GB2390849A - 3-Acyl-1,4-dihydro-1,4-di(phenyl/azinyl/diazinyl)pyridine derivatives for use as human neutrophil elastase inhibitors - Google Patents
3-Acyl-1,4-dihydro-1,4-di(phenyl/azinyl/diazinyl)pyridine derivatives for use as human neutrophil elastase inhibitors Download PDFInfo
- Publication number
- GB2390849A GB2390849A GB0216664A GB0216664A GB2390849A GB 2390849 A GB2390849 A GB 2390849A GB 0216664 A GB0216664 A GB 0216664A GB 0216664 A GB0216664 A GB 0216664A GB 2390849 A GB2390849 A GB 2390849A
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- United Kingdom
- Prior art keywords
- compounds
- amino
- general formula
- alkoxy
- alkyl
- Prior art date
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 25
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 title abstract description 29
- 102000052502 human ELANE Human genes 0.000 title abstract description 26
- 239000003591 leukocyte elastase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 81
- -1 trifluoromethoxy, amino Chemical group 0.000 claims abstract description 51
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 27
- 239000001257 hydrogen Substances 0.000 claims abstract description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 25
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 10
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 9
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 230000001154 acute effect Effects 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 6
- 230000001684 chronic effect Effects 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000008578 acute process Effects 0.000 claims abstract description 3
- 230000006020 chronic inflammation Effects 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 21
- 230000008569 process Effects 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 108010028275 Leukocyte Elastase Proteins 0.000 claims description 7
- 102000016799 Leukocyte elastase Human genes 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 6
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 4
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 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 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- 108091008642 NR6A Proteins 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000006626 methoxycarbonylamino group Chemical group 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 229920000180 alkyd Polymers 0.000 claims 1
- 125000006630 butoxycarbonylamino group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000002849 elastaseinhibitory effect Effects 0.000 claims 1
- 206010014561 Emphysema Diseases 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 210000000440 neutrophil Anatomy 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 abstract description 3
- 201000001320 Atherosclerosis Diseases 0.000 abstract description 3
- 208000003174 Brain Neoplasms Diseases 0.000 abstract description 3
- 201000003883 Cystic fibrosis Diseases 0.000 abstract description 3
- 208000019693 Lung disease Diseases 0.000 abstract description 3
- 206010035664 Pneumonia Diseases 0.000 abstract description 3
- 208000030886 Traumatic Brain injury Diseases 0.000 abstract description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 abstract description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 3
- 230000000391 smoking effect Effects 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 abstract 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000001816 cooling Methods 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000003480 eluent Substances 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 23
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 20
- 239000000377 silicon dioxide Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- WZWIQYMTQZCSKI-UHFFFAOYSA-N 4-cyanobenzaldehyde Chemical compound O=CC1=CC=C(C#N)C=C1 WZWIQYMTQZCSKI-UHFFFAOYSA-N 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 10
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- 229940093499 ethyl acetate Drugs 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 102000016387 Pancreatic elastase Human genes 0.000 description 8
- 108010067372 Pancreatic elastase Proteins 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 102000016942 Elastin Human genes 0.000 description 5
- 108010014258 Elastin Proteins 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 229920002549 elastin Polymers 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000000306 component Substances 0.000 description 4
- 201000010251 cutis laxa Diseases 0.000 description 4
- 210000000224 granular leucocyte Anatomy 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 3
- 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 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 102100033174 Neutrophil elastase Human genes 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000006911 enzymatic reaction Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 description 2
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 238000002820 assay format Methods 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 230000003246 elastolytic effect Effects 0.000 description 2
- FMVJYQGSRWVMQV-UHFFFAOYSA-N ethyl propiolate Chemical compound CCOC(=O)C#C FMVJYQGSRWVMQV-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000077 silane Inorganic materials 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000010490 three component reaction Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RLTOXDSOOSYULO-UHFFFAOYSA-N 1,4-diphenyl-4h-pyridine Chemical class C1=CN(C=2C=CC=CC=2)C=CC1C1=CC=CC=C1 RLTOXDSOOSYULO-UHFFFAOYSA-N 0.000 description 1
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- MATJPVGBSAQWAC-UHFFFAOYSA-N 2-cyano-n,n-dimethylacetamide Chemical compound CN(C)C(=O)CC#N MATJPVGBSAQWAC-UHFFFAOYSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical class C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- VGVXOXSRINSIFO-UHFFFAOYSA-N 3-(diethylaminomethyl)aniline Chemical compound CCN(CC)CC1=CC=CC(N)=C1 VGVXOXSRINSIFO-UHFFFAOYSA-N 0.000 description 1
- XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical compound NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 description 1
- RKODTPIHPRNNHD-UHFFFAOYSA-N 4-(3-nitroanilino)pent-3-en-2-one Chemical compound CC(=O)C=C(C)NC1=CC=CC([N+]([O-])=O)=C1 RKODTPIHPRNNHD-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- BEOBZEOPTQQELP-UHFFFAOYSA-N 4-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=C1 BEOBZEOPTQQELP-UHFFFAOYSA-N 0.000 description 1
- NXAIGPFVFJVPQT-UHFFFAOYSA-N 5-acetyl-2-amino-4-(4-cyanophenyl)-6-methyl-1-[3-(trifluoromethyl)phenyl]-4h-pyridine-3-carbonitrile Chemical compound CC(=O)C1=C(C)N(C=2C=C(C=CC=2)C(F)(F)F)C(N)=C(C#N)C1C1=CC=C(C#N)C=C1 NXAIGPFVFJVPQT-UHFFFAOYSA-N 0.000 description 1
- PQOVBMILOMIWMB-UHFFFAOYSA-N 6-methyl-1,4-dihydropyridine-3-carboxylic acid Chemical compound CC1=CCC(=CN1)C(=O)O PQOVBMILOMIWMB-UHFFFAOYSA-N 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
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- 235000019759 Maize starch Nutrition 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
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- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
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- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
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- 230000000845 anti-microbial effect Effects 0.000 description 1
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- JPNZKPRONVOMLL-UHFFFAOYSA-N azane;octadecanoic acid Chemical class [NH4+].CCCCCCCCCCCCCCCCCC([O-])=O JPNZKPRONVOMLL-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
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- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical class BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 1
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- IUWVDURXQOYQEP-UHFFFAOYSA-N ethyl 5-acetyl-2-amino-4-(4-bromophenyl)-6-methyl-1-(3-nitrophenyl)-4h-pyridine-3-carboxylate Chemical compound CCOC(=O)C1=C(N)N(C=2C=C(C=CC=2)[N+]([O-])=O)C(C)=C(C(C)=O)C1C1=CC=C(Br)C=C1 IUWVDURXQOYQEP-UHFFFAOYSA-N 0.000 description 1
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- YGKISBJTNIBYSW-UHFFFAOYSA-N ethyl 5-acetyl-4-(4-bromophenyl)-6-methyl-1-[3-(trifluoromethyl)phenyl]-4h-pyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C(C)=O)C1C1=CC=C(Br)C=C1 YGKISBJTNIBYSW-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000012530 fluid Substances 0.000 description 1
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- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
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- 238000010253 intravenous injection Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- CMEUDEVBFFPSEI-NFHWZJRKSA-N methyl 4-[[(2s)-1-[[(2s)-1-[(2s)-2-[[(2s)-3-methyl-1-[(4-methyl-2-oxochromen-7-yl)amino]-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoate Chemical compound COC(=O)CCC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)NC1=CC=C(C(C)=CC(=O)O2)C2=C1 CMEUDEVBFFPSEI-NFHWZJRKSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-N methyl sulfate Chemical class COS(O)(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-N 0.000 description 1
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- 210000004400 mucous membrane Anatomy 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
- 229960003966 nicotinamide Drugs 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-M nicotinate Chemical compound [O-]C(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-M 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- ZNJHFNUEQDVFCJ-UHFFFAOYSA-M sodium;2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid;hydroxide Chemical compound [OH-].[Na+].OCCN1CCN(CCS(O)(=O)=O)CC1 ZNJHFNUEQDVFCJ-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical class CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
- A61P35/00—Antineoplastic 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compounds of the general formula (I) wherein <DL TSIZE=27> <DT>R<1>, R<2>, R<3>, R<8>, R<9> and R<10><DD>independently from each other represent hydrogen, halogen, nitro, cyano, trifluoromethyl, C1-C6-alkyl, C1-C6-alkanoyl, hydroxy, C1-C6-alkoxy, trifluoromethoxy, amino, mono- or di-C1-C6-alkylamino, C1-C6-acylamino, C1-C6-alkoxycarbonylamino, carboxyl, C1-C6-alkoxycarbonyl or phenyl, wherein C1-C6-alkyl, C1-C6-alkanoyl, C1-C6-alkoxy, mono- or di-C Ü -C6-alkylamino and C1-C6-acylamino can be further substituted with one to three identical or different radicals selected from the group consisting of hydroxy, C1-C4-alkoxy, amino, mono- and di-C1-C4-alkylamino, <DT>R<4><DD>represents C1-C6-alkyl, trifluoromethyl or phenyl, <DT>R<5><DD>represents C1-C4-alkyl, which can be substituted with one to three identical or different radicals selected from the group consisting of hydroxy, C1-C4-alkoxy, amino, mono- and di-C1-C4-alkylamino, <DT>R<6><DD>represents cyano, aminocarbonyl mono- and di-C1-C4-alkylaminocarbonyl, carboxyl or C1-C6-alkoxycarbonyl, wherein the alkoxy moiety can be further substituted with a radical selected from the group consisting of hydroxy, C1-C4-alkoxy amino, mono- and di-C1-C4-alkylamino, or <DT>R<6><DD>represents a moiety of the formula wherein R<A> is selected from the group consisting of hydrogen and C1-C6-alkyl, and the symbol * next to a bond denotes the point of attachment in the molecule, <DT>R<7><DD>represents hydrogen, C1-C4-alkyl or amino, <DT>X<1>, X<2>, X<3> and X<4><DD>independently from each other represent CH or N, wherein ring A contains either 0, 1 or 2 nitrogen atoms, and <DT>Y<1>, Y<2>, Y<3>, Y<4> and Y<5><DD>independently from each other represent CH or N, </DL> ```wherein ring B contains either 0, 1 or 2 nitrogen atoms show human neutrophil elastase (HNE) inhibitory activity and are therefore suitable for the treatment of diseases associated with HNE activity, namely the treatment of acute and chronic inflammatory processes, such as rheumatoid arthritis, atherosclerosis, and especially of acute and chronic pulmonary diseases, such as lung fibrosis, cystic fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), in particular pulmonary emphysema, including smoking-induced emphysema, and chronic obstructive pulmonary diseases (COPD). They may also provide an effective treatment of brain trauma, cancer and other conditions in which neutrophil participation is involved. They may be formulated as a pharmaceutical composition.
Description
1 2390849
1,4-Dihvdro-1,4-dinhenvlpvridine derivatives The present invention relates to novel 1,4-dihydro-1,4-diphenylpyridine derivatives, processes for their preparation, and their use in medicaments, especially for the treat 5 ment of chronic obstructive pulmonary diseases.
The fibrous protein elastin, which comprises an appreciable percentage of all protein content in some tissues, such as the arteries, some ligaments and the lungs, can be hydrolysed or otherwise destroyed by a select group of enzymes classified as elastases.
10 Human leukocyte elastase (HLE, EC 3.4.21.37), also known as human neutrophil elastase (HNE), is a glycosylated, strongly basic serine protease and is found in the azurophilic granules of human polymorphonuclear leukocytes (PMN). HNE is released from activated PMN and has been implicated causally in the pathogenesis of acute and chronic inflammatory diseases. HNE is capable of degrading a wide range of matrix 15 proteins including elastin, and in addition to these actions on connective tissue HNE has a broad range of inflammatory actions including upregulation of IL-8 gene expression, oedema formation, mucus gland hyperplasia and mucus hypersecretion.
Pulmonary diseases where HNE is believed to play a role include lung fibrosis, pneumonia, acute respiratory distress syndrome (ARMS), pulmonary emphysema, 20 including smoking-induced emphysema, chronic obstructive pulmonary diseases (COPD) and cystic fibrosis. HNE has also been causally implicated in rheumatoid arthritis, atherosclerosis, brain trauma, cancer and related conditions in which neutrophil participation is involved. Thus, inhibitors of HLE activity can be potentially useful in the treatment of a number of inflammatory diseases, especially of chronic 25 obstructive pulmonary diseases [R.A. Stockley, Neutrophils and protease/antiprotease imbalance, Am. J. Respir. Crit. Care 160, S49-S52 (1999)].
Certain cationic amphiphilic 1,4-dihydropyridine derivatives useful for delivery of nucleotide containing compounds are disclosed in WO-AI01/62946. Ethyl 6-arnino 30 1,4-bis(4-chlorophenyl)-5-cyano-2-methyl-1,4dthydro-3-pyridinecarboxylate has been
- - synthesized and tested for potential antimicrobial activity as described in A.W. Erian et al., Pharrnazie 53 (11), 748-751 (1998).
The present invention relates to compounds of the general fonnula (I) R. R2 AR3 OXX 4JR6 R l Rs N R7 Ri YRa (I), wherein R', R2, R3, R8, R9 and R' independently from each other represent hydrogen, halogen, nitro, cyano, trifluoromethyl, Cl-C6-alkyl, C-C6-alkanoyl, hydroxy, I O C,-C6alkoxy, trifluoromethoxy, amino, mono- or di-C-C6-alkylamino, C -C6acylarnino, C -C6-alkoxycarbonylarnino, carboxyl, C, -C6-alkoxy carbonyl or phenyl, wherein C'-C6-alkyl, C,-C6-alkanoyl, C-C6-alkoxy, mono- or diC'-C6-alkylamino and C-C6-acylamino can be further substituted with one to three identical or different radicals selected from the 15 group consisting of hydroxy, C,-C4-alkoxy, amino, mono- and di-C,-C4-alkyl amno, R4 represents C,-C6-alkyl, trifluoromethyl or phenyl, 20 Rs represents CC4-alkyl, which can be substituted with one to three identical or different radicals selected from the group consisting of hydroxy, C-C4 alkoxy, amino, mono- and di-C'-C4-alkylamino,
- 3 R6 represents cyano, arninocarbonyl, mono- and di-C,-C4alkylaminocarbonyl, carboxyl or C-C6-alkoxycarbonyl, wherein the alkoxy moiety can be further substituted with a radical selected from the group consisting of hydroxy, C,- = 5 CJ,-alkoxy, amino, mono- and di-C-C4alkylamino, or R6 represents a moiety of the formula NR6A to or wherein RA is selected from the group consisting of hydrogen and C-Cc 1 5 alkyl, R7 represents hydrogen, C'-C4-alkyl or amino, Xt, X2, X3 and X4 independently from each other represent CH or N. wherein ring A 20 contains either 0, 1 or 2 nitrogen atoms, and yt, y2, y3, y4 and Y5 independently from each other represent CH or N. wherein 25 ring B contains either 0, 1 or 2 nitrogen atoms.
In another embodiment, the present invention relates to compounds of general formula (I), wherein
- 4 R' represents hydrogen, R2, R3, R9 and R' independently from each other represent hydrogen, halogen, nitro, 5 cyano, trifluoromethyl, Cl-C4alkyl, C-C4-alkanoyl, hydroxy, C-C4-alkoxy, trifluoromethoxy, amino, C rC4-dialkylamino, C -C4-acylamino, methoxy carbonylamino, tert.butoxycarbonylarnino, carboxyl, methoxycarbonyl or ethoxycarbonyl, wherein Cr-C4-alkyl, C-C4-alkanoyl, C,-C4-alkoxy, C,-C4 dialkylamino and C-C4-acylamino can be further substituted with one to two 10 identical or different radicals selected from the group consisting of hydroxy, methoxy, ethoxy, amino, dimethylamino and diethylamino, R4 represents methyl, ethyl, trifluoromethyl or phenyl, 15 R5 represents methyl or ethyl, Rfi represents cyano, aminocarbonyl, methylarninocarbonyl, dimethylaminocarb onyl, carboxyl or C-C4-alkoxycarbonyl, wherein the alkoxy moiety can be fiurther substituted with a radical selected from the group consisting of 20 hydroxy, methoxy, ethoxy, amino, mono- and di- C-C4-alkylamino, R7 represents hydrogen, methyl, ethyl or amino, R represents hydrogen, X', x2 and X3 represent CH, X4 represents CH or N. 30 and
( - 5
y y2 y3 y4 end Y5 represent CH In another embodiment, the present invention relates to compounds of general formula (l), wherein Rt and R2 represent hydrogen, R3 represents fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, methyl, meth oxy or hydroxy, R4 represents methyl or trifluoromethyl, Rs represents methyl, l S R6 represents cyano, aminocarbonyl, methylaminocarbonyl, dimethylamino carbonyl, carboxyl, methoxycarbonyl or ethoxycarbonyl, R7 represents hydrogen, methyl or amino, 20 Rg and R9 represent hydrogen, R represents fluoro, chloro, bromo, nitro, cyano, trifluoromethyl or methyl, X', X2, X3 and X4 represent CH, and yl y2 y3 y4 and Y5 represent CH.
30 In another embodiment, the present invention relates to compounds according to general formula (I), which have the following structure:
- - - R4JR5 R5 N R7
R10RB FAX R9 and wherein R', R2, R3, R8, R9 and R' independently from each other represent hydrogen, 5 halogen, nitro, cyano, trifluoromethyl, Cl-C6-alkyl, C-C6-alkanoyl, hydroxy, C'-C6-alkoxy, triQuoromethoxy, amino, mono- or di-C-C6 alkylamino, C-C6-acylarnino, C-C6-alkoxycarbonylamino, carboxyl, C-C6-alkoxycarbonyl or phenyl, wherein C'-Cs-alkyl, C-C6alkanoyl, C-C6-alkoxy, mono- or di-C-C6-alkylarnino and C-C6-acylamino 10 can be farther substituted with one to three identical or different radicals selected from the group consisting of hydroxy, C-C4-alkoxy, amino, mono- and di-C-C4-alkylamino, R4 represents C'-C6-alkyl, trifluoromethyl or phenyl, R5 represents C-C4-alkyl, R6 represents cyano, carboxyl or C'-C6-alkoxycarbonyl, wherein the alkoxy moiety can be further substituted with a radical selected from 20 the group consisting of hydroxy, C'-C4-alkoxy, amino, mono- and di C -C4-alkylamino, and
- 7 R7 represents hydrogen, C-C.-alkyl or amino.
5 In another embodiment, the present invention relates to compounds according to general formula (1), wherein R3 is cyano, which is located in pare-position relativ to the 1,4-dihydropyridine ring.
In another embodiment, the present invention relates to compounds according to 10 general fonnula (I), wherein R4 is methyl.
In another embodiment, the present invention relates to compounds according to general formula (1), wherein R5 is methyl.
15 In another embodiment, the present invention relates to compounds according to general fonnula (I), wherein R6 is methoxycarbonyl or ethoxycarbonyl.
In another embodiment, the present invention relates to compounds according to general formula (I), wherein R7 is hydrogen, methyl or amino.
In another embodiment, the present invention relates to compounds according to general formula (I), wherein R is trifluoromethyl, which is attached to y2 The compounds according to this invention can also be present in the form of their 25 salts, hydrates and/or solvates.
Physiologically acceptable salts are preferred in the context of the present invention.
Physiologically acceptable salts according to the invention are non-toxic salts which 30 in general are accessible by reaction of the compounds (I) with an inorganic or organic base or acid conventionally used for this purpose. Non-limiting examples of
( - 8 pharrnaccutically acceptable salts of compounds (I) include the alkali metal salts, e.g. lithium, potassium and sodium salts, the alkaline earth metal salts such as magne sium and calcium salts, the quaternary ammonium salts such as, for example, triethyl ammonium salts, acetates, benzene sulphonates, benzoates, Bicarbonates, disulphates, 5 ditartrates, berates, bromides, carbonates, chlorides' citrates, dihydrochlorides, fumarates, gluconates, glutamates, hexyl resorcinates, hydrobromides, hydro chlorides, hydroxynaphthoates, iodides, isothionates, lactates, laurates, malates, maleates, mandelates, mesylates, methylbromides, methylaitrates, methylsulphates, nitrates, oleates, oxalates, palmitates, pantothenates, phosphates, diphosphates, 10 polygalacturonates, salicylates, stearates, sulphates, succinates, tartrates, tosylates, valerates, and other salts used for medicinal purposes.
Hydrates of the compounds of the invention or their salts are stoichiometric com positions of the compounds with water, such as for example hem)-, mono-, or 1 5 dihydrates.
Solvates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with solvents.
20 The present invention includes both the individual enantiomers or diastereomers and the corresponding racemates or diastereomeric mixtures of the compounds according to the invention and their respective salts. In addition, all possible tautomeric forms of the compounds described above are included according to the present invention.
The diastereomeric mixtures can be separated into the individual isomers by 25 chromatographic processes. The racemates can be resolved into the respective enantiomers either by chromatographic processes on chiral phases or by resolution.
In the context of the present invention, the substituents, if not stated othervise, in general have the following meaning:
( Alkyl in general represents a straight-chain or branched hydrocarbon radical having I to 6, preferably I to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, hexyl, isohexyl. The same applies to radicals such as alkoxy, alkylamino, alkoxycarbonyl 5 and alkoxycarbonylamino.
Acyl or Alkanoyl in general represents a straight-chain or branched hydrocarbon radical having I to 6, preferably 1 to 4 carbon atoms which has a carbonyl function at the position of attachment. Non-limiting examples include forrnyl, acetyl, n-propionyl, 10 n-butyryl, isobutyryl, pivaloyl, n-hexanoyl. The same applies to radicals such as acylamino. Alkylarnino represents an alkylarnino radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylarnino, 15 ethylamino, n-propylarnino, isopropylarnino, tert-butylarnino, n-pentylarnino, n-hexyl amino, N,N- dimethylarnino, N,N-diethylamino, N-ethyl-N-methylarnino, N-methyl-N n- propylarnino, Nisopropyl-N-n-propylarnino, N-t-buty l-N-methylarn ino, N- ethyl-N n-pentylarnino and N-n-hexyl-N-methylamino.
20 ylannocarbonyl represents an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylaminocarbonyl, ethylaminocarbonyl, npropylarninocarbonyl, isopropylamino carbonyl, tert-butylaminocarbonyl, npentylaminocarbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl, N,Ndiethylarninocarbonyl, N-ethyl-N-methylamino 25 carbonyl, N-methyl-N-npropylaminocarbonyl, N-isopropyl-N-n-propylarninocarbonyl, N-t-butyl-Nmethylarninocarbonyl, N-ethyl-N-n-pentylarnino-carbonyl and N-n-hexyl Nmethylaminocarbonyl. When stated, that X, X2, X3 and X4 as well as y, y2, y3, y4 and Y5 represent CH or 30 N. CH shall also stand for a ring carbon atom, which is substituted with a substituent Ri, R2, R3 or R8, R9 and Ri , respectively.
( - 10
A * symbol next to a bond denotes the point of attachment in the molecule.
The letters A and B are used to designate the different rings and, for the purpose of 5 clarity, are not shown in all structures.
In another embodiment, the present invention relates to processes for synthesizing the compounds of general formula (I), characterized in that either 10 [A] compounds of the general formula (II) R8 R9 y\Y4;y3 to Q HN Y
R4Rs (11), wherein R4, R5, R8, R9, Rid and YE to Y5 have the meaning described above, 15 are condensed in the presence of a base, in a threecomponent-reaction, with compounds of the general formulas (III) and (IV) R' ORE
I:R X jx3 (111) NC R" (IV), H O wherein Rt, R2, R3 and X' to X4 have the meaning described above, and
f - It -
R" represents cyano or C'-C6-alkoxycarbonyl, to give compounds of the general fonnula (la) XIR3 R4R1 1
Rs N NH2 R' RB (Ia), S or [B] compounds of the general formulas (II) and (III) are condensed in the presence of an acid, in a three-componentreaction, with compounds of the general formula (V) H /< oR,2 (V), wherein Ri2 represents C-C6-alkyl, I S to give compounds of the general formula (Ib)
( - 12
4 3 R4';,DlOR12 R5 N H
R1R8 (Ib), or [C] compounds of the general formula (VI) -N:Y'- 3:
R120R,3 (VI),
wherein R8, R9, R' , Ri2 and Y' to Y5 have the meaning described above, to and Ri3 represents C-C4-alkyl, are condensed in the presence of an acid or a base, in a three-component l S reaction, with compounds of the general formulas (111) and (VII) O O (VII),
(- 13 wherein R4 and R5 have the meaning described above, to give compounds of the general formula (Ic) s XIR3 oX::X3 0 R4 40R'2
R5 N R13
R10: R8 (Ic).
The processes can be illustrated by the following schemes [A] to [C]:
( - 14
Scheme FA1 to fC1 ti R'0 OR' ' HN y + X jX + NCR" R R4Rs H'4O Rs NH2 0 Y' Ys a R\ B1 Xl'l^X4 R3 _ oR'2 R4 R H O H ';y' 8 tCl R1RZ HNR:R10 j R3 R4Rs R oR12 R120);R'3 H O R9
Suitable solvents for the processes [A] to [C] are generally customary organic solvents 5 which do not change under the reaction conditions. These include ethers such as diethyl ether, diisopropyl ether, 1,2dimethoxyethane, dioxan or tetrahydrofuran, ethylacetate, acetone, acetonitrile, dimethylsulfoxide, dimethylformarnide, or alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or t-butanol, or hydrocarbons such as pentane, hexane, cyc lohexane, benzene, to luene or xylene, or halo geno-hydro
! - 15
carbons such as dichloromethane, dichloroethane, trichloromethane or chlorobenzene.
For process [B] and [C] also acetic acid can be employed as solvent. It is also possible to use mixtures of the above-mentioned solvents. Preferred for process [A] is ethanol or a mixture of n-propanol and dimethylsulfoxide. For process [B] and [C] acetic acid or 5 diisopropyl ether are preferred.
Suitable bases for process [A] and [C] are generally inorganic or organic bases. These preferably include cyclic arnines, such as, for example, piperidine, morpholine, N methylmorpholine, pyridine or 4-N,Ndimethylaminopyridine, or (C-C4)-trialkyl 10 arnines, such as, for example, triethylarnine or diisopropylethylamine. Preference is given to piperidine. The base is employed in an amount from 0.1 mol to lOmol, preferably from I mol to 3 mol. relative to I mat of the compound of the general formula (II).
15 Suitable acids for process [B] and [C] are generally inorganic or organic acids. These preferably include carboxylic acids, such as, for example acetic acid or trifluoroacetic acid, or sulfonic acids, such as, for example, methanesulfonic acid or p-toluenesulfonic acid. Preference for process [B] and [C] is given to acetic acid or trifluoroacetic acid.
The acid is employed in an amount from 0.25 mol to 100 mol. relative to 1 mol of the 20 compounds of the general formulas (V) and (VII), respectively.
The processes [A] to LC] are in general carried out in a temperature range from +20 C to +150 C, preferably from +60 C to +130 C.
25 The processes [A] to [C] are generally carried out at normal pressure. However, it is also possible to carry them out at elevated pressure or at reduced pressure (for example in a range from 0.5 to 5 bar).
The compounds of general formula (II) can be synthesized by reacting compounds of 30 general formula (VII) with compounds of the general (VIII)
f - 16 --R' 1yl.Y (VIII), wherein R8, R9 R and Yt to Y5 have the meaning described above, 5 in the presence of an acid, such as acetic acid or p-toluenesulfonic acid, under water removing conditions.
The compounds of general formula (VI) can be synthesized analogously.
10 The compounds of the general formulas (III), (IV), (V), (VU) and (VIII) are known per se, or they can be prepared by customary methods.
Surprisingly, the compounds of the present invention show human neutrophil elastase (HNE) inhibitory activity and are therefore suitable for the preparation of 15 medicaments for the treatment of diseases associated with HNE activity. They may thus provide an effective treatment of acute and chronic inflammatory processes, such as rheumatoid arthritis, atherosclerosis, and especially of acute and chronic pulmonary diseases, such as lung fibrosis, cystic fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), in particular pulmonary emphysema, including smoking-induced 20 emphysema, and chronic obstructive pulmonary diseases (COPD). They may also provide an effective treatment of brain trauma, cancer and other conditions in which neutrophil participation is involved.
The compounds of formula (I) according to the invention can therefore be used as 25 active compound components for the production of medicaments. For this, they can be converted into the customary formulations such as tablets, coated tablets, aerosols, pills, granules, syrups, emulsions, suspensions and solutions in a known manner using inert, non-toxic, pharmaceutically suitable excipients or solvents. Preferably,
( - 17
the compounds according to the invention are used here in an amount such that their concentration in the total mixture is approximately 0.5% to approximately 90% by weight, the concentration, inter alla, being dependent on the corresponding indication of the medicament.
The above mentioned formulations are produced, for example, by extending the active compounds with solvents and/or excipients having the above properties, where, if appropriate, additionally emulsifiers or dispersants and, in the case of water as the solvent, alternatively an organic solvent, have to be added.
Administration is camed out in a customary manner, preferably orally, transdennally or parenterally, for example perlingually, buccally, intravenously, nasally, rectally or by inhalation. 15 For human use, in the case of oral administration, it is recommendable to administer doses of from 0.001 to 50 mglkg, preferably of 0.01 mg/kg to 20 mg/kg. In the case of parenteral administration, such as, for example, intravenously or via mucous membranes nasally, buccally or inhalationally, it is recommendable to use doses of 0.00 I mg/kg to 0.5 mglkg.
In spite of this, if appropriate, it may be necessary to depart from the amounts mentioned above, namely depending on the body weight or the type of admini-
stration route, on the individual response towards the medicament, the maimer of its formulation and the time or interval at which administration takes place. Thus, in 25 some cases it may be sufficient to manage with less than the above mentioned minimum amount, while in other cases the upper limit mentioned must be exceeded.
In the case of the administration of relatively large amounts, it may be recom mendable to divide these into several individual doses over the course of the day.
- 18 A. Evaluation of physiological activity The potential of the compounds of the invention to inhibit neutrophil elastase activity may be demonstrated, for example, using the following assays: 5 I. In vitro assays of human neutronhil elastase (HNE) Assay contents assay buffer: 0. 1 M HEPES-NaOH buffer pH 7.4, 0.5 M NaCI, 0.1% (w/v) bovine 10 serum albumin; suitable concentration (see below) of HNE (18 U/mg Iyophil., #20927.01, SEEIVA Electrophoresis GmbH, Heidelberg, Germany) in assay buffer; suitable concentration (see below) of substrate in assay buffer; suitable concentration of test compounds diluted with assay buffer from a 10 mM 15 stock solution in DMSO.
Example A
In vitro inhibition of HNE using a fluorogenic peptide substrate (continuous 20 read-out signal, 384 MTP assay format): In this protocol, the elastase substrate MeOSuc-Ala-Ala-Pro-Val-AMC (#324740, CalbiochemNovabiochem Corporation, Merck KgaA, Darmstadt, Germany) is used.
The test solution is prepared by mixing 10 foul of test compound dilution, 20 pi of 25 HNE enzyme dilution (final concentration 8 - 0.4 pU/ml, routinely 2.1 IlU/ml) and 20 pi of substrate dilution (final concentration I rnM - I M, routinely 20 '1M), respectively. The solution is incubated for 0 - 2 hrs at 37 C (routinely one hour). The fluorescence of the liberated AMC due to the enzymatic reaction is measured at 37 C (TECAN spectra fluor plus plate reader). The rate of increase of the fluorescence (ex.
30 395 nrn, em. 460 nm) is proportional to elastase activity. IC50 values are determined
- 19 by RFU-versus-[1] plots. Km and K,r,(app) values are determined by Lineweaver-Burk plots and converted to Kj values by Dixon plots.
The preparation examples had IC50 values within the range of 20 nM '1M in this 5 assay. Representative data are given in table 1: Example No. IC50 [nM 3 200 4 40 8 330 10 230
12 180
13 30 14 20 15 120
17 9000
18 30 table 1
Example B
In vitro inhibition of HNE using a fluorogenic, unsoluble elastin substrate (discontinuous read-out signal, 96 MTP assay format) In this protocol the elastase substrate elastin-fluorescein (#100620, ICN Biomedicals 15 GmbH, Eschwege, Germany) is used. The test solution is prepared by mixing 3 Ill of test compound dilution, 77 Al of HNE enzyme dilution (final concentration 0.22 U/ml - 2.2 mU/ml, routinely 21.7 pU/ml) and 80 Ill substrate suspension (final concentration 2 mg/ml). The suspension is incubated for 0 - 16 hrs at 37 C (routinely four hours) under slightly shaking conditions. To stop the enzymatic reaction, 160 Ill 20 of 0.1 M acetic acid are added to the test solution (final concentration 50 mM). The
- 20 polymeric elastin-fluorescein is pulled down by centrifugation (Eppendorf 5804 centrifuge, 3.000 rpm, 10 min). The supernatant is transferred into a new MTP and the fluorescence of the liberated peptide fluorescein due to the enzymatic reaction is measured (BMG Fluostar plate reader). The rate of fluorescence (ex. 490 nm, em.
5 520 nm) is proportional to elastase activity. ICso values are determined by RFU versus-[1] plots.
11. In vitro PMN elastolysis assay 10 This assay is used to determine the elastolytic potential of human polymorphonuclear cells (PMNs) and assess the proportion of degradation due to neutrophil elastase [cf.
Z.W. She et al., Am. J. Respir. Cell. Mol. Biol. 9, 386-392 (1993)].
Tritiated elastin, in suspension, is coated on to a 96 well plate at 10 leg per well. Test 15 and reference [ZD-0892 (J. Med. Chem. 40, 1876-1885, 3173-3181 (1997), WO 95/21855) and al protease inhibitor (alPI)] compounds are added to the wells at the appropriate concentrations. Human PMNs are separated from peripheral venous blood of healthy donors and resuspended in culture media. The neutrophils are added to the coated wells at concentrations ranging between I x 106 to I x 105 cells per 20 well. Porcine pancreatic elastase (1.3 M) is used as a positive control for the assay, and oIPI (1.2 M) is used as the positive inhibitor of neutrophil elastase. The cellular control is PMNs without compound at each appropriate cell density. The cells plus compounds are incubated in a humidified incubator at 37 C for 4 hours.
The plates are centrifuged to allow the harvest of cell supernatant only. The 25 supernatant is transferred in 75 pI volumes to corresponding wells of a 96 well Lumaplate_ (solid scintillant containing plates). The plates are dried until no liquid is visible in the wells and read in a beta counter for 3 minutes per well.
Elastolysis of the 3H-elastin results in an increase in counts in the supernatant. An 30 inhibition of this elastolysis shows a decrease, from the cellular control, of tritium in the supernatant. alPI gave 83.46 3. 97% (mean s.e.m.) inhibition at 1.2 '1M (n =
f - 21 3 different donors at 3.6 x 105 cells per well). ICso values were obtained for the reference compound ZD-0892 of 45.50 7.75 nM (mean i s.e. m.) (n = 2 different donors at 3.6 x 105 cells per well).
5 Given that ZD-0892 is a selective inhibitor of PMN elastase along with the data from Al PI inhibition, these results indicate that the majority of elastin degradation by PMNs is due to the release of neutrophil elastase, and not to another elastolytic enzyme such as matrix metalloproteases (MMPs). The compounds of this invention were evaluated for their inhibitory activity in this HNE-dependent model of neutro 10 phil elastolysis.
111. In viva model of acute lung in jury in the rat Instillation of human neutrophil elastase (HNE) into rat lung causes acute lung 15 damage. The extent of this injury can be assessed by measuring lung haemorrhage.
Rats are anaesthetised with HypnormlHypnovel/water and instilled with HNE or saline delivered by microsprayer into the lungs. Test compounds are administered by intravenous injection, by oral gavage or by inhalation at set times prior to the 20 administration of HNE. Sixty minutes after the administration of elastase animals are killed by an anaesthetic overdose (sodium pentobarbitone) and the lungs ravaged with 2 ml heparinised phosphate buffered saline (PBS). Bronchoalveolar ravage (BAL) volume is recorded and the samples kept on ice. Each BAL sample is centrifuged at 900 r.p.m. for 10 minutes at 4-10 C. The supernatant is discarded and 25 the cell pellet resuspended in PBS and the sample spun down again. The supematant is again discarded and the cell pellet resuspended in I ml 0. 1% cetyltrimethyl ammonium bromide (CTAB) / PBS to Iyse the cells. Samples are frozen until blood content is assayed. Prior to the haemorrhage assay the samples are defrosted and mixed. 100 pi of each sample are placed into a separate well of a 96 well flat 30 bottomed plate. All samples are tested in duplicate. 100 ill 0.1% CTAB/PBS is included as a blank. The absorbance of the well contents is measured at 415 nm using
( - 22 a spectrophotometer. A standard curve is constructed by measuring the OD at 415 rim of different concentrations of blood in 0.1% CTAB/PBS. Blood content values are calculated by comparison to the standard curve (included in each plate) and normalised for the volume of BAL fluid retrieved.
The compounds of this invention were evaluated intravenously, orally or by in-
halation for their inhibitory activity in this model of HNE-induced haemorrhage in the rat.
- 23 B. Examples
Abbreviations: c = concentration 5 DMSO = dimethylsulfoxide HPLC = high performance liquid chromatography LC-MS = liquid chromatography-coupled mass spectroscopy NMR = nuclear magnetic resonance spectroscopy tic = thin layer chromatography LC-MS Method: solvent A: acetonitrile solvent B: 0.3 g 30% HC1/L water 15 column oven: 50 C column: Symmetry C18 2.1 x 150 mm gradient: time [mind MA %B flow [ml/mind 0 10 90 0.9
3 90 10 1.2
20 6 90 1 0 1.2
Startine Materials: 25 Examole 1A 4-[(3 -Nitrophenyl)amino] -3 -penten-2 one H3C rNórNO2 O CH3
- 24 36.24 g (362 mmol) Acetylacetone, 10.00 g (72 mmol) 3-nitroaniline,and 1.25 g (7.2 mmol) 4-toluenesulfonic acid are dissolved in 100 ml toluene. The reaction mixture is reflexed overnight with a Dean-Stark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is 5 purified by column chromatography on silica with eluent dichloromethane.
Yield: 12.0 g (75%) tH-NMR (400 MHz, DMSO): - 2.0 (s, 3H); 2.1 (s, 3H); 5. 4 (s, 1H); 7.7 (m, 2H); 8.0 (m, 2H); 12.5 (s, IH) ppm.
10 Example 2A
4- { [3-(Trifluoromethyl)phenyl]arnino} -3-pen/en-2-one H H3C no O CH3 15 15.53 g (155 mmol) Acetylacetone, 5.00 g (31 mmol) 3trifluoromethylaniline, and 0.53 g (3.1 mmol) 4-toluenesulfonic acid are dissolved in 50 ml toluene. The reaction mixture is reflexed overnight with a Dean-Stark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethylacetate mixtures 20 as eluent.
Yield: 5.46 g (72%) H-NMR (200 MHz, DMSO): = 2.0 (s, 3H); 2.1 (s, 3H); 5. 3 (s, IH); 7.5 (m, 4H); 12.5 (s, 1H) ppm.
( - 25
Example 3A
Ethyl (2E)-3- { [3-(trifluoromethyl)phenyl]amino} -2-butenoate CF3 H CO::N; 3
4.0 g (31 mmol) Ethyl 3-orobutanoate, 5.0 g (31 mmol) 3trifluoromethylaniline, and 1.86 g (31 mmol) acetic acid are dissolved in 50 ml toluene. The reaction mixture is reflexed overnight with a DeanStark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by 10 column chromatography on silica with cyclohexane/ethylacetate mixtures as eluent.
Yield: 2.28 g (27%) H-NMR (300 MHz, DMSO): = 1.2 (t, 3H); 2.0 (s, 3H); 4. 1 (q, 2H); 4.8 (s, IH); 7.5 (m, 4H); 10.4 (s, 1H) ppm.
15 Example 4A
4- {[3-(Methyl)phenyl]amino} -3-pen/en-2-one H3C:rN CH3 O CH3 20 23.36 g (233 mmol) Acetylacetone, 5.00 g (47 mmol) 3-methylaniline, and 0.8 g (4. 7 mmol) 4-toluenesulfonic acid are dissolved in 50 ml toluene. The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethylacetate mixtures 25 as eluent.
- 26 Yield: 7.7 g (87%) IH-NMR(300 MHz, DMSO): = 2.0 (2 s, 6H); 2.3 (s, 3H); 5.2 (s, IH); 7.0 (m, 3H); 7.2 (m, IH) ppm.
S ExamoIe SA 4- { [3 -Iodo-5 -(tn fluoromethyl)pheny l] amino} -3-penten2 -one H3C j' - N CF3 O CH3 10 1.38 g (13.8 mmol) Acetylacetone, 3.95 g (13.8 mmol) 3-iodo-5-tnfluoromethyl aniline, and 0.1 g (1.6 mmol) 4toluenesulfonic acid are dissolved in 150 ml toluene.
The reaction mixture is refluxed for 7 h with a Dean-Stark trap to remove water.
After cooling down to room temperature, the suspension is filtered. The solid is purified by recrystallisation from ethanol.
15 Yield: 1.8 g (34%) IH-NMR (300 MHz, DMSO): = 2.0 (s, 3H); 2.1 (s, 3H); 5.3 (s, IH); 7.6 (s, IH); 7.8 (s, IH); 7.9 (s, IH); 12.4 (s, IH) ppm.
Example 6A
20 4-( {3-[(Diethylamino)methyl]phenyl amino)-3-penten-2-one C:H3 J H3
O CHs 1.00 g (9.99 mmol) Acetylacetone, 1.78 g (9.99 mmol) 3[(diethylamino)methyl] 25 aniline, and 0.15 g (2.5 mrnol) 4toluenesulfonic acid are dissolved in 100 ml
( - 27 toluene. The reaction mixture is reflexed overnight with a DeanStark trap to remove water. 0.05 g (0.83 mrnol) 4-toluenesulfonic acid are again added and the mixture is reflexed overnight. As tic control showed that there is some 3-[(diethylamino) methyl]aniline left, 0.2 g (2 mmol) acetylacetone are added and refluxing is 5 continued for 4 h. To drive the reaction to completion, 0.6 ml (9.98 mmol) acetic acid and 0.2 g (2 mmol) acetylacetone are added and the mixture is reflexed overnight with a Dean-Stark trap. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane/methanol mixtures as eluent.
10 Yield: 1.97 g (76%) iH-NMR (200 MHz, CDCI3): = 1.0 (t, 6H); 2.0 (s, 3H) , 2.1 (s, 3H); 2.5 (q, 4H); 3.5 (s, 2H); 5.2 (s, IH); 7.0 (m, IH); 7.1-7. 3 (m, 3H); 12.5 (s, IH) ppm.
Example 7A
15 4- { [3-Methoxy-5-(trifluoromethyl)phenyl]amino} -3-pen/en-2-one H3C FAWN:CF3
O CH3 CH3 1.57 g (15.7 mmol) Acetylacetone, 3.00 g (15.7 mmol) 3-methoxy5-(trilluoro 20 methyl)aniline, and 0.1 g (1.6 mmol) 4-toluenesulfonic acid are dissolved in 150 ml toluene. The reaction mixture is reflexed for 7 h with a Dean-Stark trap to remove water. After cooling down to room temperature, the suspension is filtered. The solid is purified by recrystallization from ethanol.
Yield: 2.8 g (60%) 25 tH-NMR (300 MHz, DMSO): = 2.0 (s, 3H); 2.1 (s, 3H); 3.8 (s, 3H); 5.3 (s, 1H); 7.1 (m, 3H); 12.4 (s, IH) ppm.
( - 28 ExampIe 8A 4-[(3-Arnino-5-trifluoromethylphenyl)amino]-3-penten-2one O CH3 CF3
NH2 1.71 g (17.0 mmol) Acetylacetone, 3.00 g (17.0 rnmol) 3-amino-5(trifluoromethyl)-
phenylamine, and 0.1 g (1.6 mmol) 4-toluenesulfonic acid are dissolved in 150 ml toluene. The reaction mixture is reflexed overnight with a DeanStark trap to remove water. After cooling down to room temperature, the solvent is removed in VACUO and 10 the residue is purified by column chromatography on silica with cyclohexane/ ethylacetate mixtures as eluent. The solid obtained by column chromatography is recrystallized from cyclohexane.
Yield: 0.35 g (8%) IH-NMR (200 MHz, DMSO): = 2.0 (s, 3H); 2.1 (s, 3H); 5. 2 (s, IH); 5.7 (s, 2 h); 15 6.5 (m, 2H); 6.6 (s, IH); 12.4 (s, IH) ppm.
- 29 Preparation Examples: Example l
()-Ethyl 5 - acetyl-2 -amino-4-(4-bromophenyl)-6-methyl- 1-( 3 nitrophenyl)- I,4-di 5 hydro-3-pyridinecarboxylate Br H3CO CH3
H3C N NH2
NO2 4.8 g (21.8 mmol) of Example 1A are dissolved in 30 ml ethanol, 4.0 g (21.8 mmol) 10 4-bromobenzaldehyde, 2.47 g (21.8 rnmol) ethyl cyanoacetate, and 3.71 g (43.6 mmol) piperidine are added. The reaction mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloromethane. 15 Yield: 1.8 g ( 17%) IH-NMR (300 MHz, DMSO): 0 = 1.2 (t, 3H); 1.9 (s, 3H); 2.2 (s, 3H); 4.0 (m, 2H); 4.9 (s, 1H); 6.8 (br.s, 2H); 7.3 (m, 2H); 7.5 (m, 2H); 7.8 (m, 2H); 8.2 (m, IH); S.4 (m, 1 H) ppm.
- 30 ExamDIe 2 (-)-Ethyl 5-acetyl-2-amino-4-(4-bromophenyl)-6-methyl- 1 (3-nitrophenyl)- 1,4-di hydro-3-pyridinecarboxylate 5 The enantiomers of Example I are separated by chiral HPLC [silane modified poly(Nmethacryloyl-L-leucin-l-menthylamide) fixed on silica; 250 x 20 mm column] with iso-hexane/ethylacetate 4:1 as eluent (20 ml/min).
[a]20 = -97.6 (\ = 589 nm, methanol, c = 456.5 mg / 100 ml) tH-NMR identical with Example 1.
Example 3
()-Ethyl 5-acetyl-2-amino-4-(4-bromophenyl)-6-methyl- 1 -[3(trifluoromethyl) phenyl]- I,4-dihydro-3-pyridinecarboxylate Br H3C:O CH3
H3C N NH2
CF3 150 mg (0.62 mmol) of Example 2A are dissolved in 2 ml ethanol, 114 mg (0.62 mmol) 4-bromobenzaldehyde, 70 mg (0.62 mmol) ethyl cyanoacetate, and 105 mg (1.23 mmol) piperidine are added. The reaction mixture is stirred under 20 reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloromethane. Yield: 43 mg (13%)
- 31 1H-NMR (300 MHz, DMSO): = 1.2 (t, 3H); 1.8 (s, 3H); 2.2 (s, 3H); 4.0 (m1 2H); 4.9 (s, IH); 6.7 (br.s, 2H); 7.3 (m, 2H); 7.5 (m, 2H); 7.7 (m, IH); 7.8 (m, IH); 7.8 (m, IH); 7.9 (m, IH) ppm.
5 ExampIe 4 ()-Ethyl 5-acetyl-2-amino-4-(4-cyanophenyl)-6-methyl- 1 -[3(tri fluoromethyl)-phen yl]- I,4-dihydro-3 -pyridinecarboxylate H3CO CH3
H3C N NH2
CF3 100 mg (0.41 mmol) of Example 2A are dissolved in 2 ml ethanol, 54 mg (0.41 mmol) 4-cyanobenzaldehyde, 47 mg (0.41 mmol) ethyl cyanoacetate, and 70 mg (0.82 mmol) piperidine are added. The reaction mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo 15 and the residue is purified by column chromatography on silica with eluent dichloromethane. Yield: 26 mg (14%) tH-NMR (400 MHz, DMSO): = 1.2 (t, 3H); 1.8 (s, 3H); 2.2 (s, 3H); 4.0 (m, 2H); 5.0 (s, IH); 6.7 (br.s, 2H); 7.5 (m, 2H); 7.7 (m, IH); 7.8 (m, 4H); 7.9 (m, IH) ppm.
- 32 Examule 5 and Example 6 (+) and (-)-Ethyl 5-acetyl-2-amino-4-(4cyanophenyl)-6-methyl-1-[3-(trifluoro-meth-
yl)phenyl] - I,4-dihydro-3-pyridinecarboxylate 5 The enantiomers of Example 4 are separated by chiral HPLC [silane modified poly(Nmethacryloyl-L-leucin-l-menthylamide) fixed on silica; 250 x 20 mm column] with iso-hexane/ethylacetate 4:1 as eluent (20 ml/min).
(+)-Enantiomer (Example 5): []20 = +88.4 (\ = 589 nm, methanol, c = 453. 5 mg / 100 ml) IO (-)-Enantiomer (Example 6): [a]20 = -91.2 (\ = 589 nm, methanol, c = 471.5 mg / 100 ml) H-NMRs for Example 5 and 6 identical with Example 4.
Example 7
15 (i)-Ethyl 5-acetyl-4-(4-bromophenyl)-6-methyl-1-[3-(trifluoromethyl) phenyl]-1,4 dihydro-3 -pyridinecarboxylate Or H3CO CH3
H3C N 20 150 mg (0.62 mmol) of Example 2A are dissolved in 2 ml acetic acid, 114 mg (0.62 mmol) 4-bromobenzaldehyde, and 60 mg (0.62 mmol) ethyl propiolate are added. The reaction mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloromethane.
- 33 Yield: 56 m8 (18%) lH-NMR (300 MHz, DMSO): = 1.1 (t, 3H); 1.9 (s, 3H) ; 2.2 (s, 3H); 4.1 (m, 2H); 5.0 (s, 1H); 7.3 (m, 3H); 7.5 (m, 2H); 7.7 (m, 2H); 7.8 (m, IH); 7.9 (s, 1H) ppm.
5 ExamnIe 8 ()-Ethyl 5-acetyl-4-(4-cyanophenyl)-6-methyl- 1 -[3(trifluoromethyl)phenyl]- 1,4 dihydro-3-pyridinecarboxylate H3COCH3
H3C N 100 mg (0.41 mmol) of Example 2A are dissolved in 2 ml acetic acid, 54 mg (0.41 mmol) 4-cyanobenzaldebyde, and 40 mg (0.41 mmol) ethyl propiolate are added. The reaction mixture is stirred under reflux ovemight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by 15 column chromatography on silica with eluent dichloromethane.
Yield: 20 mg (11%) tH-NMR (300 MHz, DMSO): 0 = 1.1 (t, 3H); 2.0 (s, 3H); 2.2 (s, 3H); 4.1 (m, 2H); 5.1 (s, IH); 7.3 (s, IH); 7.6 (m, 2H); 7.8 (m, 4H); 7.8 (m, 1H); 8.0 (s, IH) ppm.
- 34 Examrle 9 ()-Ethyl 5-acetyl-4-(4-cyanophenyl)-2,6-dimethyl- 1-(3 methylphenyl)- I,4-dihydro 3-pyridinecarboxylate CN 06 0 H3C 4OCH3
H3C N CH3
5 CH3 100 mg (0.46 mrnol) Ethyl (2E)-3-{[3-(methyl)phenyl]amino}-2butenoate, 75 mg (0.57 mmol) 4-cyanobenzaldehyde, 38 mg (0.38 mmol) 2,4pentanedione, and 87 mg (0.76 mmol) trifluoroacetic acid are dissolved in 2 ml diisopropyl ether. The reaction 10 mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed n vacuo and the residue is purified by preparative HPLC.
Yield: 11 mg (7%) H-NMR (300 MHz, DMSO): = 1.2 (t, 3H); 2.0 (s, 3H); 2.0 (s, 3H); 2.2 (s, 3H); 2.4 (s, 3H); 4.1 (q, 2H); 5.1 (s, IH); 7.0 (m, 2H); 7.3 (m, IH); 7.4 (m, IH); 7.5 (m, 2H); l5 7.8 (m, 2H)ppm.
- 35 Example 10
()-Ethyl 5-acetyl-4-(4-cyanophenyl)-2,6-dimethyl- 1 -[3-(tri fluoromethyl) phenyl] I,4-dihydro-3 -pyridinecarboxylate CN 06 0 H3C 4O CH3
H3C N CH3
CF 100 mg (0.37 mmol) of Example 3A, 60 mg (0.46 mmol) 4cyanobenzaldehyde, 31 mg (0.31 mmol) 2,4-pentanedione, and 70 mg (0.61 mmol) trifluoroacetic acid are dissolved in 2 ml diisopropyl ether. The reaction mixture is stirred under reflux over 10 night. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by preparative HPLC.
Yield: 7 mg (5%) H-NMR (300 MHz, DMSO): -1.2 (t, 3H); 1.9 (s, 3H); 2.0 (s, 3H); 2.3 (s, 3H); 4.1 (q, 2H); 5.1 (s, IH); 7.5 (m, 2H); 7.6 (m, IH); 7. 7 (m, IH); 7.8 (m, 3H); 7.9 (m, IH) t 5 ppm.
- 36 Example 1 1
Ethyl 5-acetyl-2-amino-4-(4-(trifluoromethyl)phenyl)-6-methyl-1-[3(trifluorometh-
yl)phenyl]- 1,4-dihydro-3-pyridinecarboxylate F3 H3COCH3
H3C N NH2
5 CF3 100 mg (0.41 mmol) of Example 2A are dissolved in 2 ml ethanol, 72 mg (0.41 mmol) 4-(trifluoromethyl)benzaldehyde, 47 mg (0.41 mmol) ethyl cyano acetate, and 70 mg (0.82 mmol) piperidine are added. The reaction mixture is stirred 10 under reflux ovemight. Aflcer cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloromethane.
Yield: 46 mg (22%) IH-NMR (300 MHz, DMSO): = 1.2 (t, 3H); 1.9 (s, 3H); 2. 2 (s, 3H); 4.0 (m, 2H); 15 5.0 (s, IH); 6.8 (br. s, 2H); 7.5 (m, 2H); 7.7 (m, 3H); 7.7 (m, 1H); 7.8 (m, IH); 7.9 (m, 1 H) ppm.
- 37 Example 12
Ethyl 5-acetyl-2-amino-4-(4-cyanophenyl)-6-methyl- 1 -[3-methylphenyl]- 1, 4-di hydro-3 -pyridinecarboxylate CN H3COCH3
H3C N NH2
CH3 100 mg (0.53 mmol) of Example 4A are dissolved in 2 ml ethanol, 69 mg (0.53 mmol) 4-cyanobenzaldehyde, 60 mg (0.53 mrnol) ethyl cyanoacetate, and 90 mg (1.06 mmol) pipendine are added. The reaction mixture is stirred under reflux 10 overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloro methane. Yield: 21 mg (10%) tH-NMR (200 MHz, DMSO): = 1.2 (t, 3H); 1.9 (s, 3H); 2.2 (s, 3H); 4.0 (m, 2H); 15 5.0 (s, IH); 6.7 (br. s, 2H); 7.2 (m, 2H); 7.3 (m, IH); 7.5 (m, 3H); 7.8 (m, 2H) ppm.
- 38 Example 13
5-Acetyl-2-amino-4-(4-cyanophenyl)-6-methyl- 1 -[3-(trifluoromethyl) phenyl]- 1,4-
dihydro-3-pyridinecarboxamide CN H3C:NH2
H3C N NH2
CF3 s 750 mg (3.08 mmol) of Example 2A are dissolved in 5 ml ethanol, 404 mg (3.08 mmol) 4-cyanobenzaldehyde, 260 mg (3.08 mmol) cyanoacetamide, and 26 mg (0.31 mmol) piperidine are added. The reaction mixture is stirred under reflux 10 overnight. ADer cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloromethane. Yield: 160 mg (12%) lH-NMR (300 MHz, DMSO): 0 = 1.8 (s, 3H); 2.2 (s, 3H); 4.9 (s, IH); 6.7 (br. s, 2H); 15 6.9 (br. s, 2H); 7.5 (m, 3H); 7.8 (m, 2H); 7.9 (m, IH), 8. 0 (m, 2H) ppm.
- 39 Examnle 14 5-Acetyl-4-(4-cyanophenyl)-2-imino-N,N,6-trimethyl- 1 -[3(trifluoromethyl)phenyl] 1,2,3,4-tetrahydro-3 -pyndinecarboxamide ON H3C 3 1 CF3 s 750 mg (3.08 mmol) of Example 2A are dissolved in 5 ml ethanol, 404 mg (3.08 mmol) 4-cyanobenzaldehyde, 260 mg (3.08 mrnol) 2-cyano-N,N dimethylacetamide, and 26 mg (0.31 mmol) piperidine are added. The reaction 10 mixture is stirred under reflux overnight. After cooling down to room temperature, the solvent is removed in vacua and the residue is purified by column chromatography on silica with eluent dichloromethane.
Yield: 88 mg (6%) H-NMR (300 MHz, DMSO): =2.0 (s, 3H); 2.1 (s, 3H), 2.5 (s, 3H); 2.9 (s, 3H); 4.1 15 (d, IH); 4.5 (d, IH); 7.6 (m, 3H); 7.7 (m, IH); 7.8 (m, 3H); 8.2 (s, IH) ppm.
- 40 Example lS
5-Acetyl-2-amino-4-(4-cyanophenyl)-6-methyl- 1 -[3-(trifluoromethyl) phenyl]- 1,4 dihydro-3 -pyridinecarbonitrile ON H3CJCN
H3C N NH2
CF3 750 mg (3.08 rnmol) of Example 2A are dissolved in 5 ml ethanol, 404 mg (3.08 mmol) 4-cyanobenzaldehyde, 204 mg (3.08 mmol) malononitrile, and 26 mg (0.31 mrnol) piperidine are added. The reaction mixture is stirred under reflex 10 overnight. After cooling down to room temperature, the solvent is removed in vacua and the residue is purified by column chromatography on silica with eluent cylclo hexane/ethyl acetate.
Yield: 43 mg (3%) LC-MS: retention time 3.17 min., rn/z = 423 [M+H]+.
( - 41
Example 16
Ethyl 5 -acetyl-2-amino-4-(4-cyanophenyl)- 1- [ 3 -iodo- 5 -(tri fluoromethyl)phenyl] -6-
methyl- I,4-dihydro-3-pyridinecarboxylate H3C 0 CH3
H3C N NH2
s 200 mg (0.54 mmol) of Example 5A are dissolved in 2.5 ml ethanol, 71.1 mg (0.54 mmol) 4-cyanobenzaldehyde, 61.3 mg (0.54 mmol) ethyl cyanoacetate, and 4.6 mg (0.05 mmol) piperidine are added. The reaction mixture is stirred under reflux 10 for 30 h. After cooling down to room temperature, the solvent is removed in vacua and the residue is purified by column chromatography on silica with eluent cylclo hexane/ethyl acetate. The solid obtained by column chromatography is dissolved in ethanol. Water is added until a solid precipitates. The suspension is filtered and the solvent of the filtrate is removed in vacuo.
15 Yield: 18 mg (5%) lH-NMR (300 MHz, DMSO): =1.1 (t, 3H); 1.8 (s, 3H); 2. 2 (s, 3H); 4.0 (q, 2H); 4.9 (s, IH); 6.9 (s, 2H); 7.5 (d, 2H); 7.7 (d, 2H) ; 7.8 (s, IH); 8.1 (s, IH); 8.2 (s, IH) ppm.
( - 42 Example 17
Ethyl 5-acetyl-2-amino-4-(4-cyanophenyl)- 1- { 3-[(diethylamino)methyl] phenyl} -6-
methyl- I,4-dihydro-3-pyridinecarboxylate CN H3C OCH3
H3C N NH2
CH3 5 N'CH3
500 mg (1.92 mmol) of Example 6A are dissolved in 3.0 ml ethanol, 265 mg (1.92 mmol) 4-cyanobenzaldehyde, 217 mg (1.92 mmol) ethyl cyanoacetate, and 49 mg (0.58 mmol) piperidine are added. The reaction mixture is stirred under reflux 10 for 48 h. 115 mg (1.34 mmol) piperidine are added and the mixture is stirred under reflux for another 6 h. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by preparative HPLC with eluent acetonitrile/water. Yield: 57 mg (5%) 15 tH-NMR (200 MHz, DMSO): =1.0 (t, 6H); 1.2 (t, 3H); 1.9 (s, 3H); 2.2 (s, 3H); 2.5 (m, 4H); 3.6 (s, 2H); 4.0 (q, 2H); 5.0 (s, IH); 6.7 (br. s, 2H); 7.2 (m, 2H); 7.5 (m, 4H); 7.8 (d, 2H) ppm.
( - 43
Example 18
Ethyl 5-acetyl-2-amino-4-(4-cyanophenyl)-1-3-methoxy-5-(trifluoromethyl) phenyl] 6-methyl- 1,4-dihydro-3-pyridinecarboxylate CN H3CJ5OCH3
H3C N NH2
H3Co,:CF3 200 mg (0.73 mmol) of Example 7A are dissolved in 2.5 ml ethanol, 95.9 mg (0.73 mmol) 4-cyanobenzaldehyde, 82.8 mg (0.73 mrnol) ethyl cyanoacetate, and 6.2 mg (0.07 rrunol) piperidine are added. The reaction mixture is stirred under reflux 10 ovemight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by preparative HPLC with eluent acetonitrile/water.
Yield: S9 mg (15%) H-NMR (300 MHz, DMSO): =1.2 (t, 3H); 1.9 (s, 3H); 2.2 (s, 3H); 3.9 (s, 3H); 4.0 (q, 2H); 5.0 (s, IH); 6.8 (br. s, 2H); 7.3 (m, 2H); 7.4 (s, IH); 7.5 (d, 2H); 7.8 (d, 2H) IS ppm.
- 44 Example 19
Ethyl 5-acetyl-2-amino- 1 -3-amino-5-(trifluoromethyl)phenyl]-4-(4cyanophenyl)-6 methyl- I,4-dihydro-3-pyridinecarboxylate CN 04 0 H3C J4o CH3 H3C N NH2
5H2N:9CF3
200 mg (0.77 mmol) of Example 8A are dissolved in 2.5 ml ethanol, 107 mg (0.77 mmol) 4-cyanobenzaldehyde, 87.6 mg (0.77 mmol) ethyl cyanoacetate, and 20 mg (0.23 mmol) piperidine are added. The reaction mixture is stirred under reflux 10 ovemight. ADer cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by preparative HPLC with eluent acetonitrile/water.
Yield: 50.5 mg (12%) H-NMR (300 MHz, DMSO): 0 =1.2 (t, 3H); 2.0 (s, 3H); 2.3 (s, 3H); 4.1 (q, 2H); 5.0 (s, 1H); 6.0 (s, 2H); 6.7 (s, 2H); 6.8 (s, 2H); 7.1 (s, IH); 7.4 (d, 2H); 7.7 (d, 2H) ppm.
( - 45 ExamnIe 20 Ethyl 5'-acetyl-2'-amino-6'-methyl- 1'-[3 -(tri fluoromethyl)phenyl]- I ',4'-dihydro-3,4' bipyridine-3'-carboxylate H3COCH3
H3C N NH2
5 CF3 100 mg (0.41 rnmol) of Example 2A are dissolved in 5 ml ethanol, 44 mg (0.41 mmol) nicotinaldehyde, 47 mg (0.41 mmol) ethyl cyanoacetate, and 70 mg (0.82 mmol) piperidine are added. The reaction mixture is stirred under reflux 10 overnight. After cooling down to room temperature, the solvent is removed in vacua and the residue is purified by column chromatography on silica with eluent dichloromethane. Yield: 19 mg (10%) H-NMR (300 MHz, DMSO): =2.0 (s, 3H); 1.8 (s, 3H); 2.2 (s, 3H); 4.0 (m, 2H) ; 15 4.9 (s, IH); 6.7 (m, 2H); 7.3 (m, IH); 7.7 (m, 2H); 7.8 (m, 2H); 7.9 (m, IH); 8.4 (m, IH); 8.5 (m, IH) ppm.
- 46 C. Operative examples relating to pharmaceutical compositions The compounds according to the invention can be converted into pharmaceutical preparations as follows: Tablet:
Composition: 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASE, 10 Ludwigshafen, Gennany) and 2 mg of magnesium stearate.
Tablet weight 212 ma, diameter 8 mm, curvature radius 12 mm.
Preparation: The mixture of active component, lactose and starch is granulated with a 5% solution 15 (rum) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 min. This mixture is moulded using a customary tablet press (tablet format, see above). The moulding force applied is typically 15 kN.
Orallv administrable suspension: 20 Composition: 1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
A single dose of 100 mg of the compound according to the invention is provided by 10 ml of oral suspension.
Preparation: The Rhodigel is suspended in ethanol and the active component is added to the suspension. The water is added with stirring. Stirring is continued for about 6h until the swelling of the Rhodigel is complete.
Claims (17)
1 5 C6-alkyl, R1 represents hydrogen, C-C4-alkyl or amino, X', X2, X3 and X4 independently from each other represent CH or N. wherein 20 ring A contains either 0, 1 or 2 nitrogen atoms, and yt, y2, y3, y4 and Y5 independently from each other represent CH or N. 25 wherein ring B contains either 0, 1 or 2 nitrogen atoms.
2. Compounds of general formula (l) according to claim 1, wherein
( - 49 R' represents hydrogen, R2, R3, R9 and Rt independently from each other represent hydrogen, halogen, nitro, cyano, trifluoromethyl, Cl-C4alkyl, C-C4-alkanoyl, 5 hydroxy, C-C4-alkoxy, trifluoromethoxy, amino, CC4-dialkylarnino, C, -C4-acylarnino, methoxy-carbonylamino, tert.butoxycarbonyl amino, carboxyl, methoxycarbonyl or ethoxycarbonyl, wherein C,-C4 alkyl, C,-C4-alkanoyl, C,-C4-alkoxy, C,-C4-dialkylamino and C,-C4 acylamino can be further substituted with one to two identical or 10 different radicals selected from the group consisting of hydroxy, meth oxy, ethoxy, amino, dimethylamino and diethylamino, R4 represents methyl, ethyl, trifluoromethyl or phenyl, 15 R5 represents methyl or ethyl, R6 represents cyano, arninocarbonyl, methylaminocarbonyl, dimethyl arninocarbonyl, carboxyl or C,-C4-alkoxycarbonyl, wherein the alkoxy moiety can be further substituted with a radical selected from 20 the group congisting of hydroxy, methoxy, ethoxy, amino, mono- and all-C -C4alkylarnino, R7 represents hydrogen, methyl, ethyl or amino, 25 R represents hydrogen, X', x2 and X3 represent CH, X4 represents CH or N. and
- so- Y\, Y2, Y3, Y4 and Y. represent CH.
3. Compounds of general formula (I) according to claim 1 or 2, wherein R and R2 represent hydrogen, R3 represents fluoro, chloro, bromo, nitro, cyano, tri fluoromethyl, methyl, methoxy or hydroxy, R4 represents methyl or trifluoromethyl, R5 represents methyl, 15 R6 represents cyano, aminocarbonyl, methylaminocarbonyl, dimethyl aminocarbonyl, carboxyl, methoxycarbonyl or ethoxycarbonyl, R7 represents hydrogen, methyl or amino, 20 R and R9 represent hydrogen, R' represents fluoro, chloro, bromo, nitro, cyano, trifluoromethyl or methyl, 25 X', X2, X3 and X4 represent CH, and yl yZ y3, Y4 and Y5 represent CH.
( - 51
4. Compounds of general formula (I) according to claim 1, 2 or 3, wherein R3 is cyano, which is located in pare-position relativ to the 1,4dihydropyridine nng.
5 5. Compounds of general formula (I) according to claim 1, 2 or 3, wherein R4 is methyl.
6. Compounds of general formula (I) according to claim 1, 2 or 3, wherein R5 is methyl.
7. Compounds of general formula (I) according to claim 1, 2 or 3, wherein R6 is methoxycarbonyl or ethoxycarbonyl.
8. Compounds of general formula (I) according to claim 1, 2 or 3, wherein R7 is 15 hydrogen, methyl or amino.
9. Compounds of general formula (I) according to claim 1, 2 or 3, wherein Ri is trifluoromethyl, which is attached to y2.
20
10. Processes for synthesizing the compounds of general formula (I) according to claim 1, 2 or 3, characterized in that either [A] compounds of the general formula (II) Y; iR10 1yl.Y (II), R4 R5 wherein R4, R5, R8, R9, R and Y' to Y5 have the meaning described in claim 1,
- 52 are condensed in the presence of a base with compounds of the general formulas (III) and (IV) R R2 Xll R3 xX (III) NCR (IV), H O s wherein Rt, R2, R3 and Xt to X4 have the meaning described in claim l, and to R" represents cyano or C-C6-alkoxycarbonyl, to give compounds of the general formula (la) R' R2 44 3 I R ,3 O R4R R5 N NH2
R'RB (la), R or [B] compounds of the general formulas (II) and (III) are condensed in the presence of an acid with compounds of the general formula (V)
1
11 _ _I
( - 53 H /< oR,2(V), wherein Ri2 represents Cj-Ce-alkyl, 5 to give compounds of the general formula (lb) R3 XWA O R4oR'2 R5 N H
R' Yl iR3 (lb), Rg/Y3 or 10 [C] compounds of the general formula (Vl) R:R' 1y'Y R'20J:R,3 (VI),
wherein R8, R9, R' , Ri2 and Y' to Y5 have the meaning described in claim 1, and
! - 54 R'3 represents C'-C4-alkyl, are condensed in the presence of an acid or a base with compounds of the general fonulas (111) and (VII) R4R5 n 1l (VII), wherein R4 and Rs have the meaning described in claim l, 10to give compounds of the general formula (Ic) R,wR2 R4oR42 R5 N R13
R1 - R8 (Ic).
R 11. The composition containing at least one compound of general formula (I) l 5 according to claim l, 2 or 3 and a pharmacologically acceptable diluent.
12. A composition according to claim l l for the treatment of acute and chronic inflmnmatory processes.
20
13. The process for the preparation of compositions according to claim l 1 and 12 characterized in that the compounds of general formula (I) according to claim l,
( - 55 2 or 3 together with customary auxiliaries are brought into a suitable application form.
14. Use compounds of general formula (1) according to claim 1, 2 or 3 for the 5 preparation of medicaments.
15. Use according to claim 14 for the preparation of medicaments for the treat ment of acute and chronic inflammatory processes.
I 0
16. Use according to claim 15, wherein the process is chronic obstructive pulmonary disease.
17. Process for controlling chronic obstructive pulmonary disease in humans and animals by administration of an neutrophil elastase inhibitory amount of at 15 least one compound according to any of Claims I to 3.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0216664A GB2390849A (en) | 2002-07-17 | 2002-07-17 | 3-Acyl-1,4-dihydro-1,4-di(phenyl/azinyl/diazinyl)pyridine derivatives for use as human neutrophil elastase inhibitors |
| JP2003554646A JP4486817B2 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivative |
| DE60214428T DE60214428T2 (en) | 2001-12-20 | 2002-12-09 | 1, 4-DIHYDRO-1, 4-DIPHENYLPYRIDINE DERIVATIVES |
| CA002470813A CA2470813A1 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivatives |
| AU2002361992A AU2002361992A1 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivatives |
| PCT/EP2002/013931 WO2003053930A1 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivatives |
| ES02796589T ES2271365T3 (en) | 2001-12-20 | 2002-12-09 | DERIVATIVES OF 1,4-DIHIDRO-1,4-DIFENYLPIRIDINE. |
| US10/498,967 US7199136B2 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivatives |
| EP02796589A EP1458682B1 (en) | 2001-12-20 | 2002-12-09 | 1,4-dihydro-1,4-diphenylpyridine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0216664A GB2390849A (en) | 2002-07-17 | 2002-07-17 | 3-Acyl-1,4-dihydro-1,4-di(phenyl/azinyl/diazinyl)pyridine derivatives for use as human neutrophil elastase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB0216664D0 GB0216664D0 (en) | 2002-08-28 |
| GB2390849A true GB2390849A (en) | 2004-01-21 |
Family
ID=9940681
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB0216664A Withdrawn GB2390849A (en) | 2001-12-20 | 2002-07-17 | 3-Acyl-1,4-dihydro-1,4-di(phenyl/azinyl/diazinyl)pyridine derivatives for use as human neutrophil elastase inhibitors |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2390849A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2383326A (en) * | 2001-12-20 | 2003-06-25 | Bayer Ag | Antiinflammatory dihydropyridines |
-
2002
- 2002-07-17 GB GB0216664A patent/GB2390849A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2383326A (en) * | 2001-12-20 | 2003-06-25 | Bayer Ag | Antiinflammatory dihydropyridines |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0216664D0 (en) | 2002-08-28 |
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| Date | Code | Title | Description |
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| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |