyl-4-yl), is disclosed as an intermediate in the synthesis of the pharmacological active compounds.
- R 20 is hydrogen
- R 50 is methoxy
- the ring comprising Y and Z and carrying R 21 and R 22 is 4-(4-oxo-piperidin-1 -yl)-phenyl
- WO 99/49856 which relates to very broadly defined compounds which mediate immune or inflammatory response through the CD1 1/CD18 family of cellular adhesion molecules, the compound 1 -[2-chloro-4-(3-hydroxy- benzylcarbamoyl)-benzoylamino]-cyclopropanecarboxylic acid, i.e.
- a subject of the present invention is a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof,
- ring A is a 3-membered to 12-membered monocyclic, bicyclic or spirocyclic ring which comprises 0, 1 or 2 identical or different hetero ring members chosen from the series consisting of N, N(R°), O, S, S(O) and S(O) 2 , and which is saturated or comprises 1 double bond, provided that ring A is not a bicyclo[3.1 .0]hexane or bicyclo[3.2.0]heptane ring carrying the groups N(R 20 ) and C(O)-R 50 in its position 3, and not an octahydropentalene, octahydroindene or decahydroazulene ring carrying the groups N(R 20 ) and C(O)-R 50 in its position 2, wherein ring A is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the series consisting of halogen, R 1 , R 2 , (C 2 -C6)-alkenyl
- Z is chosen from the series consisting of N and C(R 16 );
- R° is chosen from the series consisting of hydrogen and R 1 ;
- R 1 is chosen from the series consisting of (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl and (C3- C 7 )-cycloalkyl-(Ci-C 4 )-alkyl-;
- R 2 is (CrC )-alkyl which is substituted by one or more identical or different substituents chosen from the series consisting of HO- and (Ci-C )-alkyl-O-;
- R 10 is chosen from the series consisting of hydrogen and R 1 1 ;
- R 1 1 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 are, independently of each other group R 1 1 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 , chosen from the series consisting of (Ci-C 6 )- alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl and (C 3 -C 7 )-cycloalkyl-(C C 4 )-alkyl- which are all optionally substituted by one or more identical or different substituents R 70 ;
- R 12 , R 13 , R 14 , R 15 and R 16 are independently of each other chosen from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl, HO-(Ci-C 4 )-alkyl-
- R 18 independently of each other group R 18 , is chosen from the series consisting of hydrogen, fluorine and (Ci-C )-alkyl, or two of the groups R 18 bonded to the same carbon atom, together with the carbon atom carrying them, form a 3-membered to 6- membered cycloalkane ring which is optionally substituted by one more identical or different substituents chosen from the series consisting of fluorine and (Ci-C 4 )-alkyl;
- R 20 is chosen from the series consisting of hydrogen and (CrC )-alkyl; one of the groups R 21 and R 22 is a group of the formula II
- R and R is chosen from the series consisting of hydrogen, halogen, R 30 , HO-, R 30 -O-, R 30 -C(O)-O-, R 30 -S(O) 2 -O-, R 30 -S(O) m -, H 2 N-, R 30 -NH-, R 30 -N(R 30 )-, R 30 -C(O)-NH-, R 30 -C(O)-N(R 71 )-, R 30 -S(O) 2 -NH-, R 30 -S(O) 2 - N(R 71 )-, R 30 -C(O)-, HO-C(O)-, R 30 -O-C(O)-, H 2 N-C(O)-, R 30 -NH-C(O)-, R 30 -N(R 30 )- C(O)-, H 2 N-S(O) 2 -, R 30 -NH-S(O)-, R
- R 23 is a direct bond or a chain consisting of 1 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the series consisting of N(R 25 ), O, S, S(O) and S(O) 2 , but two hetero chain members can be present in adjacent positions only if one of them is chosen from the series consisting of S(O) and S(O) 2 and the other is chosen from the series consisting of N(R 25 ), O and S, and the other chain members are identical or different groups C(R 26 )(R 26 );
- R 24 is a 3-membered to 10-membered, monocyclic or bicyclic ring, which is saturated and contains 0 or 1 hetero ring members, or is unsaturated and contains 0, 1 or 2 identical or different hetero ring members, wherein the hetero ring members are chosen from the series consisting of N, N(R 32 ), O, S, S(O) and S(O) 2 , and wherein the ring is optionally substituted on ring carbon
- R 26 independently of each other group R 26 , is chosen from the series consisting of hydrogen, fluorine, (Ci-C 4 )-alkyl and HO-, or two groups R 26 bonded to the same carbon atom together are oxo, or two of the groups R 26 or one group R 25 and one group R 26 , together with the comprised chain members, form a 3-membered to 7- membered monocyclic ring which is saturated and contains 0, 1 or 2 identical or different hetero ring members chosen from the series consisting of N, N(R 34 ), O, S, S(O) and S(O) 2 , which ring is optionally substituted on ring carbon atoms by one more identical or different substituents chosen from the series consisting of fluorine and (Ci-C 4 )-alkyl;
- R 32 and R 34 are independently of each other chosen from the series consisting of hydrogen, R 35 , R 35 -S(O) 2 -, R 35 -C(O)-, R 35 -O-C(O)- and phenyl;
- R 50 is chosen from the series consisting of R 51 -O- and R 52 -N(R 53 )-;
- R 51 is chosen from the series consisting of hydrogen and R 54 ;
- R 52 is chosen from the series consisting of hydrogen, R 55 , NC- and R 56 -S(O) 2 -;
- R 53 is chosen from the series consisting of hydrogen and R 57 ;
- R 56 is chosen from the series consisting of R 58 and phenyl;
- R 60 independently of each other group R 60 , is chosen from the series consisting of hydrogen and (Ci-C 4 )-alkyl;
- R u is chosen from the series consisting of HO-, R -O-, R -C(O)-O-, R -S(O) m -, H 2 N-, R 71 -NH-, R 71 -N(R 71 )-, R 71 -C(O)-NH-, R 71 -C(O)-N(R 71 )-, R 71 -S(O) 2 -NH-,
- R 71 independently of each other group R 71 , is chosen from (Ci-C 4 )-alkyl, (C 3 -C 4 )- cycloalkyl and (C 3 -C 4 )-cycloalkyl-(Ci-C 2 )-alkyl-;
- Het 1 is a monocyclic 4-membered to 7-membered heterocyclic ring which comprises 1 or 2 identical or different hetero ring members chosen from the series consisting of N, N(R 60 ), O, S, S(O) and S(O) 2 , which ring is saturated and is optionally substituted by one or more identical or different substituents chosen from the series consisting of fluorine and (Ci-C 4 )-alkyl;
- m independently of each other number m, is an integer chosen from the series consisting of 0, 1 and 2;
- phenyl independently of each other group phenyl, is optionally substituted by one or more identical or different substituents chosen from the series consisting
- dialkylamino group for example, the alkyl groups can be identical or different.
- Alkyl groups i.e. saturated hydrocarbon residues
- the number of carbon atoms in an alkyl group can be 1 , 2, 3, 4, 5 or 6, or 1 , 2, 3 or 4, or 1 , 2 or 3, or 1 or 2, or 1 .
- a (Ci -Ce)-alkyl group present in any position of the compounds of the formula I is a (Ci -C 4 )-alkyl group, in another embodiment a (CrC 3 )-alkyl group, in another embodiment a (Ci -C 2 )-alkyl group, in another embodiment a (C-2-C3)-alkyl group, in another embodiment a methyl group, where any (Ci-C6)-alkyl group present in the compounds of the formula I can independently of each other (Ci-C6)-alkyl group be a group of any of these
- a (CrC )-alkyl group present in any position of the compounds of the formula I is a (Ci-C3)-alkyl group, in another embodiment a (Ci -C2)-alkyl group, in another embodiment a (C-2-C3)-alkyl group, in another embodiment a methyl group, where any (Ci-C 4 )-alkyl group present in the compounds of the formula I can independently of each other (Ci-C 4 )-alkyl group be a group of any of these embodiments.
- alkyl examples include methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert- butyl, pentyl including n-pentyl, 1 -methylbutyl, isopentyl, neopentyl and tert-pentyl, and hexyl including n-hexyl, 3,3-dimethylbutyl and isohexyl. Examples of
- alkyl-O- groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy.
- alkyl-S(O) m - are methylsulfanyl- (CH 3 -S-), methanesulfinyl- (CH 3 -S(O)-), methanesulfonyl (CH 3 -S(O) 2 -), ethylsulfanyl- (CH3-CH 2 -S-), ethanesulfinyl- (CH 3 -CH 2 -S(O)-), ethanesulfonyl (CH 3 -CH 2 -S(O) 2 -), 1 - methylethylsulfanyl- ((CH 3 ) 2 CH-S-), 1 -methylethanesulfinyl- ((CH 3 ) 2 CH-S(
- the number m is chosen from 0 and 2, wherein all numbers m are independent of each other and can be identical or different. In another embodiment the number m in any of its occurrences is, independent of its meaning in other occurrences, 0. In another embodiment the number m in any of its occurrences is, independent of its meaning in other occurrences, 2.
- a substituted alkyl group can be substituted in any positions, provided that the respective compound is sufficiently stable and is suitable as a pharmaceutical active compound.
- An alkyl group which is optionally substituted by one or more fluorine substituents can be unsubstituted, i.e.
- fluorine substituents not carry fluorine substituents, or substituted, for example by 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or 1 1 fluorine substituents, or by 1 , 2, 3, 4, 5, 6 or 7 fluorine substituents, or by 1 , 2, 3, 4 or 5 fluorine substituents, or by 1 , 2 or 3 fluorine substituents, which can be located in any positions.
- fluorine substituents for example, in a fluoro- substituted alkyl group one or more methyl groups can carry three fluorine
- substituents each and be present as trifluoromethyl groups, and/or one or more methylene groups (CH 2 ) can carry two fluorine substituents each and be present as difluoromethylene groups.
- the explanations with respect to the substitution of a group by fluorine also apply if the group additionally carries other substituents and/or is part of another group, for example of an alkyl-O- group.
- fluoro- substituted alkyl groups are trifluoromethyl, 2-fluoroethyl, 1 -fluoroethyl, 1 ,1 - difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3- pentafluoropropyl, 4,4,4-trifluorobutyl and heptafluoroisopropyl.
- fluoro- substituted alkyl-O- groups are trifluoromethoxy, 2,2,2-trifluoroethoxy,
- fluoro-substituted alkyl-S(O)m- groups are trifluoromethylsulfanyl- (CF 3 -S-), trifluoromethanesulfinyl- (CF 3 -S(O)-) and trifluoromethanesulfonyl (CF 3 -S(O) 2 -).
- alkenyl groups which in one embodiment of the invention contain one double bond
- alkynyl groups which in one embodiment of the invention contain one triple bond
- alkenyl groups and alkynyl groups can likewise be linear or branched, and substituted alkenyl and alkynyl groups can be substituted in any positions, provided that the resulting compound is sufficiently stable and is suitable as a pharmaceutical active compound.
- Double bonds and triple bonds can be present in any positions.
- the number of carbon atoms in an alkenyl or alkynyl group can be 2, 3, 4, 5 or 6, for example 2, 3, 4 or 5, or 2, 3 or 4.
- alkenyl and alkynyl examples include ethenyl (vinyl), prop-1 -enyl, prop-2-enyl (allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, 4-methylhex-4-enyl, ethynyl, prop-1 -ynyl, prop-2-ynyl (propargyl), but-2- ynyl, but-3-ynyl, 4-methylpent-2-ynyl, hex-4-ynyl and hex-5-ynyl.
- an alkenyl or alkynyl group contains at least three carbon atoms and is bonded to the remainder of the molecule via a carbon atom which is not part of a double bond or triple bond.
- alkyl groups (divalent alkyl groups), including chains of one or more groups C(R 26 )(R 26 ) and chains of one or more groups C(R 18 )(R 18 ) which groups as such and chains of such groups are alkanediyl groups in case R 26 and R 18 is chosen from hydrogen and (Ci-C 4 )-alkyl, or are substituted alkanediyl groups in case any of the groups R 26 and R 18 has a meaning different from hydrogen and (Ci-C 4 )-alkyl.
- alkyl part of a substituted alkyl group can also be regarded as an alkanediyl group.
- alkanediyl groups can also be linear or branched, the bonds to the adjacent groups can be located in any positions and can start from the same carbon atom or from different carbon atoms, and they can be substituted by fluorine substituents.
- alkanediyl groups are -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -,
- fluoro- substituted alkanediyl groups which can contain 1 , 2, 3, 4, 5 or 6 fluorine
- substituents or 1 , 2, 3 or 4 fluorine substituents, or 1 or 2 fluorine substituents for example, are -CHF-, -CF 2 -, -CF 2 -CH 2 -, -CH 2 -CF 2 -, -CF 2 -CF 2 -, -CF(CH 3 )-,
- the number of ring carbon atoms in a (C 3 -C 7 )-cycloalkyl group can be 3, 4, 5, 6 or 7.
- Examples of cycloalkyi are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- Cycloalkyi groups which are optionally substituted by one or more (Ci- C 4 )-alkyl substituents, can be unsubstituted, i.e.
- alkyl substituents not carry alkyl substituents, or substituted, for example by 1 , 2, 3 or 4, or by 1 or 2, identical or different (Ci-C 4 )-alkyl substituents, for example by methyl groups, which substituents can be located in any positions.
- alkyl-substituted cycloalkyi groups are 1 - methylcyclopropyl, 2,2-dimethylcyclopropyl, 1 -methylcyclopentyl, 2,3- dimethylcyclopentyl, 1 -methylcyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl, 4-tert-butylcyclohexyl and 3,3,5,5-tetramethylcyclohexyl.
- Cycloalkyi groups which are optionally substituted by one or more fluorine substituents can be unsubstituted, i.e. not carry fluorine substituents, or substituted, for example by 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or 1 1 fluorine substituents, or by 1 , 2, 3, 4, 5 or 6 fluorine substituents, or by 1 , 2, 3 or 4 fluorine substituents, or by 1 or 2 fluorine substituents.
- substituents can be located in any positions of the cycloalkyi group and can also be located in an alkyl substituent on the cycloalkyi group.
- fluoro-substituted cycloalkyl groups are 1 -fluorocyclopropyl, 2,2-difluorocyclopropyl, 3,3- difluorocyclobutyl, 1 -fluorocyclohexyl, 4,4-difluorocyclohexyl and 3,3,4,4,5,5- hexafluorocyclohexyl.
- Cycloalkyl groups can also be substituted simultaneously by fluorine and alkyl.
- Examples of the group (C3-C 7 )-cycloalkyl-(Ci-C )-alkyl- are cyclopropyl methyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, cycloheptylmethyl-, 1 -cyclopropylethyl-, 2-cyclopropylethyl-, 1 -cyclobutylethyl-, 2- cyclobutylethyl-, 1 -cyclopentylethyl-, 2-cyclopentylethyl-, 1 -cyclohexylethyl-, 2- cyclohexylethyl-, 1 -cycloheptylethyl-, 2-cycloheptylethyl-.
- cycloalkyl groups apply correspondingly to unsaturated cycloalkyl groups such as cycloalkenyl groups which can occur in the group R 24 and which in one embodiment of the invention contain one double bond which can be present in any positions, and to divalent cycloalkyl groups (cycloalkanediyl groups), which latter groups can occur in case two of the groups R 26 together with the comprised chain members form a ring or two of the groups R 18 together with the carbon atom carrying them form a ring.
- the cycloalkyl part of a substituted cycloalkyl group can also be regarded as a cycloalkanediyl group.
- bonds through which a cycloalkanediyl group, such as a ring formed by two of the groups R 26 together with the comprised chain members, is connected to the adjacent groups can be located in any positions and can start from the same ring carbon atom or from different ring carbon atoms, unless specified otherwise.
- substituted phenyl groups including phenyl groups which represent the 3- membered to 10-membered, monocyclic or bicyclic ring representing R 24
- the substituents can be located in any positions.
- the substituent can be located in the 2-position, the 3-position or the 4-position.
- the substituents can be located in 2, 3-position, 2,4- position, 2,5-position, 2,6-position, 3,4-position or 3,5-position.
- the substituents can be located in 2, 3,4-position, 2, 3,5-position, 2,3,6- position, 2,4,5-position, 2,4,6-position or 3,4,5-position.
- a phenyl group carries four substituents, some of which can be fluorine atoms, for example, the substituents can be located in 2, 3,4,5-position, 2,3,4,6-position or 2, 3,5, 6-position.
- a polysubstituted phenyl group or any other polysubstituted group such as a heteroaryl group carries different substituents, each substituent can be located in any suitable position, and the present invention comprises all positional isomers.
- the number of substituents in a substituted phenyl group can be 1 , 2, 3, 4 or 5.
- a substituted phenyl group, and likewise another substituted group such as a heteroaryl group carries 1 , 2 or 3, for example 1 or 2, identical or different
- heterocyclic groups including the group Het 1 and heterocyclic rings which can be present in structural elements in the compounds of the formula I, such as the ring A, or the 3-membered to 10-membered ring representing R 24 , or a ring formed by a group R 25 and a group R 26 together with the comprised chain members, or a ring formed by a group R 13 or R 14 with one of the groups R 21 and R 22 and the carbon atoms carrying these groups, for example, the hetero ring members specified in the respective definition can be present in any combination and located in any suitable ring positions, provided that the resulting group and the compound of the formula I are sufficiently stable and suitable as a pharmaceutical active compound.
- two oxygen atoms in any heterocyclic ring in the compounds of the formula I cannot be present in adjacent ring positions.
- heterocyclic ring in the compounds of the formula I cannot be present in adjacent ring positions.
- two hetero ring members from the series consisting of O, S and N atoms carrying a hydrogen atom or a substituent cannot be present in adjacent ring positions.
- Examples of such series are the hetero ring members O, S and N(R°), or O, S and N(R 32 ), or O, S and N(R 34 ), or O, S and N(R 60 ), or the hetero chain members O, S and N(R 17 ) which are part of a ring.
- two hetero ring members from the series consisting of S(O) and S(O)2 cannot be present in adjacent ring positions.
- an aromatic heterocyclic ring In an aromatic heterocyclic ring the choice of hetero ring members and their positions is limited by the prerequisite that the ring is aromatic, i.e. it comprises a cyclic system of six delocalized pi electrons.
- the ring nitrogen atom in such a heteroaryl group which carries the group R 32 is the ring nitrogen atom in a 5-membered ring such as pyrrole, pyrazole or imidazole to which an exocyclic atom or group such as a hydrogen atom is bonded, and can be present once only in a 5-membered aromatic ring just as the hetero ring members O and S.
- rings from which such a heteroaryl group can be derived are pyrrole, furan, thiophene, imidazole, pyrazole, oxazole ([1 ,3]oxazole), isoxazole ([1 ,2]oxazole), thiazole ([1 ,3]thiazole), isothiazole ([1 ,2]thiazole), pyridine, pyridazine, pyrimidine, pyrazine.
- a monocyclic, 5-membered or 6-membered heteroaryl group comprises one hetero ring member which is defined as indicated, and in another embodiment of the invention such a heteroaryl group is chosen from thiophenyl, thiazolyl and pyridinyl, in another embodiment from thiophenyl and pyrazolyl, in another embodiment from pyridinyl, thiophenyl and pyrazolyl, in another embodiment from thiophenyl and pyridinyl, and in another embodiment it is thiophenyl.
- a monocyclic, 5-membered or 6-membered heteroaryl group can be bonded via any ring carbon atom or, in the case of a 5-membered ring comprising a hetero ring member N(R 32 ), via a ring nitrogen atom, wherein in the latter case the bond via which the heteroaryl group is attached to the remainder of the molecule, replaces the group R 32 .
- a monocyclic, 5-membered or 6-membered heteroaryl group is bonded via a ring carbon atom.
- a thiophenyl group can be thiophen-2-yl (2-thienyl) or thiophen-3-yl (3-thienyl)
- furanyl can be furan-2-yl or furan-3-yl
- pyridinyl pyridyl
- pyrazolyl can be 1 H-pyrazol- 3-yl, 1 H-pyrazol-4-yl or 2H-pyrazol-3-yl
- imidazolyl can be 1 H-imidazol-1 -yl, 1 H- imidazol-2-yl, 1 H-imidazol-4-yl or 3H-imidazolyl-4-yl
- thiazolyl can be thiazol-2-yl, thiazol-4-yl or thiazol-5-yl.
- the substituents can be located in any positions, for example in a thiophen-2-yl group or a furan-2-yl group in the 3-position and/or in the 4-position and/or in the 5-position, in a thiophen-3-yl group or a furan-3-yl group in the 2-position and/or in the 4-position and/or in the 5-position, in a pyridin-2-yl group in the 3-position and/or in the 4- position and/or in the 5-position and/or in the 6-position, in a pyridin-3-yl group in the 2-position and/or in the 4-position and/or in the 5-position and/or in the 6-position, in a pyridin-4-yl group in the 2-position and/or in the 3-position and/or in the 5-position and/or in the 6-position.
- a substituted in a thiophen-2-yl group or a furan-2-yl group in the 3-position and/or in the 4-position and/or in the 5-
- monocyclic, 5-membered or 6-membered heteroaryl group is substituted by 1 , 2 or 3, for example 1 or 2, identical or different substituents.
- suitable ring nitrogen atoms in a monocyclic, 5-membered or 6-membered heteroaryl group representing R 24 or the aromatic ring comprising the groups Y and Z which are depicted in formula I for example the nitrogen atom in a pyridinyl group, can also carry an oxido substituent -O " and be present as an N-oxide.
- the rings of the groups Het 1 can be 4-membered, 5-membered, 6-membered or 7- membered, for example 4-membered, 5-membered or 6-membered, or 4-membered or 5-membered, or 5-membered or 6-membered.
- the group Het 1 can be bonded via any ring carbon atom or ring nitrogen atom. In one embodiment of the invention, Het 1 is bonded via a ring carbon atom.
- Het 1 from any one or more of which Het 1 can be chosen are azetidinyl including azetidin-1 -yl, oxetanyl including oxetan-3-yl, tetrahydrofuranyl including tetrahydrofuran-2-yl and tetrahydrofuran-3-yl, tetrahydrothiophenyl including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, 1 -oxo-tetrahydrothiophenyl including 1 -oxo-tetrahydrothiophen-2-yl and 1 -oxo- tetrahydrothiophen-3-yl, 1 ,1 -dioxo-tetrahydrothiophenyl including 1 ,1 -dioxo- tetrahydrothiophen-2-yl and 1 ,1 -dioxo-t
- tetrahydrothiopyranyl including tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl and tetrahydrothiopyran-4-yl
- piperidinyl including piperidin-1 -yl, piperidin-2-yl, piperidin-3- yl and piperidin-4-yl
- oxepanyl including oxepan-2-yl, oxepan-3-yl and oxepan-4-yl
- 1 ,3- dioxolanyl including 1 ,3-dioxolan-2-yl and 1 ,3-dioxolan-4-yl
- imidazolidinyl including imidazolidin-1 -yl, imidazolidin-2-
- [1 ,4]thiazepanyl Besides by oxo groups in the ring members S(O) and S(O)2 and alkyl groups representing R 60 , the group Het 1 is optionally substituted on ring carbon atoms by one or more, for example 1 , 2, 3, 4 or 5, or 1 , 2, 3 or 4, or 1 , 2 or 3, or 1 or 2, identical or different substituents as indicated, which can be located in any positions.
- the 3-membered to 10-membered, monocyclic or bicyclic ring which is saturated or unsaturated and which contains 0, 1 or 2 identical or different hetero ring members chosen from the series consisting of N, N(R 32 ), O, S, S(O) and S(O)2, which ring represents R 24 , can comprise 3, 4, 5, 6, 7, 8, 9 or 10 ring members.
- a bicyclic ring representing R 24 is fused or bridged.
- An unsaturated ring can be partially unsaturated, i.e. non-aromatic, and contain, for example, one or two double bonds within the ring, or it can be aromatic and be a ring such as a benzene ring, for example, and altogether the number of double bonds within an unsaturated ring can be one, two, three, four or five.
- the two individual rings can independently of each other be saturated or partially unsaturated or aromatic.
- a 3-membered or 4- membered ring representing R 24 is saturated.
- the 3-membered to 10-membered, monocyclic or bicyclic ring can be a carbocyclic ring, i.e. contain 0 (zero) hetero ring members, or a heterocyclic ring in which hetero ring members can be present as indicated above.
- a bicyclic heterocyclic ring one or both individual rings can contain hetero ring members.
- nitrogen atoms are present as hetero ring members in a bicyclic ring, they can also be present at a fusion position or a bridgehead position.
- the free bond via which the ring is bonded to the group R 23 can be located at any suitable ring carbon atom or ring nitrogen atom. In one embodiment of the invention the free bond is located at a ring carbon atom.
- the 3-membered to 10 membered ring is optionally substituted on ring carbon atoms by one or more, for example 1 , 2, 3, 4 or 5, or 1 , 2, 3 or 4, or 1 , 2 or 3, or 1 or 2, identical or different substituents as indicated, which can be located in any positions.
- the 3-membered to 10-membered, monocyclic or bicyclic ring representing R 24 comprises (C 3 -C 7 )-cycloalkyl groups, phenyl groups, monocyclic, 5-membered or 6- membered aromatic heterocyclic groups and monocyclic 4-membered to 7- membered saturated groups as are comprised by the definitions of the group Het 1 referred to above. All these groups thus are examples of the said 3-membered to 10- membered ring, and all explanations given above with respect to these groups apply correspondingly to the said 3-membered to 10-membered ring unless specified otherwise in the definition of the said 3-membered to 10-membered ring.
- the substituents in these groups when representing the said 3-membered to 10-membered ring can then be as is specified in the definition of R 24 .
- cyclic groups which are comprised by the said 3-membered to 10- membered ring (C 5 -C 7 )-cycloalkenyl groups, naphthalenyl groups and hydrogenated naphthalenyl groups, indenyl groups and hydrogenated indenyl groups, bicyclic heterocyclic groups, and bicycloalkyl and bicycloalkenyl groups and hetero analogs thereof may be mentioned.
- a (C 5 -C 7 )-cycloalkenyl group representing R 24 the number of ring carbon atoms can be 5, 6 or 7.
- cycloalkenyl groups are cyclopentenyl including cyclopent-1 -enyl, cyclopent-2-enyl and cyclopent-3-enyl, cyclohexyl including cyclohex-1 -enyl, cyclohex-2-enyl and cyclohex-3-enyl, and cycloheptyl including cyclohept-1 -enyl, cyclohept-2-enyl, cyclohept-3-enyl and cyclohept-4-enyl.
- Cycloalkenyl groups representing R 24 can be unsubstituted or substituted as indicated with respect to the 3-membered to 10-membered ring representing R 24 , for example by one or more, or 1 , 2, 3 or 4, or 1 , 2 or 3, identical or different (Ci-C )-alkyl substituents, for example by methyl groups, which can be located in any positions.
- alkyl-substituted cycloalkenyl groups are 1 -methylcyclopent-2-enyl, 1 -methylcyclopent-3-enyl, 2,3-dimethylcyclohex-2-enyl and 3,4-dimethylcyclohex-3- enyl.
- Cycloalkenyl groups also are optionally substituted by one or more fluorine substituents, i.e., they can be unsubstituted by fluorine and not carry any fluorine substituents, or substituted, for example by 1 , 2, 3, 4, 5, 6 or 7, or by 1 , 2, 3, 4 or 5, or by 1 , 2, 3 or 4, fluorine substituents. Cycloalkenyl groups can also be substituted simultaneously by fluorine and alkyl. The fluorine atoms can be located in any positions of the cycloalkenyl group and can also be located in an alkyl substituent on the cycloalkenyl group.
- fluoro-substituted cycloalkyl groups are 1 - fluorocyclohex-2-enyl, 1 -fluorocyclohex-3-enyl and 4,4-difluorocyclohex-2-enyl.
- Naphthalenyl groups (naphthyl groups) representing R 24 can be naphthalen-1 -yl (1 - naphthyl) and naphthalen-2-yl (2-naphthyl) groups, and are optionally substituted by one or more, for example by 1 , 2, 3, 4 or 5, or by 1 , 2 or 3, for example by 1 or 2, identical or different substituents as indicated above.
- substituted naphthalenyl group can be located in any positions, for example in the 2- position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position in the case of a monosubstituted naphthalen-1 -yl group and in the 1 -position, 3-position, 4- position, 5-position, 6-position, 7-position or 8-position in the case of a
- naphthalen-2-yl group which carries two or more substituents
- the substituents can be located in the ring to which the remainder of the molecule is bonded, and/or in the other ring.
- Examples of hydrogenated naphthalenyl groups representing R 24 are dihydronaphthalenyl including 1 ,4-dihydronaphthalenyl, tetrahydronaphthalenyl including 1 ,2,3,4- tetrahydronaphthalenyl and 5,6,7,8-tetrahydronaphthalenyl, octahydronaphthalenyl including 1 ,2,3,4, 5,6, 7, 8-octahydronaphthalenyl, and decahydronaphthalenyl.
- Hydrogenated naphthalenyl groups can be bonded to the remainder of the molecule via any ring carbon atom in a saturated or partially unsaturated or aromatic ring and are optionally substituted by one or more, for example by 1 , 2, 3, 4 or 5, or by 1 , 2 or 3, for example by 1 or 2, identical or different substituents as indicated above which can be located in any positions.
- Indenyl groups representing R 24 can be 1 H-inden-1 -yl, 1 H-inden-2-yl, 1 H-inden-3-yl, 1 H-inden-4-yl, 1 H-inden-5-yl, 1 H-inden-6-yl or 1 H-inden-7-yl, for example, and are optionally substituted by one or more, for example by 1 , 2, 3, 4 or 5, or by 1 , 2 or 3, for example by 1 or 2, identical or different substituents as indicated above which can be located in any positions.
- bicyclic heterocyclic groups representing R 24 are fused bicyclic groups in which the two rings have a bond in common, and can be saturated, partially unsaturated or aromatic as indicated above with respect to the 3- membered to 10-membered ring representing R in general. They can contain 1 , 2, 3, 4 or 5 double bonds within the rings. Both of the rings can be saturated, or one of the rings can be saturated or partially unsaturated and the other ring partially unsaturated or aromatic, or both rings can be aromatic, i.e. comprise a cyclic system of six delocalized pi electrons.
- both rings are aromatic or one of the rings is aromatic and the other ring is partially unsaturated and comprises at least one double bond due to the condensation to the aromatic ring.
- a bicyclic heterocyclic group comprises 8, 9 or 10 ring members and two fused 5-membered rings or two fused 6-membered rings or a 6-membered ring fused to a 5-membered ring or a 7-membered ring fused to a 5- membered ring, in another embodiment 9 or 10 ring members and two fused 6- membered rings or a 6-membered ring fused to a 5-membered ring.
- Hetero ring members can be present in both rings of a bicyclic heterocyclic group or in one of the rings only and the other ring contain no hetero ring members. Ring nitrogen atoms can also be common to both rings. Besides being a hetero ring member in a 3- membered to 10-membered rings representing R 24 such as saturated rings, a ring nitrogen atom carrying a group R 32 can be the ring nitrogen atom in a fused 5- membered ring in an aromatic bicyclic heterocyclic group, such as in a fused pyrrole, pyrazole or imidazole, to which an exocyclic atom or group is bonded.
- rings from which a fused bicyclic heterocyclic group can be derived are indole, isoindole, benzo[b]thiophene, benzofuran, benzo[1 ,3]dioxole ([1 ,3]benzodioxole, 1 ,2- methylenedioxybenzene), benzo[1 ,3]oxazole, benzo[1 ,3]thiazole, benzoimidazole, chromane, isochromane, benzo[1 ,4]dioxane ([1 ,4]benzodioxane, 1 ,2- ethylenedioxybenzene), quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, pyrroloazepines, imidazoazepines, thienothiophenes, thienopyrroles, thienopyridines, nap
- a bicyclic heterocyclic group can be bonded via any ring carbon atom or ring nitrogen atom. In one embodiment of the invention, a bicyclic heteroaromatic group is bonded via a ring carbon atom.
- an indolyl group can be indol- 1 -yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6- or indol-7-yl, a
- benzoimidazolyl group can be 1 H-benzoimidazol-1 -yl, 1 H-benzoimidazol-2-yl, 1 H- benzoimidazol-4-yl, 1 H-benzoimidazol-5-yl, 1 H-benzoimidazol-6-yl or 1 H- benzoimidazol-7-yl, a benzo[1 ,4]dioxanyl group can be benzo[1 ,4]dioxan-2-yl, benzo[1 ,4]dioxan-5-yl or benzo[1 ,4]dioxan-6-yl, a quinolinyl group (quinolyl group) can be quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7- yl or quinolin-8-yl, an isoquinolinyl group can be iso
- the substituents can be located in any desired positions such as, for example, in an indol-2-yl group in the 1 -position and/or the 3-position and/or the 4-position and/or the 5-position and/or the 6-position and/or the 7-position, in an indol-5-yl group in the 1 -position and/or the 2-position and/or the 3-position and/or the 4-position and/or the 6-position and/or the 7-position, in a 1 H- benzoimidazol-2-yl group in the 1 -position and/or the 4-position and/or the 5-position and/or the 6-position and/or the 7-position.
- a bicyclic heterocyclic group can also carry on suitable ring nitrogen atoms in aromatic rings, for example the nitrogen atom in a quinolinyl group or isoquinolinyl group, an oxido substituent -O " and be present as an N-oxide.
- bicycloalkyl and bicycloalkenyl groups are provided.
- R 24 are bridged 6-membered to 10-membered, in another embodiment 7-membered to 10-membered and bicyclic groups which can contain carbon atoms only as ring members, i.e. they can be derived from carbocyclic bicycloalkanes and bicycloalkenes, or which can also contain hetero ring members as indicated above, i.e. they can be derived from the respective heteroanalogous aza-, oxa- and thia- bicycloalkanes and -bicycloalkenes. If they contain hetero ring members, in one embodiment they contain one hetero ring member, for example one ring member chosen from the series consisting of N, N(R 32 ) and O.
- the hetero ring members can be present in any desired positions in the bicyclic system including positions in the bridges and, in the case of nitrogen atoms, positions at the bridgeheads.
- Bicycloalkenyl and their hetero analogs can contain one or more double bonds within the rings. In one embodiment of the invention they contain one or two double bonds, in another embodiment one double bond, within the ring.
- bicycloalkenyl can be bonded to the remainder of the molecule via any ring carbon atom or ring nitrogen atom.
- the free bond can be located in any stereochemical position, for example in an exo position or an endo position.
- Bicycloalkyl and bicycloalkenyl and their hetero analogs are optionally substituted as indicated above, for example by substituents chosen from the series consisting of (Ci-C )-alkyl, (C 2 - C 5 )-alkenyl, HO-, HO-CH 2 - (hydroxymethyl-) and oxo, in any positions.
- bicycloalkyl and bicycloalkenyl groups and hetero analogs thereof are norbornyl (bicyclo[2.2.1 ]heptyl), bicyclo[3.1 .1 ]heptyl, bicyclo[3.1 .1 ]hept-2-enyl,
- Halogen is fluorine, chlorine, bromine or iodine. In one embodiment of the invention, halogen is fluorine, chlorine or bromine, in another embodiment fluorine or chlorine, in another embodiment fluorine.
- An oxo group cannot occur as a substituent on a carbon atom in an aromatic ring such as in a phenyl group.
- the present invention comprises all stereoisomeric forms of the compounds of the formula I, for example all enantiomers and diastereomers including cis/trans isomers.
- the invention likewise comprises mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers including cis/trans isomers, in all ratios.
- Asymmetric centers contained in the compounds of the formula I, for example in unsubstituted or substituted alkyl groups, can all independently of each other have the S configuration or the R configuration.
- the invention relates to enantiomers, both the levorotatory and the dextrorotatory antipode, in
- the invention likewise relates to diastereomers in the form of pure and essentially pure diastereomers and in the form of mixtures of two or more diastereomers in all ratios.
- the invention also comprises all cis/trans isomers of the compounds of the formula I in pure form and essentially pure form, for example with a molar ratio of the cis/trans isomers of 99 :1 or greater, and in the form of mixtures of the cis isomer and the trans isomer in all ratios.
- Cis/trans isomerism can occur in substituted rings, such as the ring A, and on double bonds, for example.
- the preparation of individual stereoisomers, if desired, can be carried out by resolution of a mixture according to customary methods, for example, by chromatography or crystallization, or by use of stereochemical ly uniform starting compounds in the synthesis or by stereoselective reactions.
- a derivatization can be carried out before a separation of stereoisomers.
- the separation of a mixture of stereoisomers can be carried out at the stage of the compound of the formula I or at the stage of an intermediate in the course of the synthesis.
- the invention also comprises all tautomeric forms of the compounds of the formula I.
- Physiologically acceptable salts, including pharmaceutically utilizable salts, of the compounds of the formula I generally comprise a nontoxic salt component. They can contain inorganic or organic salt components. Such salts can be formed, for example, from compounds of the formula I which contain an acidic group, for example a carboxylic acid group (hydroxycarbonyl group, HO-C(O)-), and nontoxic inorganic or organic bases.
- Suitable bases are, for example, alkali metal compounds or alkaline earth metal compounds, such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate, or ammonia, organic amino compounds and quaternary ammonium hydroxides.
- Reactions of compounds of the formula I with bases for the preparation of the salts are in general carried out according to customary procedures in a solvent or diluent.
- Examples of salts of acidic groups thus are sodium, potassium, magnesium or calcium salts or ammonium salts which can also carry one or more organic groups on the nitrogen atom.
- Compounds of the formula I which contain a basic, i.e.
- protonatable, group for example an amino group or a basic heterocycle
- physiologically acceptable acids for example as salt with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, which in general can be prepared from the compounds of the formula I by reaction with an acid in a solvent or diluent according to customary procedures.
- the compounds of the formula I simultaneously contain an acidic and a basic group in the molecule, the invention also includes internal salts (betaines, zwitterions) in addition to the salt forms mentioned.
- the present invention also comprises all salts of the compounds of the formula I which, because of low physiological tolerability, are not directly suitable for use as a pharmaceutical, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange.
- the present invention also comprises active metabolites of compounds of the formula I and prodrugs of the compounds of the formula I, i.e. compounds which in vitro may not necessarily exhibit pharmacological activity but which in vivo are converted into pharmacologically active compounds of the formula I, for example compounds which are converted by metabolic hydrolysis into a compound of the formula I, such as compounds in which a carboxylic acid group is present in esterified form or in the form of an amide.
- the ring A can be monocyclic, i.e. comprise one ring only, or bicyclic, i.e. comprise two rings which have two or more ring members and one or more bonds in common and can thus be bridged or fused, or spirocyclic, i.e. comprise two rings which have one ring member in common.
- the number of ring members in the ring A can be 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12.
- the ring A is 3- membered to 1 1 -membered, in another embodiment 3-membered to 10-membered, in another embodiment 3-membered to 8-membered, in another embodiment 3- membered to 7-membered, in another embodiment 5-membered to 10-membered, in another embodiment 5-membered to 8-membered, in another embodiment 5- membered to 7-membered, in another embodiment 6-membered to 8-membered, in another embodiment 6-membered or 7-membered.
- a monocyclic ring representing A is 3-membered to 8-membered, in another embodiment 3-membered to 7-membered, in another embodiment 5- membered to 8-membered, in another embodiment 5-membered to 7-membered, in another embodiment 6-membered to 8-membered, in another embodiment 6- membered or 7-membered, in another embodiment 3-membered, 6-membered or 7- membered.
- a bicydic ring representing A is 6- membered to 12-membered, in another embodiment 7-membered to 12-membered, in another embodiment 6-membered to 10-membered, in another embodiment 7- membered to 10-membered, in another embodiment 6-membered to 8-membered, in another embodiment 7-membered or 8-membered.
- a spirocyclic ring representing A is 7-membered to 12-membered, in another embodiment 8-membered to 12-membered, in another embodiment 7- membered to 1 1 -membered, in another embodiment 8-membered to 1 1 -membered.
- the number of ring members in the ring A have all those values from the general number of ring members, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 1 1 and 12, which are comprised by the respective embodiment.
- the ring A is a spiro-fused ring, in one embodiment of the invention comprises the ring which does not carry the groups N(R 20 ) and C(O)-R 50 , 3, 4, 5 or 6 ring members including the spiro atom, in another embodiment 3, 4 or 5 ring members including the spiro atom.
- the ring A is a monocyclic or bicydic ring, in another embodiment a monocyclic or spirocyclic ring, in another embodiment it is a monocyclic ring, in another embodiment it is a bicydic ring, in another embodiment it is a spirocyclic ring, wherein in all these embodiments the rings are as indicated above or below herein.
- the carbon atom in the ring A which carries the two groups N(R ) and C(O)-R can be present in any ring position which allows for the binding of two groups.
- the hetero ring members in the ring A can be present in any combination and can be located in any suitable position, wherein generally the two ring members in the ring A which are adjacent to the ring carbon atom carrying the groups N(R 20 ) and C(O)-R 50 are carbon atoms, as is also depicted in formula I by the two vertices (corners) in the
- circumferential line of ring A which, like the vertex in the circumferential line representing the carbon atom which carries the two groups N(R 20 ) and C(O)-R 50 , represent carbon atoms as usual in such structural formulae.
- the hetero ring members can be present in the bridges and, in the case of nitrogen atoms, at the bridgeheads.
- heterocyclic rings in the compounds of the formula I in one embodiment of the invention two hetero ring members from the series consisting of N(R°), O and S are not present in adjacent ring positions, in another embodiment two hetero ring members from the series consisting of N(R°), O and S are separated by at least two ring carbon atoms, in another embodiment two hetero ring members are not present in adjacent ring positions, in another embodiment two hetero ring members are separated by at least two ring carbon atoms.
- the number of hetero ring members in the ring A is 0 or 1 , in another embodiment it is 1 , and in another embodiment it is 0, i.e. in this latter embodiment the ring A is a carbocyclic ring.
- the hetero ring members in a heterocyclic ring representing A are chosen from O, S, S(O) and S(O)2, in another embodiment from S, S(O) and S(O)2, in another embodiment from S(O) and S(O)2, in another embodiment from O and S, in another embodiment from O and N(R°), in another embodiment they are O atoms, in another embodiment they are S atoms, in another embodiment they are N(R°) groups.
- the double bond which can be present in the ring A can be located in any suitable position.
- the ring A is a 3-membered to 12-membered ring in case it is saturated, and a 5-membered to 12-membered ring in case it comprises a double bond, wherein in these embodiments all other features of the rings are as indicated above or below.
- the ring A is saturated and thus does not comprise a double bond in the ring, in another embodiment the ring A comprises one double bond.
- rings A from any one or more of which the ring A is chosen in one embodiment of the invention are (C3-C8)-cycloalkane rings, (Cs-CsJ-cycloalkane rings, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, (Cs-CsJ-cycloalkene rings, cyclopent-3-ene wherein the carbon atom carrying the two groups N(R 20 ) and C(O)-R 50 is in position 1 , cyclohex- 3-ene wherein the carbon atom carrying the two groups N(R 20 ) and C(O)-R 50 is in position 1 , cyclohept-3-ene wherein the carbon atom carrying the two groups N(R 20 ) and C(O)-R 50 is in position 1 , cyclohept-4-ene wherein the carbon atom carrying the carbon
- bicyclo[3.2.1 ]octane with binding position 3 bicyclo[5.1 .0]octane with binding position
- the number of the substituents which are optionally present on the ring A depends on the size and the kind of the ring A and the number of hetero ring members. In one embodiment of the invention the number of optional substituents on ring carbon atoms in ring A is 1 , 2, 3 4 or 5, in another embodiment 1 , 2, 3 or 4, in another embodiment 1 , 2 or 3, in another embodiment 1 or 2, in another embodiment 1 . In all positions on ring carbon atoms in ring A which do not carry a substituent, hydrogen atoms are present. Substituents on the ring A can be present in any suitable position.
- ring A is a 4-membered to 12-membered ring
- substituents are optionally present only on ring carbon atoms which are not adjacent to the carbon atom carrying the group N(R 20 ) and C(O)-R 50 , but not in the positions adjacent to the said carbon atom.
- the substituents which are optionally present on carbon atoms in the ring A are chosen from the series consisting of halogen, R 1 , R 2 , (C 2 -C 6 )-alkenyl, HO-, R 1 -O-, phenyl- (Ci-C 4 )-alkyl-O-, R 1 -C(O)-O-, R 1 -S(O) 2 -O-, H 2 N-, R 1 -NH-, R 1 -N(R 1 )-, R 1 -C(O)-NH-, R 1 -C(O)-N(R 1 )-, R 1 -S(O) 2 -NH-, R 1 -S(O) 2 -N(R 1 )-, R 1 -C(O)-, HO-C(O)-, R 1 -O-C(O)-, H 2 N-C(O)-, R 1 -NH-C(
- an individual carbon atom in the ring A does not carry more than one substituent chosen from the series consisting of HO-, R 1 -O-, phenyl-(Ci-C 4 )-alkyl-O-, R 1 -C(O)-O-, R 1 -S(O) 2 -O-, R 1 -S(O) m -, H 2 N-, R 1 -NH-, R 1 -N(R 1 )-, R 1 -C(O)-NH-, R 1 -C(O)-N(R 1 )-, R 1 -S(O) 2 -NH-, R 1 -S(O) 2 -N(R 1 )-, H 2 N-S(O) 2 -, R 1 -NH-S(O) 2 -, R 1 -N(R 1 )-S(O) 2 - and F 5 S-.
- the number of F 5 S- substituents on the ring A is not greater than one. In one embodiment of the invention, the number of oxo substituents on the ring A is not greater than two, and in another embodiment it is not greater than one. In one embodiment of the invention, the number of methylene substituents on the ring A is not greater than two, and in another embodiment it is not greater than one. In one embodiment of the invention, halogen substituents on the ring A are fluorine substituents.
- the compounds of the formula I can also be represented by the formulae la and lb, respectively,
- R 7 is defined as the substituents which are optionally present in the ring A in the compounds of the formula I, i.e. R 7 is chosen from the series consisting of halogen, R 1 , R 2 , (C 2 -C 6 )-alkenyl, HO-, R 1 -O-, phenyl-(Ci-C 4 )-alkyl-O-, R 1 -C(O)-O-, R 1 -S(O) 2 - O-, R 1 -S(O) m -, H 2 N-, R 1 -NH-, R 1 -N(R 1 )-, R 1 -C(O)-NH-, R 1 -C(O)-N(R 1 )-, R 1 -S(O) 2 -NH-, R 1 -S(O) 2 -N(R 1 )-, R 1 -S(O) 2 -NH-, R 1 -S(O) 2 -N(R
- the number r in the compounds of the formulae la and lb is 0, 1 , 2, 3, 4 or 5, in another embodiment 0, 1 , 2, 3 or 4, in another embodiment 0, 1 , 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1 , in another embodiment the number r is 1 , and in another embodiment the number r is 0, i.e. in this latter embodiment the cyclohexane ring or cycloheptane ring depicted in formulae and lb does not carry a substituent R 7 but only hydrogen atoms.
- the substituents R 7 can be present on any of the carbon atoms of the cyclohexane and cycloheptane ring depicted in formulae la and lb.
- the trivalent group Z is C(R 16 ). In another embodiment Z is C(R 16 ) and Y is chosen from the series consisting of S,
- R 12 , R 13 , R 15 , R 16 , R 20 to R 22 and R 50 are defined as in the compounds of the formula I or have any of their other indicated meanings.
- the group Z is C(R 16 ) and the group Y is S.
- compounds of this embodiment are compounds of the formula Ig
- R 12 , R 13 , R 15 , R 16 , R 20 to R 22 and R 50 in these compounds are defined as in the compounds of the formula I or have any of their other indicated meanings
- R 7 and r are defined as in the compounds of the formulae la and lb and, like in the compounds of the formulae la and lb, the substituents R 7 can be present on any of the carbon atoms of the cyclohexane and cycloheptane rings depicted in formulae le, If, Ig and Ih. All explanations on groups and all definitions and embodiments specified above or below with respect to the compounds of the formula I apply correspondingly to the compounds of all formulae which represent subgroups of the compounds of the formula I, including the compounds of the formulae la to Ih.
- R° is chosen from the series consisting of hydrogen and (Ci-C )-alkyl, in another embodiment from the series consisting of hydrogen and methyl. In one embodiment of the invention, R° is hydrogen. In another embodiment of the invention R° is (Ci-C 4 )-alkyl, for example methyl.
- R 1 is chosen from the series consisting of (Ci C6)-alkyl, (C3-C7)-cycloalkyl and (C3-C7)-cycloalkyl-(Ci-C2)-alkyl-, in another embodiment from the series consisting of (CrC6)-alkyl, (C3-C6)-cycloalkyl and (C3- C6)-cycloalkyl-(Ci-C2)-alkyl-, in another embodiment from the series consisting of (Ci- C6)-alkyl, (C3-C6)-cycloalkyl and (C3-C6)-cycloalkyl-CH 2 -, in another embodiment from the series consisting of (Ci-C 6 )-alkyl, (C 3 -C 4 )-cycloalkyl and (C 3 -C 4 )-cycloalkyl-CH 2 -, in another embodiment from the series consisting of (CrC 6 )-alkyl and (C
- the (Ci-C 4 )-alkyl group representing R 2 is a (Ci- Cs)-alkyl group, in another embodiment a (Ci-C2)-alkyl group, in another embodiment a methyl group.
- the number of substituents HO- and (Ci-C 4 )alkyl-O- in R 2 is 1 , 2 or 3, in another embodiment 1 or 2, in another embodiment 1 .
- an individual carbon atom in R 2 does not carry more than one substituent chosen from the series consisting of HO- and (CrC )alkyl-O-.
- R 2 from any one or more of which R 2 is chosen in one embodiment of the invention, are hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1 ,2-dihydroxyethyl, methoxymethyl, propoxymethyl, 2-methoxyethyl or 3-methoxypropyl.
- R 1 1 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 are, independently of each other group R 1 1 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 , chosen from the series consisting of (Ci-C6)-alkyl, (C2-C 4 )-alkenyl, (C2-C 4 )-alkynyl, (C3-C7)- cycloalkyl and (C3-C 7 )-cycloalkyl-(Ci-C 2 )-alkyl-, in another embodiment from the series consisting of (Ci-C 4 )-alkyl, (C2-C 4 )-alkenyl, (C2-C 4 )-alkynyl, (C3-C 7 )-cycloalkyl and (C3-C 7 )-cycloalkyl-(Ci-C2)-al
- R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 are, independently of each other group R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 , chosen from the series consisting of (Ci-C 6 )-alkyl, in another embodiment from the series consisting of (Ci-C 4 )-alkyl, which are all optionally substituted by one or more identical or different substituents R 70 .
- (C 3 -C 7 )-cycloalkyl groups occurring in R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 are, independently of each other group R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 , (C3-C6)-cycloalkyl, in another embodiment (C3-C 4 )-cycloalkyl, for example cyclopropyl, in another embodiment (C5-C6)-cycloalkyl, for example cyclohexyl.
- the number of substituents R 70 in any of the groups R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 is, independently of each other group R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 , 0, 1 , 2, 3 or 4, in another embodiment 0, 1 , 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1.
- R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 is, independently of each other group R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 , 0, 1 , 2, 3 or 4, in another embodiment 0, 1 , 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1.
- any of the groups R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 does not carry a substituent R 70 , but merely is optionally substituted by one or more fluorine substituents and, in the case of cycloalkyi groups, one or more (Ci-C 4 )-alkyl substituents.
- any of the groups R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 does neither carry a substituent R 70 nor fluorine substituents nor, in the case of cycloalkyi groups, (Ci-C 4 )-alkyl substituents.
- R 11 , R 30 , R , R , R , R , Fc r and R which examplarily carry a hydroxy or alkyl-O- group as a substituent R 70 , from any one or more of which examples any of the groups R 11 , R 30 , R 33 , R 35 , R 54 , R 55 , R 57 and R 58 is chosen in one embodiment of the invention, HO-(Ci-C 4 )-alkyl-, HO-(C 2 -C 3 )-alkyl-, HO-CH 2 -CH 2 -, CH 3 -CH(OH)-, HO-CH 2 -, (C r C 4 )-alkyl-O-(CrC 4 )-alkyl-, (Ci-C 3 )-alkyl-O-(Ci-C 3 )-alkyl-, (C r C 2 )-alkyl-O-(C 2 -C 3 )--
- R 10 is chosen from the series consisting of hydrogen and methyl. In another embodiment R 10 is hydrogen. In another
- R 10 is (Ci-C 4 )-alkyl, for example methyl.
- R 13 or R 14 together with the one of the groups R 21 and R 22 which is not the group of the formula II, forms a chain consisting of 3 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the series consisting of N(R 17 ), O and S, but two hetero chain members cannot be present in adjacent positions, and the other chain members are identical or different groups C(R 18 )(R 18 ), the group R 22 is the group of the formula II and the group R 21 forms a chain together with R 13 or R 14 .
- the formed chain, together with the carbon atom carrying R 21 and the carbon atom carrying R 13 or R 14 forms a 5-membered to 7- membered ring, which is fused to the aromatic ring comprising the groups Y and Z depicted in formula I and which has the bond between the group Y and the carbon atom carrying R 21 in common with the said ring comprising Y and Z.
- the said chain consists of 3 to 4 chain members and the formed ring thus is 5-membered to 6-membered, and in another embodiment the said chain consists of 3 chain members and the formed ring thus is 5-membered.
- the hetero chain members can be present in any position in the said chain, provided that two hetero chain members cannot be present in adjacent positions.
- hetero chain members in the said chain are chosen from N(R 17 ) and O, in another embodiment from O and S, and in another embodiment they are O (oxygen atoms).
- chains formed by R 13 or R 14 together with the one of the groups R 21 and R 22 which is not the group of the formula II, from any one or more of which the said chain is chosen in one embodiment of the invention are -CH2-CH2-CH2-,
- R 12 , R 13 , R 14 , R 15 and R 16 are independently of each other chosen from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl, HO-(Ci-C 4 )-alkyl-, (C C 4 )-alkyl-O-, H 2 N-, (C C 4 )-alkyl-NH-, (C C 4 )-alkyl-N((Ci-C 4 )- alkyl)- and NC-, in another embodiment from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl, (Ci-C 4 )-alkyl-O-, H 2 N-, (Ci-C 4 )-alkyl-NH-, (Ci-C 4 )-alkyl-N((C r C 4 )-
- R 12 and R 13 are independently of each other chosen from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl and (Ci-C )-alkyl-O-, in another embodiment from the series consisting of hydrogen, halogen and (Ci-C 4 )-alkyl-O-, in another embodiment from the series consisting of hydrogen and halogen, in another embodiment from the series consisting of hydrogen, chlorine and fluorine, in another embodiment from the series consisting of hydrogen and fluorine, or in all these embodiments R 13 , together with the one of the groups R 21 and R 22 which is not the group of the formula II, forms a chain consisting of 3 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the series consisting of N(R 17 ), O and S, but two hetero chain members cannot be present in adjacent positions, and the other chain members are identical or different groups C(R 18 )(R 18 ).
- R 12 and R 13 are independently of each other chosen from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl and (Ci-C 4 )-alkyl-O-, in another embodiment from the series consisting of hydrogen, halogen and (CrC )-alkyl-O-, in another embodiment from the series consisting of hydrogen and halogen, in another embodiment from the series consisting of hydrogen, chlorine and fluorine, in another embodiment from the series consisting of hydrogen and fluorine.
- R 12 is chosen from the series consisting of hydrogen, halogen, (Ci- C 4 )-alkyl and (Ci-C 4 )-alkyl-O-, in another embodiment from the series consisting of hydrogen, halogen and (CrC )-alkyl-O-, in another embodiment from the series consisting of hydrogen and halogen, in another embodiment from the series consisting of hydrogen, chlorine and fluorine, in another embodiment from the series consisting of hydrogen and fluorine, and R 13 , together with the one of the groups R 21 and R 22 which is not the group of the formula II, forms a chain consisting of 3 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the series consisting of N(R 17 ), O and S, but two hetero chain members cannot be present in adjacent positions, and the other chain members are identical or different groups C(R 18 )(R 18 ).
- R 12 is hydrogen and R 13 is fluorine, or R 12 is fluorine and R 13 is hydrogen. In another embodiment R 12 and R 13 are hydrogen.
- R 14 and R 15 are independently of each other chosen from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl and (Ci-C 4 )-alkyl-O-, in another embodiment from the series consisting of hydrogen, halogen and (CrC )-alkyl, in another embodiment from the series consisting of hydrogen and halogen, in another embodiment from the series consisting of hydrogen, chlorine and fluorine. In another embodiment of the invention, R 14 and R 15 are hydrogen.
- R 16 is chosen from the series consisting of hydrogen, halogen, (Ci-C )- alkyl and (Ci-C 4 )-alkyl-O-, in another embodiment from the series consisting of hydrogen, halogen and (Ci-C 4 )-alkyl, in another embodiment from the series consisting of hydrogen and halogen, in another embodiment from the series consisting of hydrogen, chlorine and fluorine. In another embodiment of the invention, R 16 is hydrogen.
- R 17 and R 25 are independently of each other chosen from the series consisting of hydrogen and methyl, in another embodiment they are hydrogen. In another embodiment of the invention, R 17 and R 25 are independently of each other chosen from the series consisting of (Ci-C 4 )-alkyl, and in another embodiment they are methyl.
- the formed cycloalkane ring is spiro-fused to the ring which is optionally formed by R 13 or R 14 together with the one of the groups R 21 and R 22 which is not the group of the formula II, and the carbon atom carrying R 21 and the carbon atom carrying R 13 or R 14 .
- the cycloalkane ring formed by two of the groups R 18 is 3-membered to 5-membered, in another embodiment it is 3-membered or 4- membered, in another embodiment it is 3-membered, i.e.
- R 18 independently of each other group R 18 , is chosen from the series consisting of hydrogen, fluorine and (Ci-C2)-alkyl, in another embodiment from the series consisting of hydrogen, fluorine and methyl, in another embodiment from the series consisting of hydrogen and fluorine, and in another embodiment the groups R 18 are hydrogen, or in all these embodiments two of the groups R 18 bonded to the same carbon atom, together with the carbon atom carrying them, form a 3-membered to 6-membered cycloalkane ring which is optionally substituted as indicated.
- R 18 independently of each other group R 18 , is chosen from the series consisting of hydrogen, fluorine and (Ci-C 2 )-alkyl, in another embodiment from the series consisting of hydrogen, fluorine and methyl, in another embodiment from the series consisting of hydrogen and fluorine, and in another embodiment the groups R 18 are hydrogen.
- not more than one cycloalkane ring which is formed by two of the groups R 18 bonded to the same carbon atom together with the carbon atom carrying them, is present in the compounds of the formula I.
- the number of substituents chosen from the series consisting of fluorine and (Ci-C 4 )-alkyl, which are optionally present on a cycloalkane ring formed by two of the groups R 18 bonded to the same carbon atom together with the carbon atom carrying them is 1 , 2, 3 or 4, in another embodiment it is 1 , 2 or 3, in another embodiment it is 1 or 2, and in another embodiment such a cycloalkane ring does not carry any substituents, i.e. in this latter embodiment it is unsubstituted.
- the substituents which are optionally present on a cycloalkane ring formed by two of the groups R 18 bonded to the same carbon atom together with the carbon atom carrying them are chosen from fluorine and methyl, and in another embodiment they are fluorine substituents.
- R 20 is chosen from the series consisting of hydrogen and methyl. In another embodiment R 20 is hydrogen. In another
- R 20 is (CrC )-alkyl, for example methyl.
- the group R 21 is the one of the groups R 21 and R 22 which is a group of the formula II, i.e. a group of the formula R 24 -R 23 - which is bonded to the remainder of the molecule through the moiety R 23 as is symbolized with respect to this group and in general by a terminal hyphen representing the free bond
- the group R 22 is chosen from the series consisting of hydrogen, halogen, R 30 , HO-, R 30 -O-, R 30 -C(O)-O-, R 30 -S(O) 2 -O-, R 30 -S(O) m -, H 2 N-, R 30 -NH-, R 30 -N(R 30 )-, R 30 -C(O)-NH-, R 30 -C(O)-N(R 71 )-, R 30 -S(O) 2 -NH-, R 30 -S(O) 2 -N(R 71 )-, R 30 -S(O)
- the group R 22 is the one of the groups R 21 and R 22 which is a group of the formula II and the group R 21 is chosen from the series consisting of hydrogen, halogen, R 30 , HO-, R 30 -O-, R 30 -C(O)-O-, R 30 -S(O) 2 -O-, R 30 -S(O) m -, H 2 N-, R 30 -NH-, R 30 -N(R 30 )-, R 30 -C(O)- NH-, R 30 -C(O)-N(R 71 )-, R 30 -S(O) 2 -NH-, R 30 -S(O) 2 -N(R 71 )-, R 30 -C(O)-, HO-C(O)-, R 30 - O-C(O)-, H 2 N-C(O)-, R 30 -NH-C(O)-, R 30 -N(R 30 )-C
- the one of the groups R 21 and R 22 which is not a group of the formula II is chosen from the series consisting of hydrogen, halogen, R 30 , R 30 -O-, R 30 -C(O)-O-, R 30 -S(O) m -, H 2 N-, R 30 -NH-, R 30 -N(R 30 )-, R 30 -C(O)-NH-, R 30 - C(O)-, NC- and Het 1 , in another embodiment from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl, HO-(d-C 4 )-alkyl-, (C C 4 )-alkyl-O-(Ci-C 4 )-alkyl-, (Ci-C 4 )-alkyl- O-, HO-(Ci-C 4 )-alkyl-O-, (Ci-C 4 )-alkyl-O-(Ci-C 4 )-
- the one of the groups R 21 and R 22 which is not a group of the formula II is chosen from the series consisting of (Ci-C 4 )-alkyl and (Ci-C 4 )-alkyl-0-.
- the one of the groups R 21 and R 22 which is not a group of the formula II is (Ci-C 4 )-alkyl-O-, for example methoxy or ethoxy.
- the group R 21 is the one of the groups R 21 and R 22 which is a group of the formula II
- the group R 22 is chosen from the series consisting of (Ci-C 4 )-alkyl and (Ci-C 4 )-alkyl-O-, and in another embodiment it is (Ci-C 4 )-alkyl-O-
- the group R 22 is the one of the groups R 21 and R 22 which is the group of the formula II
- the group R 21 is chosen from the series consisting of hydrogen, halogen, R 30 , HO-, R 30 -O-, R 30 -C(O)-O-, R 30 -S(O) 2 -O-, R 30 - S(0) m -, H 2 N-, R 30 -NH-, R 30 -N(R 30 )-, R 30 -C(O)-NH-, R 30 -C(O)-N(R 71 )-, R 30 -S(O
- the chain members in a chain representing R 23 are connected to each other by single bonds.
- the number of chain members in a chain representing R 23 can be 1 , 2, 3, 4 or 5.
- the divalent group R 23 is a direct bond, i.e. the group R is directly bonded to the ring comprising the groups Y and Z which is depicted in formula I.
- R 23 is a direct bond or a chain consisting of 1 , 2, 3 or 4 chain members.
- R 23 is a direct bond or a chain consisting of 2, 3 or 4 chain members, in another embodiment a direct bond or a chain consisting of 2 or 3 chain members, in another embodiment a direct bond or a chain consisting of 3 chain members, wherein in these embodiments the chain members are defined as above or below.
- R 23 is a chain consisting of 1 , 2, 3, 4 or 5 chain members, in another embodiment a chain consisting of 1 , 2, 3 or 4 chain members, in another embodiment a chain consisting of 2, 3 or 4 chain members, in another embodiment a chain consisting of 2 or 3 chain members, in another embodiment a chain consisting of 3 chain members, wherein in these embodiments the chain members are defined as above or below.
- the hetero chain members in a chain representing R 23 are hetero chain members, in another embodiment one of the chain members in a chain representing R 23 is a hetero chain member, and in another embodiment zero of the chain members in a chain representing R 23 is a hetero chain member, wherein in these embodiments the hetero chain members are defined as above or below.
- the hetero chain members in a chain representing R 23 are chosen from the series consisting of N(R 25 ), O, S and S(O)2.
- the hetero chain members in a chain representing R 23 are chosen from the series consisting of N(R 25 ), O and S, in another embodiment from the series consisting of N(R 25 ) and O, in another embodiment from the series consisting of O and S, in another embodiment from the series consisting of N(R 25 ), O and S(O)2, in another embodiment from the series consisting of N(R 25 ) and S(O) 2 , in another embodiment from the series consisting of O and S(O) 2 .
- the hetero chain members which can be present in a chain representing R 23 are O (oxygen), and in another embodiment the hetero chain members which can be present in a chain representing R 23 , are S.
- zero or one hetero chain member is present in a chain representing R 23 which is O (oxygen), and in another embodiment one hetero chain member is present which is O.
- zero or one hetero chain member is present in a chain representing R which is S, and in another embodiment one hetero chain member is present which is S.
- Hetero chain members in a chain representing R 23 can be present in any positions of the chain provided that the resulting moiety complies with the prerequisites specified above with respect to R 23 and the compounds of the invention in general. Hetero chain members can be present in any one of the terminal positions of the chain or in both terminal positions of the chain, and can thus be directly bonded to the group R 24 and/or the ring comprising the groups Y and Z which is depicted in formula I, and/or they can be present inside the chain.
- At least one of the terminal chain members is a hetero chain member, and in another embodiment the terminal chain member which is bonded to the group R 24 is a hetero chain member, and in another embodiment the terminal chain member which is bonded to the ring comprising the groups Y and Z is a hetero chain member.
- one of the chain members in a chain representing R 23 is a hetero chain member and this hetero chain member is the terminal chain member bonded to the group R 24 .
- one of the chain members in a chain representing R 23 is a hetero chain member and this hetero chain member is the terminal chain member bonded to the ring comprising the groups Y and Z which is depicted in formula I.
- R 23 is chosen from a direct bond and from any one or more of the chains which are present in the following examples of groups of the formula II, which groups are bonded to the ring comprising the groups Y and Z which is depicted in formula I by the free bond represented by the terminal hyphen, and from which groups of the formula II the groups R 23 themselves are obtained by removing the group R 24 :
- a 3-membered to 10-membered, monocyclic or bicyclic ring representing R 24 is a monocyclic ring, which is all optionally substituted as indicated above or below.
- a monocyclic ring representing R 24 is 3-membered to 7-membered, in another embodiment 3- membered or 5-membered to 7-membered, in another embodiment 3-membered, 5- membered or 6-membered, in another embodiment 5-membered or 6-membered, in another embodiment 6-membered, which rings are all optionally substituted as indicated above or below.
- a bicyclic ring representing R 24 is 7-membered to 10-membered which is optionally substituted as indicated above or below.
- a ring representing R 24 is a saturated ring or an unsaturated ring including a partially unsaturated, i.e.
- a non-aromatic, ring which contains zero, one, two or three, for example zero, one or two, double bonds, within the ring, or an aromatic ring, which rings are all optionally substituted as indicated above or below.
- a ring representing R 24 is a saturated ring or a partially unsaturated ring which contains zero, one, two or three, for example zero, one or two, double bonds within the ring, which rings are all optionally substituted as indicated above or below.
- a ring representing R 24 is an aromatic ring, in another embodiment an aromatic ring chosen from benzene, aromatic 5-membered and 6-membered monocyclic heterocydes, naphthalene and aromatic 9-membered and 10-membered bicyclic heterocydes, in another embodiment an aromatic ring chosen from benzene and aromatic 5-membered and 6-membered monocyclic heterocydes, in another embodiment an aromatic ring chosen from benzene and thiophene, which rings are all optionally substituted as indicated above or below.
- a ring representing R 24 is a benzene ring which is optionally substituted as indicated above or below, i.e.
- R 24 is a phenyl group which is optionally substituted as indicated above or below, i.e. by the substituents specified above or below with respect to the 3- membered to 10-membered ring representing R 24 .
- the number of hetero ring members which can be present in a saturated 3-membered to 10-membered ring representing R 24 is 0, in another embodiment it is 1 .
- the number of hetero ring members which can be present in an unsaturated 3-membered to 10- membered ring representing R 24 is 0 or 1 , and in another embodiment it is 1 or 2, in another embodiment it is 1 , and in another embodiment the number of hetero ring members is 0 (zero), i.e., in this latter embodiment a 3-membered to 10-membered ring representing R 24 is a carbocyclic ring, which rings are all optionally substituted as indicated above or below.
- the hetero ring members which can be present in a 3-membered to 10-membered ring representing R 24 are chosen from N, N(R 32 ), O, S and S(O)2, in another embodiment from N, N(R 32 ), O and S, in another embodiment from N, O and S, in another embodiment from N(R 32 ), O and S, in another embodiment from N and S, in another embodiment they are N (nitrogen), and in another embodiment they are S (sulfur).
- the number of substituents which are optionally present on ring carbon atoms in a 3-membered to 10-membered ring representing R 24 is 1 , 2, 3, 4, or 5, in another embodiment the number of substituents which are optionally present on ring carbon atoms is 1 , 2, 3 or 4, in another embodiment the number of substituents which are optionally present on ring carbon atoms is 1 , 2 or 3, in another embodiment the number of substituents which are optionally present on ring carbon atoms is 1 or 2, and in another embodiment the number of substituents which are optionally present on ring carbon atoms is 1 .
- the substituents which are optionally present on ring carbon atoms in a 3-membered to 10-membered ring representing R 24 , including a benzene ring or a phenyl group, respectively, representing R 24 are chosen from the series consisting of halogen, R 33 , oxetanyl, HO-, R 33 -O-, R 33 -S(O) m -, H 2 N-, R 33 - NH-, R 33 -N(R 33 )-, R 33 -C(O)-NH-, R 33 -C(O)-N(R 71 )-, R 33 -S(O) 2 -NH-, R 33 -S(O) 2 -N(R 71 )-, H 2 N-S(O) 2 -NH-, R 33 -NH-S(O) 2 -NH-, R 33 -N(R 33 )-S(O) 2 -NH-, R 33 -NH-S(
- R 33 -N(R 33 )-C(O)- and NC- in another embodiment from the series consisting of halogen, R 33 , oxetanyl, HO-, R 33 -O-, R 33 -S(O) m -, H 2 N-, R 33 -NH-, R 33 -N(R 33 )-,
- R 24 are independently of each other chosen from the series consisting of (Ci-C6)-alkyl, (C 3 -C7)-cycloalkyl and (C 3 -C7)-cycloalkyl-(Ci-C 4 )-alkyl-, in another embodiment from the series consisting of (Ci-C6)-alkyl, (C 3 -C6)-cycloalkyl and (C 3 - C6)-cycloalkyl-(Ci-C 2 )-alkyl-, in another embodiment from the series consisting of (Ci- C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl and (C 3 -C 6 )-cycloalkyl-CH 2 -, in another embodiment from the series consisting of (Ci-C6)-alkyl, cyclopropyl and cyclopropyl-CH 2 -, for example from the series consisting of (Ci-C6)-alkyl, in another embodiment from the series consisting
- the number of substituents R 70 which are optionally present in these groups R 33 besides any fluorine substituents and, in the case of cycloalkyl groups, any (Ci-C 4 )-alkyl substituents, is independently of each other 0, 1 , 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1 , in another embodiment 0.
- the substituents R 70 in these groups R 33 are independently of each other chosen from the series consisting of HO-, R 71 -O-, R 71 -C(O)-O-, H 2 N-, R 71 -NH-, R -N(R )-, R n -C(O)-NH-, R n -C(O)-N(R )-, R n -S(O) 2 -NH-and R -S(O) 2 -N(R n )-, in another embodiment from the series consisting of HO-, R 71 -C(O)-O-, H 2 N-, R 71 -C(O)- NH- and R 71 -S(O)2-NH-, in another embodiment from the series consisting of HO-, R 71 -C(O)-O- and R 71 -C(O)-NH-, in another embodiment from the series consisting of HO- and R 71
- the groups R 71 present in these groups R 33 are independently of each other chosen from the series consisting of (Ci- C )-alkyl, cyclopropyl and cyclopropyl-CH 2 -, in another embodiment from the series consisting of (Ci-C 4 )-alkyl and cyclopropyl, in another embodiment from the series consisting of (Ci-C 4 )-alkyl.
- the number of nitro substituents (O 2 N-) on the ring R 24 is not greater than two, in another embodiment not greater than one.
- the total number of nitro groups in a compound of the formula I is not greater than two.
- R 24 is a benzene ring or a thiophene ring, for example a benzene ring, or, in terms of the respective residues, R 24 is a phenyl group or a thiophenyl (thienyl) group, for example a phenyl group, which are all optionally substituted as indicated afore. Examples of specific residues of benzene and thiophene rings, i.e.
- R 24 of specific phenyl and thiophenyl groups, representing R 24 , from any one or more of which examples the group R 24 is chosen in one embodiment of the invention, are phenyl, 2-fluoro- phenyl, 3-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-bromo- phenyl, 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-difluoro-phenyl, 2,5-dichloro- phenyl, 2-chloro-6-fluoro-phenyl, 3,4,5-trifluoro-phenyl, 3-methyl-phenyl (m-tolyl), 3- ethyl-phenyl, 3-isopropyl-phenyl, 3-cyclopropyl-phenyl, 3-tert-butyl-phenyl, 3- trifluoromethyl-phenyl, 3-(2-hydroxy
- R 26 independently of each other group R 26 , is chosen from the series consisting of hydrogen, fluorine, methyl and HO-, in another embodiment from the series consisting of hydrogen, fluorine and (CrC 4 )-alkyl, in another embodiment from the series consisting of hydrogen, fluorine and methyl, in another embodiment from the series consisting of hydrogen and fluorine, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R 26 is hydrogen, or in all these embodiments two groups R 26 bonded to the same carbon atom together are oxo, or two of the groups R 26 or one group R 25 and one group R 26 , together with the comprised chain members, form a 3-membered to 7-membered monocyclic ring which is saturated and contains 0, 1 or 2 identical or different hetero ring members chosen from the series consisting of N, N(R 34 ), O, S, S(O) and S(O) 2 , which ring is optionally substituted on ring carbon atom
- R 26 independently of each other group R 26 , is chosen from the series consisting of hydrogen, fluorine, methyl and HO-, in another embodiment from the series consisting of hydrogen, fluorine and (Ci-C 4 )-alkyl, in another embodiment from the series consisting of hydrogen, fluorine and methyl, in another embodiment from the series consisting of hydrogen and fluorine, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R 26 is hydrogen, or in all these embodiments two of the groups R 26 or one group R 25 and one group R 26 , together with the comprised chain members, form a 3-membered to 7-membered monocyclic ring which is saturated and contains 0, 1 or 2 identical or different hetero ring members chosen from the series consisting of N, N(R 34 ), O, S, S(O) and S(O)2, which ring is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the series consisting of fluorine
- R 26 independently of each other group R 26 , is chosen from the series consisting of hydrogen, fluorine, methyl and HO-, in another embodiment from the series consisting of hydrogen, fluorine and (CrC 4 )-alkyl, in another embodiment from the series consisting of hydrogen, fluorine and methyl, in another embodiment from the series consisting of hydrogen and fluorine, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment all groups R 26 are hydrogen.
- the number of groups R in a chain is the number of groups R in a chain
- R 23 which are HO- is zero, one or two, in another embodiment zero or one, in another embodiment zero, in another embodiment one.
- a HO- group representing R 26 is not present on a carbon atom which is adjacent to a hetero chain member in a chain representing R 23 .
- the number of groups R 26 in a chain representing R 23 which are (Ci- C 4 )-alkyl such as methyl is zero, one or two, in another embodiment zero or one, in another embodiment zero, in another embodiment one, in another embodiment two.
- the number of groups R 26 in a chain representing R 23 which are fluorine is zero, one, two, three or four, in another embodiment zero, one, two or three, in another embodiment zero, one or two, in another embodiment zero or one, in another embodiment zero, in another embodiment one, in another embodiment two.
- the number of oxo substituents in a chain representing R 23 which are formed by two groups R 26 bonded to the same carbon atom is zero, one or two, in another embodiment zero or one, in another embodiment zero, in another embodiment one.
- an oxo substituent in a chain representing R 23 is not present on a carbon atom which is adjacent to a hetero chain member chosen from the series consisting of S(O) and S(O)2, in another embodiment from the series consisting of S, S(O) and S(O)2, in another embodiment from the series consisting of O, S, S(O) and S(O)2.
- the number of rings which are formed by two of the groups R 26 or one group R 25 and one group R 26 , together with the comprised chain members is zero, one or two, in another embodiment zero or one, in another embodiment one, in another embodiment zero.
- a ring formed by two of the groups R 26 or one group R 25 and one group R 26 , together with the comprised chain members is a 3-membered, 4-membered, 5-membered or 6-membered ring, in another embodiment a 3-membered, 5-membered or 6- membered ring, in another embodiment a 3-membered ring, in another embodiment a 5-membered or 6-membered ring.
- two of the groups R 26 together with the comprised chain members, to form a ring, but not for one group R 25 and one group R 26 .
- the number of chain members which is comprised by a ring formed by two of the groups R 26 or one group R 25 and one group R 26 is one, two, three or four, in another embodiment it is one, two or three, in another embodiment it is one or two, in another embodiment it is one.
- the two of the groups R 26 forming the ring are bonded to the same carbon atom in the chain and the said one chain member is the carbon atom carrying the two groups R 26 .
- rings which are formed by two groups R 26 bonded to the same carbon atom and the one comprised chain member, are cycloalkane rings such as
- cyclopropane cyclobutane, cyclopentane or cyclohexane
- heterocyclic rings such as tetrahydrothiophene, tetrahydrothiopyran, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine or piperidine, for example cyclopropane, which carry any adjacent chain members of a chain representing R 23 and/or the group R 24 and/or the ring comprising the groups Y and Z which is depicted in formula I, on the same ring carbon atom, and which rings can all be substituted as indicated.
- a ring formed by two of the groups R 26 or one group R 25 and one group R 26 , together with the comprised chain members, comprises two chain members, the two groups R 26 forming the ring are bonded to two adjacent carbon atoms in the chain or the one group R is bonded to a carbon atom which is adjacent to the group N(R ), respectively.
- rings which are formed in such case, are likewise cycloalkane rings such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, and heterocyclic rings such as tetrahydrothiophene, tetrahyd roth iopy ran, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine or piperidine, for example cyclopropane, which carry any adjacent chain members of a chain representing R 23 and/or the group R 24 and/or the ring comprising the groups Y and Z which is depicted in formula I, on two adjacent ring carbon atoms or on the ring nitrogen atom and an adjacent ring carbon atom, and which rings can all be substituted as indicated.
- cycloalkane rings such as cyclopropane, cyclobutane, cyclopentane or cyclohexane
- a ring formed by two of the groups R 26 or one group R 25 and one group R 26 , together with the comprised chain members, comprises more than one chain members, besides being the group C(R 26 )(R 26 ) the comprised chain members can also be hetero chain members including the group N(R 25 ), which then are hetero ring members of the formed ring, wherein ar least one group C(R 26 )(R 26 ) is present.
- the total number of hetero ring members in such a ring is zero, one or two, in another embodiment zero or one, in another embodiment zero, in another embodiment one.
- hetero ring members in such a ring are chosen from the series consisting of N, N(R 34 ), O and S, in another embodiment form the series consisting of N, N(R 34 ) and O, in another embodiment from the series consisting of N and N(R 34 ), in another embodiment from the series consisting of N(R 34 ) and O, in another embodiment from the series consisting of N(R 34 ), and in another embodiment hetero ring members in such a ring are N, and in still another embodiment hetero ring members in such a ring are O, wherein a hetero ring member N in a ring formed by two of the groups R 26 or one group R 25 and one group R 26 , together with the comprised chain members, is the nitrogen atom of a hetero chain member N(R 25 ).
- the number of substituents which are optionally present in a ring formed by two of the groups R 26 or one group R 25 and one group R 26 , together with the comprised chain members is 0, 1 , 2, 3 or 4, in another embodiment 0, 1 , 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1 , in another embodiment 0.
- (Ci-C 4 )-alkyl substituents which are present in a ring formed by two of the groups R 26 or one group R 25 and one group R 26 , together with the comprised chain members are methyl.
- substituents present in a ring formed by two of the groups R 26 or one group R 25 and one group R 26 , together with the comprised chain members are fluorine, in another embodiment they are identical or different (Ci-C 4 )- alkyl groups, for example methyl.
- specific groups R including specific groups R contained therein are given in the following examples of groups of the formula II, which groups are bonded to the ring comprising the groups Y and Z which is depicted in formula I by the free bond represented by the terminal hyphen or the terminal line in the structural formula, and from which groups of the formula II the groups R 23 themselves are obtained by removing the group R 24 , wherein in these groups of the formula II the group R 24 is defined as above or below:
- R 23 is chosen from a direct bond and any one or more of the chains R 23 in the preceding examples of groups of the formula II and, likewise, the group of the formula II is chosen from the group R 24 and any one or more of the preceding examples of the groups of the formula II.
- R 32 and R 34 are independently of each other chosen from the series consisting of hydrogen, R 35 , R 35 -C(O)-, R 35 -O-C(O)- and phenyl, in another embodiment from the series consisting of hydrogen, R , R -C(O)- and R 35 -O-C(O)-, in another embodiment from the series consisting of hydrogen, R 35 and R 35 -C(O)-, in another embodiment from the series consisting of hydrogen, R 35 and phenyl, in another embodiment from the series consisting of hydrogen and R 35 .
- the groups R 35 occurring in R 32 and R 34 are independently of each other chosen from (Ci-C6)-alkyl, (C 3 -C7)-cycloalkyl and (C 3 - C7)-cycloalkyl-(Ci-C 4 )-alkyl-, in another embodiment from (Ci-C6)-alkyl, (C 3 -C7)- cycloalkyl and (C 3 -C7)-cycloalkyl-(Ci-C2)-alkyl-, in another embodiment from (Ci-C-6)- alkyl, (C 3 -C 7 )-cycloalkyl and (C 3 -C 7 )-cycloalkyl-CH 2 -, in another embodiment from (Ci-C6)-alkyl and (C 3 -C7)-cycloalkyl, in another embodiment from (Ci-C6)-alkyl, in another embodiment from (Ci-C 4 )-alkyl, which are all optionally substituted
- the number of substituents R 70 which are optionally present in a group R 35 occurring in R 32 and R 34 besides any fluorine substituents and, in the case of a cycloalkyi group, alkyl substituents, is,
- substituents R 70 which are optionally present in a group R 35 occurring in R 32 and R 34 are, independently of each other group, chosen from the series consisting of HO- and R 71 -O-.
- R 50 is chosen from R 51 -O- and R 52 -NH-, in another embodiment from R 51 -O- and H 2 N-. In another embodiment R 50 is R 51 -O-.
- R 51 is hydrogen. In another embodiment of the invention, R 51 is R 54 . In one embodiment of the invention, R is chosen from the series consisting of hydrogen, R 55 and R 56 -S(O)2-, in another embodiment from the series consisting of hydrogen, (Ci-C 4 )-alkyl which is optionally substituted by one or more identical or different substituents R 70 , and R 56 -S(O) 2 -, in another embodiment from the series consisting of hydrogen, unsubstituted (CrC )-alkyl and R 56 -S(O) 2 -, in another embodiment from the series consisting of hydrogen, unsubstituted methyl and R 56 -S(O)2-, in another embodiment from the series consisting of hydrogen and (Ci- C 4 )-alkyl which is optionally substituted by one or more identical or different substituents R 70 , in another embodiment from the series consisting of hydrogen and unsubstituted (Ci-C 4 )-alkyl
- R 53 is chosen from the series consisting of hydrogen and (Ci-C 4 )-alkyl which is optionally substituted by one or more identical or different substituents R 70 , in another embodiment from the series consisting of hydrogen and unsubstituted (CrC )-alkyl, in another embodiment from the series consisting of hydrogen and unsubstituted methyl.
- R 53 is hydrogen.
- R 51 , R 52 and R 53 are independently of each other chosen from the series consisting of hydrogen and unsubstituted (CrC )-alkyl, in another embodiment from the series consisting of hydrogen and unsubstituted (Ci-C3)-alkyl, in another embodiment from the series consisting of hydrogen and unsubstituted (Ci-C2)-alkyl.
- R 54 is chosen from (CrC 6 )-alkyl, (C 3 -C 7 )- cycloalkyl and (C3-C 7 )-cycloalkyl-(Ci-C 4 )-alkyl-, in another embodiment from (C1-C6)- alkyl, (C3-C 7 )-cycloalkyl and (C3-C 7 )-cycloalkyl-(Ci-C2)-alkyl-, in another embodiment from (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl and (C3-C 7 )-cycloalkyl-CH 2 -, in another embodiment from (CrC 6 )-alkyl and (C 3 -C 7 )-cycloalkyl, in another embodiment from (Ci-C6)-alkyl, in another embodiment from (Ci-C 4 )-alkyl, in another embodiment from (Ci-C3)-alkyl
- the number of substituents R 70 which are optionally present in a group R 54 besides any fluorine substituents and, in the case of a cycloalkyi group, any alkyl substituents is 0, 1 or 2, in another embodiment 0 or 1 , in another embodiment 1 , in another embodiment 0.
- a group R 54 is neither substituted by R 70 nor by fluorine substituents nor, in the case of a cycloalkyi group, by alkyl substituents, and R 54 in this embodiment thus is chosen, for example, from the series consisting of Ci- C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl and (C 3 -C 7 )-cycloalkyl- (Ci-C 4 )-alkyl-, or from the series consisting of (Ci-C6)-alkyl, (C3-C 7 )-cycloalkyl and (C 3 -C 7 )-cycloalkyl-CH 2 -, or from the series consisting of (CrC 6 )-alkyl, or from the series consisting of (Ci-C 4 )-alkyl, or from the series
- substituents R 70 which are optionally present in a group R 54 , are independently of each other chosen from the series consisting of HO-, R 71 -O-, R 71 -C(O)-O-, HO-C(O)- and R 71 -O-C(O)-, in another embodiment from the series consisting of HO-, R 71 -O- and R 71 -C(O)-O-, in another embodiment from the series consisting of HO- and R 71 -C(O)-O-.
- R 56 is chosen from the series consisting of phenyl which is optionally substituted as indicated above or below, and unsubstituted (Ci-C 4 )-alkyl, in another embodiment from the series consisting of phenyl which is optionally substituted as indicated above or below, and unsubstituted methyl, in another embodiment from unsubstituted (C C )-alkyl, in another embodiment from unsubstituted(Ci-C-3)-alkyl. In another embodiment R 56 is unsubstituted methyl, in another embodiment phenyl which is optionally substituted as indicated.
- R 60 is chosen from the series consisting of hydrogen and methyl. In another embodiment R 60 is hydrogen. In another
- R 60 is (Ci-C 4 )-alkyl, for example methyl.
- a group R in any of its occurrences is, independently of groups R 70 in other occurrences and unless specified otherwise, chosen from the series consisting of HO-, R 71 -O-, R 71 -C(O)-O-, R 71 -S(O) m -, H 2 N-, R 71 -NH-, R 71 -N(R 71 )-, R 71 -C(O)-NH-, R 71 -C(O)-N(R 71 )-, R 71 -S(O) 2 -NH-, R 71 -S(O) 2 - N(R 71 )-, HO-C(O)-, R 71 -O-C(O)-, H 2 N-C(O)-, R 71 -NH-C(O)-, R 71 -N(R 71 )-, HO
- R 70 is HO-, wherein R 71 is defined as indicated above or below.
- a (Ci-C6)-alkyl group for example, which is optionally substituted by the said R 70 , can among others be a group such as (Ci-C6)-alkyl, HO-(Ci-C-6)- alkyl-, i.e. hydroxy-(C C 6 )-alkyl-, (HO) 2 (C 2 -C 6 )-alkyl-, i.e.
- dihydroxy-(C 2 -C 6 )-alkyl-, and a (Ci-C 4 )-alkyl group which is optionally substituted by R 70 can among others be a group such as (Ci-C 4 )-alkyl, HO-(Ci-C 4 )-alkyl-, i.e. hydroxy-(Ci-C 4 )-alkyl-,
- R is chosen from (Ci-C 4 )-alkyl, cyclopropyl and cyclopropyl-CH 2 -, in another embodiment from (Ci-C 4 )-alkyl and cyclopropyl, in another embodiment from (Ci-C 4 )-alkyl, in another embodiment from (Ci-C3)-alkyl, unless specified otherwise.
- a subject of the invention are all compounds of the formula I wherein any one or more structural elements such as groups, substituents and numbers are defined as in any of the specified embodiments or definitions of the elements or have one or more of the specific meanings which are mentioned herein as examples of elements, wherein all combinations of one or more specified embodiments and/or definitions and/or specific meanings of the elements are a subject of the present invention. Also with respect to all such compounds of the formula I, all their stereoisomeric forms and mixtures of stereoisomeric forms in any ratios, and their physiologically acceptable salts are a subject of the present invention.
- a subject of the invention also is a compound of the formula I which is chosen from any of the specific compounds of the formula I which are disclosed herein, or is any one of the specific compounds of the formula I which are disclosed herein, irrespective thereof whether they are disclosed as a free compound and/or as a specific salt, or a physiologically acceptable salt thereof, wherein the compound of the formula I is a subject of the invention in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio where applicable.
- ring A is a 3-membered to 8-membered monocyclic ring which comprises 0, 1 or 2 identical or different hetero ring members chosen from the series consisting of N, N(R°), O, S, S(O) and S(O) 2 , and which is saturated or comprises 1 double bond, wherein ring A is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the series consisting of halogen, R 1 , R 2 , (C 2 - C 6 )-alkenyl, HO-, R 1 -O-, phenyl-(Ci-C 4 )-alkyl-O-, R 1 -C(O)-O-, R 1 -S(O) 2 -O-, R 1 - S(O) m -, H 2 N-, R 1 -NH-, R 1 -N(R 1 )-, R 1 -C(O)-NH-, R 1 -C(O)-N(R
- R 20 is hydrogen
- ring A is a cyclohexane ring or cycloheptane ring which is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the series consisting of halogen, R 1 , R 2 , (C 2 -C6)-alkenyl, HO-, R 1 -O-, phenyl-(Ci-C 4 )- alkyl-O-, R 1 -C(O)-O-, R 1 -S(O) 2 -O-, R 1 -S(O) m -, H 2 N-, R 1 -NH-, R 1 -N(R 1 )-, R 1 -C(O)-NH-, R 1 -C(O)-N(R 1 )-, R 1 -S(O) 2 -NH-, R 1 -S(O) 2 -N(R 1 )-, R 1 -S(O) 2 -NH-, R 1
- Z is C(R 16 );
- R 20 is hydrogen
- R 21 is chosen from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl, HO-(Ci- C 4 )-alkyl-, (CrC ⁇ -alkyl-O-iCrC ⁇ -alkyl-, (C C 4 )-alkyl-O-, HO-(C C 4 )-alkyl-O-, (C C 4 )-alkyl-O-(Ci-C 4 )-alkyl-O-, (Ci-C 4 )-alkyl-S(O) m -, (Ci-C 4 )-alkyl-C(O)-, NC- and Het 1 , or together with R 13 or R 14 forms a chain as specified in the definition of R 13 and R 14 ;
- R 22 is a group of the formula II
- R is a direct bond or a chain consisting of 2, 3 or 4 chain members of which 0 or 1 chain members are hetero chain members chosen from the series consisting of N(R 25 ), O, S, S(O) and S(O) 2 and the other chain members are identical or different groups C(R 26 )(R 26 );
- ring A is a cyclohexane ring or a cycloheptane ring which is optionally substituted by one or two identical or different substituents chosen from the series consisting of halogen, (Ci-C 4 )-alkyl and (Ci-C 4 )-alkyl-0-;
- Z is C(R 16 );
- R 12 , R 13 , R 15 and R 16 are independently of each other chosen from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl; or R 13 forms together with R 21 a chain which is chosen from the series consisting of -O- C(R 18 )(R 18 )-O-, -CH 2 -CH 2 -CH 2 , -CH2-O-CH2-, -CH2-CH2-CH2-CH2- and -O-C(R 18 )(R 18 )- C(R 18 )(R 18 )-O;
- R 18 is chosen from the series consisting of hydrogen or fluorine;
- R 21 is chosen from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl, HO-(Ci- C 4 )-alkyl-, (C C 4 )-alkyl-O-, (C C 4 )-alkyl-C(O)-, (d-C ⁇ -alkyl-O-id-C ⁇ alkyl-, HO-(C C 4 )-alkyl-O-, (Ci-C 4 )-alkyl-O-(Ci-C 4 )-alkyl-O-, NC- and oxetanyl, or together with R 13 forms a chain as specified in the definition of R 13 ;
- R 22 is a group of the formula II
- R is a direct bond or a chain consisting of 2, 3 or 4 chain members of which 0 or 1 chain members are hetero chain members chosen from the series consisting of O and S, and the other chain members are identical or different groups C(R 26 )(R 26 );
- R 24 is a benzene ring which is optionally substituted by one or more identical or different substituents chosen from the series consisting of halogen, R 33 , oxetanyl, HO-, R 33 -O-, R 33 -S(O) m -, H 2 N-, R 33 -NH-, R 33 -N(R 33 )-, R 33 -C(O)-NH-, R 33 -S(O) 2 -NH-, HO-C(O)-, R 33 -O-C(O)-, H 2 N-C(O)-, R 33 -NH-C(O)-, R 33 -N(R 33 )-C(O)- and NC-;
- R 26 independently of each other group R 26 , is chosen from the series consisting of hydrogen, fluorine, (Ci-C 4 )-alkyl, or two of the groups R 26 which are bonded to the same carbon atom in the chain, together with the carbon atom carrying them, form a cyclopropane ring or an oxetane ring;
- R 33 independently of each other group R 33 , is chosen from the series consisting of (CrC 4 )-alkyl, (C 3 -C 7 )-cycloalkyl and (C 3 -C 7 )-cycloalkyl-(CrC 2 )-alkyl-, which are all optionally substituted by one or more identical or different substituents R 70 ;
- R 50 is chosen from the series consisting of R 51 O- and R 52 (R 53 )N-;
- R 51 , R 52 and R 53 are independently of each other chosen from the series consisting of hydrogen and (Ci-C 4 )-alkyl;
- R 70 is chosen from the series consisting of HO- and R 71 -O-;
- R 71 is (Ci-C 4 )-alkyl;
- m independently of each other number m, is an integer chosen from the series consisting of 0 and 2;
- cycloalkyi independently of each other group cycloalkyi, and independently of any other substituents on cycloalkyi, is optionally substituted by one or more identical or different substituents chosen from fluorine and (Ci-C 4 )-alkyl;
- alkyl independently of each other group alkyl, and independently of any other substituents on alkyl, is optionally substituted by one or more fluorine substituents; in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts.
- a subject of the present invention is a compound of the formula I, which is
- Cis-1 -[(3'-chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethyl- cyclohexanecarboxylic acid
- Cis-1 [(3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4- trifluoromethyl-cyclohexanecarboxylic acid, or
- Another subject of the present invention are processes for the preparation of the compounds of the formula I which are outlined below and by which the compounds are obtainable.
- the preparation of the compounds of the formula I can be carried out by reacting a compound of the formula III with a compound of the formula IV with formation of an amide bond.
- the ring A and the groups Y, Z, R to R and R in the compounds of the formulae III and IV are defined as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a precursor group which is later converted into the final group.
- the carbonitrile group NC- may by mentioned as a precursor of the group -C(O)-R 50 .
- compounds of the formula I can also be prepared by reacting a compound of the formula V, which carries a NC- group in the position of the group -C(O)-R 50 , with a compound of the formula IV to give a compound of the formula VI which likewise carries a NC- group in the position of the group -C(O)-R 50 in the compounds of the formula I, and then converting the NC- group into the desired group -C(O)-R 50 , for example into a carboxylic acid group or a carboxamide group by the well-known techniques for hydrolyzing carbonitriles.
- the NC- group can be converted into the group -C(O)-R 50 in a two step, one pot procedure by initial alcoholysis of the nitrile to the imino ester in a alcohol like ethanol or methanol in the presence of an acid such as hydrogen chloride under anhydrous conditions, and the formed imino ester converted into a carboxylic acid ester, i.e. a compound of the formula I in which R 50 is R 51 O, by subsequent addition of water.
- the ring A and the groups Y, Z, R 20 to R 22 in the compounds of the formulae V and VI are defined as in the compounds of the formula I, and additionally can functional groups be present in protected form or in the form of a precursor group.
- the group G in the compounds of the formula IV can be HO- (hydroxy), i.e. the compound of the formula IV can thus be a carboxylic acid, or another group which can be replaced by the group N(R 20 ) in the compound of the formula III or V in a substitution reaction, for example an aryloxy group such as optionally substituted phenoxy or an alkyloxy group such as a (Ci-C 4 )-alkyl-O- group, for example a (Ci- C3)-alkyl-O- group like methoxy or ethoxy, or halogen, for example chlorine or bromine, and the compound of the formula IV can thus be a reactive ester like an aryl ester or alkyl ester, for example a methyl ester or ethyl ester, or an acid halide, for example an acid chloride or acid bromide, of the respective carboxylic acid.
- a substitution reaction for example an aryloxy group such as optionally substituted phenoxy or an al
- the compound of the formulae III and V and/or the compound of the formula IV can also be employed, and the compounds of the formulae I and VI obtained, in the form of a salt, for example an acid addition salt such as an hydrohalide, for example a hydrochloride, of the compound of the formulae III and V and/or an alkaline metal salt, for example a sodium salt, of a compound of the formula IV in which G is HO-.
- a salt for example an acid addition salt such as an hydrohalide, for example a hydrochloride, of the compound of the formulae III and V and/or an alkaline metal salt, for example a sodium salt, of a compound of the formula IV in which G is HO-.
- an acid addition salt such as an hydrohalide, for example a hydrochloride
- an alkaline metal salt for example a sodium salt
- the carboxylic acid group HO-C(O)- is generally activated in situ by means of a customary amide coupling reagent or converted into a reactive carboxylic acid derivative which can be prepared in situ or isolated.
- the compound of the formula IV in which G is HO- can be converted into an acid halide, e. g.
- Customary coupling reagents which can be employed, are propanephosphonic anhydride, ⁇ , ⁇ '- carbonyldiazoles like ⁇ , ⁇ '-carbonyldiimidazole (CDI), carbodiimides like 1 ,3- diisopropylcarbodiimide (DIC), 1 ,3-dicyclohexylcarbodiimide (DCC) or 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbodiimides together with additives like 1 -hydroxy-benzotriazole (HOBT) or 1 -hydroxy-7- azabenzotriazole (HOAT), uronium-based coupling reagents like O-(7- azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O- (benzotriazol-1 -yl)-
- TOTU tetrafluoroborate
- phosphonium-based coupling reagents like
- reaction is carried out in an inert solvent, for example a hydrocarbon or chlorinated hydrocarbon like benzene, toluene, xylene,
- chlorobenzene dichloromethane, chloroform or dichloroethane
- an ether like tetrahydrofuran (THF), dioxane, dibutyl ether, diisopropyl ether or dimethoxyethane (DME), or a mixture of solvents, at elevated temperatures, for example at
- reaction is likewise carried out in an inert solvent, for example a hydrocarbon or chlorinated hydrocarbon or ether like the aforementioned ones, an ester like ethyl acetate or butyl acetate, a nitrile like acetonitrile, or water, or a mixture of solvents including a mixture of water and an organic solvent which is miscible or immiscible with water, at temperatures from about -10 °C to about 100 °C, in particular at temperatures from about 0 °C to about 80 °C, for example at about room temperature.
- an inert solvent for example a hydrocarbon or chlorinated hydrocarbon or ether like the aforementioned ones, an ester like ethyl acetate or butyl acetate, a nitrile like acetonitrile, or water, or a mixture of solvents including a mixture of water and an organic solvent which is miscible or immiscible with water, at temperatures from about -10 °C to about 100
- reaction of a compound of the formula IV in which G is halogen with a compound of the formula III or V is carried out in the presence of a base such as a tertiary amine, like triethylamine, ethyldiisopropylamine, N-methylmorpholine or pyridine, or an inorganic base such as an alkaline metal hydroxide, carbonate or
- hydrogencarbonate like sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate.
- the reaction is generally carried out under anhydrous conditions in an inert aprotic solvent, for example an ether like THF, dioxane or DME, an amide like N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP), at temperatures from about -10 °C to about 40 °C, in particular at temperatures from about 0 °C to about 30 °C in the presence of a base such as a tertiary amine, like triethylamine, ethyldiisopropylamine or N- methylmorpholine.
- a base such as a tertiary amine, like triethylamine, ethyldiisopropylamine or N- methylmorpholine.
- protective groups which may be mentioned, are benzyl protective groups which may occur in the form of benzyl ethers of hydroxy groups and benzyl esters of carboxylic acid groups from which the benzyl group can be removed by catalytic hydrogenation in the presence of a palladium catalyst, tert-butyl protective groups which may occur in the form of tert-butyl esters of carboxylic acid groups from which the tert-butyl group can be removed by treatment with trifluoroacetic acid, acyl protective groups which may be used to protect hydroxy groups and amino groups in the form of esters and amides and which can be cleaved by acidic or basic hydrolysis, and alkyloxycarbonyl protective groups which may occur in the form of tert-butoxycarbonyl derivatives of amino groups which can be cleaved by treatment with trifluoroacetic acid.
- carboxylic acid groups for example the carboxylic acid group present in the compound of the formula III in case R 50 is HO-
- R 50 is HO-
- carboxylic acid groups for example the carboxylic acid group present in the compound of the formula III in case R 50 is HO-
- other esters for example in the form of alkyl esters like the methyl or ethyl ester which can be cleaved by hydrolysis, for example by means of an alkaline metal hydroxide like sodium hydroxide or lithium hydroxide.
- precursor groups besides cyano groups NC-, N ⁇ C-
- nitro groups which can be converted into amino groups by catalytic hydrogenation or by reduction with sodium dithionite, for example.
- a further example of a precursor group is an oxo group, which may initially be present in the course of the synthesis of compounds of the formula I containing a hydroxy group, and which can be reduced, for example with a complex hydride such as sodium borohydride, or reacted with an
- organometallic compound for example a Grignard compound. If any protective groups or precursor groups are present in the compounds of the formulae III, IV and V and the direct product of the reaction of the compound of the formula III or V with the compound of the formula IV is not yet the desired final compound, the removal of the protective group or conversion into the desired compound can in general also be carried out in situ.
- the compounds of the formula IV are commercially available or can be obtained according to, or analogously to, procedures described in the literature. Customarily, in synthetic procedures for the preparation of compounds of the formula IV
- the group G in the compounds of the formula IV is a group like (Ci-C 4 )-alkyl-O- and the group G-C(O)- thus is a (Ci-C 4 )-alkyl ester group, or the group G-C(O)- is any other ester group such as a benzyl ester phenyl- CH 2 -O-C(O)- and the group G thus is a benzyloxy group.
- Compounds of the formula IV in which G is HO- can be obtained from such compounds of the formula IV by acidic or basic hydrolysis of alkyl esters or by hydrogenation of benzyl esters under standard conditions.
- the groups Y, Z and R 24 are defined as in the compounds of the formula I.
- the group R 80 is chosen from the series consisting of hydrogen, halogen, R 30 , HO-, R 30 -O-, R 30 -C(O)-O-, R 30 -S(O) 2 -O-, R 30 -S(O) m -, H 2 N-, R 30 -NH-, R 30 -N(R 30 )-, R 30 -C(O)-NH-, R 30 -C(O)-N(R 71 )-, R 30 -S(O) 2 - NH-, R 30 -S(O) 2 -N(R 71 )-, R 30 -C(O)-, HO-C(O)-, R 30 -O-C(O)-, H 2 N-C(O)-, R 30 -
- R 80 has the meaning of the one of the groups R 21 and R 22 in the compounds of the formula I which is not a group of the formula II. Additionally, functional groups in the compounds of the formulae IVa, VII and VIII can be present in protected form or in the form of a precursor group which is later converted into the final group.
- the group G 1 -C(O)- is an ester group and the group G 1 a group such as (Ci-C 4 )-alkyl-O- or benzyloxy.
- the group X is a hetero chain member as specified in the definition of R 23 , i.e. a group chosen from the series consisting of N(R 25 ), O, S, S(O) and S(O) 2 , in particular from the series consisting of N(R 25 ), O and S.
- the groups R 23a and X together represent the group R 23 as specified above wherein a terminal chain member which is a hetero chain member, is bonded to the ring comprising the groups Y and Z.
- R 23a thus is a direct bond or a chain consisting of 1 to 4 chain members of which 0 or 1 chain member is a hetero chain member chosen from the series consisting of N(R 25 ), O, S, S(O) and S(O) 2 , provided that the terminal chain member adjacent to the group L 2 can only be a hetero chain member which leads to the formation of compound of the formula IVa in which one of the group X and the said terminal chain member is chosen from the series consisting of S(O) and S(O)2 and the other is chosen from the series consisting of N(R ), O and S, and the other chain members are identical or different groups C(R 26 )(R 26 ).
- R 80 can be located on the ring carbon which is adjacent to the group Y and the other of the two groups on the ring carbon atom which is adjacent to the group Z, as well as R 80 can be located on the ring carbon which is adjacent to the group Z and the other of the two groups on the ring carbon atom which is adjacent to the group Y. This applies to all compounds defined below containing a group R 80 and a second group in which the bonds connecting the group to the ring comprising the groups Y and Z are not directed to a specific ring carbon atoms.
- the group L 2 in the compounds of the formula VIII is a leaving group which can be replaced with the group X, such as halogen, fore example chlorine or bromine, a sulfonyloxy group, for example methanesulfonyloxy, trifluoromethanesulfonyloxy or toluene-4-sulfonyloxy, or hydroxy, for example.
- group X such as halogen, fore example chlorine or bromine
- a sulfonyloxy group for example methanesulfonyloxy, trifluoromethanesulfonyloxy or toluene-4-sulfonyloxy, or hydroxy, for example.
- reaction of a compound of the formula VII with a compound of the formula VIII is a nucleophilic substitution reaction which can be carried out under standard conditions for such reactions which are well known to a person skilled in the art.
- the reaction is performed in an inert solvent, for example a hydrocarbon or chlorinated hydrocarbon like benzene, toluene, xylene, chlorobenzene,
- a base for example a tertiary amine, such as triethylamine, ethyldiisopropylamine or N-methylmorpholine, or an inorganic base such as an alkaline metal hydride, hydroxide, carbonate or hydrogencarbonate like sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydrogencarbonate, or an alkoxide or amide such as sodium methoxide, sodium ethoxide, potassium
- a compound of the formula VII can also be treated with a base and converted into a salt in a separate step.
- Compounds of the formula VIII in which the group L 2 is hydroxy can favorably be reacted with compounds of the formula VII under the conditions of the Mitsunobu reaction in the presence of an azodicarboxylate like diethyl azodicarboxylate or diisopropyl azodicarboxylate and a phosphine like triphenylphosphine or tributylphosphine in an inert aprotic solvent such as an ether like THF or dioxane (cf. O. Mitsunobu, Synthesis (1981 ), 1 -28).
- compounds of the formula IVa can be obtained by reacting a compound of the formula IX with a compound of the formula X.
- the groups Y, Z and R are defined as in the compounds of the formula I.
- the group R 80 is defined as in the compounds of the formulae IVa and VII, i.e. it has the meaning of the one of the groups R 21 and R 22 in the compounds of the formula I which is not a group of the formula II. Additionally, functional groups in the compounds of the formulae IX and X can be present in protected form or in the form of a precursor group which is later converted into the final group.
- the group G 1 -C(O)- is an ester group and the group G 1 a group such as (Ci-C 4 )-alkyl-O- or benzyloxy.
- the group X is a hetero chain member as specified in the definition of R , i.e. a group chosen from the series consisting of N(R ), O, S, S(O) and S(O)2, in particular from the series consisting of N(R 25 ), O and S.
- R a hetero chain member as specified in the definition of R
- the groups R 23a and X together represent the group R 23 as specified above wherein a terminal chain member which is a hetero chain member, is bonded to the ring comprising the groups Y and Z in the obtained compounds of the formula IVa.
- R 23a thus is a direct bond or a chain consisting of 1 to 4 chain members of which 0 or 1 chain member is a hetero chain member chosen from the series consisting of N(R 25 ), O, S, S(O) and S(O)2, provided that the terminal chain member adjacent to the group X can only be a hetero chain member if one of the group X and the said terminal chain member is chosen from the series consisting of S(O) and S(O)2 and the other is chosen from the series consisting of N(R 25 ), O and S, and the other chain members are identical or different groups C(R 26 )(R 26 ).
- the group L 3 in the compounds of the formulae IX is a leaving group which can be replaced with the group X, such as halogen like fluorine, chlorine, bromine or iodine, or a sulfonyloxy group like methanesulfonyloxy or trifluoromethanesulfonyloxy, for example.
- the reaction of a compound of the formula IX with a compound of the formula X formally is a nucleophilic substitution reaction at the ring comprising the groups Y and Z which can in particular be performed in case of compounds of the formulae IX which are susceptible to such a reaction because of the presence of electron-withdrawing substituents or ring hetero atoms.
- reaction can be carried out under standard conditions for such reactions which are well known to a person skilled in the art.
- reaction conditions such as solvents or bases which are favorably added, which are given above with respect to the reaction of a compound of the formula VII with a compound of the formula VIII apply correspondingly to the reaction of a compound of the formula IX with a compound of the formula X.
- the groups Y, Z and R are defined as in the compounds of the formula I.
- the group R 80 is defined as in the compounds of the formulae IVa and VII, i.e. it has the meaning of the one of the groups R 21 and R 22 in the compounds of the formula I which is not a group of the formula II.
- functional groups in the compounds of the formulae IX and X can be present in protected form or in the form of a precursor group which is later converted into the final group. Additionally, functional groups in the compounds of the formulae IVb, XI and XII can be present in protected form or in the form of a precursor group which is later converted into the final group.
- the group G 1 -C(O)- is an ester group and the group G 1 a group such as (C-i-C 4 )-alkyl-O- or benzyloxy.
- the group X is a hetero chain member as specified in the definition of R 23 , i.e.
- R 23 comprises only one hetero chain member
- the group R 23b in the compounds of the formulae IVb and XI is a chain consisting of 1 to 4 identical or different groups C(R 26 )(R 26 )
- the group R 23c in the compounds of the formulae IVb and XII is a direct bond or a chain consisting of 1 to 3 identical or different groups C(R 26 )(R 26 ), provided that the total number of groups C(R 26 )(R 26 ) is not greater than 4.
- a further hetero chain member chosen from the series consisting of N(R 25 ), O, S, S(O) and S(O)2 can be present instead of one of the groups C(R )(R ), provided that such further hetero chain member can only be present in the terminal position adjacent to the group L 2 if one of the group X and the said chain member in the terminal position is chosen from the series consisting of S(O) and S(O) 2 and the other is chosen from the series consisting of N(R 25 ), O and S.
- the leaving group L 2 in the compounds of the formula XII is defined as in the compounds of the formula VIII.
- compounds of the formula IVa which can be prepared by reacting a compound of the formula VII with a compound of the formula VIII as well as by reacting a compound of the formula IX with a compound of the formula X
- compounds of the formula IVb can also be prepared by reacting a compound which is defined as the compound of the formula XI but contains a group L 2 instead of the group XH, with a compound which is defined as the compound of the formula XII but contains a group XH instead of the group L 2 .
- the groups Y, Z and R 24 are defined as in the compounds of the formula I.
- the group R 80 is defined as in the compounds of the formulae IVa and VII, i.e. it has the meaning of the one of the groups R 21 and R 22 in the compounds of the formula I which is not a group of the formula II.
- functional groups in the compounds of the formulae IVc to IVf, XIII, XIV and XV can be present in protected form or in the form of a precursor group which is later converted into the final group.
- the group G 1 -C(O)- is an ester group and the group G 1 a group such as (Ci-C 4 )-alkyl-O- or benzyloxy.
- the groups R a and R b are independently of each other chosen from hydrogen and (C C 4 )-alkyl.
- the group R 23d is a direct bond or a chain consisting of 1 to 3 identical or different groups C(R 26 )(R 26 ), the group R 23e a direct bond or a chain consisting of 1 to 4 identical or different groups C(R 26 )(R 26 ).
- the group L 4 in the compounds of the formula XIV is group which allows for the formation of a double bond between the carbon atom carrying the group L 4 and the carbon atom of the aldehyde group or ketone group carrying the group R a in the compound of the formula XIII in a condensation reaction.
- suitable condensation reactions are the Wittig reaction and the Wittig- Horner reaction, and examples of suitable groups L 4 thus are trisubstituted
- the group L 5 in the compounds of the formula XV is a metal such as lithium or a magnesium halide group like MgCI, MgBr or Mgl, and the compound of the formula XV thus an organolithium compound or a Grignard compound.
- the Wittig reaction and Wittig-Horner reaction and the addition of the organometallic compound of the formula XV to the compound of the formula XIII can be performed under standard conditions in an inert solvent such as a hydrocarbon like benzene or toluene or an ether like diethyl ether, THF, dioxane or DME.
- the Wittig reaction and the Wittig-Horner reaction are performed in the presence of a base such as a hydride like sodium hydride, an amide like sodium amide or lithium diisopropylamide, or an alkoxide like potassium tert-butoxide.
- a base such as a hydride like sodium hydride, an amide like sodium amide or lithium diisopropylamide, or an alkoxide like potassium tert-butoxide.
- a base such as a hydride like sodium hydride, an amide like sodium amide or lithium diisopropylamide, or an alk
- hydrogenation of the double bond in the compounds of the formula IVc to give the compounds of the formulae IVd, or of the benzylic hydroxy group in the compounds of the formulae IVe to give the compounds of the formulae IVf can be performed in the presence of a hydrogenation catalyst such as palladium on charcoal.
- the groups Y and Z are defined as in the compounds of the formula I.
- the group R 24a in the compounds of the formulae IVg to IVn and XVI is a group R 31 or a 3-membered to 10-membered ring as it can represent the group R 24 in the compounds of the formula I which is bonded via a ring carbon atom, in particular an aromatic ring such as an optionally substituted phenyl, naphthyl or heteroaryl group.
- the group R 80 is defined as in the compounds of the formulae IVa and VII, i.e. it has the meaning of the one of the groups R 21 and R 22 in the compounds of the formula I which is not a group of the formula II.
- the group G 1 -C(O)- is an ester group and the group G 1 a group such as (Ci-C 4 )-alkyl-O- or benzyloxy.
- the reaction of a compound of the formula XI I la with a compound of the formula XIV to give an aldol addition product of the formula IVm or a condensation product of the formula IVg can be carried under standard conditions for the aldol reaction in the presence of a base, such as an alkaline metal hydroxide like sodium hydroxide or potassium hydroxide, an alkoxide like sodium methoxide or sodium ethoxide or an amide like lithium diisopropylamide, in a solvent such as an alcohol like methanol or ethanol or an ether like diethyl ether, THF or dioxane.
- a base such as an alkaline metal hydroxide like sodium hydroxide or potassium hydroxide, an alkoxide like sodium methoxide or sodium ethoxide or an amide like lithium diisopropylamide, in a solvent such as an alcohol like methanol or ethanol or an ether like diethyl ether, THF or dioxane.
- the compound of the formula IVm can be obtained, at higher temperatures, for example at temperatures from about 10 °C to about 60 °C, or by treatment of the compound of the formula IVm with an acid, the compound of the formula IVg can be obtained.
- the ketone function in the compounds of the formulae IVg and IVm can be reduced to an alcohol function, for example with a complex hydride such as a borohydride like lithium borohydride or sodium borohydride, to give a compound of the formula IVh or IVn, respectively, which can be converted into a compound of the formula IVk by dehydration in the presence of an acid and/or hydrogenation in the presence of a catalyst such as palladium on charcoal, for example.
- a complex hydride such as a borohydride like lithium borohydride or sodium borohydride
- transition metal-catalyzed C-C coupling reactions may be mentioned by which compounds can be obtained wherein the group R 23 is a direct bond.
- Such compounds can be obtained from a compound of the formula IX and a boronic acid, for example an optionally substituted phenylboronic acid, cycloalkylboronic acid or heteroarylboronic acid.
- a palladium compound such as bis(triphenylphosphine)palladium(ll) chloride or tetrakis(triphenylphosphine)palla- dium(0) and a copper compound such as copper(l) iodide can be used.
- a compound of the formula III can also be reacted with a compound of the formula VII or a compound of the formula IX and the obtained compound of the formula XVII or XVIII reacted with a compound of the formula VIII or X, respectively, to give a compound of the formula Ik.
- This reaction sequence can also be performed with compounds of the formula V instead of with compounds of the formula III, and in the obtained compounds the nitrile group converted into the group -C(O)-R 50 to give compounds of the formula Ik.
- the ring A and the groups Y, Z, R 20 , R 24 and R 50 are defined as in the compounds of the formula I.
- the groups X, R 23a and R 80 are defined as in the compounds of the formula IVa.
- R 80 has the meaning of the one of the groups R 21 and R 22 in the compounds of the formula I which is not a group of the formula II.
- the group X is a hetero chain member as specified in the definition of R 23 , i.e. a group chosen from the series consisting of N(R 25 ), O, S, S(O) and S(O) 2 , in particular from the series consisting of N(R 25 ), O and S.
- the groups R 23a and X together represent the group R 23 as specified above wherein a terminal chain member which is a hetero chain member, is bonded to the ring comprising the groups Y and Z.
- R 23a thus is a direct bond or a chain consisting of 1 to 4 chain members of which 0 or 1 chain member is a hetero chain member chosen from the series consisting of N(R ), O, S, S(O) and S(O)2, provided that the terminal chain member adjacent to the group X can only be a hetero chain member if one of the group X and the said terminal chain member is chosen from the series consisting of S(O) and S(O) 2 and the other is chosen from the series consisting of N(R 25 ), O and S, and the other chain members are identical or different groups
- a compound of the formula XVIII can be employed in a transition-metal catalyzed C-C coupling reaction as referred to above, or a compound of the formula XI I la can be reacted with a compound of the formula III and the obtained compound modified at the CH 3 -C(O)- group to give a compound of the formula I.
- the compounds of the formulae III and V are commercially available or can be obtained according to, or analogously to, procedures described in the literature, for example according to the Bucherer-Bergs hydantoin procedure or the Strecker procedure for the preparation of amino acids and amino acid nitriles, respectively.
- the following scheme illustrates the Bucherer- Bergs hydantoin procedure for the synthesis of amino acids.
- a ketone of the formula XIX is converted into a hydantoin of the formula XX by reaction with a cyanide source, such as an alkaline metal cyanide like sodium cyanide (NaCN), and ammonium carbonate ((NH ) 2 CO3) in an inert solvent like a mixture of an alcohol such as a (Ci-C3)-alkanol and water, for example a mixture of ethanol and water, at temperatures from about 0 °C to about 150 °C, in particular at temperatures from about 20 °C to about 120 °C, for example at the reflux temperature of the employed solvent.
- a cyanide source such as an alkaline metal cyanide like sodium cyanide (NaCN), and ammonium carbonate ((NH ) 2 CO3)
- an inert solvent like a mixture of an alcohol such as a (Ci-C3)-alkanol and water, for example a mixture of ethanol and water, at temperatures from about 0 °C to
- the obtained hydantoin can be converted into the respective amino acid of the formula Ilia by hydrolysis, for example by hydrolysis with an aqueous acid like sulfuric acid or hydrochloric acid or by hydrolysis with an aqueous bases like sodium hydroxide or potassium hydroxide, at elevated temperatures, for example at the reflux temperature of the reaction mixture.
- hydrolysis for example by hydrolysis with an aqueous acid like sulfuric acid or hydrochloric acid or by hydrolysis with an aqueous bases like sodium hydroxide or potassium hydroxide, at elevated temperatures, for example at the reflux temperature of the reaction mixture.
- the amino acid of the formula Ilia can be protected by conversion into an amino acid ester of the formula Illb in which R 90 is a group such as (Ci-C )-alkyl, for example methyl or ethyl, or benzyl, by standard methods which are well known to a person skilled in the art, for example by esterification with an alcohol like methanol or ethanol in the presence of an acid like hydrogen chloride.
- R 90 is a group such as (Ci-C )-alkyl, for example methyl or ethyl, or benzyl
- the group A in the compounds of the formulae XIX, XX, Ilia and Illb is defined as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a precursor group which is later converted into the final group.
- the following scheme illustrates the Strecker procedure for the synthesis of amino acid nitriles.
- a ketone of the formula XIX is converted into the corresponding amino acid nitrile of the formula V by reaction with a cyanide source, such as an alkaline metal cyanide like potassium cyanide (KCN), and a salt of an amine of the formula R 20 -NH 2 , wherein R 20 is defined as in the compounds of the formula I, for example ammonium chloride (NH CI) in case R 20 is hydrogen or methylammonium chloride (CH 3 -NH 3 CI) in case R 20 is methyl, in an inert solvent like water or an alcohol such as a (Ci-C3)-alkanol like methanol or ethanol or a mixture thereof with water, for example a mixture of ethanol and water, at temperatures from about 0 °C to about 150 °C, in particular at temperatures from about 20 °C to about 120 °C or at temperatures from room temperature to the reflux temperature of the employed solvent.
- a cyanide source such as an alkaline metal cyanide like potassium
- the obtained amino acid nitrile of the formula V can be hydrolyzed to the amino acid of the formula lllc, for example by hydrolysis with an aqueous acid like sulfuric acid or hydrochloric acid, or by hydrolysis with an aqueous base like sodium hydroxide or potassium hydroxide, at elevated temperature, for example at temperatures from about 50 °C to about 150 °C, for example at the reflux
- the amino acid nitrile of the formula V can directly be reacted with a compound of the formula IV and the nitrile group hydrolyzed subsequently, as outlined above.
- the groups A and R 20 in the compounds of the formulae lllc and Illd and in the amines of the formula R -NH 2 are defined as in the compounds of the formula I and additionally functional groups can be present in protected form or in the form of a precursor group which is later converted into the final group.
- the group R 90 in the compounds of the formula llld is defined as in the compounds of the formula 1Mb.
- the Bucherer-Bergs procedure delivers products in which the substituent is in cis position with respect to the amino group in the obtained amino acid in case the substituent is in 2-position or 4-position of the ring, but products in which the substituent is in trans position with respect to the amino group in case the substituent is in the 3-position of the ring, whereas the Strecker procedure delivers products in which the substituent is in trans position with respect to the amino group in case the substituent is in 2-position or 4-position, but products in which the substituent is in cis position with respect to the amino group in case the substituent is in the 3-position.
- cyclic ketones of the formula XIX which are employed in the Bucherer-Bergs procedure and the Strecker procedure, are commercially available or can be synthesized by a broad variety of synthetic methods which are well known to a person skilled in the art.
- a cyclic ketone of the formula XIX can be synthesized by ring expansion of the respective ketone of smaller ring size of the formula XXI, which contains one ring carbon less, with diazomethane (CH 2 N 2 ), for example according to the procedure described in F. Alonso et al., Tetrahedron 51 (1995), 10259-10280.
- the ring expansion reaction with diazomethane is generally carried out in an inert solvent, for example an ether like diethyl ether, tetrahydrofuran (THF), dioxane, dibutyl ether, diisopropyl ether or dimethoxyethane (DME), ethanol, methanol, a hydrocarbon, dichloromethane, chloroform or dichloroethane, or a mixture of solvents, at temperatures from about -78 °C to 50 °C, in particular at temperatures from about -40 °C to about room temperature, for example at about 0 °C.
- an inert solvent for example an ether like diethyl ether, tetrahydrofuran (THF), dioxane, dibutyl ether, diisopropyl ether or dimethoxyethane (DME), ethanol, methanol, a hydrocarbon, dichloromethane, chloroform or dichloroethane, or
- Diazomethane can be used as solution in an inert solvent, for example diethyl ether or THF, or can be generated in situ from an appropriate source for diazomethane like N-methyl-N-nitroso-p-toluenesulfonamide (Diazald ® ) or N-methyl-N-nitrosourea.
- N-methyl-N-nitroso-p-toluenesulfonamide can be added to a solution of the ketone in an inert solvent like a mixture of ethanol, methanol and water containing a base like potassium hydroxide to generate diazomethane in situ.
- trimethylsilyl diazomethane can be added to a solution of the ketone and an acid or silyl scavanger like boron trifluoride etherate in an inert solvent like dichloromethane to generate a diazomethane equivalent and to perform the ring enlargement reaction.
- the reaction conditions for ring enlargement of a ketone depend on the particulars of the specific case, for example on the substituents on the ring A.
- the moiety A' in the divalent alkylating compound of the formula XXII corresponds to the ring A in the compounds of the formula I except that it does not contain the ring carbon atom present in A which carries the groups N(R 20 ) and C(O)-R 50 , and is defined accordingly, and the groups L 11 and L 12 are leaving groups such as halogen, for example chlorine or bromine, or sulfonyloxy groups, for example
- the groups PG 1 and PG 2 in the malonic acid derivative of the formula XXIII and the compounds of the formulae XXIV, XXV, XXVI and XXVII have the function of protective groups of the carboxylic acid groups and can be identical or different groups such as (C C 4 )-alkyl, for example methyl, ethyl or tert-butyl, or benzyl.
- the alkylation reaction of the compounds of the formulae XXII and XXXIII is generally carried out in the presence of a base, for example an alkaline metal hydride such as sodium hydride or an alkaline metal alkoxide such as potassium tert-butoxide, in an inert solvent such as an ether like THF or diethyl ether or an amide like DMF or NMP or a nitrile like acetonitrile at temperatures from about 0 °C to about 100 °C, depending on the particulars of the specific case.
- a base for example an alkaline metal hydride such as sodium hydride or an alkaline metal alkoxide such as potassium tert-butoxide
- an inert solvent such as an ether like THF or diethyl ether or an amide like DMF or NMP or a nitrile like acetonitrile at temperatures from about 0 °C to about 100 °C, depending on the particulars of the specific
- one of the protective groups for example PG 2
- PG 2 is cleaved, for example by treatment with an aqueous base like sodium hydroxide or potassium hydroxide in the case of methyl or ethyl group.
- an aqueous base like sodium hydroxide or potassium hydroxide in the case of methyl or ethyl group.
- the free carboxylic acid group be degraded to an amino group by degradation reactions which are well known to a person skilled in the art.
- the carboxylic acid can be activated by formation of a mixed anhydride, for example by reaction with a chloroformic acid ester like isobutyl chloroformate in the presence of a base like triethylamine or N-methylmorpholine in an inert solvent like acetone, the mixed anhydride reacted in situ with an alkaline metal azide like sodium azide to give the acid azide of the formula XXVI, which is subsequently heated in an inert solvent, for example a hydrocarbon like toluene or xylene, to give the degraded isocyanate which can be hydrolyzed, for example with aqueous acid like hydrochloric acid to give the amino acid derivative of the formula XXVII which already constitutes a compound of the formula 1Mb or in which the protective group PG 1 can be cleaved to give a compound of the formula Ilia which can in turn be esterified as mentioned above to give a compound of the formula 1Mb.
- the free carboxylic acid group in the compound of the formula XXV can be reacted with an azide transfer reagent like diphenylphosphoryl azide to yield the acid azide of the formula XXVI which can be degraded as indicated.
- an azide transfer reagent like diphenylphosphoryl azide
- the group A in the compounds of the formulae XXIV, XXV, XXVI and XXVII is defined as in the compounds of the formula I and additionally can functional groups be present in protected form or in the form of a precursor group which is later converted into the final group.
- the starting compounds and building blocks for the synthesis of the compounds of the formula I can generally be prepared according to procedures described in the literature or analogously to such procedures, or are commercially available.
- an optionally alkyl-substituted acetic acid ester for example acetic acid tert-butyl ester or isobutyric acid methyl ester
- a base such as lithium dicyclohexylamide
- an optionally substituted aryl bromide in the presence of a palladium compound such as bis(dibenzylideneacetone)palladium or tris(dibenzylideneactone)dipalladium and tri(tert-butyl)phosphine to give a 2-
- hydroxy groups can be esterified to give a carboxylic acid ester or a sulfonic acid ester, or etherified.
- Etherifications of hydroxy groups can favorably be performed by alkylation with the respective halogen compound, for example a bromide or iodide, in the presence of a base such an alkali metal carbonate like potassium carbonate or cesium carbonate in an inert solvent such as an amide like DMF or NMP or a ketone like acetone or butan-2-one, or with the respective alcohol under the conditions of the Mitsunobu reaction referred to above.
- a hydroxy group can be converted into a halide by treatment with a halogenating agent.
- a halogen atom can be replaced with a variety of groups in a substitution reaction which may also be a transition-metal catalyzed reaction.
- a nitro group can be reduced to an amino group, for example by catalytic hydrogenation.
- An amino group can be modified under standard conditions for alkylation, for example by reaction with a halogen compound or by reductive amination of a carbonyl
- a carboxylic ester group can be hydrolyzed under acidic or basic conditions to give a carboxylic acid.
- a carboxylic acid group can be activated or converted into a reactive derivative as outlined above with respect to the compounds of the formula IX and reacted with an alcohol or an amine or ammonia to give an ester or amide.
- a primary amide can be dehydrated to give a nitrile.
- a sulfur atom in an alkyl-S- group or in a heterocyclic ring or a sulfur atom occurring in a chain representing the group R 23 can be oxidized with a peroxide like hydrogen peroxide or a peracid to give a sulfoxide moiety S(O) or a sulfone moiety S(O) 2 .
- a carboxylic acid group, carboxylic acid ester group and a ketone group can be reduced to an alcohol, for example with a complex hydride such al lithium aluminium hydride, lithium borohydride or sodium borohydride. All reactions in the preparation of the
- Another subject of the present invention are the novel starting compounds and intermediates occurring in the synthesis of the compounds of the formula I, including the compounds of the formulae III, Ilia, 1Mb, lllc, llld, IV, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVk, IVm, IVn, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI and XXVII wherein the ring A and the groups G, G 1 , L 2 , L 3 , L 11 , L 12 , PG 1 , PG 2 , X, Y, Z, R 20 to R 23 , R 23a , R 23b , R 23c , R 24
- a subject of the invention are in particular the novel specific starting compounds and intermediates described herein. Independently thereof whether they are described as a free compound and/or as a specific salt, they are a subject of the invention both in the form of the free compounds and in the form of their salts, and if a specific salt is described, additionally in the form of this specific salt.
- the compounds of the formula I inhibit the Edg-2 receptor (L- ⁇ receptor) as can be demonstrated in the pharmacological test described below and in other tests which are known to a person skilled in the art.
- the compounds of the formula I and their physiologically acceptable salts are valuable pharmaceutical active compounds.
- cardiovascular diseases such as heart failure including systolic heart failure, diastolic heart failure, diabetic heart failure and heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, myocardial remodeling including myocardial remodeling after infarction or after cardiac surgery, vascular remodeling including vascular stiffness, hypertension including pulmonary diseases, cardiovascular diseases such as heart failure including systolic heart failure, diastolic heart failure, diabetic heart failure and heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, myocardial remodeling including myocardial remodeling after infarction or after cardiac surgery, vascular remodeling including vascular stiffness, hypertension including pulmonary diseases, cardiovascular diseases such as heart failure including systolic heart failure, diastolic heart failure, diabetic heart failure and heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, myocardial remodeling including myocardial remodeling after infarction or after cardiac surgery, vascular remodeling including vascular stiffness, hypertension including
- pulmonary diseases such as chronic obstructive pulmonary disease (COPD), asthma or acute respiratory dystress syndrome (ARDS), immunological diseases, allergic diseases, tumor growth, metastasis, metabolic diseases, fibrotic diseases such as pulmonary fibrosis including idiopathic lung fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis including renal tubulointerstitial fibrosis, liver fibrosis, fibrosing skin
- diseases are to be understood as meaning both the therapy of existing pathological changes or malfunctions of the organism or of existing symptoms with the aim of relief, alleviation or cure, and the prophylaxis or prevention of pathological changes or malfunctions of the organism or of symptoms in humans or animals which are susceptible thereto and are in need of such a prophylaxis or prevention, with the aim of a prevention or suppression of their occurrence or of an attenuation in the case of their occurrence.
- the compounds of the formula I and their physiologically acceptable salts can therefore be used in animals, in particular in mammals and specifically in humans, as a pharmaceutical or medicament on their own, in mixtures with one another or in the form of pharmaceutical compositions.
- a subject of the present invention also are the compounds of the formula I and their physiologically acceptable salts for use as a pharmaceutical, as well as pharmaceutical compositions and medicaments which comprise an efficacious dose of at least one compound of the formula I and/or a physiologically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier, i.e. one or more pharmaceutically innocuous, or nonhazardous, vehicles and/or excipients, and optionally one or more other pharmaceutical active compounds.
- a subject of the present invention furthermore are the compounds of the formula I and their physiologically acceptable salts for use in the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example heart failure or fibrotic diseases such as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis, liver fibrosis or fibrosing skin conditions, the use of the compounds of the formula I and their physiologically acceptable salts for the manufacture of a medicament for the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example heart failure or fibrotic diseases such as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis, liver fibrosis or fibrosing skin conditions, wherein the treatment of diseases comprises their therapy and prophylaxis as mentioned above, as well as their use for the manufacture of a medicament for the inhibition of the Edg-2 receptor (LPAi receptor).
- a subject of the invention also are methods for the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example heart failure or fibrotic diseases such as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis, liver fibrosis or fibrosing skin conditions, which comprise administering an efficacious amount of at least one compound of the formula I and/or a physiologically acceptable salt thereof to a human or an animal which is in need thereof.
- the compounds of the formula I and pharmaceutical compositions and medicaments comprising them can be administered enterally, for example by oral, sublingual or rectal administration, parenterally, for example by intravenous, intramuscular, subcutaneous or
- intraperitoneal injection or infusion or by another type of administration such as topical, percutaneous, transdermal, intra-articular, intranasal or intraocular
- the compounds of the formula I and their physiologically acceptable salts can also be used in combination with other pharmaceutical active compounds, wherein in such a combination use the compounds of the formula I and/or their physiologically acceptable salts and one or more other pharmaceutical active compounds can be present in one and the same pharmaceutical composition or in two or more
- compositions for separate, simultaneous or sequential administration are angiotensin converting enzyme (ACE) inhibitors, ramipril, angiotensin II receptor subtype 1 (AT1 ) antagonists, irbesartan, antiarrhythmics, dronedarone, peroxisome proliferator- activated receptor-alpha (PPAR-a) activators, peroxisome proliferator-activated receptor-gamma (PPAR- ⁇ ) activators, pioglitazone, rosiglitazone, prostanoids, endothelin receptor antagonists, bosentan, elastase inhibitors, calcium antagonists, beta blockers, diuretics, aldosterone receptor antagonists, eplerenone, renin inhibitors, rho kinase inhibitors, soluble guanylate cyclase (sGC) activators, sGC sensitizers, phosphodiesterase (PDE) inhibitors, phosphodiesterase type 5 (P
- ACE angiotens
- compositions and medicaments according to the invention normally contain from about 0.5 to about 90 percent by weight of compounds of the formula I and/or physiologically acceptable salts thereof, and an amount of active ingredient of the formula I and/or its physiologically acceptable salt which in general is from about 0.2 mg to about 1000 mg, in particular from about 0.2 mg to about 500 mg, for example from about 1 mg to about 300 mg, per unit dose. Depending on the kind of the pharmaceutical composition and other particulars of the specific case, the amount may deviate from the indicated ones.
- the production of the pharmaceutical compositions and medicaments can be carried out in a manner known per se.
- the compounds of the formula I and/or their physiologically acceptable salts are mixed together with one or more solid or liquid vehicles and/or excipients, if desired also in combination with one or more other pharmaceutical active compounds such as those mentioned above, and brought into a suitable form for dosage and administration, which can then be used in human medicine or veterinary medicine.
- excipients As vehicles, which may also be looked upon as diluents or bulking agents, and excipients suitable organic and inorganic substances can be used which do not react in an undesired manner with the compounds of the formula I.
- excipients, or additives As examples of types of excipients, or additives, which can be contained in the pharmaceutical
- compositions and medicaments lubricants, preservatives, thickeners, stabilizers, disintegrants, wetting agents, agents for achieving a depot effect, emulsifiers, salts, for example for influencing the osmotic pressure, buffer substances, colorants, flavorings and aromatic substances may be mentioned.
- vehicles and excipients are water, vegetable oils, waxes, alcohols such as ethanol, isopropanol, 1 ,2-propanediol, benzyl alcohols, glycerol, polyols, polyethylene glycols or
- polypropylene glycols glycerol triacetate, polyvinylpyrrolidone, gelatin, cellulose, carbohydrates such as lactose or starch like corn starch, sodium chloride, stearic acid and its salts such as magnesium stearate, talc, lanolin, petroleum jelly, or mixtures thereof, for example saline or mixtures of water with one or more organic solvents such as mixtures of water with alcohols.
- compositions such as, for example, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, suppositories, solutions, including oily, alcoholic or aqueous solutions, syrups, juices or drops, furthermore suspensions or emulsions, can be used.
- parenteral use for example by injection or infusion
- pharmaceutical forms such as solutions, for example aqueous solutions
- pharmaceutical forms such as ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions or powders
- Further suitable pharmaceutical forms are, for example, implants and patches and forms adapted to inhalation.
- the compounds of the formula I and their physiologically acceptable salts can also be lyophilized and the obtained lyophilizates used, for example, for the production of injectable compositions. In particular for topical application, also liposomal compositions are suitable.
- the pharmaceuticallyophilized and the obtained lyophilizates used, for example, for the production
- compositions and medicaments can also contain one or more other active
- ingredients and/or, for example, one or more vitamins are ingredients and/or, for example, one or more vitamins.
- the daily dose can be administered in the form of a single dose or divided into a number of individual doses, for example two, three or four individual doses.
- the administration can also be carried out continuously, for example by continuous injection or infusion. Depending on the individual behavior in a specific case, it may be necessary to deviate upward or downward from the indicated dosages.
- the compounds of the formula I can also be employed as an aid in biochemical investigations or as a scientific tool or for diagnostic purposes, for example in in-vitro diagnoses of biological samples, if an inhibition of the Edg-2 receptor is intended.
- the compounds of the formula I and their salts can also be used as intermediates for the preparation of further pharmaceutical active substances.
- the prepared compounds were in general characterized by spectroscopic data and chromatographic data, in particular mass spectra (MS) and HPLC retention times (Rt; in min) which were obtained by combined analytical HPLC/MS characterization (LC/MS), and/or thin layer chromatography (TLC) Rf values, and/or nuclear magnetic resonance (NMR) spectra. Unless specified otherwise, 1 H-NMR spectra were recorded at 500 MHz in D 6 -DMSO as solvent at 298 K.
- the ionization method was electrospray ionization (ESI).
- ESI electrospray ionization
- Step 1 3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester
- 2-(2-Fluoro-5-methyl-phenyl)-ethanol 508 mg, 3.29 mmol) was dissolved in THF (23 ml).
- Triphenylphosphine (1 .08 g, 4.12 mmol) and 3-hydroxy-4-methoxy-benzoic acid methyl ester (500 mg, 2.75 mmol) were added, the mixture was cooled in an ice bath, and DIAD (832 mg, 4.12 mmol) was added slowly with stirring. The ice bath was removed and stirring was continued overnight at room temperature. The volatiles were evaporated in vacuo, and the residue was purified by RP HPLC (water/ACN gradient) to give 530 mg of the title compound.
- step 1 The compound of step 1 (530 mg, 1 .66 mmol) was dissolved in dioxane (8.3 ml). Lithium hydroxide (8.3 ml of an aqueous 1 M solution) was added and the mixture was kept for 20 min at 60 °C. After cooling, the mixture was partitioned between an excess of 2 N hydrochloric acid and EA and the aqueous phase extracted with EA. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was stirred overnight with a mixture of diethyl ether and HEP, filtered, and the solid was dried in vacuo to give 500 mg of the title compound.
- Step 3 1 - ⁇ 3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoylamino ⁇ - cycloheptanecarboxylic acid methyl ester
- step 2 The compound of step 2 (285 mg, 0.937 mmol) was dissolved in an excess of thionyl chloride (0.7 ml) and stirred for 20 min at 60 °C. The solution was evaporated to dryness in vacuo. The residue was dissolved in a little DCM and added to a well- stirred mixture of 1 -amino-cycloheptanecarboxylic acid methyl ester hydrochloride (195 mg, 0.937 mmol), EA and an excess of a saturated aqueous sodium
- Step 4 1 - ⁇ 3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoylamino ⁇ - cycloheptanecarboxylic acid
- step 3 The compound of step 3 (160 mg, 0.35 mmol) was dissolved in dioxane (1 .8 ml). 1 M aqueous lithium hydroxide (1 .8 ml) was added, the mixture was stirred at 60 °C for 30 min, cooled, and partitioned between 2 N hydrochloric acid and EA. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. The residue was stirred in ether and the solid material which formed was filtered and dried in vacuo to yield the title
- Step 1 4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid
- Step 2 1 -[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid
- Step 1 1 -(3-Acetoxy-4-methoxy-benzoylannino)-cycloheptanecarboxylic acid methyl ester
- Step 2 1 -(3-Hydroxy-4-methoxy-benzoylamino)-cycloheptanecarboxylic acid methyl ester
- step 1 The compound of step 1 (10.6 g, 29.4 mmol) was dissolved in methanol (100 ml), potassium carbonate (812 mg, 5.88 mmol) was added and the mixture was stirred overnight at room temperature. An excess of 2 N hydrochloric acid was added, the methanol was evaporated in vacuo and the residue partitioned between EA and water. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness to give the title compound (6.81 g).
- step 2 The compound of step 2 (80 mg, 0.249 mmol) and triphenylphosphine (98 mg, 0.374 mmol) were dissolved in THF. 2-(5-Chloro-2-fluoro-phenyl)-ethanol (48 mg, 0.274 mmol) and DIAD (80.3 mg, 0.374 mmol) were added and the mixture was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo and the residue was purified by preparative RP HPLC (water/ACN gradient) to give 85 mg of the title compound.
- Step 4 1 - ⁇ 3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino ⁇ - cycloheptanecarboxylic acid
- step 3 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
- example compounds of the formula 1-1 listed in table 1 were prepared.
- the compounds can be named as 1 -[3-(R 101 -oxy)-4-methoxy- benzoylamino]-cycloheptanecarboxylic acid, for example as 1 - ⁇ 3-[2-(thiophen-3-yl)- ethoxy]-4-methoxy-benzoylamino]-cycloheptanecarboxylic acid in the case of example 1 1 .
- the title compound was synthesized in analogy to example 3 using 1 -amino- cyclooctanecarboxylic acid methyl ester hydrochloride instead of 1 -amino- cycloheptanecarboxylic acid methyl ester hydrochloride.
- the amino acid methyl esters or the amino acids were commercially available or were prepared from the respective ketone in analogy to example 25.
- the line crossed with the symbol represents the free bond via which the group R 102 is bonded to the nitrogen atom of the amide group depicted in formula I-2.
- the terminal endpoint of the line crossed with the said symbol ends on the nitrogen atom of the amide group.
- Step 1 N-(trans-1 -Cyano-4-methyl-cyclohexyl)-4-methoxy-3-(2-m-tolyl-ethoxy)- benzamide
- Step 2 trans-1 -[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl- cyclohexanecarboxylic acid ethyl ester
- step 1 The compound of step 1 (810 mg, 1 .99 mmol) was dissolved in ethanol (10 ml). The solution was cooled in an acetone/dry ice bath, acetyl chloride (2.3 ml, 30 mmol) was added and the mixture was warmed to room temperature and stirred for 3 days. Then 2 N hydrochloric acid was added and the mixture was stirred overnight to hydrolyze the imino ester. After evaporation of the ethanol, the residue was partitioned between EA and 2 N hydrochloric acid. The phases were separated, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (DCM/EA gradient) to yield the title compound (0.78 g).
- DCM/EA gradient silica gel chromatography
- Step 3 trans- 1 -[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl- cyclohexanecarboxylic acid
- step 2 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
- Step 1 8-Benzyloxycarbonylamino-1 ,4-dioxa-spiro[4.6]undecane-8-carboxylic acid and 1 -benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid
- the intermediate was suspended in dioxane/water (2.5 ml/5 ml), sodium carbonate (0.732 g, 6.90 mmol) was added, the mixture was cooled in an ice bath and benzyl chloroformate (0.392 ml, dissolved in 2.5 ml of dioxane) was added with stirring.
- Step 2 8-Benzyloxycarbonylamino-1 ,4-dioxa-spiro[4.6]undecane-8-carboxylic acid methyl ester and 1 -benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl ester
- step 1 The mixture obtained in step 1 (200 mg) was dissolved in DMF (2 ml), cesium carbonate (280 mg, 0.86 mmol), EDIA (149 mg, 1 .14 mmol) and iodomethane (121 mg, 0.858 mmol) were added and the mixture was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo, the residue was partitioned between EA and saturated aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC
- Step 3 8-Amino-1 ,4-dioxa-spiro[4.6]undecane-8-carboxylic acid methyl ester 66 mg of 8-benzyloxycarbonylamino-1 ,4-dioxa-spiro[4.6]undecane-8-carboxylic acid methyl ester was dissolved in methanol and hydrogenated in an H-cubeTM
- Step 4 8-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1 ,4-dioxa- spiro[4.6]undecane-8-carboxylic acid
- the title compound was prepared from the compound of step 3 and 4-methoxy-3-(2- m-tolyl-ethoxy)-benzoic acid in analogy to steps 3 and 4 of example 1 .
- Step 1 1 -[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo- cycloheptanecarboxylic acid methyl ester
- Step 2 4-Hydroxy-1 -[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]- cycloheptanecarboxylic acid methyl ester
- step 1 The compound of step 1 (67 mg, 0.148 mmol) was dissolved in THF (1 ml) and cooled in an ice bath. Sodium borohydride (5.7 mg, 0.148 mmol) was added.
- Step 3 4-Hydroxy-1 -[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]- cycloheptanecarboxylic acid
- step 2 The compound of step 2 (63 mg, 0.138 mmol) was hydrolyzed in analogy to step 4 of example 1 to yield the title compound (49 mg) as mixture of diastereomers.
- Step 1 1 -[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo- cyclohexanecarboxylic acid methyl ester
- Step 2 1 -[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo- cyclohexanecarboxyl ic acid
- step 1 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
- Step 1 1 -[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methylene- cyclohexanecarboxylic acid methyl ester
- Methyltriphenylphosphonium bromide (4.88 g, 13.7 mmol) was suspended in THF. Potassium bis(trimethylsilyl)amide (13.6 mmol, solution in toluene) was added slowly and the mixture was stirred at room temperature for 1 h. The mixture was cooled in a acetone/dry ice bath and the compound of step 1 of example 55 (3.00 g, 6.83 mmol) was added. The mixture was warmed to room temperature and stirred overnight. Methanol and an aqueous sodium dihydrogenphosphate solution were added. The mixture was extracted with diethyl ether, the combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound (1 .40 g).
- Step 2 1 -[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methylene- cyclohexanecarboxylic acid
- step 1 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
- step 1 of example 56 400 mg, 0.91 mmol was dissolved in toluene (8 ml) and diethylzinc (2.7 ml, 2.7 mmol, solution in hexane) was added. The mixture was heated to 60 °C and diiodomethane (1 .10 g, 4.1 1 mmol) was added with stirring. This mixture was reacted at 60 °C overnight, the addition of diethyl zinc and diiodomethane was repeated and stirring continued for another night.
- Step 1 4-Hydroxymethyl-1 -[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoyl
- step 1 of example 56 500 mg, 1 .14 mmol was dissolved in THF (5 ml) and cooled to -25 °C.
- Borane-tetrahydrofuran complex (2.29 ml of a 1 M solution in THF, 2.29 mmol) was added and the mixture was kept overnight at 0 °C.
- Hydrogen peroxide 2.5 ml, 30 % in water
- sodium hydroxide 2.5 ml, 20 % in water
- the mixture was partitioned between water and EA, the aqueous phase extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness.
- the residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound.
- Step 2 4-Hydroxymethyl-1 -[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]- cyclohexanecarboxylic acid
- step 1 The compound of step 1 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound as mixture of the cis isomer and the trans isomer.
- step 1 of example 58 100 mg, 0.220 mmol was dissolved in DCM (2 ml), diethylaminosulfur trifluoride (35 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 72 h. The mixture was partitioned between EA and aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and
- Step 1 1 -(4-Acetyl-3-hydroxy-benzoylamino)-cycloheptanecarboxylic acid methyl ester
- Step 2 1 -[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylannino]-cycloheptanecarboxylic acid methyl ester
- step 1 The compound of step 1 and 2-m-tolylethanol were reacted in analogy to step 1 of example 1 to yield the title compound.
- Step 3 1 -[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid
- the compound of step 2 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
- the compound of example 61 (100 mg) was dissolved in ethanol (10 ml) and hydrogenated in an H-cubeTM hydrogenation reactor at a hydrogen pressure of 10 bar at 35 °C over a cartridge with 10 % palladium on charcoal.
- the reaction mixture was evaporated to dryness and purified by RP HPLC (water/ACN gradient) to yield the title compound (60 mg).
- step 2 of example 60 The compound of step 2 of example 60 (1 10 mg, 0.244 mmol) was dissolved in methanol (1 .1 ml) and cooled in an ice bath. Sodium borohydride (9.2 mg, 0.244 mmol) was added and stirring continued for 1 h. This mixture was partitioned between EA and saturated sodium hydrogencarbonate solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue (100 mg) was dissolved in DCM (2 ml) and diethylaminosulfur trifluoride (36 mg, 0.22 mmol) was added.
- step 1 The compound of step 1 (200 mg, 0.932 mmol) was dissolved in DCM (16 ml), DMF (12 mg) and oxalyl chloride (362 mg, 2.80 mmol) were added and the mixture was stirred at room temperature until completion of the reaction. The volatiles were evaporated in vacuo and the residue dissolved in DCM. The solution was added to a stirred mixture of 1 -amino-cycloheptanecarboxylic acid methyl ester hydrochloride (194 mg, 0.932 mmol) in EA saturated sodium hydrogencarbonate solution with cooling in an ice bath. Stirring continued at room temperature for 2 h.
- Step 3 1 -(4-Chloro-3-hydroxy-benzoylamino)-cycloheptanecarboxylic acid methyl ester
- step 2 The compound of step 2 (400 mg, 1 .088 mmol) was dissolved in methanol (3.5 ml), potassium carbonate (3 mg, 0.02 mmol) was added, and the mixture was stirred at room temperature for 6 h and evaporated to dryness to yield the title compound (300 mg).
- Step 4 1 -[4-Chloro-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid
- the compound of step 3 was etherified with 2-m-tolylethanol in analogy to step 1 of example 1 , and the intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
- Step 1 1 -Amino-2-benzyloxy-cyclopentanecarbonitrile, diastereomer 1 and diastereomer 2
- Step 2a 2-Benzyloxy-1 -[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]- cyclopentanecarboxylic acid, diastereomer 1
- step 1 diastereomer 1
- step 2 diastereomer 1
- step 3 carboxylic acid chloride
- step 4 the obtained ethyl ester
- Step 2b 2-Benzyloxy-1 -[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]- cyclopentanecarboxylic acid, diastereomer 2
- step 1 diastereomer 2
- step 2a The compound of step 1 , diastereomer 2
- Diastereomer 1 and diastereomer 2 of the compound of example 66 were separately dissolved in ethanol and hydrogenated with palladium 10 % on charcoal at room temperature with 1 bar hydrogen pressure until completion of the reaction. After filtration, the solutions were evaporated to dryness and the residues purified by RP HPLC (water/ACN gradient) to yield the two diastereomers of the title compound separately.
- Step 1 3-Fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester and 2-Fluoro-3- hydroxy-4-methoxybenzoic acid methyl ester
- Step 2 1 -[2-Fluoro-4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]- cycloheptanecarboxylic acid
- Step 1 Trifluoromethanesulfonic acid 2,2-difluoro-2-phenyl-ethyl ester
- Step 2 1 -[3-(2,2-Difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]- cycloheptanecarboxylic acid methyl ester
- Step 3 1 -[3-(2,2-Difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]- cycloheptanecarboxylic acid
- the compound of step 2 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
- Step 1 1 -[3-(1 ,3-Dihydroxy-3-m-tolyl-propyl)-4-methoxy-benzoylamino]- cycloheptanecarboxylic acid methyl ester
- diisopropylamide obtained by addition of n-butyllithium in n-hexane (0.317 ml, 2.5 M solution) to diisopropylamine (80.1 mg, 0.792 mmol) in THF (3 ml) at 0 °C and stirring for 10 min
- 3-methylbenzaldehyde 86.5 mg, 0.720 mmol
- 2 N hydrochloric acid and EA were added, the cooling bath was removed, the mixture was brought to room temperature.
- step 1 The compound of step 1 (140 mg, 0.424 mmol) was dissolved in ethanol (10 ml), 12 N hydrochloric acid (0.2 ml) and palladium on charcoal (10 %) was added, and the mixture was hydrogenated at a hydrogen pressure of 6 bar at room temperature overnight. After filtration and evaporation, the residue was purified by silica gel chromatography (HEP/EA gradient) to give 80 mg of the title compound.
- Step 3 1 -[4-Methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-cycloheptanecarboxylic acid From the compound of step 2, the title compound was obtained by hydrolysis of the ester group in analogy to example 1 step 2, reaction of the obtained carboxylic acid with 1 -amino-cycloheptanecarboxylic acid methyl ester hydrochloride in analogy to step 3 of example 1 , and hydrolysis of the ester group in analogy to step 4 of example 1 .
- Step 1 4-Methoxy-3-(2-oxo-2-m-tolyl-ethoxy)-benzoic acid methyl ester 3-Hydroxy-4-methoxybenzoic acid methyl ester (2.50 g, 13.7 mmol) was dissolved in methanol (20 ml), potassium carbonate (3.72 g, 27.4 mmol) and 2-bromo-1 -m-tolyl- ethanone (2.92 g, 13.7 mmol) were added and the mixture was stirred overnight at room temperature. The volatiles were evaporated, the crude material was partitioned between EA and water, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to yield the title compound.
- Step 2 1 -[4-Methoxy-3-(2-oxo-2-m-tolyl-ethoxy)-benzoylamino]- cycloheptanecarboxylic acid ethyl ester
- step 2 was hydrolyzed in analogy to step 2 of example 1 , and the carboxylic acid intermediate was coupled to 1 -amino-cycloheptanecarboxylic acid ethyl ester hydrochloride in analogy to step 1 of example 3 to yield the title
- Step 3 1 -[3-(2-Hydroxy-2-m-tolyl-ethoxy)-4-methoxy-benzoylamino]- cycloheptanecarboxylic acid
- step 2 was reduced with sodium borohydride in analogy to step 2 of example 53, the ester intermediate purified by RP HPLC (water/ACN gradient) and hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
- Step 1 1 -Amino-3-methyl-cyclobutanecarboxylic acid ethyl ester hydrochloride 3-Methyl-cyclobutane-1 ,1 -dicarboxylic acid ethyl ester (V. Prelog et al., Helv. Chim. Acta 65 (1982), 2622-2644; 200 mg, 1 .074 mmol) was suspended in acetone (20 ml) and stirred in an ice bath.
- Triethylamine 152 mg, 1 .50 mmol
- isobutyl chloroformate (191 mg, 1 .40 mmol) were added, the mixture was stirred at 0 °C for 30 min, then sodium azide (129 mg, 1 .99 mmol) as solution in water (10 ml) was added, and stirring was continued for 15 min.
- diethyl ether 50 ml was added, the phases were separated. The organic layer was washed with water, dried over sodium sulfate, filtered and added to refluxing toluene in a flask with distillation bridge.
- Step 2 1 -[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-3-methyl- cyclobutanecarboxylic acid
- step 1 The compound of step 1 (65 mg, 0.413 mmol) was coupled to 4-methoxy-3-(2-m- tolyl-ethoxy)-benzoic acid in analogy to step 1 of example 3.
- the ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound as mixture of the cis isomer and the trans isomer.
- 6-Chloro-5-nitro-nicotinic acid methyl ester was prepared according to the procedure described in WO 2005/021544 and transformed into 5-hydroxy-6-methoxy-nicotinic acid methyl ester according to the procedure described in WO 95/04045.
- the intermediate was transformed into the title compound by etherification with 2-m-tolyl- ethanol in analogy to step 1 of example 1 , hydrolysis of the ester group in analogy to step 2 of example 1 , reaction of the obtained carboxylic acid with 1 -amino- cycloheptanecarboxylic acid methyl ester hydrochloride in analogy to step 3 of example 1 and hydrolysis in analogy to step 4 of example 1 .
- the title compound was synthesized in analogy to example 77 using 1 -amino- cyclooctanecarboxylic acid methyl ester hydrochloride instead of 1 -amino- cycloheptanecarboxylic acid methyl ester hydrochloride.
- the title compound was synthesized in analogy to example 77 using cis-1 -amino-4- methyl-cyclohexanecarboxylic acid methyl ester hydrochloride (prepared in analogy to example 25) instead of 1 -amino-cycloheptanecarboxylic acid methyl ester hydrochloride.
- the title compound was synthesized in analogy to example 79 using 2-(2,5-dimethyl- phenyl)-ethanol in the etherification step.
- the title compound was synthesized in analogy to example 80 using 1 -amino-4-tert- butyl-cyclohexanecarbonit le in the amide coupling step.
- the title compound was synthesized in analogy to example 90 using cis-1 -amino-4- methyl-cyclohexanecarboxylic acid methyl ester hydrochloride instead of trans-1 - amino-4-methyl-cyclohexanecarboxylic acid methyl ester hydrochloride.
- step 1 The compound of step 1 (1 .85 g, 7.97 mmol) was dissolved in thionyl chloride (6 ml) and stirred for 30 min at 60 °C. The volatiles were evaporated in vacuo, the residue was dissolved in DCM and added to a stirred mixture of 1 -amino- cycloheptanecarboxylic acid methyl ester hydrochloride, EA and saturated sodium hydrogencarbonate solution with ice cooling. The mixture was stirred at room temperature overnight, the phases were separated and the aqueous phase was extracted with EA. The combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the title compound (2.80 g).
- step 2 The compound of step 2 (300 mg, 0.779 mmol), 3-cyano-phenylboronic acid (171 mg, 1 .17 mmol), tris(dibenzylideneacetone)dipalladium(0) (214 mg, 0.234 mmol), potassium fluoride (149 mg, 2.57 mmol) and tri-tert-butylphosphonium
- Step 4 1 - ⁇ [5-(3-Cyano-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino ⁇ - cycloheptanecarboxylic acid
- step 3 The compound of step 3 was hydrolyzed in analogy to step 4 of example 1 at a hydrolysis temperature of 40 °C.
- the residue obtained after evaporation of the EA extracts was purified by RP HPLC (water/ACN gradient) to yield the title compound.
- 1 H-NMR: ⁇ 12.1 (s, 1 H); 8.68 (d, 1 H); 8.32 (s, 1 H); 8.24 (d, 1 H); 8.09 (s, 1 H); 7.96 (d, 1 H); 7.88 (d, 1 H); 7.69 (t, 1 H); 3.95 (s, 3H); 2.15-2.04 (m, 4H); 1 .60-1 .45 (m, 8H)
- the example compounds of the formula I-4 listed in table 4 were prepared by using the respective substituted phenylboronic acid instead of 3- cyano-phenylboronic acid.
- the compounds of the formula I-4 listed in table 4 can be named as 1 -[(5-R 104 -6-methoxy-pyridine-3-carbonyl)-amino]-cycloheptanecarboxylic acid, for example as 1 - ⁇ [5-(3-chloro-phenyl)-6-methoxy-pyridyl-3-carbonyl]-amino ⁇ - cycloheptanecarboxylic acid in the case of example 94.
- the compound can be prepared in analogy to example 92.
- the compound can be prepared in analogy to example 92.
- the example compounds of the formula I-5 listed in table 5 were prepared by synthesizing the intermediate 1 -(3-bromo-4-methoxy- benzoylamino)-cycloheptanecarboxylic acid methyl ester in analogy to step 2 of example 92 using 3-bromo-4-methoxybenzoic acid instead of 5-bromo-6-methoxy- nicotinic acid.
- the intermediate was transformed into the example compounds in analogy to example 92, steps 3 and 4, using the appropriate phenylboronic acid.
- the compounds can be named as 1 -[(substituted biphenyl-3-carbonyl)-amino]- cycloheptanecarboxylic acid, for example as 1 -[(3'-cyano-6-methoxy-biphenyl-3- carbonyl)-amino]-cycloheptanecarboxylic acid in the case of example 104 in which the group R 105 is 3-chloro-phenyl and the group 3-(R 105 )-4-methoxy-phenyl-C(O) depicted in formula I-5 thus is the group 3'-cyano-6-methoxy-biphenyl-3-carbonyl.
- Step 1 3- ⁇ 2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy ⁇ -4-methoxy-benzoic acid
- step 1 The compound of step 1 (280 mg, 0.885 mmol) was dissolved in DMF (1 .3 ml) and HOBT (24 mg), 1 -amino-cycloheptanecarboxylic acid methyl ester hydrochloride (221 mg, 1 .06 mmol) and EDIA (578 mg, 4.43 mmol) were added. The mixture was cooled in an ice bath and EDC (254 mg, 1 .33 mmol) was added. The mixture was stirred at room temperature for 3 days and partitioned between EA and water. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC
- Step 3 1 -(3- ⁇ 2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy ⁇ -4-methoxy-benzoylamino)- cycloheptanecarboxylic acid
- step 2 The compound of step 2 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound (89 mg).
- 1 H-NMR: ⁇ 12.0 (s, 1 H); 8.07 (s, 1 H); 7.50 (dd, 1 H); 7.40 (s, 1 H); 7.23-7.18 (m, 2H); 7.15 (d, 1 H); 7.06 (d, 1 H); 7.01 (d, 1 H); 4.61 (t, 1 H); 4.21 (t, 2H); 3.80 (s, 3H); 3.59 (dt, 2H); 3.02 (t, 2H); 2.70 (t, 2H); 2.12-2.02 (m, 4H); 1 .57-1 .42 (m, 8H)
- Example 108 12.0 (s, 1 H); 8.07 (s, 1 H); 7.50 (dd, 1 H); 7.40 (s, 1 H); 7.23-7.18 (m, 2H); 7.15 (d, 1 H); 7.06 (d, 1 H); 7.01 (d, 1 H
- the title compound was synthesized in analogy to example 107 using 1 -amino- cyclooctanecarboxylic acid methyl ester hydrochloride instead of 1 -amino- cycloheptanecarboxylic acid methyl ester hydrochloride.
- the title compound was synthesized in analogy to example 107 using cis-1 -amino-4- methyl-cyclohexanecarboxylic acid methyl ester hydrochloride instead of 1 -amino- cycloheptanecarboxylic acid methyl ester hydrochloride.
- the title compound was synthesized in analogy to example 107 using trans-1 -amino- 4-methyl-cyclohexanecarboxylic acid methyl ester hydrochloride instead of 1 -amino- cycloheptanecarboxylic acid methyl ester hydrochloride.
- the title compound was synthesized in analogy to example 107 using cis-1 -amino-4- ethyl-cyclohexanecarboxylic acid methyl ester hydrochloride instead of 1 -amino- cycloheptanecarboxylic acid methyl ester hydrochloride.
- the title compound was synthesized in analogy to example 107 using trans-1 -amino- 4-ethyl-cyclohexanecarboxylic acid methyl ester hydrochloride instead of 1 -amino- cycloheptanecarboxylic acid methyl ester hydrochloride.
- Step 1 3-Acetoxy-4-hydroxy-benzoic acid ethyl ester 3,4-Dihydroxy-benzoic acid ethyl ester (550 mg, 3.02 mmol) was dissolved in DMF (5 ml), potassium tert-butylate (210 mg, 2.87 mmol) was added and the mixture stirred for 10 min. Acetic anhydride (339 mg, 3.32 mmol) was added and stirring continued for 10 min. The mixture was partitioned between EA and 2 N hydrochloric acid, the aqueous phase extracted with EA, the combined organic phases were dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the title compound.
- Step 2 3-Acetoxy-4-benzyloxy-benzoic acid ethyl ester
- step 1 The compound of step 1 (20 g, 89.2 mmol) was dissolved in DMF (100 ml) and cooled in an ice bath. Potassium carbonate (18.4 g, 134 mmol) and, immediately thereafter, benzyl bromide (15.2 g, 89.2 mmol) were added. This mixture was stirred for 30 min at room temperature, poured on a mixture of 2 N hydrochloric acid and diethyl ether, filtered and washed repeatedly with diethyl ether. The combined ethereal phases were washed with water, dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound (21 g).
- Step 3 4-Benzyloxy-3-hydroxy-benzoic acid ethyl ester
- step 2 The compound of step 2 (10 g, 31 .8 mmol) was dissolved in methanol, potassium carbonate (88 mg, 0.636 mmol) was added and the mixture was stirred for 2 h under reflux. The solution was evaporated to dryness and the residue used without further purification.
- Step 4 4-Benzyloxy-3-[2-(3-chloro-phenyl)-ethoxy]-benzoic acid ethyl ester
- the compound of step 3 was coupled to 2-(3-chloro-phenyl)-ethanol in analogy to step 1 of example 1 to yield the title compound.
- step 4 was hydrolyzed in analogy to step 2 of example 1 to yield the title compound.
- Step 6 cis-1 - ⁇ 4-Benzyloxy-3-[2-(3-chloro-phenyl)-ethoxy]-benzoylamino ⁇ -4-methyl- cyclohexanecarboxylic acid methyl ester
- step 5 The compound of step 5 was coupled to cis-1 -amino-4-methyl-cyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 2 of example 64 to yield the title compound.
- Step 7 cis-1 - ⁇ 3-[2-(3-Chloro-phenyl)-ethoxy]-4-hydroxy-benzoylamino ⁇ -4-methyl- cyclohexanecarboxylic acid methyl ester
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Neurosurgery (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Psychiatry (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Obesity (AREA)
- Oncology (AREA)
- Vascular Medicine (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2010313162A AU2010313162A1 (en) | 2009-11-02 | 2010-11-02 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
JP2012537183A JP5847088B2 (en) | 2009-11-02 | 2010-11-02 | Acylamino substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
BR112012010282A BR112012010282A2 (en) | 2009-11-02 | 2010-11-02 | acylamino substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
MX2012004739A MX2012004739A (en) | 2009-11-02 | 2010-11-02 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals. |
EP10776045.6A EP2496556B1 (en) | 2009-11-02 | 2010-11-02 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
CN2010800603352A CN102858745A (en) | 2009-11-02 | 2010-11-02 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
RU2012122805/04A RU2012122805A (en) | 2009-11-02 | 2010-11-02 | DERIVATIVES OF ACYLAMIN-SUBSTITUTED CYCLIC CARBONIC ACID AND THEIR APPLICATION AS PHARMACEUTICALS |
CA2779268A CA2779268A1 (en) | 2009-11-02 | 2010-11-02 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
TNP2012000160A TN2012000160A1 (en) | 2009-11-02 | 2012-04-04 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
ZA2012/02635A ZA201202635B (en) | 2009-11-02 | 2012-04-12 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
IL219354A IL219354A0 (en) | 2009-11-02 | 2012-04-22 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
US13/461,264 US8618304B2 (en) | 2009-11-02 | 2012-05-01 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
MA34905A MA33772B1 (en) | 2009-11-02 | 2012-05-30 | Alternative cyclo-carboxylic acid derivatives with acilamino used as pharmaceuticals |
US14/091,511 US9018383B2 (en) | 2009-11-02 | 2013-11-27 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09290831 | 2009-11-02 | ||
EP09290831.8 | 2009-11-02 | ||
US31961910P | 2010-03-31 | 2010-03-31 | |
US61/319,619 | 2010-03-31 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/461,264 Continuation US8618304B2 (en) | 2009-11-02 | 2012-05-01 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011053948A1 true WO2011053948A1 (en) | 2011-05-05 |
Family
ID=42040612
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2010/055035 WO2011053948A1 (en) | 2009-11-02 | 2010-11-02 | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals |
Country Status (23)
Country | Link |
---|---|
US (2) | US8618304B2 (en) |
EP (1) | EP2496556B1 (en) |
JP (1) | JP5847088B2 (en) |
KR (1) | KR20120101429A (en) |
CN (1) | CN102858745A (en) |
AR (1) | AR079022A1 (en) |
AU (1) | AU2010313162A1 (en) |
BR (1) | BR112012010282A2 (en) |
CA (1) | CA2779268A1 (en) |
CO (1) | CO6541540A2 (en) |
CR (1) | CR20120203A (en) |
DO (1) | DOP2012000121A (en) |
EC (1) | ECSP12011861A (en) |
IL (1) | IL219354A0 (en) |
MA (1) | MA33772B1 (en) |
MX (1) | MX2012004739A (en) |
PE (1) | PE20121477A1 (en) |
RU (1) | RU2012122805A (en) |
TN (1) | TN2012000160A1 (en) |
TW (1) | TW201127379A (en) |
UY (1) | UY32990A (en) |
WO (1) | WO2011053948A1 (en) |
ZA (1) | ZA201202635B (en) |
Cited By (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013070879A1 (en) | 2011-11-10 | 2013-05-16 | Bristol-Myers Squibb Company | Methods for treating spinal cord injury with lpa receptor antagonists |
US20130296326A1 (en) * | 2012-05-07 | 2013-11-07 | Translational Genomics Research Institute | Susceptibility of tumors to tyrosine kinase inhibitors and treatment thereof |
US8884034B2 (en) | 2009-07-08 | 2014-11-11 | Dermira (Canada), Inc. | TOFA analogs useful in treating dermatological disorders or conditions |
US8975235B2 (en) | 2011-03-20 | 2015-03-10 | Intermune, Inc. | Lysophosphatidic acid receptor antagonists |
EP2934514A4 (en) * | 2012-12-21 | 2016-06-08 | Univ Leland Stanford Junior | Transthyretin stabilizers and their use for inhibiting transthyretin amyloidosis and protein-protein interactions |
WO2016197009A1 (en) | 2015-06-05 | 2016-12-08 | Vertex Pharmaceuticals Incorporated | Triazoles for the treatment of demyelinating diseases |
US9845319B2 (en) | 2014-10-30 | 2017-12-19 | Janssen Pharmaceutiuca NV | Amide substituted thiazoles as modulators of RORyt |
US9850236B2 (en) | 2014-10-30 | 2017-12-26 | Janssen Pharmaceutica Nv | Trifluoromethyl alcohols as modulators of RORγt |
US9861618B2 (en) | 2014-10-30 | 2018-01-09 | Janssen Pharmaceutica Nv | Thiazoles as modulators of RORγt |
WO2018106641A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Pyrazoles for the treatment of demyelinating diseases |
WO2018106646A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Aminotriazoles for the treatment of demyelinating diseases |
WO2018106643A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Heterocyclic azoles for the treatment of demyelinating diseases |
US10513497B2 (en) | 2017-02-17 | 2019-12-24 | Eidos Therapeutics, Inc. | Process for preparing AG-10, its intermediates, and salts thereof |
WO2020021097A1 (en) * | 2018-07-26 | 2020-01-30 | F. Hoffmann-La Roche Ag | Compounds for use in treating kidney disorders |
US10633384B2 (en) | 2012-06-13 | 2020-04-28 | Hoffmann-La Roche Inc. | Diazaspirocycloalkane and azaspirocycloalkane |
US10640472B2 (en) | 2015-09-04 | 2020-05-05 | Hoffman-La Roche Inc. | Phenoxymethyl derivatives |
US10647719B2 (en) | 2015-09-24 | 2020-05-12 | Hoffmann-La Roche Inc. | Bicyclic compounds as dual ATX/CA inhibitors |
US10654857B2 (en) | 2014-03-26 | 2020-05-19 | Hoffman-La Roche Inc. | Bicyclic compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors |
US10669268B2 (en) | 2012-09-25 | 2020-06-02 | Hoffmann-La Roche Inc. | Bicyclic derivatives |
US10669285B2 (en) | 2014-03-26 | 2020-06-02 | Hoffmann-La Roche Inc. | Condensed [1,4] diazepine compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors |
US10676446B2 (en) | 2015-04-10 | 2020-06-09 | Hoffmann-La Roche Inc. | Bicyclic quinazolinone derivatives |
US10738053B2 (en) | 2015-09-24 | 2020-08-11 | Hoffmann-La Roche Inc. | Bicyclic compounds as dual ATX/CA inhibitors |
US10787459B2 (en) | 2015-09-24 | 2020-09-29 | Hoffmann-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US10800786B2 (en) | 2015-09-24 | 2020-10-13 | Hoffman-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US10849881B2 (en) | 2013-11-26 | 2020-12-01 | Hoffmann-La Roche Inc. | Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl |
US10882857B2 (en) | 2017-03-16 | 2021-01-05 | Hoffmann-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US10913745B2 (en) | 2013-03-12 | 2021-02-09 | Hoffmann-La Roche Inc. | Octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors |
US10975037B2 (en) | 2018-06-18 | 2021-04-13 | Janssen Pharmaceutica Nv | Phenyl substituted pyrazoles as modulators of RORγt |
US10975057B2 (en) | 2018-06-18 | 2021-04-13 | Janssen Pharmaceutica Nv | 6-aminopyridin-3-yl pyrazoles as modulators of RORgT |
US10975068B2 (en) | 2016-04-27 | 2021-04-13 | Janssen Pharmaceutica Nv | 6-aminopyridin-3-yl thiazoles as modulators of RORγT |
US11034658B2 (en) | 2018-06-18 | 2021-06-15 | Janssen Pharmaceutica Nv | Pyridinyl pyrazoles as modulators of RORγT |
US11058668B2 (en) | 2018-03-23 | 2021-07-13 | Eidos Therapeutics, Inc. | Methods of treating TTR amyloidosis using AG10 |
US11059794B2 (en) | 2017-03-16 | 2021-07-13 | Hoffmann-La Roche Inc. | Heterocyclic compounds useful as dual ATX/CA inhibitors |
US11260047B2 (en) | 2018-08-17 | 2022-03-01 | Eidos Therapeutics, Inc. | Formulations of AG10 |
US11345666B2 (en) | 2018-06-18 | 2022-05-31 | Janssen Pharmaceutica Nv | Phenyl and pyridinyl substituted imidazoles as modulators of RORγT |
US11548871B2 (en) | 2019-11-15 | 2023-01-10 | Gilead Sciences, Inc. | Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof |
US11584738B2 (en) | 2020-06-03 | 2023-02-21 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
US11702407B2 (en) | 2020-06-03 | 2023-07-18 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
US11884627B2 (en) | 2022-02-25 | 2024-01-30 | Lhotse Bio, Inc. | Compounds and compositions for treating conditions associated with LPA receptor activity |
US11939318B2 (en) | 2021-12-08 | 2024-03-26 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
US11980609B2 (en) | 2021-05-11 | 2024-05-14 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101798840B1 (en) | 2017-05-17 | 2017-11-17 | 주식회사 레고켐 바이오사이언스 | Novel Compounds as Autotaxin Inhibitors and Pharmaceutical Compositions Comprising the Same |
US10961242B2 (en) | 2017-05-17 | 2021-03-30 | Legochem Biosciences, Inc. | Compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same |
CN108276307A (en) * | 2018-01-17 | 2018-07-13 | 常熟浸大科技有限公司 | The synthetic method of 3- cyano -4- oxyl benzoic ethers |
KR102224677B1 (en) * | 2018-08-23 | 2021-03-08 | 가천대학교 산학협력단 | Thiazolopiperazine derivatives and composition for preventing or treating autoimmune diseases comprising the same |
CN111574389B (en) * | 2020-05-14 | 2023-08-18 | 河北威远生物化工有限公司 | Process for preparing cis-isomer of 1-amino-4-substituted cyclohexylcarboxylic acid and salts thereof |
Citations (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4871387A (en) | 1985-12-05 | 1989-10-03 | Bayer Aktiengesellschaft | Pyri(mi)dyl-oxy-and -thio-benzoic acid derivatives useful as herbicides and plant growth regulants |
WO1995004045A1 (en) | 1993-07-28 | 1995-02-09 | Rhone-Poulenc Rorer Limited | Compounds as pde iv and tnf inhibitors |
WO1999049856A2 (en) | 1998-03-27 | 1999-10-07 | Genentech, Inc. | Antagonists for treatment of cd11/cd18 adhesion receptor mediated disorders |
WO2002004665A2 (en) | 2000-07-08 | 2002-01-17 | Aventis Pharma Deutschland Gmbh | Method with a wide range of applications, for identifying modulators of g-protein-coupled receptors |
WO2002006232A1 (en) | 2000-07-17 | 2002-01-24 | Wyeth | Cyclic amine phenyl beta-3 adrenergic receptor agonists |
US6358960B1 (en) * | 1998-02-17 | 2002-03-19 | Ono Pharmaceutical Co., Ltd. | Amidino derivatives and drugs containing the same as the active ingredient |
WO2002029001A2 (en) | 2000-10-03 | 2002-04-11 | University Of Virginian Patent Foundation | Novel lysophosphatidic acid receptor agonists and antagonists |
EP1258484A1 (en) | 2000-02-18 | 2002-11-20 | Kirin Beer Kabushiki Kaisha | Novel isoxazole and thiazole compounds and use thereof as drugs |
WO2003062392A2 (en) | 2002-01-18 | 2003-07-31 | Ceretek Llc | Methods of treating conditions associated with an edg receptor |
WO2004011457A1 (en) | 2002-07-26 | 2004-02-05 | Yuhan Corporation | 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof |
WO2004052921A1 (en) | 2002-12-05 | 2004-06-24 | Axys Pharmaceuticals, Inc. | Cyanomethyl derivatives as cysteine protease inhibitors |
WO2005009389A2 (en) | 2003-07-23 | 2005-02-03 | Exelixis, Inc. | Anaplastic lymphoma kinase modulators and methods of use |
WO2005021544A2 (en) | 2003-08-21 | 2005-03-10 | Osi Pharmaceuticals, Inc. | N3-substituted imidazopyridine-derivatives as c-kit inhibitors |
EP1533294A1 (en) | 2002-05-28 | 2005-05-25 | Ono Pharmaceutical Co., Ltd. | Beta-alanine derivative and use thereof |
WO2005115150A2 (en) | 2004-05-06 | 2005-12-08 | University Of Virginia Patent Foundation | Novel lysophosphatidic acid receptor selective antagonists |
WO2006044775A2 (en) * | 2004-10-15 | 2006-04-27 | Bayer Pharmaceuticals Corporation | Preparation and use of biphenyl-4-yl-carbonylamino acid derivatives for the treatment of obesity |
EP1695955A1 (en) | 2003-12-19 | 2006-08-30 | Ono Pharmaceutical Co., Ltd. | Compounds having lysophosphatidic acid receptor antagonism and uses thereof |
WO2008000409A1 (en) * | 2006-06-28 | 2008-01-03 | Sanofi-Aventis | New cxcr2 inhibitors |
EP1972615A1 (en) * | 2006-01-11 | 2008-09-24 | Seikagaku Corporation | Cycloalkanecarboxamide derivative and method for producing same |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5259644A (en) * | 1975-11-11 | 1977-05-17 | Sankyo Co Ltd | Stabilizer for polymer |
WO2000055125A2 (en) * | 1999-03-15 | 2000-09-21 | Axys Pharmaceuticals, Inc. | N-cyanomethyl amides as protease inhibitors |
EP1644336B1 (en) | 2003-06-06 | 2011-01-19 | Fibrogen, Inc. | Nitrogen-containing heteroaryl compounds and their use in increasing endogeneous erythropoietin |
US7683097B2 (en) * | 2004-05-27 | 2010-03-23 | Propharmacon Inc. | Topoisomerase inhibitors |
GB2414403B (en) | 2004-05-28 | 2009-01-07 | Cilag Ag Int | Injection device |
ATE502025T1 (en) | 2004-10-19 | 2011-04-15 | Compass Pharmaceuticals Llc | ARYLCARBOXAMIDES AND THEIR USE AS ANTI-TUMOR AGENTS |
RU2007119427A (en) * | 2004-11-09 | 2008-12-20 | СмитКлайн Бичем Корпорейшн (US) | COMPOUNDS WHICH ARE GYCLOGENFOSPHORILASE INHIBITORS AND PHARMACEUTICAL COMPOSITIONS ON THE BASIS |
JPWO2006088246A1 (en) | 2005-02-18 | 2008-07-10 | 武田薬品工業株式会社 | GPR34 receptor function regulator |
JP5463034B2 (en) | 2005-05-20 | 2014-04-09 | アラントス・フアーマシユーテイカルズ・ホールデイング・インコーポレイテツド | Pyrimidine or triazine fused bicyclic metalloprotease inhibitors |
ES2265276B1 (en) | 2005-05-20 | 2008-02-01 | Laboratorios Almirall S.A. | DERIVATIVES OF 4- (2-AMINO-1-HYDROXYETHYL) Phenol as agonists of the BETA2 ADRENERGIC RECEIVER. |
US20100016295A1 (en) * | 2005-07-29 | 2010-01-21 | Bayer Healthcare Llc | Preparation and Use of Biphenyl Amino Acid Derivatives for the Treatment of Obesity |
FR2904827B1 (en) * | 2006-08-11 | 2008-09-19 | Sanofi Aventis Sa | 5,6-BISARYL-2-PYRIDINE CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE AS UROTENSIN II RECEPTOR ANTIGANISTS |
SG190620A1 (en) | 2008-05-05 | 2013-06-28 | Sanofi Aventis | Acylamino-substituted fused cyclopentanecarboxylic acid derivatives and their use as pharmaceuticals |
JP2011524893A (en) * | 2008-06-18 | 2011-09-08 | ファイザー・リミテッド | Nicotinamide derivatives |
-
2010
- 2010-10-29 AR ARP100104007 patent/AR079022A1/en not_active Application Discontinuation
- 2010-11-01 TW TW99137400A patent/TW201127379A/en unknown
- 2010-11-01 UY UY32990A patent/UY32990A/en not_active Application Discontinuation
- 2010-11-02 BR BR112012010282A patent/BR112012010282A2/en not_active IP Right Cessation
- 2010-11-02 MX MX2012004739A patent/MX2012004739A/en not_active Application Discontinuation
- 2010-11-02 CN CN2010800603352A patent/CN102858745A/en active Pending
- 2010-11-02 AU AU2010313162A patent/AU2010313162A1/en not_active Abandoned
- 2010-11-02 RU RU2012122805/04A patent/RU2012122805A/en not_active Application Discontinuation
- 2010-11-02 WO PCT/US2010/055035 patent/WO2011053948A1/en active Application Filing
- 2010-11-02 EP EP10776045.6A patent/EP2496556B1/en active Active
- 2010-11-02 KR KR20127014323A patent/KR20120101429A/en not_active Application Discontinuation
- 2010-11-02 PE PE2012000558A patent/PE20121477A1/en not_active Application Discontinuation
- 2010-11-02 JP JP2012537183A patent/JP5847088B2/en not_active Expired - Fee Related
- 2010-11-02 CA CA2779268A patent/CA2779268A1/en not_active Abandoned
-
2012
- 2012-04-04 TN TNP2012000160A patent/TN2012000160A1/en unknown
- 2012-04-12 ZA ZA2012/02635A patent/ZA201202635B/en unknown
- 2012-04-22 IL IL219354A patent/IL219354A0/en unknown
- 2012-04-25 CR CR20120203A patent/CR20120203A/en unknown
- 2012-04-26 DO DO2012000121A patent/DOP2012000121A/en unknown
- 2012-04-30 EC ECSP12011861 patent/ECSP12011861A/en unknown
- 2012-05-01 US US13/461,264 patent/US8618304B2/en not_active Expired - Fee Related
- 2012-05-02 CO CO12071019A patent/CO6541540A2/en unknown
- 2012-05-30 MA MA34905A patent/MA33772B1/en unknown
-
2013
- 2013-11-27 US US14/091,511 patent/US9018383B2/en not_active Expired - Fee Related
Patent Citations (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4871387A (en) | 1985-12-05 | 1989-10-03 | Bayer Aktiengesellschaft | Pyri(mi)dyl-oxy-and -thio-benzoic acid derivatives useful as herbicides and plant growth regulants |
WO1995004045A1 (en) | 1993-07-28 | 1995-02-09 | Rhone-Poulenc Rorer Limited | Compounds as pde iv and tnf inhibitors |
US6358960B1 (en) * | 1998-02-17 | 2002-03-19 | Ono Pharmaceutical Co., Ltd. | Amidino derivatives and drugs containing the same as the active ingredient |
WO1999049856A2 (en) | 1998-03-27 | 1999-10-07 | Genentech, Inc. | Antagonists for treatment of cd11/cd18 adhesion receptor mediated disorders |
EP1258484A1 (en) | 2000-02-18 | 2002-11-20 | Kirin Beer Kabushiki Kaisha | Novel isoxazole and thiazole compounds and use thereof as drugs |
WO2002004665A2 (en) | 2000-07-08 | 2002-01-17 | Aventis Pharma Deutschland Gmbh | Method with a wide range of applications, for identifying modulators of g-protein-coupled receptors |
WO2002006232A1 (en) | 2000-07-17 | 2002-01-24 | Wyeth | Cyclic amine phenyl beta-3 adrenergic receptor agonists |
WO2002029001A2 (en) | 2000-10-03 | 2002-04-11 | University Of Virginian Patent Foundation | Novel lysophosphatidic acid receptor agonists and antagonists |
WO2003062392A2 (en) | 2002-01-18 | 2003-07-31 | Ceretek Llc | Methods of treating conditions associated with an edg receptor |
EP1533294A1 (en) | 2002-05-28 | 2005-05-25 | Ono Pharmaceutical Co., Ltd. | Beta-alanine derivative and use thereof |
WO2004011457A1 (en) | 2002-07-26 | 2004-02-05 | Yuhan Corporation | 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof |
WO2004052921A1 (en) | 2002-12-05 | 2004-06-24 | Axys Pharmaceuticals, Inc. | Cyanomethyl derivatives as cysteine protease inhibitors |
WO2005009389A2 (en) | 2003-07-23 | 2005-02-03 | Exelixis, Inc. | Anaplastic lymphoma kinase modulators and methods of use |
WO2005021544A2 (en) | 2003-08-21 | 2005-03-10 | Osi Pharmaceuticals, Inc. | N3-substituted imidazopyridine-derivatives as c-kit inhibitors |
EP1695955A1 (en) | 2003-12-19 | 2006-08-30 | Ono Pharmaceutical Co., Ltd. | Compounds having lysophosphatidic acid receptor antagonism and uses thereof |
WO2005115150A2 (en) | 2004-05-06 | 2005-12-08 | University Of Virginia Patent Foundation | Novel lysophosphatidic acid receptor selective antagonists |
WO2006044775A2 (en) * | 2004-10-15 | 2006-04-27 | Bayer Pharmaceuticals Corporation | Preparation and use of biphenyl-4-yl-carbonylamino acid derivatives for the treatment of obesity |
EP1972615A1 (en) * | 2006-01-11 | 2008-09-24 | Seikagaku Corporation | Cycloalkanecarboxamide derivative and method for producing same |
WO2008000409A1 (en) * | 2006-06-28 | 2008-01-03 | Sanofi-Aventis | New cxcr2 inhibitors |
Non-Patent Citations (47)
Title |
---|
"Organic Reactions", JOHN WILEY & SONS |
A. B. SMITH ET AL., J. AM. CHEM. SOC., vol. 108, 1986, pages 3040 - 3048 |
A. BOUCHARABA ET AL., PROC. NATL. ACAD. SCI., vol. 103, 2006, pages 9643 - 9648 |
A. M. TAGER ET AL., NAT. MED., vol. 14, 2008, pages 45 - 54 |
A. PALMETSHOFER ET AL., THROMB. HAEMOST., vol. 82, 1999, pages 1532 - 1537 |
A. WARM ET AL., HELV. CHIM. ACTA, vol. 70, 1987, pages 690 - 700 |
B. CREMERS ET AL., J. MOL. CELL. CARDIOL., vol. 35, 2003, pages 71 - 80 |
B. FOEHLISCH ET AL., CHEM. BER., vol. 120, 1987, pages 1951 - 1960 |
D. J. PASTO ET AL., ORGANIC REACTIONS, vol. 40, 1991, pages 91 - 155 |
D. SHIDA ET AL., CANCER RES., vol. 63, 2003, pages 1706 - 1711 |
E. ROTHER ET AL., CIRCULATION, vol. 108, 2003, pages 741 - 747 |
EUR. J. ORG. CHEM., vol. 1, 2004, pages 64 |
F. ALONSO ET AL., TETRAHEDRON, vol. 51, 1995, pages 10259 - 10280 |
H. LEE ET AL., AM. J. PHYSIOL., vol. 287, 2004, pages C1657 - C1666 |
HOUBEN-WEYL: "Methods of Organic Chemistry", THIEME |
I. L. MUNDAY, J. CHEM. SOC., 1961, pages 4372 - 4379 |
ISHII ET AL., ANNU. REV. BIOCHEM., vol. 73, 2004, pages 321 - 354 |
J. CHEN ET AL., CELL. BIOCHEM., vol. 103, 2008, pages 1718 - 1731 |
J. CHEN ET AL., FEBS LETTERS, vol. 580, 2006, pages 4737 - 4745 |
J. P. PRADERE ET AL., J. AM. SOC. NEPHROL., vol. 18, 2007, pages 3110 - 3118 |
J. W. TSANG ET AL., J. MED. CHEM., vol. 27, 1984, pages 1663 - 1668 |
K. HAMMER ET AL., TETRAHEDRON, vol. 53, 1997, pages 2309 - 2322 |
K. YOSHIDA ET AL., CIRCULATION, vol. 108, 2003, pages 1746 - 1752 |
M. D. OKUSA ET AL., AM. J. PHYSIOL. RENAL PHYSIOL., vol. 285, 2003, pages F565 - F574 |
M. INOUE ET AL., NAT. MED., vol. 10, 2004, pages 712 - 718 |
M. JORGENSEN ET AL., J. AM. CHEM. SOC., vol. 124, 2002, pages 12557 - 12565 |
M. OBA ET AL., TETRAHEDRON, vol. 61, 2005, pages 593 - 598 |
N. MIYAURA ET AL., CHEM. REV., vol. 95, 1995, pages 2457 - 2483 |
O. MITSUNOBU, SYNTHESIS, 1981, pages 1 - 28 |
P. G. M. WUTS; T. W. GREENE: "Greene's Protective Groups in Organic Synthesis", 2007, JOHN WILEY & SONS |
R. C. LAROCK: "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 1999, JOHN WILEY & SONS |
R. CHINCHILLA ET AL., CHEM. REV., vol. 107, 2007, pages 874 - 922 |
R. GUO ET AL., ENDOCRINOLOGY, vol. 147, 2006, pages 4883 - 4892 |
R. HILAL-DANDAN ET AL., J. MOL. CELL. CARDIOL., vol. 36, 2004, pages 481 - 493 |
S. BRAULT ET AL., AM. J. PHYSIOL. REGUL. INTEGR. COMP. PHYSIOL., vol. 292, 2007, pages R1174 - R1183 |
S. SEEWALD ET AL., ATHEROSCLEROSIS, vol. 130, 1997, pages 121 - 131 |
T. KLINE ET AL., J. MED. CHEM., vol. 45, 2002, pages 3112 - 3129 |
T. N. WHEELER, SYNTH. COMMUN., vol. 18, 1988, pages 141 - 149 |
T. SANO, J. BIOL. CHEM., vol. 277, 2002, pages 21197 - 21206 |
U. KANEYUKI ET AL., VASCULAR PHARMACOLOGY, vol. 46, 2007, pages 286 - 292 |
V. PRELOG ET AL., HELV. CHIM. ACTA, vol. 65, 1982, pages 2622 - 2644 |
W. J. THOMPSON ET AL., J. ORG. CHEM., vol. 49, 1984, pages 5237 - 5243 |
W. LINZ ET AL., JRAAS, vol. 7, 2006, pages 155 - 161 |
W. SIESS ET AL., PROC. NATL. ACAD. SCI., vol. 96, 1999, pages 6931 - 6936 |
X. CHEN ET AL., SCAND. J. CLIN. LAB. INVEST., vol. 63, 2003, pages 497 - 503 |
Y. XING ET AL., AM. J. PHYSIOL. CELL PHYSIOL., vol. 287, 2004, pages F1250 - F1257 |
Y.-J. XU ET AL., BIOCHEMICAL PHARMACOLOGY, vol. 59, 2000, pages 1163 - 1171 |
Cited By (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9434718B2 (en) | 2009-07-08 | 2016-09-06 | Dermira (Canada), Inc. | TOFA analogs useful in treating dermatological disorders or conditions |
US9782382B2 (en) | 2009-07-08 | 2017-10-10 | Dermira (Canada), Inc. | TOFA analogs useful in treating dermatological disorders or conditions |
US8884034B2 (en) | 2009-07-08 | 2014-11-11 | Dermira (Canada), Inc. | TOFA analogs useful in treating dermatological disorders or conditions |
US8975235B2 (en) | 2011-03-20 | 2015-03-10 | Intermune, Inc. | Lysophosphatidic acid receptor antagonists |
WO2013070879A1 (en) | 2011-11-10 | 2013-05-16 | Bristol-Myers Squibb Company | Methods for treating spinal cord injury with lpa receptor antagonists |
US9254288B2 (en) * | 2012-05-07 | 2016-02-09 | The Translational Genomics Research Institute | Susceptibility of tumors to tyrosine kinase inhibitors and treatment thereof |
US20130296326A1 (en) * | 2012-05-07 | 2013-11-07 | Translational Genomics Research Institute | Susceptibility of tumors to tyrosine kinase inhibitors and treatment thereof |
US10633384B2 (en) | 2012-06-13 | 2020-04-28 | Hoffmann-La Roche Inc. | Diazaspirocycloalkane and azaspirocycloalkane |
US10669268B2 (en) | 2012-09-25 | 2020-06-02 | Hoffmann-La Roche Inc. | Bicyclic derivatives |
EP2934514A4 (en) * | 2012-12-21 | 2016-06-08 | Univ Leland Stanford Junior | Transthyretin stabilizers and their use for inhibiting transthyretin amyloidosis and protein-protein interactions |
US10398681B2 (en) | 2012-12-21 | 2019-09-03 | The Board Of Trustees Of The Leland Stanford Junior University | Compounds and compositions that bind and stabilize transthyretin and their use for inhibiting transthyretin amyloidosis and protein-protein interactions |
US10842777B2 (en) | 2012-12-21 | 2020-11-24 | The Board Of Trustees Of The Leland Stanford Junior University | Compounds and compositions that bind and stabilize transthyretin and their use for inhibiting transthyretin amyloidosis and protein-protein interactions |
US9913826B2 (en) | 2012-12-21 | 2018-03-13 | The Board Of Trustees Of The Leland Stanford Junior University | Compounds and compositions that bind and stabilize transthyretin and their use for inhibiting transthyretin amyloidosis and protein-protein interactions |
US10913745B2 (en) | 2013-03-12 | 2021-02-09 | Hoffmann-La Roche Inc. | Octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors |
US10849881B2 (en) | 2013-11-26 | 2020-12-01 | Hoffmann-La Roche Inc. | Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl |
US10654857B2 (en) | 2014-03-26 | 2020-05-19 | Hoffman-La Roche Inc. | Bicyclic compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors |
US11098048B2 (en) | 2014-03-26 | 2021-08-24 | Hoffmann-La Roche Inc. | Bicyclic compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors |
US10669285B2 (en) | 2014-03-26 | 2020-06-02 | Hoffmann-La Roche Inc. | Condensed [1,4] diazepine compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors |
US10150762B2 (en) | 2014-10-30 | 2018-12-11 | Janssen Pharmaceutica, Nv | Trifluoromethyl alcohols as modulators of RORγt |
US9861618B2 (en) | 2014-10-30 | 2018-01-09 | Janssen Pharmaceutica Nv | Thiazoles as modulators of RORγt |
US9845319B2 (en) | 2014-10-30 | 2017-12-19 | Janssen Pharmaceutiuca NV | Amide substituted thiazoles as modulators of RORyt |
US10080744B2 (en) | 2014-10-30 | 2018-09-25 | Janssen Pharmaceutica Nv | Thiazoles as modulators of RORγt |
US9850236B2 (en) | 2014-10-30 | 2017-12-26 | Janssen Pharmaceutica Nv | Trifluoromethyl alcohols as modulators of RORγt |
US10676446B2 (en) | 2015-04-10 | 2020-06-09 | Hoffmann-La Roche Inc. | Bicyclic quinazolinone derivatives |
WO2016197009A1 (en) | 2015-06-05 | 2016-12-08 | Vertex Pharmaceuticals Incorporated | Triazoles for the treatment of demyelinating diseases |
US11352330B2 (en) | 2015-09-04 | 2022-06-07 | Hoffmann-La Roche Inc. | Phenoxymethyl derivatives |
US10640472B2 (en) | 2015-09-04 | 2020-05-05 | Hoffman-La Roche Inc. | Phenoxymethyl derivatives |
US10889588B2 (en) | 2015-09-24 | 2021-01-12 | Hoffmann-La Roche Inc. | Bicyclic compounds as dual ATX/CA inhibitors |
US10738053B2 (en) | 2015-09-24 | 2020-08-11 | Hoffmann-La Roche Inc. | Bicyclic compounds as dual ATX/CA inhibitors |
US10787459B2 (en) | 2015-09-24 | 2020-09-29 | Hoffmann-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US10800786B2 (en) | 2015-09-24 | 2020-10-13 | Hoffman-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US10647719B2 (en) | 2015-09-24 | 2020-05-12 | Hoffmann-La Roche Inc. | Bicyclic compounds as dual ATX/CA inhibitors |
US10975068B2 (en) | 2016-04-27 | 2021-04-13 | Janssen Pharmaceutica Nv | 6-aminopyridin-3-yl thiazoles as modulators of RORγT |
WO2018106646A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Aminotriazoles for the treatment of demyelinating diseases |
WO2018106641A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Pyrazoles for the treatment of demyelinating diseases |
WO2018106643A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Heterocyclic azoles for the treatment of demyelinating diseases |
US11078162B2 (en) | 2017-02-17 | 2021-08-03 | Eidos Therapeutics, Inc. | Processes for preparing AG-10, its intermediates, and salts thereof |
US11919865B2 (en) | 2017-02-17 | 2024-03-05 | Eidos Therapeutics, Inc. | Processes for preparing AG-10, its intermediates, and salts thereof |
US10513497B2 (en) | 2017-02-17 | 2019-12-24 | Eidos Therapeutics, Inc. | Process for preparing AG-10, its intermediates, and salts thereof |
US11673888B2 (en) | 2017-03-16 | 2023-06-13 | Hoffmann-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US10882857B2 (en) | 2017-03-16 | 2021-01-05 | Hoffmann-La Roche Inc. | Bicyclic compounds as ATX inhibitors |
US11059794B2 (en) | 2017-03-16 | 2021-07-13 | Hoffmann-La Roche Inc. | Heterocyclic compounds useful as dual ATX/CA inhibitors |
US11058668B2 (en) | 2018-03-23 | 2021-07-13 | Eidos Therapeutics, Inc. | Methods of treating TTR amyloidosis using AG10 |
US10975037B2 (en) | 2018-06-18 | 2021-04-13 | Janssen Pharmaceutica Nv | Phenyl substituted pyrazoles as modulators of RORγt |
US11034658B2 (en) | 2018-06-18 | 2021-06-15 | Janssen Pharmaceutica Nv | Pyridinyl pyrazoles as modulators of RORγT |
US11345666B2 (en) | 2018-06-18 | 2022-05-31 | Janssen Pharmaceutica Nv | Phenyl and pyridinyl substituted imidazoles as modulators of RORγT |
US10975057B2 (en) | 2018-06-18 | 2021-04-13 | Janssen Pharmaceutica Nv | 6-aminopyridin-3-yl pyrazoles as modulators of RORgT |
WO2020021097A1 (en) * | 2018-07-26 | 2020-01-30 | F. Hoffmann-La Roche Ag | Compounds for use in treating kidney disorders |
US12005043B2 (en) | 2018-08-17 | 2024-06-11 | Eidos Therapeutics, Inc. | Formulations of AG10 |
US11260047B2 (en) | 2018-08-17 | 2022-03-01 | Eidos Therapeutics, Inc. | Formulations of AG10 |
US11548871B2 (en) | 2019-11-15 | 2023-01-10 | Gilead Sciences, Inc. | Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof |
US11999717B2 (en) | 2019-11-15 | 2024-06-04 | Gilead Sciences, Inc. | Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof |
US11912686B2 (en) | 2020-06-03 | 2024-02-27 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
US11584738B2 (en) | 2020-06-03 | 2023-02-21 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
US11702407B2 (en) | 2020-06-03 | 2023-07-18 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
US11980609B2 (en) | 2021-05-11 | 2024-05-14 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
US11939318B2 (en) | 2021-12-08 | 2024-03-26 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
US11884627B2 (en) | 2022-02-25 | 2024-01-30 | Lhotse Bio, Inc. | Compounds and compositions for treating conditions associated with LPA receptor activity |
Also Published As
Publication number | Publication date |
---|---|
ZA201202635B (en) | 2013-01-30 |
US20140088158A1 (en) | 2014-03-27 |
EP2496556B1 (en) | 2018-12-26 |
US9018383B2 (en) | 2015-04-28 |
CO6541540A2 (en) | 2012-10-16 |
JP2013509446A (en) | 2013-03-14 |
UY32990A (en) | 2011-05-31 |
BR112012010282A2 (en) | 2016-03-29 |
MX2012004739A (en) | 2012-05-22 |
PE20121477A1 (en) | 2012-11-14 |
TN2012000160A1 (en) | 2013-12-12 |
MA33772B1 (en) | 2012-11-01 |
KR20120101429A (en) | 2012-09-13 |
RU2012122805A (en) | 2013-12-10 |
IL219354A0 (en) | 2012-06-28 |
AU2010313162A1 (en) | 2012-05-24 |
US20120264790A1 (en) | 2012-10-18 |
ECSP12011861A (en) | 2012-10-30 |
CA2779268A1 (en) | 2011-05-05 |
CN102858745A (en) | 2013-01-02 |
AR079022A1 (en) | 2011-12-21 |
DOP2012000121A (en) | 2012-07-31 |
EP2496556A1 (en) | 2012-09-12 |
US8618304B2 (en) | 2013-12-31 |
CR20120203A (en) | 2012-06-01 |
TW201127379A (en) | 2011-08-16 |
JP5847088B2 (en) | 2016-01-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9018383B2 (en) | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals | |
KR101649482B1 (en) | Acylamino-substituted fused cyclopentanecarboxylic acid derivatives and their use as pharmaceuticals | |
IL159418A (en) | Compounds for use as anti-inflammatory, immunomodulatory and anti-proliferatory agents, uses thereof and process for their preparation | |
JP2023552793A (en) | 4-(2-fluoro-4-methoxy-5-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2 as an RXFP1 modulator for the treatment of heart failure -yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid derivatives and similar compounds | |
PH12014000274B1 (en) | Power converter | |
OA17884A (en) | Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals. | |
BRPI0912224B1 (en) | FUSED CYCLOPENTANECARBOXYLIC ACID DERIVATIVES SUBSTITUTED BY ACYLAMINE, PROCESS FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITION CONTAINING THEM AND THEIR USE | |
JP2023179389A (en) | pharmaceutical composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201080060335.2 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10776045 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 219354 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2012/004739 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 000558-2012 Country of ref document: PE Ref document number: CR2012-000203 Country of ref document: CR |
|
ENP | Entry into the national phase |
Ref document number: 0155712 Country of ref document: KE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2779268 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012001142 Country of ref document: CL Ref document number: 2010313162 Country of ref document: AU Ref document number: 3812/CHENP/2012 Country of ref document: IN Ref document number: 12012500852 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012537183 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1201002069 Country of ref document: TH Ref document number: 12071019 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010776045 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2010313162 Country of ref document: AU Date of ref document: 20101102 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: A201206711 Country of ref document: UA |
|
ENP | Entry into the national phase |
Ref document number: 20127014323 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012122805 Country of ref document: RU |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112012010282 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112012010282 Country of ref document: BR Kind code of ref document: A2 Effective date: 20120430 |