SG183336A1 - Compounds as bradykinin b1 antagonists - Google Patents
Compounds as bradykinin b1 antagonists Download PDFInfo
- Publication number
- SG183336A1 SG183336A1 SG2012060620A SG2012060620A SG183336A1 SG 183336 A1 SG183336 A1 SG 183336A1 SG 2012060620 A SG2012060620 A SG 2012060620A SG 2012060620 A SG2012060620 A SG 2012060620A SG 183336 A1 SG183336 A1 SG 183336A1
- Authority
- SG
- Singapore
- Prior art keywords
- general formula
- salts
- amino
- phenyl
- enantiomers
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 101
- 239000005557 antagonist Substances 0.000 title description 15
- 101800004538 Bradykinin Proteins 0.000 title description 2
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 title description 2
- 102100035792 Kininogen-1 Human genes 0.000 title description 2
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 55
- 239000000203 mixture Substances 0.000 claims abstract description 40
- 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 claims abstract description 30
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 8
- 150000007524 organic acids Chemical class 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims description 55
- 208000002193 Pain Diseases 0.000 claims description 28
- 239000000126 substance Substances 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 208000004296 neuralgia Diseases 0.000 claims description 7
- 230000002757 inflammatory effect Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 230000001154 acute effect Effects 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- 208000021722 neuropathic pain Diseases 0.000 claims description 5
- 201000008482 osteoarthritis Diseases 0.000 claims description 5
- 206010045171 Tumour pain Diseases 0.000 claims description 4
- 208000005298 acute pain Diseases 0.000 claims description 4
- 210000000929 nociceptor Anatomy 0.000 claims description 4
- 208000009935 visceral pain Diseases 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 208000027109 Headache disease Diseases 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 101100301524 Drosophila melanogaster Reg-5 gene Proteins 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 12
- -1 cyciobutyl Chemical group 0.000 description 88
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 60
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 49
- 239000000543 intermediate Substances 0.000 description 36
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 239000002253 acid Substances 0.000 description 18
- 238000011282 treatment Methods 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 235000019253 formic acid Nutrition 0.000 description 15
- 238000001819 mass spectrum Methods 0.000 description 14
- 241001655883 Adeno-associated virus - 1 Species 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 150000004677 hydrates Chemical class 0.000 description 12
- 239000012453 solvate Substances 0.000 description 12
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 230000008878 coupling Effects 0.000 description 11
- 238000010168 coupling process Methods 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- FIMXSEMBHGTNKT-RZVDLVGDSA-N scopine Chemical compound C([C@@H]1N2C)[C@H](O)C[C@@H]2[C@@H]2[C@H]1O2 FIMXSEMBHGTNKT-RZVDLVGDSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 230000002265 prevention Effects 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 7
- 239000003246 corticosteroid Substances 0.000 description 7
- 229960001334 corticosteroids Drugs 0.000 description 7
- 229940121647 egfr inhibitor Drugs 0.000 description 7
- 230000002503 metabolic effect Effects 0.000 description 7
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 7
- 229940044551 receptor antagonist Drugs 0.000 description 7
- 239000002464 receptor antagonist Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 6
- 239000000808 adrenergic beta-agonist Substances 0.000 description 6
- 230000003454 betamimetic effect Effects 0.000 description 6
- 150000003842 bromide salts Chemical class 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 210000003494 hepatocyte Anatomy 0.000 description 6
- 150000002923 oximes Chemical class 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 235000019759 Maize starch Nutrition 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 5
- 208000006673 asthma Diseases 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000000812 cholinergic antagonist Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000005635 hydromethanesulphonate group Chemical group 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- WHZFQZPLYVKTAE-UHFFFAOYSA-N 6-oxo-1h-pyridazine-4-carboxamide Chemical group NC(=O)C1=CN=NC(O)=C1 WHZFQZPLYVKTAE-UHFFFAOYSA-N 0.000 description 4
- PSMIHCDKMNXTAY-UHFFFAOYSA-N 6-oxo-1h-pyridazine-4-carboxylic acid Chemical compound OC(=O)C=1C=NNC(=O)C=1 PSMIHCDKMNXTAY-UHFFFAOYSA-N 0.000 description 4
- 102100038496 Cysteinyl leukotriene receptor 1 Human genes 0.000 description 4
- 241000702421 Dependoparvovirus Species 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 206010006451 bronchitis Diseases 0.000 description 4
- 230000002440 hepatic effect Effects 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- CQRYARSYNCAZFO-UHFFFAOYSA-N o-hydroxybenzyl alcohol Natural products OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 230000000241 respiratory effect Effects 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- GXAMYUGOODKVRM-UHFFFAOYSA-M 9-hydroxyfluorene-9-carboxylate Chemical compound C1=CC=C2C(O)(C([O-])=O)C3=CC=CC=C3C2=C1 GXAMYUGOODKVRM-UHFFFAOYSA-M 0.000 description 3
- DTZDZCNXNYMMOW-UHFFFAOYSA-N 9-hydroxyxanthene-9-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)(O)C3=CC=CC=C3OC2=C1 DTZDZCNXNYMMOW-UHFFFAOYSA-N 0.000 description 3
- PUPWRKQSVGUBQS-UHFFFAOYSA-N 9-methylfluorene-9-carboxylic acid Chemical compound C1=CC=C2C(C)(C(O)=O)C3=CC=CC=C3C2=C1 PUPWRKQSVGUBQS-UHFFFAOYSA-N 0.000 description 3
- CBNOKZSYCBHRAD-UHFFFAOYSA-N 9-methylxanthene-9-carboxylic acid Chemical compound C1=CC=C2C(C)(C(O)=O)C3=CC=CC=C3OC2=C1 CBNOKZSYCBHRAD-UHFFFAOYSA-N 0.000 description 3
- 102000017916 BDKRB1 Human genes 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 108050001116 Cysteinyl leukotriene receptors Proteins 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 201000002661 Spondylitis Diseases 0.000 description 3
- 150000001242 acetic acid derivatives Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 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 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 230000008733 trauma Effects 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- GQMYQEAXTITUAE-UHFFFAOYSA-N 1H-indole-5-carboxamide Chemical compound NC(=O)C1=CC=C2NC=CC2=C1 GQMYQEAXTITUAE-UHFFFAOYSA-N 0.000 description 2
- ZMXHONJJTQSZKY-UHFFFAOYSA-N 2,2-bis(3,4-difluorophenyl)-2-hydroxyacetic acid Chemical compound C=1C=C(F)C(F)=CC=1C(O)(C(=O)O)C1=CC=C(F)C(F)=C1 ZMXHONJJTQSZKY-UHFFFAOYSA-N 0.000 description 2
- RCORMCWYMRPHPO-UHFFFAOYSA-N 2,2-bis(3-fluorophenyl)-2-hydroxyacetic acid Chemical compound C=1C=CC(F)=CC=1C(O)(C(=O)O)C1=CC=CC(F)=C1 RCORMCWYMRPHPO-UHFFFAOYSA-N 0.000 description 2
- YKZXWNCXGVYCKF-UHFFFAOYSA-N 2,2-bis(4-fluorophenyl)-2-hydroxyacetic acid Chemical compound C=1C=C(F)C=CC=1C(O)(C(=O)O)C1=CC=C(F)C=C1 YKZXWNCXGVYCKF-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- MAGCRYYXZYUDSY-UHFFFAOYSA-N 2-fluoro-2,2-diphenylacetic acid Chemical compound C=1C=CC=CC=1C(F)(C(=O)O)C1=CC=CC=C1 MAGCRYYXZYUDSY-UHFFFAOYSA-N 0.000 description 2
- ZMPRRFPMMJQXPP-UHFFFAOYSA-N 2-sulfobenzoic acid Chemical class OC(=O)C1=CC=CC=C1S(O)(=O)=O ZMPRRFPMMJQXPP-UHFFFAOYSA-N 0.000 description 2
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 description 2
- UTUUPXBCDMQYRR-HSZRJFAPSA-N 4-[(2r)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine Chemical compound COC1=CC=C([C@H](CC=2C=CN=CC=2)C=2C=CC=CC=2)C=C1OC1CCCC1 UTUUPXBCDMQYRR-HSZRJFAPSA-N 0.000 description 2
- BHEFSGMUMYBJRZ-UHFFFAOYSA-N 9-fluorofluorene-9-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)(F)C3=CC=CC=C3C2=C1 BHEFSGMUMYBJRZ-UHFFFAOYSA-N 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- 241000702423 Adeno-associated virus - 2 Species 0.000 description 2
- 241000202702 Adeno-associated virus - 3 Species 0.000 description 2
- 206010003645 Atopy Diseases 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 2
- 108010044231 Bradykinin B1 Receptor Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 2
- 102100036166 C-X-C chemokine receptor type 1 Human genes 0.000 description 2
- QGBIFMJAQARMNQ-QISPFCDLSA-N C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3O[C@@H](CCC)O[C@@]3(SC)[C@@]2(C)C[C@@H]1O Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3O[C@@H](CCC)O[C@@]3(SC)[C@@]2(C)C[C@@H]1O QGBIFMJAQARMNQ-QISPFCDLSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- NYNKCGWJPNZJMI-UHFFFAOYSA-N Clebopride malate Chemical compound [O-]C(=O)C(O)CC(O)=O.COC1=CC(N)=C(Cl)C=C1C(=O)NC1CC[NH+](CC=2C=CC=CC=2)CC1 NYNKCGWJPNZJMI-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 229940124056 Histamine H1 receptor antagonist Drugs 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 208000005615 Interstitial Cystitis Diseases 0.000 description 2
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 2
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 2
- 208000007101 Muscle Cramp Diseases 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- 208000005392 Spasm Diseases 0.000 description 2
- 208000007156 Spondylarthritis Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 206010042496 Sunburn Diseases 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- ZZHLYYDVIOPZBE-UHFFFAOYSA-N Trimeprazine Chemical compound C1=CC=C2N(CC(CN(C)C)C)C3=CC=CC=C3SC2=C1 ZZHLYYDVIOPZBE-UHFFFAOYSA-N 0.000 description 2
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000000954 anitussive effect Effects 0.000 description 2
- 229940124584 antitussives Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 206010003230 arteritis Diseases 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229960004436 budesonide Drugs 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 230000001364 causal effect Effects 0.000 description 2
- CFBUZOUXXHZCFB-OYOVHJISSA-N chembl511115 Chemical compound COC1=CC=C([C@@]2(CC[C@H](CC2)C(O)=O)C#N)C=C1OC1CCCC1 CFBUZOUXXHZCFB-OYOVHJISSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 208000007451 chronic bronchitis Diseases 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000005713 exacerbation Effects 0.000 description 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 239000000938 histamine H1 antagonist Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 229960005127 montelukast Drugs 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- DPHDSIQHVGSITN-UHFFFAOYSA-N n-(3,5-dichloropyridin-4-yl)-2-[1-[(4-fluorophenyl)methyl]-5-hydroxyindol-3-yl]-2-oxoacetamide Chemical compound C1=C(C(=O)C(=O)NC=2C(=CN=CC=2Cl)Cl)C2=CC(O)=CC=C2N1CC1=CC=C(F)C=C1 DPHDSIQHVGSITN-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 230000008764 nerve damage Effects 0.000 description 2
- 125000002560 nitrile group Chemical group 0.000 description 2
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 2
- 229960001972 panitumumab Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 125000005547 pivalate group Chemical group 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 201000007094 prostatitis Diseases 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 201000003068 rheumatic fever Diseases 0.000 description 2
- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 2
- 229960005294 triamcinolone Drugs 0.000 description 2
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 208000019553 vascular disease Diseases 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 229960004764 zafirlukast Drugs 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- GUHPRPJDBZHYCJ-SECBINFHSA-N (2s)-2-(5-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C([C@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-SECBINFHSA-N 0.000 description 1
- NPSVXOVMLVOMDD-SXRVEDALSA-N (2s)-2-[[(3s,6s,9s,12s)-12-[[(2s)-4-[[(2r,3r,4r,5s,6r)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]amino]-2-amino-4-oxobutanoyl]amino]-6-benzyl-9-(1h-indol-3-ylmethyl)-5,8,11,14-tetraoxo-1,4,7,10-tetrazacyclotetradecane-3-carbonyl]amino]-4-methyl Chemical compound C([C@H](N)C(=O)N[C@H]1CC(=O)NC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C3=CC=CC=C3NC=2)NC1=O)C(=O)N[C@@H](CC(C)C)C(O)=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O NPSVXOVMLVOMDD-SXRVEDALSA-N 0.000 description 1
- HUTHJVYJUPXHDF-DEOSSOPVSA-N (2s)-n-[2-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-[4-(cyclopropylmethyl)piperazin-1-yl]-n-methyl-2-phenylacetamide Chemical compound O=C([C@@H](N1CCN(CC2CC2)CC1)C=1C=CC=CC=1)N(C)CCC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 HUTHJVYJUPXHDF-DEOSSOPVSA-N 0.000 description 1
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 1
- QZUCKCLSVBFSOS-INIZCTEOSA-N (3s)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-n-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-2,3-dihydro-1,4-benzoxazine-8-carboxamide Chemical compound N1=CC(C)=CC=C1N1C(C=CC=C2C(=O)NC=3C=NC(OCC(F)(F)F)=CC=3)=C2OC[C@@H]1CO QZUCKCLSVBFSOS-INIZCTEOSA-N 0.000 description 1
- GAVZMMTZFBMDFG-SFHVURJKSA-N (3s)-3-amino-n-[[2-fluoro-4-[2-(trifluoromethyl)anilino]phenyl]methyl]oxolane-3-carboxamide Chemical compound C=1C=C(NC=2C(=CC=CC=2)C(F)(F)F)C=C(F)C=1CNC(=O)[C@]1(N)CCOC1 GAVZMMTZFBMDFG-SFHVURJKSA-N 0.000 description 1
- KVTGSXXWEUEWGC-SFHVURJKSA-N (3s)-3-amino-n-[[4-[4-chloro-2-(trifluoromethyl)anilino]phenyl]methyl]oxolane-3-carboxamide Chemical compound C=1C=C(NC=2C(=CC(Cl)=CC=2)C(F)(F)F)C=CC=1CNC(=O)[C@]1(N)CCOC1 KVTGSXXWEUEWGC-SFHVURJKSA-N 0.000 description 1
- BBPUGMCHIXRDEJ-SFHVURJKSA-N (3s)-3-amino-n-[[4-[4-fluoro-2-(trifluoromethyl)anilino]phenyl]methyl]oxolane-3-carboxamide Chemical compound C=1C=C(NC=2C(=CC(F)=CC=2)C(F)(F)F)C=CC=1CNC(=O)[C@]1(N)CCOC1 BBPUGMCHIXRDEJ-SFHVURJKSA-N 0.000 description 1
- XTNYQMSCYWBFJX-KRWDZBQOSA-N (4r)-1-[(4-bromophenyl)methyl]-4-(2-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-one Chemical compound C([C@H](CC1=O)C2=CC=C(C=C2OC2CCCC2)OC)N1CC1=CC=C(Br)C=C1 XTNYQMSCYWBFJX-KRWDZBQOSA-N 0.000 description 1
- YTKFKKLZSIVJMX-ZDUSSCGKSA-N (6s)-4-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxyethyl]-6-methylmorpholin-2-one Chemical compound C=12C=C(OCCN3CC(=O)O[C@@H](C)C3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 YTKFKKLZSIVJMX-ZDUSSCGKSA-N 0.000 description 1
- MCKJPJYRCPANCC-XLXYOEISSA-N (8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-17-carboxylic acid Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(O)=O)[C@@H]4[C@@H]3CCC2=C1 MCKJPJYRCPANCC-XLXYOEISSA-N 0.000 description 1
- NDAUXUAQIAJITI-LBPRGKRZSA-N (R)-salbutamol Chemical compound CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-LBPRGKRZSA-N 0.000 description 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KCXAZEJYKXXQIS-UHFFFAOYSA-N 1-[4-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-methoxyethanone Chemical compound C1CN(C(=O)COC)CCC1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=C(F)C(Cl)=C1 KCXAZEJYKXXQIS-UHFFFAOYSA-N 0.000 description 1
- JLXUOMMQRMSKFX-UHFFFAOYSA-N 1-[4-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-methoxyethanone Chemical compound C1CN(C(=O)COC)CCC1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 JLXUOMMQRMSKFX-UHFFFAOYSA-N 0.000 description 1
- OGNYWUNSVMPCQM-UHFFFAOYSA-N 1-amino-n-[[5-[4-fluoro-2-(trifluoromethyl)anilino]pyridin-2-yl]methyl]cyclopropane-1-carboxamide Chemical compound C=1C=C(NC=2C(=CC(F)=CC=2)C(F)(F)F)C=NC=1CNC(=O)C1(N)CC1 OGNYWUNSVMPCQM-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- CFJMRBQWBDQYMK-UHFFFAOYSA-N 1-phenyl-1-cyclopentanecarboxylic acid 2-[2-(diethylamino)ethoxy]ethyl ester Chemical compound C=1C=CC=CC=1C1(C(=O)OCCOCCN(CC)CC)CCCC1 CFJMRBQWBDQYMK-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 1
- LITNEAPWQHVPOK-FFSVYQOJSA-N 2(1h)-pyrimidinone, 5-[3-[(1s,2s,4r)-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl]tetrahydro- Chemical compound C1=C(O[C@@H]2[C@H]3CC[C@H](C3)C2)C(OC)=CC=C1C1CNC(=O)NC1 LITNEAPWQHVPOK-FFSVYQOJSA-N 0.000 description 1
- ODELFXJUOVNEFZ-UHFFFAOYSA-N 2,2-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C(C(O)=O)(C)C1=CC=CC=C1 ODELFXJUOVNEFZ-UHFFFAOYSA-N 0.000 description 1
- XCPPIJCBCWUBNT-UHFFFAOYSA-N 2-(1,3-benzothiazol-2-yl)-2-[2-[[4-(morpholin-4-ylmethyl)phenyl]methoxy]pyrimidin-4-yl]acetonitrile Chemical compound N=1C2=CC=CC=C2SC=1C(C#N)C(N=1)=CC=NC=1OCC(C=C1)=CC=C1CN1CCOCC1 XCPPIJCBCWUBNT-UHFFFAOYSA-N 0.000 description 1
- JHVHEDNLONERHY-UHFFFAOYSA-N 2-(2-chloro-5-methylsulfanylphenyl)-1-methyl-1-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N(C)C(N)=NC=2C(=CC=C(SC)C=2)Cl)=C1 JHVHEDNLONERHY-UHFFFAOYSA-N 0.000 description 1
- PDYTYRKWKWQHNC-AWEZNQCLSA-N 2-[(4R)-4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]butanoic acid Chemical compound C1NC(=C(C(O)=O)CC)C[C@@H]1C1=CC=C(OC)C(OC2CCCC2)=C1 PDYTYRKWKWQHNC-AWEZNQCLSA-N 0.000 description 1
- KRQUFUKTQHISJB-YYADALCUSA-N 2-[(E)-N-[2-(4-chlorophenoxy)propoxy]-C-propylcarbonimidoyl]-3-hydroxy-5-(thian-3-yl)cyclohex-2-en-1-one Chemical compound CCC\C(=N/OCC(C)OC1=CC=C(Cl)C=C1)C1=C(O)CC(CC1=O)C1CCCSC1 KRQUFUKTQHISJB-YYADALCUSA-N 0.000 description 1
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 description 1
- OEZADIAHVKNQKD-UHFFFAOYSA-N 2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]pyridin-2-yl]-4-pyridin-3-ylphthalazin-1-one Chemical compound C=12C=C(OCC)C(OCC)=CC2=CC(CO)=C(CO)C=1C(C=1)=CC=NC=1N(C(C1=CC=CC=C11)=O)N=C1C1=CC=CN=C1 OEZADIAHVKNQKD-UHFFFAOYSA-N 0.000 description 1
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 description 1
- AFTCWZSEWTXWTL-BTQNPOSSSA-N 2-hydroxy-n,n-dimethyl-3-[[2-[[(1r)-1-(5-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzamide;hydrate Chemical compound O.N([C@H](CC)C=1OC(C)=CC=1)C(C(C1=O)=O)=C1NC1=CC=CC(C(=O)N(C)C)=C1O AFTCWZSEWTXWTL-BTQNPOSSSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical class OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 description 1
- DDYUBCCTNHWSQM-UHFFFAOYSA-N 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(1,3-dioxoisoindol-2-yl)propanamide Chemical compound COC1=CC=C(C(CC(N)=O)N2C(C3=CC=CC=C3C2=O)=O)C=C1OC1CCCC1 DDYUBCCTNHWSQM-UHFFFAOYSA-N 0.000 description 1
- IYAPTCLOOXJPNX-VWLOTQADSA-N 3-[3-[7-[[(2r)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]heptoxy]propyl]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC(CCCOCCCCCCCNC[C@H](O)C=2C=C(CO)C(O)=CC=2)=C1 IYAPTCLOOXJPNX-VWLOTQADSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZAQVAMIBXWWRPQ-NSHDSACASA-N 4-(3-chloro-4-fluoroanilino)-6-[(3S)-oxolan-3-yl]oxyquinazolin-7-ol Chemical compound C=12C=C(O[C@@H]3COCC3)C(O)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 ZAQVAMIBXWWRPQ-NSHDSACASA-N 0.000 description 1
- RPTZNTIYFSSTLN-UHFFFAOYSA-N 4-(aminomethyl)-3-fluoro-n-[2-(trifluoromethyl)phenyl]aniline Chemical compound C1=C(F)C(CN)=CC=C1NC1=CC=CC=C1C(F)(F)F RPTZNTIYFSSTLN-UHFFFAOYSA-N 0.000 description 1
- KCSMMAIVRGAGSF-UHFFFAOYSA-N 4-(aminomethyl)-3-fluoro-n-[4-fluoro-2-(trifluoromethyl)phenyl]aniline Chemical compound C1=C(F)C(CN)=CC=C1NC1=CC=C(F)C=C1C(F)(F)F KCSMMAIVRGAGSF-UHFFFAOYSA-N 0.000 description 1
- AIJJEHQNXUMBHK-UHFFFAOYSA-N 4-(aminomethyl)-n-[4-chloro-2-(trifluoromethyl)phenyl]-3-fluoroaniline Chemical compound C1=C(F)C(CN)=CC=C1NC1=CC=C(Cl)C=C1C(F)(F)F AIJJEHQNXUMBHK-UHFFFAOYSA-N 0.000 description 1
- CMKZQSHWRVZOOY-PMERELPUSA-N 4-[(1r)-2-[6-[4-(3-cyclopentylsulfonylphenyl)butoxy]hexylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCCCCCOCCCCC=2C=C(C=CC=2)S(=O)(=O)C2CCCC2)=C1 CMKZQSHWRVZOOY-PMERELPUSA-N 0.000 description 1
- CVDXFPBVOIERBH-JWQCQUIFSA-N 4-[(4ar,10bs)-9-ethoxy-8-methoxy-2-methyl-3,4,4a,10b-tetrahydro-1h-benzo[c][1,6]naphthyridin-6-yl]-n,n-di(propan-2-yl)benzamide Chemical compound N([C@@H]1CCN(C)C[C@@H]1C=1C=C(C(=CC=11)OC)OCC)=C1C1=CC=C(C(=O)N(C(C)C)C(C)C)C=C1 CVDXFPBVOIERBH-JWQCQUIFSA-N 0.000 description 1
- UEYNRDAAZHSJHD-SFHVURJKSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-[[(2s)-oxolan-2-yl]methoxy]quinazolin-7-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1OC[C@H]1OCCC1 UEYNRDAAZHSJHD-SFHVURJKSA-N 0.000 description 1
- DAIBLUSVAFXMJJ-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C=12C=C(OCCN3CC(C)(C)OC(=O)C3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 DAIBLUSVAFXMJJ-UHFFFAOYSA-N 0.000 description 1
- IOVGROKTTNBUGK-UHFFFAOYSA-N 4-[2-[[1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]phenol Chemical compound C=1C=C(O)C=CC=1C(O)C(C)NCCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-UHFFFAOYSA-N 0.000 description 1
- DYJUTMKGOQMFFN-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxy-n-(2-methoxyethyl)-n-methylpiperidine-1-carboxamide Chemical compound C1CN(C(=O)N(C)CCOC)CCC1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=C(F)C(Cl)=C1 DYJUTMKGOQMFFN-UHFFFAOYSA-N 0.000 description 1
- JAFDYPYUQHLWBH-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidine-1-carbonitrile Chemical compound C=12C=C(OC3CCN(CC3)C#N)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 JAFDYPYUQHLWBH-UHFFFAOYSA-N 0.000 description 1
- XRYJULCDUUATMC-CYBMUJFWSA-N 4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(O)C=C1 XRYJULCDUUATMC-CYBMUJFWSA-N 0.000 description 1
- CFBUZOUXXHZCFB-UHFFFAOYSA-N 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-cyclohexanecarboxylic acid Chemical compound COC1=CC=C(C2(CCC(CC2)C(O)=O)C#N)C=C1OC1CCCC1 CFBUZOUXXHZCFB-UHFFFAOYSA-N 0.000 description 1
- AEKVBBNGWBBYLL-UHFFFAOYSA-N 4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1 AEKVBBNGWBBYLL-UHFFFAOYSA-N 0.000 description 1
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 1
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 1
- IHOXNOQMRZISPV-YJYMSZOUSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-methoxyphenyl)propan-2-yl]azaniumyl]ethyl]-2-oxo-1h-quinolin-8-olate Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C2=C1C=CC(=O)N2 IHOXNOQMRZISPV-YJYMSZOUSA-N 0.000 description 1
- JRRKWFRTDFOWAB-SANMLTNESA-N 5-[(1r)-2-[2-[4-[4-(2-amino-2-methylpropoxy)anilino]phenyl]ethylamino]-1-hydroxyethyl]-8-hydroxy-1h-quinolin-2-one Chemical compound C1=CC(OCC(C)(N)C)=CC=C1NC(C=C1)=CC=C1CCNC[C@H](O)C1=CC=C(O)C2=C1C=CC(=O)N2 JRRKWFRTDFOWAB-SANMLTNESA-N 0.000 description 1
- GPXAWLDGWSBLKM-MWLCHTKSSA-N 5-[(1r,5s)-3,6-diazabicyclo[3.2.0]heptan-6-yl]pyridine-3-carbonitrile Chemical compound N#CC1=CN=CC(N2[C@@H]3CNC[C@@H]3C2)=C1 GPXAWLDGWSBLKM-MWLCHTKSSA-N 0.000 description 1
- WZBUHTUPJDSSQM-UHFFFAOYSA-N 6-(aminomethyl)-n-[4-chloro-2-(trifluoromethyl)phenyl]pyridin-3-amine Chemical compound C1=NC(CN)=CC=C1NC1=CC=C(Cl)C=C1C(F)(F)F WZBUHTUPJDSSQM-UHFFFAOYSA-N 0.000 description 1
- DHPYQVWZICTSAR-UHFFFAOYSA-N 6-(aminomethyl)-n-[4-fluoro-2-(trifluoromethyl)phenyl]pyridin-3-amine Chemical compound C1=NC(CN)=CC=C1NC1=CC=C(F)C=C1C(F)(F)F DHPYQVWZICTSAR-UHFFFAOYSA-N 0.000 description 1
- XDBHURGONHZNJF-UHFFFAOYSA-N 6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4-yl]pyridine-2-carboxylic acid Chemical compound C1=C(OCC)C(OCC)=CC=C1C1=NC(C=2N=C(C=CC=2)C(O)=O)=CS1 XDBHURGONHZNJF-UHFFFAOYSA-N 0.000 description 1
- IPOSJTCJFRYTSQ-UHFFFAOYSA-N 6-hydroxy-8-[1-hydroxy-2-[[2-methyl-4-[2-oxo-5-(trifluoromethyl)-3h-benzimidazol-1-yl]butan-2-yl]amino]ethyl]-4h-1,4-benzoxazin-3-one Chemical compound N1C(=O)COC2=C1C=C(O)C=C2C(O)CNC(C)(C)CCN1C(=O)NC2=CC(C(F)(F)F)=CC=C21 IPOSJTCJFRYTSQ-UHFFFAOYSA-N 0.000 description 1
- AOPRUUFSCRVFEE-QHCPKHFHSA-N 6-oxo-n-[(3s)-3-[[4-[2-(trifluoromethyl)anilino]phenyl]methylcarbamoyl]oxolan-3-yl]-1h-pyridazine-4-carboxamide Chemical compound FC(F)(F)C1=CC=CC=C1NC(C=C1)=CC=C1CNC(=O)[C@@]1(NC(=O)C2=CC(=O)NN=C2)COCC1 AOPRUUFSCRVFEE-QHCPKHFHSA-N 0.000 description 1
- OSNANICDBBZIMG-UHFFFAOYSA-N 7-[2-[2-[3-[2-(2-chlorophenyl)ethylamino]propylsulfanyl]ethylamino]-1-hydroxyethyl]-4-hydroxy-3h-1,3-benzothiazol-2-one Chemical compound C=1C=C(O)C=2NC(=O)SC=2C=1C(O)CNCCSCCCNCCC1=CC=CC=C1Cl OSNANICDBBZIMG-UHFFFAOYSA-N 0.000 description 1
- DDQOJAMIFVBVFA-UHFFFAOYSA-N 8-[2-[[1-(2,4-difluorophenyl)-2-methylpropan-2-yl]amino]-1-hydroxyethyl]-6-hydroxy-4h-1,4-benzoxazin-3-one Chemical compound C=1C(O)=CC=2NC(=O)COC=2C=1C(O)CNC(C)(C)CC1=CC=C(F)C=C1F DDQOJAMIFVBVFA-UHFFFAOYSA-N 0.000 description 1
- JALKRHQYYXOVJR-UHFFFAOYSA-N 8-[2-[[1-(4-ethoxyphenyl)-2-methylpropan-2-yl]amino]-1-hydroxyethyl]-6-hydroxy-4h-1,4-benzoxazin-3-one Chemical compound C1=CC(OCC)=CC=C1CC(C)(C)NCC(O)C1=CC(O)=CC2=C1OCC(=O)N2 JALKRHQYYXOVJR-UHFFFAOYSA-N 0.000 description 1
- NFLLKCVHYJRNRH-UHFFFAOYSA-N 8-chloro-1,3-dimethyl-7H-purine-2,6-dione 2-(diphenylmethyl)oxy-N,N-dimethylethanamine Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC(Cl)=N2.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 NFLLKCVHYJRNRH-UHFFFAOYSA-N 0.000 description 1
- DYAYSTQAIZXXIH-QHCPKHFHSA-N 8-hydroxy-5-[(1r)-1-hydroxy-2-[6-(2-phenylethylamino)hexylamino]ethyl]-1h-quinolin-2-one Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCCCCNCCC1=CC=CC=C1 DYAYSTQAIZXXIH-QHCPKHFHSA-N 0.000 description 1
- XMOAAORIXBPOCZ-UHFFFAOYSA-N 9-(difluoromethyl)xanthene-9-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)(C(F)F)C3=CC=CC=C3OC2=C1 XMOAAORIXBPOCZ-UHFFFAOYSA-N 0.000 description 1
- ZRDOWGBNGIHJTG-UHFFFAOYSA-N 9-(hydroxymethyl)xanthene-9-carboxylic acid Chemical compound C1=CC=C2C(CO)(C(O)=O)C3=CC=CC=C3OC2=C1 ZRDOWGBNGIHJTG-UHFFFAOYSA-N 0.000 description 1
- QWECFCKUHAMUOT-UHFFFAOYSA-N 9-[(2-fluorophenyl)methyl]-n-methyl-2-(trifluoromethyl)purin-6-amine Chemical compound C1=NC=2C(NC)=NC(C(F)(F)F)=NC=2N1CC1=CC=CC=C1F QWECFCKUHAMUOT-UHFFFAOYSA-N 0.000 description 1
- QPVQJRWUNUHSJL-UHFFFAOYSA-N 9-ethylxanthene-9-carboxylic acid Chemical compound C1=CC=C2C(CC)(C(O)=O)C3=CC=CC=C3OC2=C1 QPVQJRWUNUHSJL-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000580270 Adeno-associated virus - 4 Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010001889 Alveolitis Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 208000033116 Asbestos intoxication Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 108060003359 BDKRB1 Proteins 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 208000007596 Byssinosis Diseases 0.000 description 1
- CPYZOSMOOHLXBK-OTVXOJSOSA-N C1C[C@@H](NC)CC[C@H]1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=C(F)C(Cl)=C1 Chemical compound C1C[C@@H](NC)CC[C@H]1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=C(F)C(Cl)=C1 CPYZOSMOOHLXBK-OTVXOJSOSA-N 0.000 description 1
- CYBRSHQMQMRQGS-MQMHXKEQSA-N C=12C=C(O[C@@H]3CC[C@@H](N)CC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 Chemical compound C=12C=C(O[C@@H]3CC[C@@H](N)CC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 CYBRSHQMQMRQGS-MQMHXKEQSA-N 0.000 description 1
- JEFIMDCWCOALTI-WGSAOQKQSA-N C=12C=C(O[C@@H]3CC[C@H](CC3)N(C)C(=O)N3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 Chemical compound C=12C=C(O[C@@H]3CC[C@H](CC3)N(C)C(=O)N3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 JEFIMDCWCOALTI-WGSAOQKQSA-N 0.000 description 1
- FOMMTKFJEREKRS-WKILWMFISA-N C=12C=C(O[C@@H]3CC[C@H](CC3)N(C)C)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 Chemical compound C=12C=C(O[C@@H]3CC[C@H](CC3)N(C)C)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 FOMMTKFJEREKRS-WKILWMFISA-N 0.000 description 1
- PEHNBYTXRHCHKF-WKILWMFISA-N C=12C=C(O[C@@H]3CC[C@H](CC3)N(C)S(C)(=O)=O)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 Chemical compound C=12C=C(O[C@@H]3CC[C@H](CC3)N(C)S(C)(=O)=O)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 PEHNBYTXRHCHKF-WKILWMFISA-N 0.000 description 1
- OTLJXOJEXWTEBW-SAABIXHNSA-N C=12C=C(O[C@@H]3CC[C@H](CC3)NS(=O)(=O)N3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 Chemical compound C=12C=C(O[C@@H]3CC[C@H](CC3)NS(=O)(=O)N3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 OTLJXOJEXWTEBW-SAABIXHNSA-N 0.000 description 1
- FJNIWTSYKPLARM-CTYIDZIISA-N C=12C=C(O[C@@H]3CC[C@H](CC3)NS(C)(=O)=O)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 Chemical compound C=12C=C(O[C@@H]3CC[C@H](CC3)NS(C)(=O)=O)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 FJNIWTSYKPLARM-CTYIDZIISA-N 0.000 description 1
- LACBJYAZTCFDGP-MAEOIBBWSA-N C=12C=C(O[C@H]3CC[C@H](CC3)NC(=O)N3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 Chemical compound C=12C=C(O[C@H]3CC[C@H](CC3)NC(=O)N3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 LACBJYAZTCFDGP-MAEOIBBWSA-N 0.000 description 1
- 229940124803 CXCR2 antagonist Drugs 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 239000005461 Canertinib Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000006561 Cluster Headache Diseases 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 208000018035 Dental disease Diseases 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 229940123907 Disease modifying antirheumatic drug Drugs 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 206010015226 Erythema nodosum Diseases 0.000 description 1
- 208000028387 Felty syndrome Diseases 0.000 description 1
- RBBWCVQDXDFISW-UHFFFAOYSA-N Feprazone Chemical compound O=C1C(CC=C(C)C)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 RBBWCVQDXDFISW-UHFFFAOYSA-N 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 239000003691 GABA modulator Substances 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- 229940119240 Histamine H4 receptor antagonist Drugs 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000947174 Homo sapiens C-X-C chemokine receptor type 1 Proteins 0.000 description 1
- 101000882759 Homo sapiens Cysteinyl leukotriene receptor 1 Proteins 0.000 description 1
- 101100236208 Homo sapiens LTB4R gene Proteins 0.000 description 1
- 101001017969 Homo sapiens Leukotriene B4 receptor 2 Proteins 0.000 description 1
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 1
- 101000628949 Homo sapiens Mitogen-activated protein kinase 10 Proteins 0.000 description 1
- 101000950695 Homo sapiens Mitogen-activated protein kinase 8 Proteins 0.000 description 1
- 101000950669 Homo sapiens Mitogen-activated protein kinase 9 Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 108010018976 Interleukin-8A Receptors Proteins 0.000 description 1
- 108010018951 Interleukin-8B Receptors Proteins 0.000 description 1
- 102000002791 Interleukin-8B Receptors Human genes 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 102100033374 Leukotriene B4 receptor 1 Human genes 0.000 description 1
- 102100033375 Leukotriene B4 receptor 2 Human genes 0.000 description 1
- 102000003680 Leukotriene B4 receptors Human genes 0.000 description 1
- 108090000093 Leukotriene B4 receptors Proteins 0.000 description 1
- ZCGOMHNNNFPNMX-YHYDXASRSA-N Levocabastinum Chemical compound C1([C@@]2(C(O)=O)CCN(C[C@H]2C)C2CCC(CC2)(C#N)C=2C=CC(F)=CC=2)=CC=CC=C1 ZCGOMHNNNFPNMX-YHYDXASRSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 108010092101 MEN 11420 Proteins 0.000 description 1
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 1
- 102100026931 Mitogen-activated protein kinase 10 Human genes 0.000 description 1
- 102100023482 Mitogen-activated protein kinase 14 Human genes 0.000 description 1
- 102100037808 Mitogen-activated protein kinase 8 Human genes 0.000 description 1
- 102100037809 Mitogen-activated protein kinase 9 Human genes 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- IJHNSHDBIRRJRN-UHFFFAOYSA-N N,N-dimethyl-3-phenyl-3-(2-pyridinyl)-1-propanamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=CC=C1 IJHNSHDBIRRJRN-UHFFFAOYSA-N 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- 102000004129 N-Type Calcium Channels Human genes 0.000 description 1
- 108090000699 N-Type Calcium Channels Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 102100040460 P2X purinoceptor 3 Human genes 0.000 description 1
- 101710189970 P2X purinoceptor 3 Proteins 0.000 description 1
- 208000000450 Pelvic Pain Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 208000004983 Phantom Limb Diseases 0.000 description 1
- 206010056238 Phantom pain Diseases 0.000 description 1
- VQDBNKDJNJQRDG-UHFFFAOYSA-N Pirbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=N1 VQDBNKDJNJQRDG-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010036030 Polyarthritis Diseases 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 208000036838 Postoperative fever Diseases 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- BPZSYCZIITTYBL-YJYMSZOUSA-N R-Formoterol Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-YJYMSZOUSA-N 0.000 description 1
- 206010038419 Renal colic Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- RUOGJYKOQBFJIG-UHFFFAOYSA-N SCH-351591 Chemical compound C12=CC=C(C(F)(F)F)N=C2C(OC)=CC=C1C(=O)NC1=C(Cl)C=[N+]([O-])C=C1Cl RUOGJYKOQBFJIG-UHFFFAOYSA-N 0.000 description 1
- 102100027720 SH2 domain-containing protein 1A Human genes 0.000 description 1
- VPMWDFRZSIMDKW-YJYMSZOUSA-N Salmefamol Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 VPMWDFRZSIMDKW-YJYMSZOUSA-N 0.000 description 1
- 101100437750 Schizosaccharomyces pombe (strain 972 / ATCC 24843) blt1 gene Proteins 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 1
- 108010045517 Serum Amyloid P-Component Proteins 0.000 description 1
- 201000010001 Silicosis Diseases 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 208000020339 Spinal injury Diseases 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 208000014151 Stomatognathic disease Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- 102000000551 Syk Kinase Human genes 0.000 description 1
- 108010016672 Syk Kinase Proteins 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 208000004760 Tenosynovitis Diseases 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- 208000008548 Tension-Type Headache Diseases 0.000 description 1
- DXEXNWDGDYUITL-FXSSSKFRSA-N Tipredane Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](SC)(SCC)[C@@]1(C)C[C@@H]2O DXEXNWDGDYUITL-FXSSSKFRSA-N 0.000 description 1
- DHCOPPHTVOXDKU-UHFFFAOYSA-N Tofimilast Chemical compound C1CN2C(C=3SC=CC=3)=NN=C2C2=C1C(CC)=NN2C1CCCC1 DHCOPPHTVOXDKU-UHFFFAOYSA-N 0.000 description 1
- 206010048873 Traumatic arthritis Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- UFLGIAIHIAPJJC-UHFFFAOYSA-N Tripelennamine Chemical compound C=1C=CC=NC=1N(CCN(C)C)CC1=CC=CC=C1 UFLGIAIHIAPJJC-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000003728 Vulvodynia Diseases 0.000 description 1
- 206010069055 Vulvovaginal pain Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- ZLLPOXZGRDWOKF-LBFFRULKSA-N [(3R)-1-(1-phenylethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] 9H-xanthene-9-carboxylate Chemical class C1CC([C@H](C2)OC(=O)C3C4=CC=CC=C4OC4=CC=CC=C43)CC[N+]12C(C)C1=CC=CC=C1 ZLLPOXZGRDWOKF-LBFFRULKSA-N 0.000 description 1
- ANGKOCUUWGHLCE-HKUYNNGSSA-N [(3s)-1,1-dimethylpyrrolidin-1-ium-3-yl] (2r)-2-cyclopentyl-2-hydroxy-2-phenylacetate Chemical class C1[N+](C)(C)CC[C@@H]1OC(=O)[C@](O)(C=1C=CC=CC=1)C1CCCC1 ANGKOCUUWGHLCE-HKUYNNGSSA-N 0.000 description 1
- HOAKOHHSHOCDLI-TUFAYURCSA-N [(8s,9s,10r,11s,13s,14s,17r)-11-hydroxy-10,13-dimethyl-3-oxo-17-(2-sulfanylacetyl)-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl] butanoate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CS)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O HOAKOHHSHOCDLI-TUFAYURCSA-N 0.000 description 1
- YPFLFUJKZDAXRA-UHFFFAOYSA-N [3-(carbamoylamino)-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl] methanesulfonate Chemical compound O1C2=CC(OS(=O)(=O)C)=CC=C2C(NC(N)=O)=C1C(=O)C1=CC=C(Cl)C=C1Cl YPFLFUJKZDAXRA-UHFFFAOYSA-N 0.000 description 1
- WKHOPHIMYDJVSA-UHFFFAOYSA-N [3-[2-(tert-butylamino)-1-hydroxyethyl]-5-(2-methylpropanoyloxy)phenyl] 2-methylpropanoate Chemical compound CC(C)C(=O)OC1=CC(OC(=O)C(C)C)=CC(C(O)CNC(C)(C)C)=C1 WKHOPHIMYDJVSA-UHFFFAOYSA-N 0.000 description 1
- DBESJEGRRAZRSW-SANMLTNESA-N [3-[4-[6-[[(2r)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]hexoxy]butyl]-5-methylphenyl]urea Chemical compound NC(=O)NC1=CC(C)=CC(CCCCOCCCCCCNC[C@H](O)C=2C=C(CO)C(O)=CC=2)=C1 DBESJEGRRAZRSW-SANMLTNESA-N 0.000 description 1
- GDZDVSVAWGOPPB-CALCHBBNSA-N [4-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-[(2r,6s)-2,6-dimethylmorpholin-4-yl]methanone Chemical compound C=12C=C(OC3CCN(CC3)C(=O)N3C[C@@H](C)O[C@@H](C)C3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 GDZDVSVAWGOPPB-CALCHBBNSA-N 0.000 description 1
- SGPQZLAIXLGTBH-UHFFFAOYSA-N [4-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-morpholin-4-ylmethanone Chemical compound C=12C=C(OC3CCN(CC3)C(=O)N3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 SGPQZLAIXLGTBH-UHFFFAOYSA-N 0.000 description 1
- GCFQYHBVQUQWIX-UHFFFAOYSA-N [4-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-piperidin-1-ylmethanone Chemical compound C=12C=C(OC3CCN(CC3)C(=O)N3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 GCFQYHBVQUQWIX-UHFFFAOYSA-N 0.000 description 1
- SFYAXIFVXBKRPK-QFIPXVFZSA-N abediterol Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCCCCOCC(F)(F)C1=CC=CC=C1 SFYAXIFVXBKRPK-QFIPXVFZSA-N 0.000 description 1
- 229960004892 acemetacin Drugs 0.000 description 1
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 1
- ASMXXROZKSBQIH-VITNCHFBSA-N aclidinium Chemical class C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=CC=C1 ASMXXROZKSBQIH-VITNCHFBSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- 229960003790 alimemazine Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 229960004663 alminoprofen Drugs 0.000 description 1
- FPHLBGOJWPEVME-UHFFFAOYSA-N alminoprofen Chemical compound OC(=O)C(C)C1=CC=C(NCC(C)=C)C=C1 FPHLBGOJWPEVME-UHFFFAOYSA-N 0.000 description 1
- 208000006682 alpha 1-Antitrypsin Deficiency Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 208000028462 aluminosis Diseases 0.000 description 1
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 1
- 229960005174 ambroxol Drugs 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229940051880 analgesics and antipyretics pyrazolones Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229960002469 antazoline Drugs 0.000 description 1
- REYFJDPCWQRWAA-UHFFFAOYSA-N antazoline Chemical compound N=1CCNC=1CN(C=1C=CC=CC=1)CC1=CC=CC=C1 REYFJDPCWQRWAA-UHFFFAOYSA-N 0.000 description 1
- 208000010123 anthracosis Diseases 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940111133 antiinflammatory and antirheumatic drug oxicams Drugs 0.000 description 1
- 229940111131 antiinflammatory and antirheumatic product propionic acid derivative Drugs 0.000 description 1
- 229940124433 antimigraine drug Drugs 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 description 1
- 229960001164 apremilast Drugs 0.000 description 1
- 229960001692 arformoterol Drugs 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 206010003441 asbestosis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229950006944 atizoram Drugs 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 229960001671 azapropazone Drugs 0.000 description 1
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 1
- 229960000383 azatadine Drugs 0.000 description 1
- SEBMTIQKRHYNIT-UHFFFAOYSA-N azatadine Chemical compound C1CN(C)CCC1=C1C2=NC=CC=C2CCC2=CC=CC=C21 SEBMTIQKRHYNIT-UHFFFAOYSA-N 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 229960003060 bambuterol Drugs 0.000 description 1
- ANZXOIAKUNOVQU-UHFFFAOYSA-N bambuterol Chemical compound CN(C)C(=O)OC1=CC(OC(=O)N(C)C)=CC(C(O)CNC(C)(C)C)=C1 ANZXOIAKUNOVQU-UHFFFAOYSA-N 0.000 description 1
- 229960002526 bamipine Drugs 0.000 description 1
- VZSXTYKGYWISGQ-UHFFFAOYSA-N bamipine Chemical compound C1CN(C)CCC1N(C=1C=CC=CC=1)CC1=CC=CC=C1 VZSXTYKGYWISGQ-UHFFFAOYSA-N 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
- 229950006785 bentamapimod Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229960004620 bitolterol Drugs 0.000 description 1
- FZGVEKPRDOIXJY-UHFFFAOYSA-N bitolterol Chemical compound C1=CC(C)=CC=C1C(=O)OC1=CC=C(C(O)CNC(C)(C)C)C=C1OC(=O)C1=CC=C(C)C=C1 FZGVEKPRDOIXJY-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 229960000725 brompheniramine Drugs 0.000 description 1
- ZDIGNSYAACHWNL-UHFFFAOYSA-N brompheniramine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Br)C=C1 ZDIGNSYAACHWNL-UHFFFAOYSA-N 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 229950008847 broxaterol Drugs 0.000 description 1
- JBRBWHCVRGURBA-UHFFFAOYSA-N broxaterol Chemical compound CC(C)(C)NCC(O)C1=CC(Br)=NO1 JBRBWHCVRGURBA-UHFFFAOYSA-N 0.000 description 1
- IJTPQQVCKPZIMV-UHFFFAOYSA-N bucloxic acid Chemical compound ClC1=CC(C(=O)CCC(=O)O)=CC=C1C1CCCCC1 IJTPQQVCKPZIMV-UHFFFAOYSA-N 0.000 description 1
- 229950005608 bucloxic acid Drugs 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229950001167 butixocort Drugs 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- 229930003827 cannabinoid Natural products 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- OFAIGZWCDGNZGT-UHFFFAOYSA-N caramiphen Chemical compound C=1C=CC=CC=1C1(C(=O)OCCN(CC)CC)CCCC1 OFAIGZWCDGNZGT-UHFFFAOYSA-N 0.000 description 1
- 229960004160 caramiphen Drugs 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 229960001386 carbuterol Drugs 0.000 description 1
- KEMXXQOFIRIICG-UHFFFAOYSA-N carbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(NC(N)=O)=C1 KEMXXQOFIRIICG-UHFFFAOYSA-N 0.000 description 1
- 229950010713 carmoterol Drugs 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229960003728 ciclesonide Drugs 0.000 description 1
- 229950001653 cilomilast Drugs 0.000 description 1
- 229960002881 clemastine Drugs 0.000 description 1
- 229960001117 clenbuterol Drugs 0.000 description 1
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 208000012696 congenital leptin deficiency Diseases 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- RGBVWCQARBEPPW-UHFFFAOYSA-N cyclobut-3-ene-1,2-dione Chemical compound O=C1C=CC1=O RGBVWCQARBEPPW-UHFFFAOYSA-N 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- HSDBULQDKRYING-UHFFFAOYSA-N cyclopropyltropine benzilate Chemical compound C1C(C2C3C2)N(C)C3CC1OC(=O)C(O)(C=1C=CC=CC=1)C1=CC=CC=C1 HSDBULQDKRYING-UHFFFAOYSA-N 0.000 description 1
- 229960001140 cyproheptadine Drugs 0.000 description 1
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 229960001145 deflazacort Drugs 0.000 description 1
- FBHSPRKOSMHSIF-GRMWVWQJSA-N deflazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O FBHSPRKOSMHSIF-GRMWVWQJSA-N 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 229960001271 desloratadine Drugs 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- QMQBBUPJKANITL-MYXGOWFTSA-N dextropropoxyphene hydrochloride Chemical compound [H+].[Cl-].C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 QMQBBUPJKANITL-MYXGOWFTSA-N 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical class OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 1
- MVMQESMQSYOVGV-UHFFFAOYSA-N dimetindene Chemical compound CN(C)CCC=1CC2=CC=CC=C2C=1C(C)C1=CC=CC=N1 MVMQESMQSYOVGV-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- 229960000879 diphenylpyraline Drugs 0.000 description 1
- OWQUZNMMYNAXSL-UHFFFAOYSA-N diphenylpyraline Chemical compound C1CN(C)CCC1OC(C=1C=CC=CC=1)C1=CC=CC=C1 OWQUZNMMYNAXSL-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- MVCOAUNKQVWQHZ-UHFFFAOYSA-N doramapimod Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCCN3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 MVCOAUNKQVWQHZ-UHFFFAOYSA-N 0.000 description 1
- 229950005521 doramapimod Drugs 0.000 description 1
- 229960005178 doxylamine Drugs 0.000 description 1
- HCFDWZZGGLSKEP-UHFFFAOYSA-N doxylamine Chemical compound C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 HCFDWZZGGLSKEP-UHFFFAOYSA-N 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 229960001971 ebastine Drugs 0.000 description 1
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 229960002472 eletriptan Drugs 0.000 description 1
- OTLDLQZJRFYOJR-LJQANCHMSA-N eletriptan Chemical compound CN1CCC[C@@H]1CC1=CN=C2[C]1C=C(CCS(=O)(=O)C=1C=CC=CC=1)C=C2 OTLDLQZJRFYOJR-LJQANCHMSA-N 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- JTXYEERBIZXLJC-DCJXKKNWSA-N ethyl (8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-17-carboxylate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)OCC)(O)[C@@]1(C)C[C@@H]2O JTXYEERBIZXLJC-DCJXKKNWSA-N 0.000 description 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229960001022 fenoterol Drugs 0.000 description 1
- 229960000489 feprazone Drugs 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- 229950000014 figopitant Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960000676 flunisolide Drugs 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002714 fluticasone Drugs 0.000 description 1
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- OATDVDIMNNZTEY-DAXLTYESSA-N flutropium Chemical class C[N@@+]1(CCF)[C@H]2CC[C@@H]1C[C@@H](C2)OC(=O)C(O)(C1=CC=CC=C1)C1=CC=CC=C1 OATDVDIMNNZTEY-DAXLTYESSA-N 0.000 description 1
- 229960002848 formoterol Drugs 0.000 description 1
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- SCMLRESZJCKCTC-KMYQRJGFSA-N gtpl8173 Chemical compound C12=CC=C(CSCC)C=C2C2=C(CNC3=O)C3=C3C4=CC(CSCC)=CC=C4N4C3=C2N1[C@]1(C)[C@@](O)(C(=O)OC)C[C@H]4O1 SCMLRESZJCKCTC-KMYQRJGFSA-N 0.000 description 1
- OXLZNBCNGJWPRV-UHFFFAOYSA-N hexoprenaline Chemical compound C=1C=C(O)C(O)=CC=1C(O)CNCCCCCCNCC(O)C1=CC=C(O)C(O)=C1 OXLZNBCNGJWPRV-UHFFFAOYSA-N 0.000 description 1
- 239000003396 histamine H4 receptor antagonist Substances 0.000 description 1
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229950002451 ibuterol Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960004078 indacaterol Drugs 0.000 description 1
- QZZUEBNBZAPZLX-QFIPXVFZSA-N indacaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 QZZUEBNBZAPZLX-QFIPXVFZSA-N 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 229950011455 isoxepac Drugs 0.000 description 1
- QFGMXJOBTNZHEL-UHFFFAOYSA-N isoxepac Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 229960001508 levocetirizine Drugs 0.000 description 1
- 229950008204 levosalbutamol Drugs 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229950008462 lirimilast Drugs 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 229960001798 loteprednol Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- JSJCTEKTBOKRST-UHFFFAOYSA-N mabuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(C(F)(F)F)=C1 JSJCTEKTBOKRST-UHFFFAOYSA-N 0.000 description 1
- 229950004407 mabuterol Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- HTMIBDQKFHUPSX-UHFFFAOYSA-N methdilazine Chemical compound C1N(C)CCC1CN1C2=CC=CC=C2SC2=CC=CC=C21 HTMIBDQKFHUPSX-UHFFFAOYSA-N 0.000 description 1
- 229960004056 methdilazine Drugs 0.000 description 1
- MEQKIBIRCVJSRK-UHFFFAOYSA-N methyl 2,2-bis(4-fluorophenyl)-2-hydroxyacetate Chemical compound C=1C=C(F)C=CC=1C(O)(C(=O)OC)C1=CC=C(F)C=C1 MEQKIBIRCVJSRK-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 229950001768 milveterol Drugs 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960001664 mometasone Drugs 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- 208000001022 morbid obesity Diseases 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- OKFDRAHPFKMAJH-UHFFFAOYSA-N n-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-8-(methanesulfonamido)dibenzofuran-1-carboxamide Chemical compound C=12C3=CC(NS(=O)(=O)C)=CC=C3OC2=C(OC(F)F)C=CC=1C(=O)NC1=C(Cl)C=NC=C1Cl OKFDRAHPFKMAJH-UHFFFAOYSA-N 0.000 description 1
- NNAIRLNUMRYQDU-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-(1-ethylpiperidin-4-yl)oxy-7-methoxyquinazolin-4-amine Chemical compound C1CN(CC)CCC1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=C(F)C(Cl)=C1 NNAIRLNUMRYQDU-UHFFFAOYSA-N 0.000 description 1
- XFENZNCAYAJOQE-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-methoxy-6-(1-methylsulfonylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C=C(OC3CCN(CC3)S(C)(=O)=O)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XFENZNCAYAJOQE-UHFFFAOYSA-N 0.000 description 1
- WZBWYRUTRBGTAL-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-methoxy-6-(oxan-3-yloxy)quinazolin-4-amine Chemical compound C=12C=C(OC3COCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 WZBWYRUTRBGTAL-UHFFFAOYSA-N 0.000 description 1
- RZYANQUZIRWZBS-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-methoxy-6-piperidin-3-yloxyquinazolin-4-amine Chemical compound C=12C=C(OC3CNCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 RZYANQUZIRWZBS-UHFFFAOYSA-N 0.000 description 1
- YOBLCEDHQQYBEJ-UHFFFAOYSA-N n-(3-ethynylphenyl)-7-methoxy-6-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C=C(OC3CCN(C)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 YOBLCEDHQQYBEJ-UHFFFAOYSA-N 0.000 description 1
- QROHAWMNESUZHZ-UHFFFAOYSA-N n-(3-ethynylphenyl)-7-methoxy-6-(oxan-4-yloxy)quinazolin-4-amine Chemical compound C=12C=C(OC3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 QROHAWMNESUZHZ-UHFFFAOYSA-N 0.000 description 1
- FPGNKXCEPARJDI-ZDUSSCGKSA-N n-[(1s)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluorobenzimidazol-1-yl)acetamide Chemical compound C1([C@@H](NC(=O)CN2C3=C(F)C(F)=CC=C3N=C2)C)=CC=C(C(C)(C)C)C=C1 FPGNKXCEPARJDI-ZDUSSCGKSA-N 0.000 description 1
- ZMNXBJPTUAHLCW-QHCPKHFHSA-N n-[(3s)-3-[[2-fluoro-4-[2-(trifluoromethyl)anilino]phenyl]methylcarbamoyl]oxolan-3-yl]-6-oxo-1h-pyridazine-4-carboxamide Chemical compound C=1C=C(CNC(=O)[C@]2(COCC2)NC(=O)C2=CC(=O)NN=C2)C(F)=CC=1NC1=CC=CC=C1C(F)(F)F ZMNXBJPTUAHLCW-QHCPKHFHSA-N 0.000 description 1
- SZOSXOFRDVSJAB-QHCPKHFHSA-N n-[(3s)-3-[[4-[4-bromo-2-(trifluoromethyl)anilino]phenyl]methylcarbamoyl]oxolan-3-yl]-6-oxo-1h-pyridazine-4-carboxamide Chemical compound FC(F)(F)C1=CC(Br)=CC=C1NC(C=C1)=CC=C1CNC(=O)[C@@]1(NC(=O)C2=CC(=O)NN=C2)COCC1 SZOSXOFRDVSJAB-QHCPKHFHSA-N 0.000 description 1
- ZVULMJYRVAVKCP-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-n-[2-[2-(4-hydroxy-2-oxo-3h-1,3-benzothiazol-7-yl)ethylamino]ethyl]-3-(2-naphthalen-1-ylethoxy)propanamide Chemical compound C1=CC=C2C(CCOCCC(=O)N(CCNCCC=3C=4SC(=O)NC=4C(O)=CC=3)CCN(CC)CC)=CC=CC2=C1 ZVULMJYRVAVKCP-UHFFFAOYSA-N 0.000 description 1
- QDYICOKSXMTYPO-UHFFFAOYSA-N n-[2-[4-(3-chloro-4-fluoroanilino)-6-(oxan-4-yloxy)quinazolin-7-yl]oxyethyl]acetamide Chemical compound C=12C=C(OC3CCOCC3)C(OCCNC(=O)C)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 QDYICOKSXMTYPO-UHFFFAOYSA-N 0.000 description 1
- MWHCFCZAROGOAF-UHFFFAOYSA-N n-[2-[4-(3-chloro-4-fluoroanilino)-6-(oxan-4-yloxy)quinazolin-7-yl]oxyethyl]methanesulfonamide Chemical compound C=12C=C(OC3CCOCC3)C(OCCNS(=O)(=O)C)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 MWHCFCZAROGOAF-UHFFFAOYSA-N 0.000 description 1
- YBTWSPCOMHYEKP-UHFFFAOYSA-N n-[2-[4-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]ethyl]acetamide Chemical compound C=12C=C(OC3CCN(CCNC(C)=O)CC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 YBTWSPCOMHYEKP-UHFFFAOYSA-N 0.000 description 1
- BMKINZUHKYLSKI-SKCDSABHSA-N n-[2-hydroxy-5-[(1r)-1-hydroxy-2-[2-[4-[(2-hydroxy-2-phenylethyl)amino]phenyl]ethylamino]ethyl]phenyl]formamide Chemical compound C([C@H](O)C=1C=C(NC=O)C(O)=CC=1)NCCC(C=C1)=CC=C1NCC(O)C1=CC=CC=C1 BMKINZUHKYLSKI-SKCDSABHSA-N 0.000 description 1
- BMKINZUHKYLSKI-DQEYMECFSA-N n-[2-hydroxy-5-[(1r)-1-hydroxy-2-[2-[4-[[(2r)-2-hydroxy-2-phenylethyl]amino]phenyl]ethylamino]ethyl]phenyl]formamide Chemical compound C1([C@@H](O)CNC2=CC=C(C=C2)CCNC[C@H](O)C=2C=C(NC=O)C(O)=CC=2)=CC=CC=C1 BMKINZUHKYLSKI-DQEYMECFSA-N 0.000 description 1
- KMAPIHHPUBUULD-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-[2-methoxyethyl(methyl)amino]but-2-enamide Chemical compound N1=CN=C2C=C(OCC3CC3)C(NC(=O)C=CCN(C)CCOC)=CC2=C1NC1=CC=C(F)C(Cl)=C1 KMAPIHHPUBUULD-UHFFFAOYSA-N 0.000 description 1
- QLVAINZHTQIWQM-QHCPKHFHSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[2-[4-[(2s)-5-oxooxolane-2-carbonyl]piperazin-1-yl]ethoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCN3CCN(CC3)C(=O)[C@H]3OC(=O)CC3)=C(NC(=O)C=C)C=C12 QLVAINZHTQIWQM-QHCPKHFHSA-N 0.000 description 1
- HLPYLODZNZDOPK-UHFFFAOYSA-N n-[4-(aminomethyl)phenyl]-2-(trifluoromethyl)aniline Chemical compound C1=CC(CN)=CC=C1NC1=CC=CC=C1C(F)(F)F HLPYLODZNZDOPK-UHFFFAOYSA-N 0.000 description 1
- IBNDDRMLOYKSRZ-UHFFFAOYSA-N n-[4-(aminomethyl)phenyl]-4-bromo-2-(trifluoromethyl)aniline Chemical compound C1=CC(CN)=CC=C1NC1=CC=C(Br)C=C1C(F)(F)F IBNDDRMLOYKSRZ-UHFFFAOYSA-N 0.000 description 1
- AEVVJAYIFDAGBX-UHFFFAOYSA-N n-[4-(aminomethyl)phenyl]-4-fluoro-2-(trifluoromethyl)aniline Chemical compound C1=CC(CN)=CC=C1NC1=CC=C(F)C=C1C(F)(F)F AEVVJAYIFDAGBX-UHFFFAOYSA-N 0.000 description 1
- BWQSBRAYEGDIFF-UHFFFAOYSA-N n-[5-[2-[[4-(4,4-diethyl-6-fluoro-2-oxo-3,1-benzoxazin-1-yl)-2-methylbutan-2-yl]amino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide Chemical compound C12=CC=C(F)C=C2C(CC)(CC)OC(=O)N1CCC(C)(C)NCC(O)C1=CC=C(O)C(NS(C)(=O)=O)=C1 BWQSBRAYEGDIFF-UHFFFAOYSA-N 0.000 description 1
- VSLMGOFNNZVUIK-UHFFFAOYSA-N n-[5-[2-[[4-(4,4-diethyl-6-methoxy-2-oxo-3,1-benzoxazin-1-yl)-2-methylbutan-2-yl]amino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide Chemical compound C12=CC=C(OC)C=C2C(CC)(CC)OC(=O)N1CCC(C)(C)NCC(O)C1=CC=C(O)C(NS(C)(=O)=O)=C1 VSLMGOFNNZVUIK-UHFFFAOYSA-N 0.000 description 1
- RHTFXIJREGOKBI-OAQYLSRUSA-N n-[7-(cyclopropylmethoxy)-4-[[(1r)-1-phenylethyl]amino]quinazolin-6-yl]-4-[ethyl(2-methoxyethyl)amino]but-2-enamide Chemical compound C1([C@@H](C)NC2=C3C=C(C(=CC3=NC=N2)OCC2CC2)NC(=O)C=CCN(CCOC)CC)=CC=CC=C1 RHTFXIJREGOKBI-OAQYLSRUSA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229960005254 naratriptan Drugs 0.000 description 1
- UNHGSHHVDNGCFN-UHFFFAOYSA-N naratriptan Chemical compound C=12[CH]C(CCS(=O)(=O)NC)=CC=C2N=CC=1C1CCN(C)CC1 UNHGSHHVDNGCFN-UHFFFAOYSA-N 0.000 description 1
- 229950000640 nepadutant Drugs 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 230000002474 noradrenergic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 229950000175 oglemilast Drugs 0.000 description 1
- 229960004114 olopatadine Drugs 0.000 description 1
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 description 1
- 229960002657 orciprenaline Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- NVOYVOBDTVTBDX-PMEUIYRNSA-N oxitropium Chemical class CC[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)[C@H](CO)C1=CC=CC=C1 NVOYVOBDTVTBDX-PMEUIYRNSA-N 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 208000005877 painful neuropathy Diseases 0.000 description 1
- 229960003436 pentoxyverine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960001190 pheniramine Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 description 1
- 229960005414 pirbuterol Drugs 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 description 1
- 229960000851 pirprofen Drugs 0.000 description 1
- 206010035653 pneumoconiosis Diseases 0.000 description 1
- 208000030428 polyarticular arthritis Diseases 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229960004583 pranlukast Drugs 0.000 description 1
- UAJUXJSXCLUTNU-UHFFFAOYSA-N pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 description 1
- 229960003101 pranoprofen Drugs 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- 229960002288 procaterol Drugs 0.000 description 1
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- DQORBCOTYYJLTB-UHFFFAOYSA-N propan-2-yl 4-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidine-1-carboxylate Chemical compound C=12C=C(OC3CCN(CC3)C(=O)OC(C)C)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 DQORBCOTYYJLTB-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 150000005599 propionic acid derivatives Chemical class 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- BHJIBOFHEFDSAU-LBPRGKRZSA-N ralfinamide Chemical compound C1=CC(CN[C@@H](C)C(N)=O)=CC=C1OCC1=CC=CC=C1F BHJIBOFHEFDSAU-LBPRGKRZSA-N 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229960002720 reproterol Drugs 0.000 description 1
- WVLAAKXASPCBGT-UHFFFAOYSA-N reproterol Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCCNCC(O)C1=CC(O)=CC(O)=C1 WVLAAKXASPCBGT-UHFFFAOYSA-N 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 229960001457 rimiterol Drugs 0.000 description 1
- IYMMESGOJVNCKV-SKDRFNHKSA-N rimiterol Chemical compound C([C@@H]1[C@@H](O)C=2C=C(O)C(O)=CC=2)CCCN1 IYMMESGOJVNCKV-SKDRFNHKSA-N 0.000 description 1
- 229950004432 rofleponide Drugs 0.000 description 1
- IXTCZMJQGGONPY-XJAYAHQCSA-N rofleponide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O IXTCZMJQGGONPY-XJAYAHQCSA-N 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
- 229960002586 roflumilast Drugs 0.000 description 1
- CSYSULGPHGCBQD-UHFFFAOYSA-N s-ethylisothiouronium diethylphosphate Chemical compound CCSC(N)=N.CCOP(O)(=O)OCC CSYSULGPHGCBQD-UHFFFAOYSA-N 0.000 description 1
- 229940058287 salicylic acid derivative anticestodals Drugs 0.000 description 1
- 150000003872 salicylic acid derivatives Chemical class 0.000 description 1
- 229950001879 salmefamol Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- PGKXDIMONUAMFR-AREMUKBSSA-N saredutant Chemical compound C([C@H](CN(C)C(=O)C=1C=CC=CC=1)C=1C=C(Cl)C(Cl)=CC=1)CN(CC1)CCC1(NC(C)=O)C1=CC=CC=C1 PGKXDIMONUAMFR-AREMUKBSSA-N 0.000 description 1
- 229950004387 saredutant Drugs 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 230000000862 serotonergic effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000004003 siderosis Diseases 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000003195 sodium channel blocking agent Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 208000037959 spinal tumor Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- QJQCSXAKSADYBA-UHFFFAOYSA-N tert-butyl 4-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]oxypiperidine-1-carboxylate Chemical compound C=12C=C(OC3CCN(CC3)C(=O)OC(C)(C)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 QJQCSXAKSADYBA-UHFFFAOYSA-N 0.000 description 1
- 229950002896 tetomilast Drugs 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 description 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 229960001312 tiaprofenic acid Drugs 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 229950001669 tipredane Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229950003899 tofimilast Drugs 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 229960003223 tripelennamine Drugs 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- OYYDSUSKLWTMMQ-JKHIJQBDSA-N trospium Chemical class [N+]12([C@@H]3CC[C@H]2C[C@H](C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 OYYDSUSKLWTMMQ-JKHIJQBDSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000001319 vasomotor rhinitis Diseases 0.000 description 1
- DAFYYTQWSAWIGS-DEOSSOPVSA-N vilanterol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCCCCCOCCOCC=2C(=CC=CC=2Cl)Cl)=C1 DAFYYTQWSAWIGS-DEOSSOPVSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- BPKIMPVREBSLAJ-QTBYCLKRSA-N ziconotide Chemical compound C([C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]2C(=O)N[C@@H]3C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC2)C(N)=O)=O)CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CSSC3)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(N1)=O)CCSC)[C@@H](C)O)C1=CC=C(O)C=C1 BPKIMPVREBSLAJ-QTBYCLKRSA-N 0.000 description 1
- 229960002811 ziconotide Drugs 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- XJBCFFLVLOPYBV-UHFFFAOYSA-N zinterol Chemical compound C=1C=C(O)C(NS(C)(=O)=O)=CC=1C(O)CNC(C)(C)CC1=CC=CC=C1 XJBCFFLVLOPYBV-UHFFFAOYSA-N 0.000 description 1
- 229950004209 zinterol Drugs 0.000 description 1
- 229960001360 zolmitriptan Drugs 0.000 description 1
- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/54—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings
- C07C211/56—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to the compounds of general formula I F2 0 R50 R R4R NI 2R R" 5wherein n, R1, R2, R3, R4, R6, R6, 122, 128, R9, R10, R11 and X are defined as described hereinafter, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases, which have valuable properties, the preparation thereof, the medicamentsrn containing the pharmacologically effective compounds, the preparation thereof and the use thereof.
Description
COMPOUNDS AS BRADYKININ B1 ANTAGONISTS
The present invention relates to the compounds of general formula
R’ 0 R® R®
R' nA X._ R" R® hi vo 37 Na oR R R?
R® = N R 2 11
R R , (n wherein n, R", R% R?, R* R®, R%, R", R%, R®, R", R" and X are as defined hereinafter, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases, which have valuable properties, the preparation thereof, the medicaments containing the pharmacologically effective compounds, the preparation thereof and the use thereof.
The present invention relates to 3-oxo-pyridazine compounds and their use as B1- receptor antagonists, pharmaceutical compositions containing these compounds and methods of using them for the prevention or treatment of acute pain, visceral pain, neuropathic pain, inflammatory pain and pain receptor-mediated pain, tumour pain and headaches.
PRIOR ART
Compounds with a B1-antagonistic activity have already been described in International
Patent Application PCT/EP2010/052232 or in the priority application on which it is based.
One aim of the present invention was to provide new compounds which are suitable in particular as pharmaceutical active substances that can be used for the treatment of diseases at least partly mediated by the B1 receptor.
An essential structural feature of the new compounds is the 6-oxo-1,6-dihydro-pyridazine- 4-carboxylic acid amide group that is present in tautomeric equilibrium with the 6-hydroxy- pyridazine-4-carboxylic acid amide group: wy Yt 0 0
Compared with the compounds from the prior art, the new substances are characterised in that they exhibit a strong B1-receptor blocking activity and at the same time have improved metabolic stability.
In the above general formula | in one embodiment 1 _N
HN SS aol
R' denotes the group
R? denotes H or CH,
R® and R* together with the carbon atom to which they are bound denote a Ca6- cycloalkylene group wherein a -CH, unit may be replaced by an oxygen atom, rR’ denotes H or CH,
R® denotes H, F, Cl or methyl, 5 R’ denotes H, F, Cl, Br, -CN, Cy4-alkyl, CFs, CHF,,
R® denotes H,
R® denotes F, Cl, Br, Cy4-alkyl, -O-C,_4-alkyl, -S-C44-alkyl,
R' denotes H,
R'" denotes F, Cl, Br, -CN, Cy4-alkyl, CF5;, CHF,, and
X denotes CH or N, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
An embodiment 2 of the present invention comprises the compounds of general formula I, wherein n, R', R®, R*, R®, R®, R’, R%, R?, R"’, R"" and X are defined as described hereinbefore in embodiment 1 and
R? denotes H, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
The following are mentioned for example as most particularly preferred compounds of the above general formula I:
Ne smu
Ne
HN H O o = N N Na F (1) a FU
H
F r F
Ng
HN H o o 07 NF “xX NY Na 2) 0 : Ay
H
F EF te | swewe
FIVE 0
ON F
0 ” N @®) I oS TCL _ 0 N
He
F F
Ng 0 ZL ON © rg 5
O N
HE
F7 oF
Tod
Pe /,
H
(5) °o\_/J \
H F F
F
ANS yo 9 0 % Hr, F (6) © gd N
H F F
F
N
= N, Cl
IG
(7) © Lg ok N
He F
F
N
Oo ‘a YL
H
(8) °o\_/ \
H F F
F
_N
HN 3 y 2
AN N XX oo ©) o ("LAK o H
F FF the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
TERMS AND DEFINITIONS USED
Unless otherwise stated, all the substituents are independent of one another. If for example there are a plurality of C,.4-alkyl groups as substituents in one group, in the case of three substituents C;4-alkyl, one may represent methyl, one n-propyl and one tert-butyl.
Within the scope of this application, in the definition of possible substituents, these may also be represented in the form of a structural formula. If present, an asterisk (*) in the structural formula of the substituent is to be understood as being the linking point to the rest of the molecule.
Also included in the subject matter of this invention are the compounds according to the invention, including the salts thereof, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
By the term "C,4-alkyl" (including those that are part of other groups) are meant alkyl groups with 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionally also be used for the above-mentioned groups. Unless stated otherwise, the definitions propyl and butyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl.
Moreover the definitions mentioned previously also include those groups wherein each methylene group may be substituted by up to two and each methyl group may be substituted by up to three fluorine atoms.
By the term "Cs ¢-cycloalkyl" (including those that are part of other groups) are meant cyclic alkyl groups with 3 to 6 carbon atoms. Examples include: cyclopropyl, cyciobutyl, cyclopentyl or cyclohexyl.
If they contain suitable basic functions, for example amino groups, compounds of general formula | may be converted, particularly for pharmaceutical use, into the physiologically acceptable salts thereof with inorganic or organic acids. Examples of inorganic acids for this purpose include hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or p-toluenesulphonic acid, while organic acids that may be used include malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid or citric acid.
In addition, the compounds of general formula |, if they contain suitable carboxylic acid functions, may be converted into the physiologically acceptable salts thereof with inorganic or organic bases, particularly for pharmaceutical applications. Examples of inorganic bases include alkali or alkaline earth metal hydroxides, e.g. sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxides; examples of organic amines include diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine or dicyclohexylamine.
The compounds according to the invention may be present as racemates, provided that they have only one chiral element, but may also be obtained as pure enantiomers, i.e. In the (R) or (S) form.
However, the application also includes the individual diastereomeric pairs of antipodes or mixtures thereof, which are obtained if there is more than one chiral element in the compounds of general formula I, as well as the individual optically active enantiomers of which the above-mentioned racemates are made up.
Compounds with a carbon double bond may be present in both the E and Z form.
If a compound is present in different tautomeric forms, the compound prepared is not limited to one tautomeric form but includes all the tautomeric forms. This also applies particularly to nitrogen-containing heteroaryls:
H
CX « * = *
PREPARATION METHODS
According to the invention the compounds of general formula | are obtained by methods known per se, for example by the following methods: (A) amide coupling: rR’ Rr’
R! v I + aS ¥ ¥ hi Son R? I, RY _ (1 oR R R), RR" (ny (mn)
The linking of carboxylic acids of general formula Il as shown, wherein all the groups are as hereinbefore defined, with amines of general formula Ill, wherein all the groups are as hereinbefore defined, to form carboxylic acid amides of general formula | wherein all the groups are as hereinbefore defined, may be carried out by conventional methods of amide formation.
The coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)- N,N-N',N'- tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP).
By adding 1-hydroxybenzotriazole (HOB) or 3-hydroxy-4-oxo- 3,4-dihydro-1,2,3-benzotriazine (HOObt) the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylipyrrolidone (NMP) or mixtures. If necessary, an auxiliary base such as diisopropylethylamine (DIPEA,
Hlnig base) is additionally used.
B) Amide coupling:
R’ o FR R® 7 8 wn LL xe Le oo
RY R' R? + —
R XJ/ = N R" 0 (h (R®),, R2 rR" (IV) (v)
An alternative method of preparing compounds of general formula I consists in linking carboxylic acids of general formula V, wherein all the groups are as hereinbefore defined, with amines of general formula IV, wherein all the groups are as hereinbefore defined.
The compounds of general formula V are either commercially obtainable or may be prepared by methods known from the literature
It is also possible to convert the carboxylic acids of general formula V into carboxylic acid chlorides and then react these with amines of general formula IV. Carboxylic acid chlorides are synthesised by methods known from the literature (cf. e.g. Houben-Weyl,
Methoden der Organischen Chemie, vol. E5/1). (C) Reduction of the nitrile group:
Re RS rR?
NS xR rR’ X._ R% R® me
X = N rR" R? X = N rR"
R9), RR" R), RR" (VI) (ny
The reduction of a nitrile of general formula VI to an amine of general formula Ill, wherein the group R? at the amine nitrogen denotes hydrogen and all the other groups are as hereinbefore defined, may be carried out under standard conditions of catalytic hydrogenolysis with a catalyst such as Raney nickel, for example, in a solvent such as ammoniacal methanol or ethanol or with a reducing agent such as lithium aluminium hydride or sodium borohydride in a solvent such as tetrahydrofuran, optionally in the presence of a Lewis acid such as aluminium chloride.
Compounds of general formula lll, wherein the group R? at the amine nitrogen denotes not hydrogen but an alkyl group, for example, may also be prepared from compounds of general formula VI. Thus, for example, the reaction of a nitrile of general formula VI with an alkyl Grignard reagent produces ketones which can be converted by reductive amination into the compounds of general formula lll. The reductive amination is carried out using known methods, for example with a reducing agent such as sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride, conveniently in a solvent such as tetrahydrofuran or dichloromethane optionally substituted by the addition of acetic acid.
Alternatively the ketones obtained may also be converted into oximes. The subsequent reduction of the oximes then yields compounds of general formula HI. (D) nucleophilic aromatic substitution or transition-metal-catalysed coupling:
Na R® Nao 7 R® 9 + — X 7 ha " 1 Re (RS) - jo R' © n R® R n (VI) (Vill) (VI)
The reaction of an aniline of general formula VIll, wherein all the groups are as hereinbefore defined, with a nitrile of general formula VII, wherein X, Rg and n are as hereinbefore defined, and Hal denotes a fluorine, chlorine or bromine atom, is carried out using known methods, for example in a solvent such as tetrahydrofuran, dimethylformamide or dimethylsulphoxide and conveniently in the presence of a base such as triethylamine, sodium hydroxide solution or potassium carbonate at a temperature of 20°C to 160°C. If the aniline of general formula VIII is liquid, the reaction may also be carried out without a solvent and additional base.
An alternative method of preparing compounds of general formula Vl is the palladium- catalysed reaction of a nitrile of general formula VII, wherein Hal denotes bromine or chlorine, with an aniline of general formula Vil. Reaction conditions for this reaction, which is also known as a Buchwald-Hartwig reaction, are known from the literature.
Description of the method of binding the cynoBK1-receptor
CHO cells that express the cynomolgus BK1-receptor are cultivated in "HAMS F-12
Medium". The medium is removed from confluent cultures, the cells are washed with PBS buffer, scraped off or detached using Versene and isolated by centrifuging. Then the cells are homogenised in suspension, the homogenate is centrifuged and resuspended. After the protein content has been determined 200 pl of the homogenate (50 to 250 ug protein/assay) are incubated for 60-180 minutes at ambient temperature with 0.5 to 5.0 nM kallidine (DesArg10,Leu9), [3,4-Prolyl-3,43H(N)] and increasing concentrations of the test substance in a total volume of 250 ul. The incubation is stopped by rapid filtration through GF/B glass fibre filters that have been pre-treated with polyethyleneimine (0.3%).
The radioactivity bound to the protein is measured with a TopCount NXT. The radioactivity bound in the presence of 1.0 uM kallidine (DesArg10) is defined as non- specific binding. The concentration binding curve may be analysed using computer-aided non-linear curve fitting to determine the corresponding K; value for the test substance.
Test results of the cynoBK1-receptor binding assay: ree | a oes
An essential structural feature of the new compounds is the 6-oxo-1,6-dihydro-pyridazine- 4-carboxylic acid amide group which is contained in all the compounds according to the invention and is in tautomeric equilibrium with the 6-hydroxy-pyridazine-4-carboxylic acid amide group:
WN
AA oT oA o 0
Compared with the compounds from the prior art the new substances are characterised in that they exhibit a very strong B1-receptor blocking activity and at the same time have much better metabolic stability. The metabolic stability can be measured by determining the decomposition in human hepatocytes and using the rate of decomposition to calculate the clearance, which in turn is expressed as a percentage of the human hepatic blood flow (%Qh). A substance with a high metabolic clearance (e.g. >70%Qh) will presumably exhibit a shorter duration of activity in the human body than a substance that is metabolically more stable and thus has a lower clearance (e.g. <30%Qh). Thus, in the interests of achieving a long duration of activity it is highly advantageous if the active substance has a high metabolic stability (low clearance). Surprisingly the new substances exhibit a low clearance in human hepatocytes, as is apparent from the following Table: omens || ry
Example No. [%Qh] eo | ee |e
Description of method for determining metabolic clearance in human hepatocytes
The metabolic breakdown of the test substance is determined in a hepatocyte suspension.
Cryopreserved primary human hepatocytes are incubated in a suitable incubation medium (e.g. Dulbecco’s modified eagle medium, DMEM) which contains 5% human serum. After 30 minutes’ pre-incubation in the incubator (37°C, 10% carbon dioxide) 5 pL of the test compound (80 pM, prepared from a 2 mM stock solution in dimethylsulphoxide and diluted 1:25 with incubation medium) are added to 395 pL of hepatocyte suspension (cell density in the range from 0.25 - 1 million cells/mL, typically 1 million cells/mL; final concentration of the test compound 1uM). The cells are incubated for 6 hours in an incubator with an orbital agitator. Attimes 0, 0.5, 1,2, 4 and 6 h, 25 pL of the medium are removed in each case. The medium removed is mixed with an excess of acetonitrile and centrifuged for 5 minutes. The supernatant is removed, evaporated to dryness under nitrogen and taken up in a mixture of 25% methanol and 0.1% formic acid. The reduction in the concentration of the test substance in the incubation medium is determined by coupling liquid chromatography with electrospray mass spectrometry. The linear phase of the decrease in the concentration of the test substance in the medium is used for the calculation. The intrinsic clearance is calculated as follows: CL_INTRINSIC = dose / AUC = (C0/CD) / (AUD + clast/k) x 1000/60. CO: initial concentration in the incubation [uM], CD: cell density of the vital cells [10e6cells/mL], AUD: area under the curve [uM x h], clast: concentration of the last data point [uM], k: increase in the regression lines for the reduction in the test substance [h-1]. The intrinsic in vitro clearance calculated is now converted into the intrinsic in vivo clearance:
CL_INTRINSIC_INVIVO [ml/min/kg] = (CL_INTRINSIC [uL/min/10e6cells] x hepatocellularity [10e6 cells/g liver] x liver factor [g/kg body weight]) / 1000 and the estimated human clearance is calculated using the well-stirred model:
CL [mi/min/kg] = CL_INTRINSIC_INVIVO [ml/min/kg] x hepatic blood flow [ml/min/kg] / (CL_INTRINSIC_INVIVO [ml/min/kg] + hepatic blood flow [ml/min/kg]).
The following parameters are used for the calculation: hepatocellularity, human: 120x10e6 cells / g liver; liver factor, human: 25.7 g liver / kg body weight; hepatic blood flow, human: 21 ml/(min x kg).
INDICATIONS
In view of their pharmacological properties, the novel compounds and their physiologically acceptable salts are suitable for treating diseases and symptoms of diseases caused at least to some extent by stimulation of bradykinin-B1 receptors, or in which antagonisation of the of bradykinin-B1 receptor can bring about an improvement in symptoms.
In a further aspect the present invention encompasses the compounds of the above- mentioned general formula I according to the invention for use as medicaments.
In view of their pharmacological effect the substances are suitable for the treatment of
(a) acute pain such as for example toothache, peri- and postoperative pain, traumatic pain, muscle pain, the pain caused by burns, sunburn, trigeminal neuralgia, pain caused by colic, as well as spasms of the gastro-intestinal tract or uterus; (b) visceral pain such as for example chronic pelvic pain, gynaecological pain, pain before and during menstruation, pain caused by pancreatitis, peptic ulcers, interstitial cystitis, renal colic, cholecystitis, prostatitis, angina pectoris, pain caused by irritable bowel, non-ulcerative dyspepsia and gastritis, prostatitis, non-cardiac thoracic pain and pain caused by myocardial ischaemia and cardiac infarct; (c) neuropathic pain such as for example painful neuropathies, pain of diabetic neuropathy, AIDS-associated neuropathic pain non-herpes-associated neuralgia, post- zoster neuralgia, nerve damage, cerebro-cranial trauma, pain of nerve damage caused by toxins or chemotherapy, phantom pain, pain of multiple sclerosis, nerve root tears and painful traumatically-caused damage to individual nerves, and central pain such as for example pain after stroke, spinal injuries or tumours; d) inflammatory / pain receptor-mediated pain in connection with diseases such as for example osteoarthritis, rheumatoid arthritis, rheumatic fever, tendo-synovitis, bursitis, tendonitis, gout and gout-arthritis, traumatic arthritis, vulvodynia, damage to and diseases of the muscles and fascia, juvenile arthritis, spondylitis, psoriasis-arthritis, myositides, dental disease, influenza and other viral infections such as colds, systemic lupus erythematodes or pain caused by burns, (e) tumour pain associated with cancers such asfe lymphatic or myeloid leukaemia,
Hodgkin's disease, non-Hodgkin's lymphomas, lymphogranulomatosis, lymphosarcomas, solid malignant tumours and extensive metastases; (f) headache diseases of various origins, such as for example cluster headaches, migraine (with or without aura) and tension headaches. (9) painful conditions of mixed origin, such as for example chronic back pain including lumbago, or fibromyalgia.
The compounds are also suitable for treating (h) inflammatory complaints or phenomena caused by sunburn and burns, inflammation of the gums, oedema after burns trauma, cerebral oedema and angiooedema, intestinal complaints including Crohn's disease and ulcerative colitis, irritable bowel syndrome,
pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis; inflammatory skin diseases (such as psoriasis and eczema), vascular diseases of the connective tissue, sprains and fracture, and musculoskeletal diseases with inflammatory symptoms such as acute rheumatic fever, polymyalgia rheumatica, reactive arthritis, rheumatoid arthritis, spondylarthritis, and also osteoarthritis, and inflammation of the connective tissue of other origins, and collagenoses of all origins such as systemic lupus erythematodes, scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, Still's disease or Felty syndrome;
(i) inflammatory changes connected with diseases of the airways such as bronchial asthma, including allergic asthma (atopic and non-atopic) as well as bronchospasm on exertion, occupationally induced asthma, viral or bacterial exacerbation of an existing asthma and other non-allergically induced asthmatic diseases;
(j) chronic bronchitis and chronic obstructive pulmonary disease (COPD) including pulmonary emphysema, viral or bacterial exacerbation of chronic bronchitis or chronic obstructive bronchitis, acute adult respiratory distress syndrome (ARDS), bronchitis, lung inflammation, allergic rhinitis (seasonal and all year round) vasomotor rhinitis and diseases caused by dust in the lungs such as aluminosis, anthracosis, asbestosis, chalicosis, siderosis, silicosis, tabacosis and byssinosis, exogenous allergic alveolitis, cystic fibrosis, bronchiectasis, pulmonary diseases in alpha1-antitrypsin deficiency and cough;
(k) diabetes mellitus and its effects (such as e.g. diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy) and diabetic symptoms in insulitis (for example hyperglycaemia, diuresis, proteinuria and increased renal excretion of nitrite and kallikrein);
(I) sepsis and septic shock after bacterial infections or after trauma,
(m) syndromes that cause itching and allergic skin reactions;
(n) damage to the central nervous system; (0) wounds and tissue damage; (p) benign prostatic hyperplasia and hyperactive bladder,
(q) vascular diseases such as panarteriitis nodosa, polyarthritis nodosa, periarteriitis nodosa, arteriitis temporalis, Wegner's granulomatosis, giant cell arteriitis, arteriosclerosis and erythema nodosum; inflammation of the gums; (r) disorders of the motility or spasms of respiratory, genito-urinary, gastro-intestinal including biliary or vascular structures and organs; (s) post-operative fever; (t) for the treatment and prevention of cardiovascular diseases such as high blood pressure and related complaints; (u) for the treatment and prevention of cancer and related complaints; (v) for the treatment and prevention of psychiatric diseases such as depression; (w) for the treatment and prevention of urinary incontinence and related complaints; (x) for the treatment and prevention of morbid obesity and related complaints; (y) for the treatment and prevention of atherosclerosis and related complaints. (2) for the treatment and prevention of epilepsy.
The substances are suitable for causal treatment in the sense of slowing down or stopping the progress of chronically progressive diseases, particularly osteoarthritis, rheumatoid arthritis and spondylarthritis.
In another aspect the present invention encompasses the use of the compounds of the above-mentioned general formula | according to the invention for preparing a medicament for therapeutic use in the above-mentioned indications.
Preferably, the compounds of general formula | according to the invention are used for the treatment of osteoarthritis, rheumatoid arthritis or COPD.
The term "treatment" or "therapy" refers to a therapeutic treatment of patients with a manifest, acute or chronic indication, including on the one hand symptomatic (palliative) treatment to relieve the symptoms of the disease and on the other hand causal or curative treatment of the indication with the aim of ending the pathological condition, reducing the severity of the pathological condition or delaying the progression of the pathological condition, depending on the nature or gravity of the indication.
The present invention further relates to the use of a compound of general formula | for preparing a medicament for the acute and prophylactic treatment of acute pain, visceral pain, neuropathic pain, inflammatory / pain receptor-mediated pain, tumour pain, headache pain and pain of mixed causes and other diseases as mentioned above. This use is characterised in that it comprises administering an effective amount of a compound of general formula | or a physiologically acceptable salt thereof to a patient requiring such treatment.
The term "patient" preferably refers to a human being.
In addition to their suitability as therapeutic drugs for humans, these substances are also useful in the veterinary medical treatment of domestic pets, exotic animals and farmed animals.
COMBINATIONS
For treating pain, it may be advantageous to combine the compounds according to the invention with stimulating substances such as caffeine or other pain-alleviating active compounds. If active compounds suitable for treating the cause of the pain are available, these can be combined with the compounds according to the invention.
The following compounds may be used for combination therapy, for example:
Non-steroidal antirheumatics (NSAR) such as for example propionic acid derivatives which may be selected from among alminoprofen bucloxic acid, carprofen, fenoprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, pirprofen, pranoprofen and tiaprofenic acid; acetic acid derivatives which may be selected from among indomethacin, acemetacin, alclofenac, isoxepac, sulindac and tolmetin; fenamic derivatives which may be selected from among meclofenamic acid, mefenamic acid and tolfenamic acid; biphenyl-carboxylic acid derivatives; oxicams which may be selected from among meloxicam, piroxicam and tenoxicam; salicylic acid derivatives which may be selected from among acetylsalicylic and sulphasalazine; pyrazolones which may be selected from among apazone and feprazone; and coxibs which may be selected from among celecoxib and etoricoxib).
Opiate receptor agonists which may for example be selected from among morphine,
Darvon, tramadol and buprenorphine;
Cannabinoid agonists such as for example GW-1000;
Sodium channel blockers which may for example be selected from among carbamazepine, mexiletin, pregabalin, tectin and ralfinamide.
N-type calcium channel blockers such as for example ziconotide.
Serotonergic and noradrenergic modulators which may be selected from among for example duloxetine and amitriptyline.
Corticosteroids which may be selected from among for example betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
Histamine H1-receptor antagonists which may for example be selected from among bromopheniramine, chloropheniramine, dexchloropheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine.
Leukotriene antagonists and 5-lipoxygenase inhibitors which may for example be selected from among zafirlukast, montelukast, pranlukast and zileuton.
Local anaesthetics which may for example be selected from among ambroxol and lidocaine. TRVP1 antagonists which may for example be selected from among AZD-1386, JTS-653 and PHE-377.
Nicotine receptor agonists such as for example A-366833.
P2X3-receptor antagonists such as e.g. A-317491. anti-NGF antibodies and NGF antagonists which may for example be selected from among JNJ-42160443 and PPH 207.
NK1 and NK2 antagonists such as e.g. CP-728663.
NMDA antagonists which may for example be selected from among CNS-5161, AZ-756 and V-3381.
Potassium channel modulators such as e.g. CL-888.
GABA modulators such as e.g. baclofen.
Anti-migraine drugs such as e.g. sumatriptan, zolmitriptan, naratriptan and eletriptan.
For treating one or more of the above-mentioned respiratory complaints it may be advantageous to combine the compounds of general formula | according to the invention with other active substances for treating respiratory complaints. If suitable active substances for treating the cause of the respiratory complaints are available, these may be combined with the compounds according to the invention.
The compounds of general formula | may optionally also be used in conjunction with other pharmacologically active substances. It is preferable to use active substances of the type selected from among the betamimetics, anticholinergics, corticosteroids, other PDE4- inhibitors, LTD4-receptor (CysLT1, CysLT2, CysLT3) antagonists, inhibitors of MAP kinases such as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, LTB4- receptor (BLT1, BLT2) antagonists, EGFR-inhibitors, H1-receptor antagonists, antihistamines, H4-receptor antagonists, PAF-antagonists and PI3-kinase inhibitors
CXCR1 and/or CXCR2 receptor antagonists and anti-tussives.
The compounds of general formula | may also be used in the form of double or triple combinations thereof, such as for example combinations of compounds of formula | with one or two compounds selected from among e betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors and LTD4- antagonists, e anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors and
LTD4-antagonists, eo PDE4-inhibitors, corticosteroids, EGFR-inhibitors and LTD4-antagonists, oe EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists, + EGFR-inhibitors and LTD4-antagonists, e CCR3-inhibitors, iINOS-inhibitors (inducible nitric oxide synthase-inhibitors), (6R)-L- erythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to as "BH4") and the derivatives thereof which are mentioned in WO 2006/120176, and SYK-inhibitors (spleen tyrosine kinase inhibitors), e anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors and MRP4-inhibitors.
Combinations of three active substances of one of the above mentioned categories of compounds are also covered by the invention.
Betamimetics used according to the invention are preferably compounds selected from among arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterole, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenalin, ibuterol, isoetharin, isoprenalin, levosalbutamol, mabuterol, meluadrin, metaproterenol, milveterol, orciprenalin, pirbuterol, procaterol, reproterol, rimiterol, ritodrin, salmefamol, soterenaol, sulphonterol, terbutalin, tiaramid, tolubuterol and zinterol or e 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}- 4H-benzo[1,4]Joxazin-3-one, e 8-{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy- 4H-benzo[1,4]oxazin-3-one, eo 8-{2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy- 4H-benzo[1,4]Joxazin-3-one, eo 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy- 4H-benzo[1,4]oxazin-3-one, eo 8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy- 4H-benzo[1,4]joxazin-3-one, eo N-(5-{2-[3-(4.4-diethyl-2-ox0-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]- 1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide,
o N-(5-{2-[3-(4,4-diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl- propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide, e N-(5-{2-[3-(4,4-diethyl-6-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl}-1,1-dimethyl- propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide, eo N-(5-{2-[1,1-dimethyl-3-(2-0x0-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-yl)-propylamino]- 1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide, e 8-{2-[1,1-dimethyl-3-(2-0x0-2,3-dihydro-benzimidazol-1-yl)-propylamino}-1-hydroxy- ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, e 8-{2-[1,1-dimethyl-3-(6-methyl-2-0x0-2,3-dihydro-benzimidazol-1-yl)-propylamino]- 1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, eo 8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)- propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, eo 8-{2-[1,1-dimethyl-3-(3-methyl-2-ox0-2,3-dihydro-benzimidazol-1-yl)-propylamino]- 1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, e N-[2-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]- ethylamino}-ethyl)-phenyl]-formamide, e 8-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl}- ethylamino}-ethyl)-1H-quinolin-2-one, e 8-hydroxy-5-[(1R)-1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-2- one, e 5-[(1R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)- 1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, eo [3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}- butyl)-5-methyl-phenyl]-urea, eo 4-((1R)-2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)- 2-hydroxymethyl-phenol, eo 3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino}-hexyloxy}- butyl)-benzenesuiphonamide, eo 3-(3-{7-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}- propyl)-benzenesulphonamide, eo 4-((1R)-2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy- ethyl)-2-hydroxymethyl-phenol,
eo N-1-Adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)- phenyllethyllamino)propyllphenyl}acetamide, e (1R)-5-{2-[6-(2.2-difluoro-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}-8-hydroxy- 1H-quinolin-2-one eo (R,S)-4-(2-{[6-(2.2-difluoro-4-phenylbutoxy)hexyllamino}-1-hydroxy-ethyl)-2-(hydroxyl- methyl}phenol, eo (R,S)-4-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexylJamino}-1-hydroxy-ethyl)-2-(hydroxyl- methyl)phenol, oe (R,8)-4-(2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyljJamino}-1-hydroxy-ethyl)-2-(hydroxyl- methyl)phenol, o (R,S)-4-(2-{[6-(4,4-difluoro-4-phenylbutoxy)hexyl]lamino}-1-hydroxy-ethyl)-2-(hydroxyl- methyl)phenol, oe (R,S)-5-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexyljamino}-1-hydroxy-ethyl)-8- hydroxyquinolin-2(1H)-one, eo (R,S)-[2-({6-[2.2-difluoro-2-(3-methyiphenyl)ethoxy]hexyl}amino)-1- hydroxyethyl} 2-(hydroxymethyl)phenol, e 4-(1R)-2-{[6-(2.2-difluoro-2-phenylethoxy)hexyljamino}-1-hydroxyethyl)-2-(hydroxyl- methyl}phenol, e (R,8)-2-(hydroxymethyl)-4-(1-hydroxy-2-{[4.4.515-tetrafluoro-6-(3-phenylpropoxy)- hexyllamino}ethyl)phenol, e (R,S)-[5-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexyllamino}-1-hydroxy-ethyl)-2-hydroxy- phenyl]formamide, eo (R,8)-4-[2-({6-[2-(3-bromophenyl)-2.2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]- 2-(hydroxymethyl)phenol, eo (R, S)-N-[3-(1.1 -difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl}- ethyl}amino)hexylloxy}ethyl)phenyl]-urea, e 3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]lethyl}- amino )hexyl]oxy}ethyl)phenyljimidazolidin-2,4-dione, ¢ (R,S)-4-[2-({6-[2.2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]- 2-(hydroxymethyl)phenol, e 5-((1R)-2-{[6-(2.2-difluoro-2-phenylethoxy)hexyllamino}- 1-hydroxyethyl)-8- hydroxyquinolin-2(1H)-one,
e 4-((1R)-2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyllamino}-1-hydroxy-ethyl)-2-(hydroxyl- methyl)phenol, oe (R,S)-4-(2-{[6-(3.3-difluoro-3-phenylpropoxy)hexyllamino}-1-hydroxy-ethyl)-2- (hydroxylmethyl)phenol, eo (R,S)(2-{[6-(2.2-difluoro-2-phenylethoxy)-4,4-difluorohexyljamino}-1-hydroxyethyl)- 2-(hydroxymethyl)phenol, eo (R,S)-4-(2-{[6-(2.2-difluoro-3-phenylpropoxy)hexyllamino}-1-hydroxyethyl)-2-(hydroxyl- methylphenol, e 3-[2-(3-chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-ox0-2,3- dihydro-benzothiazole-7-yl)-ethylamino}-ethyl}-propionamide, e N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazole-7-yl)- ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide, eo 7-[2-(2-{3-[2-(2-chloro-phenyl)-ethylamino]-propylsulphanyl}-ethylamino)-1-hydroxy- ethyl]-4-hydroxy-3H-benzothiazol-2-one, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
Preferably, according to the invention, the acid addition salts of the betamimetics are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesuiphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
Anticholinergics used according to the invention are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, Ipratropiumsalzen, preferably the bromide salt, aclidinium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine, (3R)-1-phenethyl-3-(9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2,2,2]octane salts. In the above-mentioned salts the cations are the pharmacologically active constituents. As anions X the above-mentioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while the chloride, bromide,
iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter- ions. Of all the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.
Other anticholinergics may be selected from among eo tropenol 2,2-diphenylpropionate-methobromide, e scopine 2,2-diphenylpropionate-methobromide, e scopine 2-fluoro-2,2-diphenylacetate methobromide, e tropenol 2-fluoro-2,2-diphenylacetate methobromide, e tropenol 3,3',4,4'-tetrafluorobenzilate methobromide, eo scopine 3,3',4,4'-tetrafluorobenzilate methobromide, e tropenol 4,4'-difluorobenzilate methobromide, e scopine 4,4'-difluorobenzilate methobromide, e tropenol 3,3'-difluorobenzilate methobromide, e scopine 3,3'-difluorobenzilate methobromide, eo tropenol 9-hydroxy-fluorene-9-carboxylate methobromide, e tropenol 9-fluoro-fluorene-9-carboxylate methobromide, e scopine 9-hydroxy-fluorene-9-carboxylate methobromide, e scopine 9-fluoro-fluorene-9-carboxylate methobromide, e tropenol 9-methyl-fluorene-9-carboxylate methobromide, eo scopine 9-methyl-fluorene-9-carboxylate methobromide, e cyclopropyltropine benzilate methobromide, e cyclopropyltropine 2,2-diphenylpropionate methobromide, » cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide, e cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide, eo cyclopropyltropin 9-methyl-xanthene-9- carboxylate methobromide, e cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide, e cyclopropyltropine methyl 4,4'-difluorobenzilate methobromide, e tropenol 9-hydroxy-xanthene-9-carboxylate methobromide, e scopine 9-hydroxy-xanthene-9-carboxylate methobromide, eo tropenol 9-methyl-xanthene-9-carboxylate methobromide, e scopine 9-methyl-xanthene-9-carboxylate methobromide, e tropenol 9-ethyl-xanthene-9-carboxylate methobromide, e tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide, and e scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide.
The above-mentioned compounds may also be used as salts within the scope of the present invention, wherein the metho-X salts are used instead of the methobromide, where X may have the meanings given for X hereinbefore.
Corticosteroids used according to the invention are preferably compounds selected from among beclomethasone betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone and tipredane orpregna-1,4-dien- 3,20-dione, 6-fluoro-11-hydroxy-16.17-[(1-methylethyliden)-bis(oxy)]-21-[[4- [(nitroxy)methyllbenzoylloxy], (6-alpha,11-beta, 16-alpha)-(9Cl) (NCX-1024) e 16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-3-one (RPR-106541), eo (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo- androsta-1,4-diene-17-carbothionate, e (S)-(2-oxo-tetrahydrofuran-3S-yl) 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17- propionyloxy-androsta-1,4-diene-17-carbothionate, and e cyanomethyl 6-alpha,9-alpha-difluoro-11-beta-hydroxy-16alpha-methyi-3-oxo-17alpha- (2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxylate, optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof. Every reference to steroids includes a reference to any salts or derivatives, hydrates or solvates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. PDE4-inhibitors used according to the invention are preferably compounds selected from among enprofyliin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, apremilast, arofyliin, atizoram, oglemilast and tetomilast or e 5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamid]-8-methoxy-quinoline (D-4418),
e N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamid]-8-methoxy-2-(trifluoromethyl)- quinoline (D-4396 (Sch-351591)),N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5- hydroxy-indol-3-yllglyoxylamide (AWD-12-281 (GW-842470)), 9-[(2- fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purin-6-amine (NCS-613),
eo 4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl}-pyridine (CDP-840),
eo N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepin- 3-yl}-4-pyridinecarboxamide (PD-168787),
e 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl}-1-(2-methoxyethyl)-2(1H)- pyridinone (T-440),
eo 2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)- 1(2H)-phthalazinone (T-2585),
e (3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine (V- 11294A),
e beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-
2-propanamide (CDC-801),
e imidazo[1,5-alpyrido[3,2-e]lpyrazin-6(5H)-one, 9-ethyl-2-methoxy-7-methyi-5-propyl- (D-22888)
e 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl], (3S,5S)-2-piperi- dinone (HT-0712),
eo 4-[1-[3,4-bis(difluoromethoxy)phenyl}-2-(3-methyl-1-oxido-4-pyridinyl)ethyl]- alpha,alpha-bis(trifluoromethyl)-benzenemethanol (L-826141),
¢ N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3- cyclopropyimethoxybenzamide,
eo (-)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s]-
[1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,
so (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,
e 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methyl-isothioureido]- benzyl)-2-pyrrolidone,
e cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid],
eo 2-carbomethoxy-4-cyano-4-(3-cyclopropyimethoxy-4-difluoromethoxyphenyl)- cyclohexan-1-one,
e cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],
eo (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,
eo (S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidenelacetate, e 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thieny!)-9H-pyrazolo[3,4-c]-1,2,4-triazolo- [4.3-a]pyridine and e 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(fert-butyl)-9H-pyrazoio[3,4-c}-1,2,4-triazolo- [4.3-a]pyridine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
Preferably, according to the invention, acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p- toluenesulphonate.
EGFR-inhibitors used according to the invention are preferably compounds selected from among cetuximab, trastuzumab, panitumumab (= ABX-EGF), Mab ICR-62, gefitinib, canertinib and erlotinib or e 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-ylJamino}- 7-cyclopropylmethoxy-quinazoline, eo 4-[(3-chloro-4-fluorophenyl)aminol-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-ylJamino}- 7-cyclopropylmethoxy-quinazoline, e 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yllamino}-7-cyclopropylmethoxy-quinazoline, e 4-[(R)~(1-phenyl-ethyl)amino}-6-{[4-(morpholin-4-yl}-1-oxo-2-buten-1-yllamino}- 7-cyciopentyloxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo- 2-buten-1-ylJamino}-7-cyclopropylmethoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo- 2-buten-1-yllamino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl}- 1-ox0-2-buten-1-ylJamino}-7-cyclopropyimethoxy-quinazoline, o 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]- 7-methoxy-quinazoline,
e 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl}-N-methyl-amino]-1-oxo- 2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, s 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yllamino}-7-cyclopentyloxy-quinazoline, eo 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten- 1-ylJlamino}-7-cyclopropylmethoxy-quinazoline, e 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo- 2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, e 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)}-N-methyl-amino]-1-oxo- 2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, s 4-[(R)-{1-phenyl-ethyllamino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo- 2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, o 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yllamino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline, eo 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yllamino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, s 4-[(3-chloro-4-fluorophenyl)amino}-6-({4-[N-(2-methoxy-ethy!)-N-methyl-amino]-1-oxo- 2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, e 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2- buten-1-ylJamino}-7-cyclopentyloxy-quinazoline, s 4-[(3-chloro-4-fluocrophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yllamino}-7-[(R)-(tetrahydrofuran-2-yl)methoxyl-quinazoline, e 4-[(3-chloro-4-fluorophenyl)yamino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1- yllamino}-7-[(S)-(tetrahydrofuran-2-ylymethoxy]-quinazoline, eo 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, o 4-[(3-chloro-4-fluorophenyl)aminol-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)- aminol-quinazoline, e 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, ¢ 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten- 1-yllamino}-7-ethoxy-quinoline, s 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyljamino}-6-(5-{[(2-methanesulphonyl- ethyl)amino]methyl}-furan-2-ylquinazoline,
eo 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten- 1-yllamino}-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluorophenyl)aminol]-6-{[4-(morpholin-4-yl}-1-oxo-2-buten-1-yllamino}- 7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, eo 4-[(3-chloro-4-fluorophenyl)amino}-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo- 2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, e 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl}-1-oxo-2-buten- 1-yllamino}-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]- 7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)aminol-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]- 7-[(R)-(tetrahydrofuran-2-yl)methoxy}-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl}-ethoxy]- 6-[(S)-(tetrahydrofuran-2-yl)methoxyl]-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)aminol]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl}- ethoxy}-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino}-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]- 7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexane-1-yloxy)-7-methoxy- quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexane- 1-yloxy)-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy- quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)aminol-6-(1-methyl-piperidin-4-yloxy)-7-methoxy- guinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}- 7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}- 7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]- 7-methoxy-quinazoline,
e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy- quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)- quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]- cyclohexane-1-yloxy}-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino}-6-{trans-4-[(morpholin-4-yl)carbonylamino]- cyclohexane-1-yloxy}-7-methoxy-quinazoline, eo 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]- cyclohexane-1-yloxy}-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino- ethoxy)-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2- methanesulphonylamino-ethoxy)-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}- 7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonyimethyl-piperidin-4-yloxy)- 7-methoxy-quinazoline, eo 4-[(3-chloro-4-fluoro-phenyl)aminol]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-
N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino}-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl- amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino}-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl- amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline, s 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexane-1- yloxy)-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesuiphonyl-piperidin-4-yloxy)-7- ethoxy-quinazoline, eo 4-[(3-chloro-4-fluoro-phenyl)amino}-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2- methoxy-ethoxy)-quinazoline, o 4-[(3-chloro-4-fluoro-phenyl)amino}-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]- 7-(2-methoxy-ethoxy)-quinazoline,
e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexane-1-yloxy)-7- methoxy-quinazoline, e 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy- quinazoline, eo 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl}-N-methyl- amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)aminol-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-
N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline, eo 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]- cyclohexane-1-yloxy}-7-methoxy-quinazoline, e 4-[(3-chioro-4-fluoro-phenyl)aminol-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4- yloxy}-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}- 7-(2-methoxy-ethoxy)-quinazoline, eo 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, e 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, e 4-[(3-ethynyl-phenyl)amino}-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy- quinazoline, eo 4-[(3-chloro-4-fluoro-phenyl)aminol]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy- ethoxy)-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)- 7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexane-1-yloxy)- 7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino}- cyclohexane-1-yloxy}-7-methoxy-quinazoline, e 4-[(3-ethynyl-phenyl)aminol-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, e 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy- quinazoline, e 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl}-piperidin-4-yloxy}- 7-methoxy-quinazoline,
e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]- piperidin-4-yloxy}-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyljamino}-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin- 4-yloxy}-7-methoxy-quinazoline, eo 4-[(3-chloro-4-fluoro-phenyi)amino}-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)- carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl- amino )carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy- quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl}-piperidin-4-yloxy}- 7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin- 4-yloxy}-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)- cyclohexane-1-yloxy]-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexane- 1-yloxy]-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino}-6-(trans-4-methylamino-cyclohexane-1-yloxy)- 7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)- cyclohexane-1-yloxy]-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexane-1-yloxy)- 7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl- amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl}-ethoxy]- 7-[(S)-(tetrahydrofuran-2-yl)methoxyl-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7- methoxy-quinazoline, e 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy- quinazoline,
e 3-cyano-4-[(3-chloro-4-fluorophenyl)aminol-6-{{4-(N,N-dimethylamino)-1-oxo-2-buten- 1-yllamino}-7-ethoxy-quinoline; e [4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]- amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, eo 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]- piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline, e 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]- 6-[(vinylcarbonyl)aminol-quinazoline, e 4-[(3-chloro-4-fluorophenyl)aminol-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]- 6-[(vinylcarbonyl)aminol]-quinazoline, e 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]- 6-[(vinylcarbonyl)aminol]-quinazoline, and e 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N-[(ethoxy- carbonyl)methyljamino}-1-oxo-2-buten-1-yl)aminol-7-cyclopropylmethoxy-quinazoline, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. Preferably, according to the invention, acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p- toluenesulphonate.
LTD4-receptor antagonists used according to the invention are preferably compounds selected from among montelukast, praniukast and zafirlukast, or(E)-8-[2-[4-[4-(4- fluorophenyl)butoxylphenyllethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one (MEN-91507), e 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxyl- butyric acid (MN-001), eo 1-(((R)~(3-(2-(8,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2- propyl)phenyljthio)methylcyclopropane-acetic acid, eo 1-(((1(R)-3(3-(2~(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid and eo [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyljJoxymethyllphenyllacetic acid, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
Preferably, according to the invention, acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p- toluenesulphonate. By salts or derivatives which the LTD4-receptor antagonists may optionally be capable of forming are meant, for example: alkali metal salts, such as for example sodium or potassium salts, alkaline earth salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
Histamine H1 receptor antagonists used according to the invention are preferably compounds selected from among epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadin, mizolastin, ketotifen, emedastin, dimetinden, clemastin, bamipin, cexchlorpheniramin, pheniramin, doxylamine, chlorophenoxamin, dimenhydrinat, diphenhydramin, promethazin, ebastin, olopatadine, desloratidin and meclozin, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
Preferably, according to the invention, the acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p- toluenesulphonate.
Histamine H4 receptor antagonists used according to the invention are preferably compounds such as for example (5-chloro-1H-indol-2-y!}-(4-methyl-1-piperazinyl)- methanone (UNJ-7777120), optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. Preferably, according to the invention, acid addition salts selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate are used.
MAP Kinase inhibitors used according to the invention are preferably compounds selected from among: ¢ Bentamapimod (AS-602801) eo Doramapimod, e 5-carbamoylindole (SD-169), e B-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3- pyridinecarboxamide (VX-702), e alpha-[2-[[2-(3-pyridinyl)ethyllamino]-4-pyrimidinyl]-2-benzothiazoleacetonitrile (AS- 601245), e 9,12-epoxy-1H-diindolo[1,2,3-fg:3'.2".1"-kl]pyrrolo[3,4-i][1.6]benzodiazocine-10- carboxylic acid (CEP-1347), and e 4-[3-(4-chiorophenyl)-5-(1-methyl-4-piperidinyl}-1H-pyrazol-4-yl]-pyrimidine (SC-409), optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates thereof.
Neurokinin (NK1 or NK2) antagonists used according to the invention are preferably compounds selected from among: Saredutant, Nepadutant and Figopitant, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates thereof.
Antitussive substances used according to the invention are preferably compounds selected from among hydrocodone, caramiphen, carbetapentane and dextramethorphane, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates thereof.
Substances of preferred CXCR1 or CXCR2 antagonists used according to the invention are preferably compounds such as e.g. 3-[[3-[(dimethylamino)carbonyl]-2-
hydroxyphenyllamino]-4-[[(R)-1-(5-methylfuran-2-yl)propyllamino]cyclobut-3-ene-1,2-dione (SCH-527123), optionally in the form of its racemates, enantiomers, diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates.
The dosage necessary for obtaining a pain-alleviating effect is, in the case of intravenous administration, expediently from 0.01 to 3 mg/kg of body weight, preferably from 0.1 to 1 mg/kg, and, in the case of oral administration, from 0.1 to 8 mg/kg of body weight, preferably from 0.5 to 3 mg/kg, in each case one to three times per day. The compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, aerosol formulations being particularly suitable for inhalation. They can be incorporated into customary pharmaceutical preparations, such as tablets, coated tablets, capsules, powders, suspensions, solutions, metered-dose aerosols or suppositories, if appropriate together with one or more customary inert carriers and/or diluents, for example with maize starch, lactose, cane sugar, microcrystalline celluiose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyicellulose or fatty substances, such as hardened fat, or suitable mixtures thereof.
EXPERIMENTAL SECTION
Generally, there are mass spectra and 'H NMR spectra for the compounds that have been prepared. The ratios given for the eluants are in volume units of the solvents in question.
For ammonia, the given volume units are based on a concentrated solution of ammonia in water.
Unless indicated otherwise, the acid, base and salt solutions used for working up the reaction solutions are aqueous systems having the stated concentrations.
For chromatographic purification, silica gel from Millipore (MATREX™, 35 to 70 um) or
Alox (E. Merck, Darmstadt, Alumina 90 standardized, 63 to 200 ym, article No.
1.01097.9050) is used.
In the descriptions of the experiments, the following abbreviations are used:
TLC thin layer chromatograph
DMSO dimethylsulphoxide
RP reverse phase
R, retention time tert tertiary TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate
THF tetrahydrofuran
The following analytical HPLC methods were used:
Method 1: Column: Interchim Strategy C18, 5 uM, 4.6 x 50 mm
Detection: 220 —- 320 nm
Eluant A: water / 0.1% acetic acid
Eluant B: acetonitrile
Gradient: ov [wo [sw
Method 2: Column: Merck Cromolith Flash RP18e, 4.6 x 25 mm
Eluant A: water / 0.1% formic acid
Eluant B: acetonitrile / 0.1% formic acid
Gradient: ov me ws jw rm lms fw
Wms me [tw wwe ws [wm
Method 3: Column: YMC-Pack ODS-AQ, 3 uM, 4.6 x 75 mm
Eluant A: water / 0.15% formic acid
Eluant B: acetonitrile
Gradient: oo me [mmm
IEC LI LL me ms wm 55 [we [me Je
Method 4: Column: Zorbax Stable Bond C18, 1.8 uM, 3 x 30 mm
Eluant A: water / 0.15% formic acid
Eluant B: acetonitrile
Gradient: rE mw me mew [Tew mw
Method 5: Column: Sunfire C18, 3.5 uM, 4.6 x 50 mm
Detection: 180 — 820 nm
Eluant A: water / 0.1% trifluoroacetic acid
Eluant B: acetonitrile / 0.1% trifluoroacetic acid
Temperature: 40°C
Gradient:
IEC I LE
20 Je mee [ 25 jee men wm
Method 6: Column: Sunfire C18, 3.5 uM, 4.6 x 50 mm
Detection: 180 — 820 nm
Eluant A: water / 0.1% trifluoroacetic acid
Eluant B: acetonitrile / 0.1% trifluoroacetic acid
Temperature: 40°C
Gradient: oo me mw
IEC LC LC LE
Sooo [mes
Method 7: Column: YMC-Pack ODS-AQ, 3 uM, 4.6 x 75 mm
Eluant A: water / 0.15% formic acid
Eluant B: acetonitrile
Gradient: ov me mw 9s [wo we Je
So [wo we Je
Sm [we [we
Method 8: Column: Zorbax Stable Bond C18, 1.8 uM, 3 x 30 mm
Eluant A: water / 0.15% formic acid
Eluant B: acetonitrile
Gradient: ov me mw
PE me me wm
Tm we (ms 6
Method 9: Column: Zorbax Stable Bond C18, 1.8 uM, 3 x 30 mm
Eluant A: water / 0.15% formic acid
Eluant B: acetonitrile
Gradient: ov ms Ew
TE Twe jms Jw
Tm we jw wm
Method 10: Column: Zorbax Stable Bond C18, 3.5 uM, 4.6 x 75 mm
Eluant A: water / 0.15% formic acid
Eluant B: acetonitrile
Gradient: ov ws [sw wwe mew
Tr me me mw
Emme [wn [wm
Method 11: Column: X Terra C18, 3.5 uM, 4.6 x 50 mm
Detection: 180 — 820 nm
Eluant A: water / 0.1% trifluoroacetic acid
Eluant B: acetonitrile / 0.1% trifluoroacetic acid
Temperature: 40°C
Gradient: (or Ee mw [rm me meme
Method 12: Column: Merck Cromolith Flash RP18e, 4.6 x 25 mm
Eluant A: water / 0.1% formic acid
Eluant B: acetonitrile / 0.1% formic acid
Gradient:
Orme [we wm] 7 [me (wow
IE CL
Method 13: Column: Merck Cromolith SpeedROD RP-18e, 4.6 x 50 mm
Eluant A: water / 0.1% formic acid
Eluant B: acetonitrile / 0.1% formic acid
Gradient: oo [wo me ww jm jw we mew
Method 14: Column: Zorbax Stable Bond C18, 3.5 uM, 4.6 x 75 mm
Eluant A: water / 0.15% formic acid
Eluant B: acetonitrile
Gradient: [Es ww
Tm [me jmn jw [mmr mew (FF _ we me wm
The following preparative methods were used for the reversed-phase chromatography:
Method 1: Column: Atlantis C18, 5 uM, 100 x 30 mm
Detection: 210-500 nm
Eluant A: water / 0.1% trifluoroacetic acid
Eluant B: acetonitrile
Gradient: mms mE (Ew mm mE mem
Method 2: Column: Varian Pursuit 5 uM, 50 x 200 mm
Eluant A: water / 0.1% trifluoroacetic acid
Eluant B: acetonitrile / 0.1% trifluoroacetic acid
Gradient: or me jm wm
Method 3: Column: YMC-Pack ODS-AQ 5 uM, 30 x 100 mm
Eluant A: water / 0.15% formic acid
Eluant B: acetonitrile
Gradient: ov (EE Ew ems jms wm
Cer we jm m mms me Jw
Preparation of the starting compounds:
The compounds of general formula | may be prepared from the following intermediates A,
Band C:
R’ o FR R®
RL._ N X._ RE R® hi oY 37 a oR R RR XxXy_— 10 ¥ 1 i N R (RS), R? rR"
B: ]
A
C i
R.__N
AAV1 + AAV2 —— ~ Sn 3 4
OR R Rg?
B
R”"” o FR R®
HN X._ R R _ N
AAV1 + AAV3 RY R* R? X_/ ~ wo
N R
(R%), 42 RM
Cc
Ro FR R® R® 0 FR’ R®
ROH ANAS R’ R® RA AA R’ R®
Tr ek] TT RY RB? x 0 R XJ. = N RY Oo R Xz N R™ (RS), RZ rR (RS), R? R'
Cc , RS rR? R* 0 rR? rR?
R 0 7 9 1 7 9 cL NS R R RM Ay AN XS R R hid NH * fe 3 —_— rR Le J = 10 0 R XY = 10 0 rR? rR* rR’ N R N R (R®), R? RY" (RS), R2 R'
B A
AAV 1:amide coupling
A solution of the carboxylic acid component (1 mol-equivalent), triethylamine (2.5 mol- equivalents) and TBTU (1.1 mol-equivalents) in THF was stirred for 30 minutes at ambient temperature. Then the amine component (1.1 mol-equivalent as hydrochloride) was added and stirring was continued overnight. Then the mixture was evaporated down, mixed with water, made alkaline with dilute potassium carbonate solution and extracted with ethyl acetate. The product was isolated and purified by column chromatography (either silica gel or reversed phase chromatography).
AAV 2:Ester hydrolysis 2N sodium hydroxide solution (2 mol-equivalents) was added to a solution of the ester (1 mol-equivalent) in methanol and the mixture was stirred for 1 to 5 hours at ambient temperature. Then it was acidified with acetic acid and the mixture was evaporated to dryness in vacuo. The crude product thus obtained was purified in the normal way by column chromatography on silica gel.
AAV 3:Cleaving the fert-butyloxycarbonyl protective group
A solution of the tert-butoxycarbonyl-amino compound (1 mol-equivalent) in dichloromethane was combined with trifluoroacetic acid (3 to 10 mol-equivalents) and stirred at ambient temperature until the protective group had been cleaved completely.
The reaction mixture was then evaporated to dryness and the crude product thus obtained was purified by chromatography.
AAV 4:Preparation of the intermediate A rR?
A x RY R®
Lt —
Zk HN RY (RS), R"
Re HH R®
NS xR R® X._ R. R® ~ a. HN ~N
ZN R" ZN R"
Re), H gn Re), Hon
Alkyl Rr Alkyl R®
X._ RZ Rr’ HO. = X._ R Rr’ “10 — 0
ZN R" ZN R"
RH, Han Re, H gn
Alkyl R®
X._ RY Rr’
HN | x = N R™ (RS), H Rr
A solution of the aniline component (1 mol-equivalent) and a strong base such as e.g. potassium-tert-butoxide (1 mol-equivalent) in DMSO was stirred for one hour at ambient temperature, then combined with the 4-fluoro-benzonitrile component (1 mol-equivalent) and stirred overnight at approx. 80°C. For working up the mixture was filtered through
Alox and evaporated to dryness in vacuo.
The nitrile group of the diphenylamine intermediate product thus obtained was then reduced to the aminomethyl group with the addition of Raney nickel at 55°C and 3 bar excess hydrogen pressure and the product obtained was purified by chromatography.
In order to prepare the intermediate A with an alpha-alkylbenzyl group (e.g. A1, A4, A5) the nitrile derivative (1 mol-equivalent) was dissolved in diethyl ether and at 0 to 5°C it was added with stirring to a solution of alkylmagnesium bromide (4 mol-equivalents) in diethyl ether and then stirred for another 30 minutes approx. The reaction mixture was then stirred into 1M hydrochloric acid at -5°C and the alkylketone thus obtained was isolated and purified by chromatography in the usual way.
A solution of the ketone thus obtained (1 mol-equivalent) in acetonitrile was combined with triethylamine (2 mol-equivalents) and hydroxylamine-hydrochloride (1.3 mol-equivalents) and refluxed for 4 hours. Then water was added and the mixture was extracted with dichloromethane. The resulting oxime was isolated from the organic phase and purified by conventional methods.
A solution of the oxime (1 mol-equivalent) in methanol was combined with methanolic hydrochloric acid (6.6 mol-equivalents). After the addition of zinc powder (1.4 mol- equivalents) the mixture was refluxed for 3 hours with stirring. After cooling the mixture was combined with water and extracted with dichloromethane. If necessary, the amine thus obtained was purified by chromatography.
Another possible way of reducing the oxime to the corresponding amine is by catalytic hydrogenation. For this, the oxime was hydrogenated in methanolic ammonia solution after the addition of Raney nickel at 50°C and at an excess hydrogen pressure of 50 psi until the uptake of hydrogen had ended. If necessary, the amine thus obtained was purified by chromatography.
Preparation of the Intermediates A
Rr’ Rr
X._ Rl R® mT
R® Xu - N RY (R®), R? Rr
The following intermediates A1 to A31 were prepared according to general working method AAV4: intermediate A1: (6-aminomethyl-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)- amine
N Cl
Za
H
FF
F
HPLC: R;=1.74 minutes (method 13)
Mass spectrum (ESI); [M+H]+ = 302 intermediate A2: (4-aminomethyl-phenyl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
F es
N
H
FOF
F
Mass spectrum (ESI): [M+H]+ = 285 thin layer chromatogram (silica gel, CH,Cl,/ethanol 19:1): R= 0.16 intermediate A3: (6-aminomethyl-pyridin-3-yl}-(4-fluoro-2-trifluoromethyl-phenyl)- amine
N F
Z
N
H
FF
F
HPLC: R;= 2.06 minutes (method 3)
Mass spectrum (ESI): [M+H]+ = 286; [M-H]- = 284 intermediate A4: (4-aminomethyl-3-fluoro-phenyl)-(4-fluoro-2-trifluoromethyl-phenyl)- amine
F je
F N
H
F7\F
F
Mass spectrum (ESI): [M+H]+ = 303 thin layer chromatogram (silica gel, CH,Cl,/ethanol 19:1). Ry = 0.08 intermediate A5: (4-aminomethyl-3-fluoro-phenyl)-(2-trifluoromethyl-phenyl)-amine phew
F N
H
F7F
F
Mass spectrum (ESI): [M-H]- = 283 thin layer chromatogram (silica gel, CH;Cly/ethanol 19:1): Ry = 0.09 intermediate AB: (4-aminomethyl-phenyl)-(2-trifluoromethyl-phenyl)-amine
N
H
FTF
F
HPLC: R;=1.36 minutes (method 1)
Mass spectrum (ESI): [M+H-NH;]+ = 250 intermediate A7: (4-aminomethyl-phenyl)-(4-chloro-2-trifluoromethyl-phenyl)}-amine
Cl "CL
N
MH
F7\F
F
Mass spectrum (ESI): [M+H-NH;]+ = 284/286 intermediate A8: (4-aminomethyl-3-fluoro-phenyl)-(4-chloro-2-trifluoromethyl-phenyl)- amine
Cl
F N
H
FTF
F
HPLC: R;= 1.83 minutes (method 2) intermediate A9: (4-aminomethyl-phenyl)-(4-bromo-2-trifluoromethyl-phenyl)-amine
Br =
N
H
F7 UF
F
HPLC: R;= 1.81 minutes (method 2)
Preparation of the Intermediates B
Ge) ;
R N con o RY R*
The following Intermediate B1 was prepared by amide coupling according to general working method AAV1 and subsequent ester saponification according to general working method AAV2: intermediate B1: (S)-3-[(6-0x0-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydro- furan-3-carboxylic acid _N
HNT SS 0
N
A < 0
O
HPLC: R= 0.33 minutes (method 2)
Mass spectrum (ESI); [M+H]+ = 254
The following Intermediate B2 may be prepared analogously : intermediate B2: 1-[(6-ox0-1,6-dihydro-pyridazine-4-carbonyl)-amino]- cyclopropanecarboxylic acid _N
HN™ SS 0
NL
AA OH
0
Preparation of the intermediates C
R”” o FR R®
A A 7 9
HN X._ R R
N ~~
R® R* rR’ IL rR" (R®), R? Rr"
The following Intermediates C1 to C6 were prepared by amide coupling according to general working method AAV1 and subsequent cleaving of the fert-butyloxycarbonyl- protective group according to general working method AAV3: intermediate C1: 1-amino-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl- phenylamino)-pyridin-2-ylmethyl}-amide 0
LS N cl
N x
CTL :
ZN
H
FF
F
HPLC: R;= 1.55 minutes {method 13)
Mass spectrum (ESI): [M-H]- = 383 intermediate C2: 1-amino-cyclopropanecarboxylic acid-[5-(4-fluoro-2-trifluoromethyl- phenylamino)-pyridin-2-ylmethyl]-amide
0
BS N F
N aN
YL : =
N
H
FF" UF
F
HPLC: R;=2.33 minutes (method 7)
Mass spectrum (ESI): [M+H]+ = 369; [M-H]- = 367 intermediate C3: (S)-3-amino-tetrahydrofuran-3-carboxlic acid-2-fluoro-4-(4-fluoro-2- trifluoromethyl-phenylamino)-benzylamide 0
H
0 F N
F™ UF
F
Mass spectrum (ESI); [M+H]+ = 416 intermediate C4: (S)-3-amino-tetrahydrofuran-3-carboxylic acid-4-(4-fluoro-2- trifluoromethyl-phenylamino}-benzylamide 0
H o N
FOF
F
HPLC: R;= 1.99 minutes (method 2)
Mass spectrum (ESI); [M+H]+ = 398 intermediate C5: (S)-3-amino-tetrahydrofuran-3-carboxylic acid-4-(4-chloro-2- trifluoromethyl-phenylamino)-benzylamide 0
H
2 N
FOF
F
HPLC: R;=2.41 minutes (method 2) intermediate C6: (S)-3-amino-tetrahydrofuran-3-carboxylic acid 2-fluoro-4-(2- trifluoromethyl-phenylamino)-benzylamide 0
H
0 F N
F7AF
F
Mass spectrum (ESI): [M+H]+ = 398
Preparation of the End Compounds:
Example 1: 6-o0x0-5,6-dihydro-pyridazine-4-carboxylic acid-(1-{[5-(4-fluoro-2- trifluoromethyl-phenylamino)-pyridin-2-yimethyl}-carbamoyl}-cyclopropyl)- amide _N
HN™ 0
H
0 N 3 0 CTL
ZN :
H
F F
F
Prepared from intermediate C2 and 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according to AAV1.
CooH1sF4N6O3 (490.42)
R; = 2.80 minutes (method 7)
Example 2: 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-(1-{[5-(4-chloro-2- trifluoromethyl-phenylamino)-pyridin-2-ylmethyl}-carbamoyl}-cyclopropyl)- amide _N
HN oO 0 N N 0 FL od
N
H
F™ FF
Prepared from intermediate C1 and 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according to AAV1.
CoH 1sCIF3NgO4 (506.87)
R; = 2.13 minutes (method 2)
Example 3: (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[4-(4-fluoro-2- trifluoromethyl-phenylamino)-benzylcarbamoylj-tetrahydrofuran-3-yl}-amide _N
HN 0 0 “ON
H
O “TCL, o H
FCF
Prepared from intermediate C4 and 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according to AAV1.
CosHoy FiN5O4 (51 9.45)
R; = 2.39 minutes (method 2)
Example 4: (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[4-(4-chloro-2- trifluoromethyl-phenylamino)-benzylcarbamoyl}-tetrahydrofuran-3-yl}-amide _N
HN O
0 " N
H
Oo CL, 0 H
F F
F
Prepared from intermediates A7 and B1 according to AAV1.
Cu4H21CIF3N5O4 (535.91)
R; = 2.28 minutes (method 2)
Example 5: (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[4-(2-trifluoromethyl- phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide _N
HN™ 0 0 “ON
H
0] “CL, © H
F E F
Prepared from intermediates A6 and B1 according to AAV1.
Ca4H2oF3N:O, (501.46)
R¢=2.09 minutes (method 2)
Example 6: (S)-6-oxo0-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[2-fluoro-4-(4-fluoro- 2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}- amide _N
HN™ 0 0 “<< ON
H
© BOY 0 H
F F
F
Prepared from intermediates A4 and B1 according to AAV1.
CaaH20FsNsO, (537.44)
R; = 2.15 minutes (method 2)
-h55.
Example 7: (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[4-(4-chloro-2- trifluoromethyl-phenylamino)-2-fluoro-benzylcarbamoyl}-tetrahydrofuran-3- yl}-amide _N
HN" 0
H
OW] Cl 0] V N
H oO I< CL © H
FOF
Prepared from intermediates A8 and B1 according to AAV1.
Co4H20CIFsN:O, (553.90)
R; = 2.31 minutes (method 2)
Example 8: (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[4-(4-bromo-2- trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide _N
HN™ 0]
H
= N., Br
H
0 < “TL © H
F™ LF
Prepared from intermediates AQ and B1 according to AAV1.
Co4H21BrF;NsO, (580.35)
R{ = 2.32 minutes (method 2)
Example 9: (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid {3-[2-fluoro-4-(2- trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}- amide _N
HN™ 0
H
= N.,
AA ., N
H
© < BON 0 H
F E F
Prepared from intermediates A5 and B1 according to AAV1.
Co4H21F4NsO,4 (519.45)
R; = 1.35 minutes (method 7) mass spectroscopy (ESI): [M+H]" = 520 [M-H] = 518
The following Examples describe pharmaceutical formulations which contain as active substance any desired compound of general formula I, without restricting the scope of the present invention thereto:
Dry ampoule with 75 mg of active compound per 10 ml
Composition:
Active compound 75.0 mg
Mannitol 500 mg
Water for injection ad 10.0 ml
Production:
Active compound and mannitol are dissolved in water. The charged ampoules are freeze dried. Water for injection is used to dissolve to give the solution ready for use.
Example II
Tablet with 50 mg of active compound
Composition: (1) Active compound 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0 mg
Production: (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is admixed to the dry granules. Tablets are compressed from this mixture, biplanar with a bevel on both sides and dividing groove on one side.
Diameter of the tablets: 9 mm.
Example lI
Tablet with 350 mg of active compound
Composition: (1) Active compound 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg
Production: (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is admixed to the dry granules. Tablets are compressed from this mixture, biplanar with a bevel on both sides and dividing groove on one side.
Diameter of the tablets: 12 mm.
Example IV
Capsule with 50 mg of active compound
Composition: (1) Active compound 50.0 mg (2) Maize starch dried 58.0 mg (3) Lactose powdered 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg
Production: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into hard gelatine two-piece capsules of size 3 in a capsule-filling machine.
Example V
Capsules with 350 mg of active compound
Composition: (1) Active compound 350.0 mg (2) Maize starch dried 46.0 mg (3) Lactose powdered 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg
Production: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous stirring.
This powder mixture is packed into hard gelatine two-piece capsules of size 0 in a capsule-filling machine.
Example VI
Suppositories with 100 mg of active compound 1 suppository comprises:
Active compound 100.0 mg
Polyethylene glycol (M.W. 1500) 600.0 mg
Polyethylene glycol (M.W. 6000) 460.0 mg
Polyethylene sorbitan monostearate 840.0 mg 2000.0 mg
Claims (18)
1. Compounds of general formula R’ 0 R® R® rR! nA SON R® hi RE 3 4 oR R Rg? _ R® N rR 2 11 R R 0) wherein _N ANT = ol R' denotes the group R? denotes H or CH, R3 and R* together with the carbon atom to which they are bound denote a Cj.4- cycloalkylene group wherein a -CH, unit may be replaced by an oxygen atom, R® denotes H or CHs, R® denotes H, F, Cl or methyl, R’ denotes H, F, Cl, Br, -CN, Cy-alkyl, CF3, CHF, R® denotes H, R® denotes F, Cl, Br, C,4-alkyl, -O-C,_4-alkyl, -S-C,4-alkyl, RY denotes H, R" denotes F, Cl, Br, -CN, Cy_4-alkyl, CF;, CHF,, and
X denotes CH or N, the enantiomers, the diastereomers, the mixtures and the salts thereof.
2. Compounds of general formula | according to claim 1, wherein R', R®, R*, R®, R®, R’ R® R® R' R'", n and X are defined as in claim 1 and R? denotes H, the enantiomers, the diastereomers, the mixtures and the salts thereof.
3. The following compounds of general formula | according to claim 1: Ne | swews Ng Toon bo - AS (1) 0 Ay H FOLF Ng HN H Oo o AICS (2) 0 Ay H F Ee F _N HN NN Oo ON F 0 “ N CL 0 © 0 N HE F F Ny Tk J g 0 N : TL (4) 5 i LJ Hf F7 OF
JN H (5) °\_/ \ He F
F .N HN™ ~~ H Oo . (6) Og k N He F F HN 0 Ad Ci 7 ° o F N He F F _N HN H Oo . (8) o \_{ \ He F F ns 0 lo} » N ©) 6 (1) BON o H FoF the enantiomers, the diastereomers, the mixtures and the salts thereof.
4. The following compound of general formula | according to claim 1: ANS 0 i N F O 7 KC (1) 0 Ay H FEF the enantiomers, the diastereomers, the mixtures and the salts thereof.
5. The following compounds of general formula | according to claim 1: we | smewe H Ns loa . O = Wr, (2) oO LZ N H FTLF the enantiomers, the diastereomers, the mixtures and the salts thereof.
6. The following compounds of general formula | according to claim 1: ne | smewe nhs IO: J F 0 ” N ® reg 5 0 N HE FTF the enantiomers, the diastereomers, the mixtures and the salts thereof.
7. The following compounds of general formula | according to claim 1: Ne | smewe Ng Tk 3 0 0 ez N @ FY OL 5 O N Hr F7 OF the enantiomers, the diastereomers, the mixtures and the salts thereof.
-B3-
8. The following compounds of general formula | according to claim 1: Ne | smn 7 ’ H (5) 0 \_{4 N H F F F the enantiomers, the diastereomers, the mixtures and the salts thereof.
9. The following compounds of general formula I according to claim 1: re | sme .N HN™ ho 9 i (6) ° Ld ¢ N H F F EF the enantiomers, the diastereomers, the mixtures and the salts thereof.
10. The following compounds of general formula | according to claim 1: Ne | swewe HS H 0 EO (7) © Ld N H F F F the enantiomers, the diastereomers, the mixtures and the salts thereof.
11. The following compounds of general formula | according to claim 1:
Ne | sews = , r H (8) ° gs N H F F F the enantiomers, the diastereomers, the mixtures and the salts thereof.
12. The following compounds of general formula | according to claim 1: te | smu _N HN 0 AK ( ) 0 J E = Ny F F F the enantiomers, the diastereomers, the mixtures and the salts thereof.
13. Physiologically acceptable salts of the compounds according to one of claims 1, 2, 3,4,5,6,7,8,9, 10, 11 or 12 with inorganic or organic acids or bases.
14. Medicaments, containing a compound according to at least one of claims 1, 2, 3, 4,5,6,7,8,9, 10, 11 or 12 or a physiologically acceptable salt according to claim 13 optionally together with one or more inert carriers and/or diluents.
15. Compound of general formula | according to one of claims 1, 2, 3,4, 5,6,7, 8, 9, 10, 11, 12 or 13 for use as medicaments. 206
16. Compound of general formula | according to one of claims 1, 2, 3,4, 5,6,7, 8, 9, 10, 11, 12 or 13 for preparing a medicament for the acute and prophylactic treatment of acute pain, visceral pain, neuropathic pain, inflammatory / pain receptor-mediated pain, tumour pain and headache diseases.
17. Use of a compound according to at least one of claims 1, 2, 3,4, 5,6, 7, 8, 9, 10, 11, 12 or 13 for preparing a medicament for the acute and prophylactic treatment of osteoarthritis.
18. Process for preparing a medicament according to claim 14, characterised in that a compound according to at least one of claims 1, 2, 3,4, 5,6,7,8,9,10, 11,12 0r 13 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP2010/052232 WO2010097372A1 (en) | 2009-02-26 | 2010-02-23 | Compounds as bradykinin b1 antagonists |
PCT/EP2011/052512 WO2011104203A1 (en) | 2010-02-23 | 2011-02-21 | Compounds as bradykinin b1 antagonists |
Publications (1)
Publication Number | Publication Date |
---|---|
SG183336A1 true SG183336A1 (en) | 2012-09-27 |
Family
ID=43981434
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SG2012060620A SG183336A1 (en) | 2010-02-23 | 2011-02-21 | Compounds as bradykinin b1 antagonists |
Country Status (23)
Country | Link |
---|---|
EP (1) | EP2539323B3 (en) |
JP (1) | JP5603955B2 (en) |
KR (1) | KR101843341B1 (en) |
CN (2) | CN102781916B (en) |
AP (1) | AP3218A (en) |
AR (1) | AR080249A1 (en) |
AU (1) | AU2011219885C1 (en) |
CA (1) | CA2790952C (en) |
CY (1) | CY1116182T1 (en) |
DK (1) | DK2539323T6 (en) |
ES (1) | ES2531663T7 (en) |
HK (1) | HK1175171A1 (en) |
IL (1) | IL220680A (en) |
MA (1) | MA34008B1 (en) |
MX (1) | MX2012009224A (en) |
NZ (1) | NZ601194A (en) |
PE (1) | PE20121805A1 (en) |
PL (1) | PL2539323T6 (en) |
PT (1) | PT2539323E (en) |
SG (1) | SG183336A1 (en) |
SI (1) | SI2539323T1 (en) |
TW (1) | TWI499589B (en) |
WO (1) | WO2011104203A1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102007034620A1 (en) | 2007-07-25 | 2009-01-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New B1 antagonists |
ATE550321T1 (en) | 2007-08-29 | 2012-04-15 | Boehringer Ingelheim Int | NEW BRADYKININ B1 ANTAGONISTS |
KR101843341B1 (en) | 2010-02-23 | 2018-03-30 | 베링거 인겔하임 인터내셔날 게엠베하 | Compounds as bradykinin b1 antagonists |
US8937073B2 (en) | 2010-08-20 | 2015-01-20 | Boehringer Ingelheim International Gmbh | Disubstituted tetrahydrofuranyl compounds and their use as B1-receptor antagonists |
WO2012022794A1 (en) * | 2010-08-20 | 2012-02-23 | Boehringer Ingelheim International Gmbh | Pyridazin derivatives as antagonists of the bradykinin b1 receptor |
JP7376582B2 (en) * | 2018-10-22 | 2023-11-08 | イーオーイー オレオ ゲーエムベーハー | Additive for powder materials for compression into compacts |
WO2021198534A1 (en) | 2020-04-04 | 2021-10-07 | Oxurion NV | Plasma kallikrein inhibitors for use in the treatment of coronaviral disease |
WO2023148016A1 (en) | 2022-02-04 | 2023-08-10 | Oxurion NV | Biomarker for plasma kallikrein inhibitor therapy response |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6919343B2 (en) * | 2002-02-08 | 2005-07-19 | Merck & Co., Inc. | N-biphenyl(substituted methyl) aminocycloalkane-carboxamide derivatives |
CA2495914A1 (en) * | 2002-08-29 | 2004-03-11 | Merck & Co., Inc. | N-biarylmethyl aminocycloalkanecarboxamide derivatives |
EP1654232A4 (en) * | 2003-08-07 | 2008-11-12 | Merck & Co Inc | Sulfonyl substituted n-(biarylmethyl) aminocyclopropanecarboxamides |
JP2007526311A (en) | 2004-03-02 | 2007-09-13 | メルク エンド カムパニー インコーポレーテッド | Aminocyclopropanecarboxamide derivatives as bradykinin antagonists |
AU2006245770A1 (en) | 2005-05-11 | 2006-11-16 | Nycomed Gmbh | Combination of the PDE4 inhibitor roflumilast and a tetrahydrobiopterin derivative |
HUP0600809A3 (en) * | 2006-10-27 | 2008-09-29 | Richter Gedeon Nyrt | New phenylsulfamoyl-benzamide derivatives as bradykinin antagonists, process and intermediates for their preparation and pharmaceutical compositions containing them |
WO2010097372A1 (en) * | 2009-02-26 | 2010-09-02 | Boehringer Ingelheim International Gmbh | Compounds as bradykinin b1 antagonists |
KR101843341B1 (en) | 2010-02-23 | 2018-03-30 | 베링거 인겔하임 인터내셔날 게엠베하 | Compounds as bradykinin b1 antagonists |
-
2011
- 2011-02-21 KR KR1020127021929A patent/KR101843341B1/en active IP Right Grant
- 2011-02-21 NZ NZ601194A patent/NZ601194A/en not_active IP Right Cessation
- 2011-02-21 PL PL11705858T patent/PL2539323T6/en unknown
- 2011-02-21 SI SI201130402T patent/SI2539323T1/en unknown
- 2011-02-21 WO PCT/EP2011/052512 patent/WO2011104203A1/en active Application Filing
- 2011-02-21 MA MA35153A patent/MA34008B1/en unknown
- 2011-02-21 ES ES11705858.6T patent/ES2531663T7/en active Active
- 2011-02-21 AP AP2012006330A patent/AP3218A/en active
- 2011-02-21 AU AU2011219885A patent/AU2011219885C1/en not_active Ceased
- 2011-02-21 PT PT117058586T patent/PT2539323E/en unknown
- 2011-02-21 MX MX2012009224A patent/MX2012009224A/en active IP Right Grant
- 2011-02-21 SG SG2012060620A patent/SG183336A1/en unknown
- 2011-02-21 CN CN201180009563.1A patent/CN102781916B/en not_active Expired - Fee Related
- 2011-02-21 DK DK11705858.6T patent/DK2539323T6/en active
- 2011-02-21 CA CA2790952A patent/CA2790952C/en not_active Expired - Fee Related
- 2011-02-21 CN CN201410206948.2A patent/CN103980258B/en not_active Expired - Fee Related
- 2011-02-21 EP EP11705858.6A patent/EP2539323B3/en active Active
- 2011-02-21 JP JP2012553341A patent/JP5603955B2/en active Active
- 2011-02-21 PE PE2012001250A patent/PE20121805A1/en not_active Application Discontinuation
- 2011-02-22 TW TW100105851A patent/TWI499589B/en active
- 2011-02-22 AR ARP110100542A patent/AR080249A1/en not_active Application Discontinuation
-
2012
- 2012-06-28 IL IL220680A patent/IL220680A/en not_active IP Right Cessation
-
2013
- 2013-02-26 HK HK13102358.7A patent/HK1175171A1/en not_active IP Right Cessation
-
2015
- 2015-03-02 CY CY20151100211T patent/CY1116182T1/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8372838B2 (en) | Compounds as bradykinin B1 antagonists | |
DK2539323T6 (en) | Compounds as bradykinin B1 antagonists | |
AU2011290727B2 (en) | Disubstituted tetrahydofuranyl compounds as antagonists of the bradykinin B1 receptor | |
US8901127B2 (en) | Pyridazin derivatives as antagonists of the bradykinin B1 receptor | |
AU2015271888B2 (en) | Compounds as bradykinin B1 antagonists | |
OA16324A (en) | Disubstituted tetrahydrofuranyl compounds as antagonists of the bradykinin B1 receptor. |