CN1964964A - 用于治疗趋化因子介导的疾病的哌啶衍生物 - Google Patents
用于治疗趋化因子介导的疾病的哌啶衍生物 Download PDFInfo
- Publication number
- CN1964964A CN1964964A CNA2005800184589A CN200580018458A CN1964964A CN 1964964 A CN1964964 A CN 1964964A CN A2005800184589 A CNA2005800184589 A CN A2005800184589A CN 200580018458 A CN200580018458 A CN 200580018458A CN 1964964 A CN1964964 A CN 1964964A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- formula
- piperidines
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 39
- 201000010099 disease Diseases 0.000 title claims abstract description 34
- 238000011282 treatment Methods 0.000 title claims abstract description 34
- 102000019034 Chemokines Human genes 0.000 title claims abstract description 9
- 108010012236 Chemokines Proteins 0.000 title claims abstract description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 title 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 168
- 230000001404 mediated effect Effects 0.000 claims abstract description 7
- -1 N-oxide compound Chemical class 0.000 claims description 78
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 47
- 150000003839 salts Chemical class 0.000 claims description 41
- 239000003814 drug Substances 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000002904 solvent Substances 0.000 claims description 34
- 238000002360 preparation method Methods 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 150000003053 piperidines Chemical class 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 241000124008 Mammalia Species 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 230000002969 morbid Effects 0.000 claims description 4
- OTKFCIVOVKCFHR-UHFFFAOYSA-N (Methylsulfinyl)(methylthio)methane Chemical compound CSCS(C)=O OTKFCIVOVKCFHR-UHFFFAOYSA-N 0.000 claims description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 150000002940 palladium Chemical class 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims 1
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 abstract description 7
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 65
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 206010039083 rhinitis Diseases 0.000 description 53
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000002585 base Substances 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 239000003112 inhibitor Substances 0.000 description 31
- 239000000243 solution Substances 0.000 description 30
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 230000008878 coupling Effects 0.000 description 24
- 238000010168 coupling process Methods 0.000 description 24
- 238000005859 coupling reaction Methods 0.000 description 24
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 208000006673 asthma Diseases 0.000 description 19
- 239000000543 intermediate Substances 0.000 description 17
- 230000014759 maintenance of location Effects 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- 239000005557 antagonist Substances 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 16
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 15
- 238000001819 mass spectrum Methods 0.000 description 15
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 14
- 229960001340 histamine Drugs 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 102100023688 Eotaxin Human genes 0.000 description 12
- 101710139422 Eotaxin Proteins 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 11
- 229910052801 chlorine Inorganic materials 0.000 description 10
- 229940017219 methyl propionate Drugs 0.000 description 10
- 239000001301 oxygen Substances 0.000 description 10
- 208000030507 AIDS Diseases 0.000 description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 210000000222 eosinocyte Anatomy 0.000 description 9
- 208000011580 syndromic disease Diseases 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 235000015320 potassium carbonate Nutrition 0.000 description 8
- 235000019260 propionic acid Nutrition 0.000 description 8
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 8
- 210000003491 skin Anatomy 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 206010011224 Cough Diseases 0.000 description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000000370 acceptor Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 230000001154 acute effect Effects 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 7
- 239000002464 receptor antagonist Substances 0.000 description 7
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 6
- 239000005695 Ammonium acetate Substances 0.000 description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 206010039361 Sacroiliitis Diseases 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 229940043376 ammonium acetate Drugs 0.000 description 6
- 235000019257 ammonium acetate Nutrition 0.000 description 6
- 230000001684 chronic effect Effects 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 210000003714 granulocyte Anatomy 0.000 description 6
- 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 6
- 210000004072 lung Anatomy 0.000 description 6
- 206010025135 lupus erythematosus Diseases 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 6
- 229940044551 receptor antagonist Drugs 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 4
- 201000008283 Atrophic Rhinitis Diseases 0.000 description 4
- 102100022718 Atypical chemokine receptor 2 Human genes 0.000 description 4
- 206010012335 Dependence Diseases 0.000 description 4
- 201000004624 Dermatitis Diseases 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 101000678892 Homo sapiens Atypical chemokine receptor 2 Proteins 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- 102000015696 Interleukins Human genes 0.000 description 4
- 108010063738 Interleukins Proteins 0.000 description 4
- 208000012659 Joint disease Diseases 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- 206010037660 Pyrexia Diseases 0.000 description 4
- 206010039088 Rhinitis atrophic Diseases 0.000 description 4
- 208000036284 Rhinitis seasonal Diseases 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 208000006045 Spondylarthropathies Diseases 0.000 description 4
- 230000036428 airway hyperreactivity Effects 0.000 description 4
- 208000026935 allergic disease Diseases 0.000 description 4
- 230000007815 allergy Effects 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 210000000621 bronchi Anatomy 0.000 description 4
- 206010006451 bronchitis Diseases 0.000 description 4
- 230000035605 chemotaxis Effects 0.000 description 4
- 201000009151 chronic rhinitis Diseases 0.000 description 4
- 230000003750 conditioning effect Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene Chemical compound C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 description 4
- 239000000428 dust Substances 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000000938 histamine H1 antagonist Substances 0.000 description 4
- 230000001969 hypertrophic effect Effects 0.000 description 4
- 206010022000 influenza Diseases 0.000 description 4
- 201000009240 nasopharyngitis Diseases 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 229960002429 proline Drugs 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 4
- 201000005671 spondyloarthropathy Diseases 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 208000001319 vasomotor rhinitis Diseases 0.000 description 4
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 3
- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 3
- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- 102100025074 C-C chemokine receptor-like 2 Human genes 0.000 description 3
- 102000009410 Chemokine receptor Human genes 0.000 description 3
- 108050000299 Chemokine receptor Proteins 0.000 description 3
- 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 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 3
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 3
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000024780 Urticaria Diseases 0.000 description 3
- 229940062527 alendronate Drugs 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 230000005784 autoimmunity Effects 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000013016 damping Methods 0.000 description 3
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 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 3
- 229960002584 gefitinib Drugs 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 229960000905 indomethacin Drugs 0.000 description 3
- 150000002617 leukotrienes Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000003448 neutrophilic effect Effects 0.000 description 3
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 3
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 description 2
- MMSNEKOTSJRTRI-LLVKDONJSA-N 1-[(2r)-4-[5-[(4-fluorophenyl)methyl]thiophen-2-yl]but-3-yn-2-yl]-1-hydroxyurea Chemical compound S1C(C#C[C@@H](C)N(O)C(N)=O)=CC=C1CC1=CC=C(F)C=C1 MMSNEKOTSJRTRI-LLVKDONJSA-N 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- AXUZQJFHDNNPFG-LHAVAQOQSA-N 3-[(r)-[3-[(e)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-[3-(dimethylamino)-3-oxopropyl]sulfanylmethyl]sulfanylpropanoic acid Chemical compound CN(C)C(=O)CCS[C@H](SCCC(O)=O)C1=CC=CC(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)=C1 AXUZQJFHDNNPFG-LHAVAQOQSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 208000035939 Alveolitis allergic Diseases 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 208000028185 Angioedema Diseases 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- 108010081589 Becaplermin Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 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
- 102100031172 C-C chemokine receptor type 1 Human genes 0.000 description 2
- 101710149814 C-C chemokine receptor type 1 Proteins 0.000 description 2
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 2
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 2
- 102100037853 C-C chemokine receptor type 4 Human genes 0.000 description 2
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 2
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 2
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 2
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 2
- 102100036305 C-C chemokine receptor type 8 Human genes 0.000 description 2
- 102100036166 C-X-C chemokine receptor type 1 Human genes 0.000 description 2
- 102100028989 C-X-C chemokine receptor type 2 Human genes 0.000 description 2
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 description 2
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 2
- 108010017316 CCR3 Receptors Proteins 0.000 description 2
- 102000004499 CCR3 Receptors Human genes 0.000 description 2
- 208000015943 Coeliac disease Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 102100027995 Collagenase 3 Human genes 0.000 description 2
- 206010010356 Congenital anomaly Diseases 0.000 description 2
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- 206010012442 Dermatitis contact Diseases 0.000 description 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 2
- 206010014950 Eosinophilia Diseases 0.000 description 2
- 206010014989 Epidermolysis bullosa Diseases 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- 208000027445 Farmer Lung Diseases 0.000 description 2
- 206010016228 Fasciitis Diseases 0.000 description 2
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 208000005577 Gastroenteritis Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 101000777558 Homo sapiens C-C chemokine receptor type 10 Proteins 0.000 description 2
- 101000716068 Homo sapiens C-C chemokine receptor type 6 Proteins 0.000 description 2
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 2
- 101000716063 Homo sapiens C-C chemokine receptor type 8 Proteins 0.000 description 2
- 101000716070 Homo sapiens C-C chemokine receptor type 9 Proteins 0.000 description 2
- 101000947174 Homo sapiens C-X-C chemokine receptor type 1 Proteins 0.000 description 2
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 description 2
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 2
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 2
- 201000003838 Idiopathic interstitial pneumonia Diseases 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
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 108010018951 Interleukin-8B Receptors Proteins 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 229930182821 L-proline Natural products 0.000 description 2
- 206010024227 Lepromatous leprosy Diseases 0.000 description 2
- 206010024229 Leprosy Diseases 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- 208000035268 Mast Cell Activation disease Diseases 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 2
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 2
- 206010029164 Nephrotic syndrome Diseases 0.000 description 2
- 102000006538 Nitric Oxide Synthase Type I Human genes 0.000 description 2
- 108010008858 Nitric Oxide Synthase Type I Proteins 0.000 description 2
- 206010031264 Osteonecrosis Diseases 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 102100037602 P2X purinoceptor 7 Human genes 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 241000721454 Pemphigus Species 0.000 description 2
- 206010065159 Polychondritis Diseases 0.000 description 2
- 206010036774 Proctitis Diseases 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 206010037549 Purpura Diseases 0.000 description 2
- 241001672981 Purpura Species 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- 208000032183 Scleromalacia Diseases 0.000 description 2
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 2
- 229940121742 Serine/threonine kinase inhibitor Drugs 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- PNNXBWWSFIVKQW-UHFFFAOYSA-N [O].CCCCCCCCCCCCCCCC Chemical compound [O].CCCCCCCCCCCCCCCC PNNXBWWSFIVKQW-UHFFFAOYSA-N 0.000 description 2
- 229960002964 adalimumab Drugs 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 208000002205 allergic conjunctivitis Diseases 0.000 description 2
- 208000004631 alopecia areata Diseases 0.000 description 2
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 2
- 229960000836 amitriptyline Drugs 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- CKMXBZGNNVIXHC-UHFFFAOYSA-L ammonium magnesium phosphate hexahydrate Chemical compound [NH4+].O.O.O.O.O.O.[Mg+2].[O-]P([O-])([O-])=O CKMXBZGNNVIXHC-UHFFFAOYSA-L 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000002052 anaphylactic effect Effects 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- NUZWLKWWNNJHPT-UHFFFAOYSA-N anthralin Chemical compound C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O NUZWLKWWNNJHPT-UHFFFAOYSA-N 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 150000001499 aryl bromides Chemical class 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000010072 bone remodeling Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229960004436 budesonide Drugs 0.000 description 2
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 description 2
- 229960002882 calcipotriol Drugs 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000002975 chemoattractant Substances 0.000 description 2
- 230000003399 chemotactic effect Effects 0.000 description 2
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 2
- 208000013116 chronic cough Diseases 0.000 description 2
- 208000017760 chronic graft versus host disease Diseases 0.000 description 2
- 208000010247 contact dermatitis Diseases 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 210000004087 cornea Anatomy 0.000 description 2
- 229940111134 coxibs Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- UVKZSORBKUEBAZ-UHFFFAOYSA-N cyclizine Chemical compound C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UVKZSORBKUEBAZ-UHFFFAOYSA-N 0.000 description 2
- 229960003564 cyclizine Drugs 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229960002311 dithranol Drugs 0.000 description 2
- 229960003530 donepezil Drugs 0.000 description 2
- 229960003804 efavirenz Drugs 0.000 description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 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
- 229960001433 erlotinib Drugs 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 208000022195 farmer lung disease Diseases 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 229960002885 histidine Drugs 0.000 description 2
- 230000000642 iatrogenic effect Effects 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 208000022653 infective arthritis Diseases 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 229960000598 infliximab Drugs 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 2
- 201000010260 leiomyoma Diseases 0.000 description 2
- 201000011486 lichen planus Diseases 0.000 description 2
- 229960004194 lidocaine Drugs 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- 230000000414 obstructive effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000027758 ovulation cycle Effects 0.000 description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 201000001245 periodontitis Diseases 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 208000015768 polyposis Diseases 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- JCRIVQIOJSSCQD-UHFFFAOYSA-N propylhexedrine Chemical compound CNC(C)CC1CCCCC1 JCRIVQIOJSSCQD-UHFFFAOYSA-N 0.000 description 2
- 229960000786 propylhexedrine Drugs 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 201000003068 rheumatic fever Diseases 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- 201000000306 sarcoidosis Diseases 0.000 description 2
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 2
- 229960002646 scopolamine Drugs 0.000 description 2
- 208000008742 seborrheic dermatitis Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 229960001203 stavudine Drugs 0.000 description 2
- 229910052567 struvite Inorganic materials 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 229960000195 terbutaline Drugs 0.000 description 2
- 229960003433 thalidomide Drugs 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010043554 thrombocytopenia Diseases 0.000 description 2
- 230000001519 thymoleptic effect Effects 0.000 description 2
- 206010043778 thyroiditis Diseases 0.000 description 2
- MIQPIUSUKVNLNT-UHFFFAOYSA-N tolcapone Chemical group C1=CC(C)=CC=C1C(=O)C1=CC(O)=C(O)C([N+]([O-])=O)=C1 MIQPIUSUKVNLNT-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 201000005539 vernal conjunctivitis Diseases 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 2
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 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
- 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
- LKRBJGQCGJSSSX-UHFFFAOYSA-N (3-bromophenyl)methyl acetate Chemical compound CC(=O)OCC1=CC=CC(Br)=C1 LKRBJGQCGJSSSX-UHFFFAOYSA-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
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- DAPLJCSYWNJZLU-UHFFFAOYSA-N (4-aminophenyl)methyl acetate Chemical compound CC(=O)OCC1=CC=C(N)C=C1 DAPLJCSYWNJZLU-UHFFFAOYSA-N 0.000 description 1
- IJDMYWWFBYRZJQ-UHFFFAOYSA-N (4-bromophenyl)methyl acetate Chemical compound CC(=O)OCC1=CC=C(Br)C=C1 IJDMYWWFBYRZJQ-UHFFFAOYSA-N 0.000 description 1
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- QUPFKBITVLIQNA-KPKJPENVSA-N (5e)-2-sulfanylidene-5-[[5-[3-(trifluoromethyl)phenyl]furan-2-yl]methylidene]-1,3-thiazolidin-4-one Chemical compound FC(F)(F)C1=CC=CC(C=2OC(\C=C\3C(NC(=S)S/3)=O)=CC=2)=C1 QUPFKBITVLIQNA-KPKJPENVSA-N 0.000 description 1
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5s,5ar,8ar,9r)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical class COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- NWBCRWCKZUXDNV-UHFFFAOYSA-N 1-(ethylsulfinylmethylsulfanyl)ethane Chemical compound CCSCS(=O)CC NWBCRWCKZUXDNV-UHFFFAOYSA-N 0.000 description 1
- ZXOFAHRGRROAQR-UHFFFAOYSA-N 1-(isocyanomethylsulfonyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1S(=O)(=O)C[N+]#[C-] ZXOFAHRGRROAQR-UHFFFAOYSA-N 0.000 description 1
- OLZHFFKRBCZHHT-SNVBAGLBSA-N 1-[(2r)-4-[5-(4-fluorophenoxy)furan-2-yl]but-3-yn-2-yl]-1-hydroxyurea Chemical compound O1C(C#C[C@@H](C)N(O)C(N)=O)=CC=C1OC1=CC=C(F)C=C1 OLZHFFKRBCZHHT-SNVBAGLBSA-N 0.000 description 1
- MWXPQCKCKPYBDR-UHFFFAOYSA-N 1-[4-[3-(4-fluorophenoxy)phenyl]but-3-yn-2-yl]-1-hydroxyurea Chemical compound NC(=O)N(O)C(C)C#CC1=CC=CC(OC=2C=CC(F)=CC=2)=C1 MWXPQCKCKPYBDR-UHFFFAOYSA-N 0.000 description 1
- RJCGZNCCVKIBHO-UHFFFAOYSA-N 1-chloro-4-fluorobenzene Chemical compound FC1=CC=C(Cl)C=C1 RJCGZNCCVKIBHO-UHFFFAOYSA-N 0.000 description 1
- VSWPGAIWKHPTKX-UHFFFAOYSA-N 1-methyl-10-[2-(4-methyl-1-piperazinyl)-1-oxoethyl]-5H-thieno[3,4-b][1,5]benzodiazepin-4-one Chemical compound C1CN(C)CCN1CC(=O)N1C2=CC=CC=C2NC(=O)C2=CSC(C)=C21 VSWPGAIWKHPTKX-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- BRUWSFUBFQYNPG-UHFFFAOYSA-N 1-phenoxypiperidine Chemical class C1CCCCN1OC1=CC=CC=C1 BRUWSFUBFQYNPG-UHFFFAOYSA-N 0.000 description 1
- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 1
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 description 1
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 1
- WOHLSTOWRAOMSG-UHFFFAOYSA-N 2,3-dihydro-1,3-benzothiazole Chemical compound C1=CC=C2SCNC2=C1 WOHLSTOWRAOMSG-UHFFFAOYSA-N 0.000 description 1
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 description 1
- GMDWHBVEZCVCHU-UHFFFAOYSA-N 2-(2-methoxyethoxy)quinazolin-4-amine Chemical compound C1=CC=CC2=NC(OCCOC)=NC(N)=C21 GMDWHBVEZCVCHU-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- YGWFCQYETHJKNX-UHFFFAOYSA-N 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]-4,5-dihydro-1h-imidazol-3-ium;chloride Chemical compound [Cl-].CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCC[NH2+]1 YGWFCQYETHJKNX-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 1
- XQCZBXHVTFVIFE-UHFFFAOYSA-N 2-amino-4-hydroxypyrimidine Chemical compound NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 description 1
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 1
- KQDJTBPASNJQFQ-UHFFFAOYSA-N 2-iodophenol Chemical compound OC1=CC=CC=C1I KQDJTBPASNJQFQ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical compound C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 description 1
- KSWRJISIQSPBCJ-UHFFFAOYSA-N 2h-isoquinoline Chemical compound C1=CC=C2[CH]NC=CC2=C1 KSWRJISIQSPBCJ-UHFFFAOYSA-N 0.000 description 1
- DFPFVXLATMRBDM-UHFFFAOYSA-N 3,4-dihydro-1h-2,1-benzothiazine Chemical compound C1=CC=C2NSCCC2=C1 DFPFVXLATMRBDM-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- HDBQZGJWHMCXIL-UHFFFAOYSA-N 3,7-dihydropurine-2-thione Chemical compound SC1=NC=C2NC=NC2=N1 HDBQZGJWHMCXIL-UHFFFAOYSA-N 0.000 description 1
- BIAVGWDGIJKWRM-FQEVSTJZSA-N 3-hydroxy-2-phenyl-n-[(1s)-1-phenylpropyl]quinoline-4-carboxamide Chemical compound N([C@@H](CC)C=1C=CC=CC=1)C(=O)C(C1=CC=CC=C1N=1)=C(O)C=1C1=CC=CC=C1 BIAVGWDGIJKWRM-FQEVSTJZSA-N 0.000 description 1
- BOHCMQZJWOGWTA-UHFFFAOYSA-N 3-methylbenzonitrile Chemical compound CC1=CC=CC(C#N)=C1 BOHCMQZJWOGWTA-UHFFFAOYSA-N 0.000 description 1
- RTZZCYNQPHTPPL-UHFFFAOYSA-N 3-nitrophenol Chemical class OC1=CC=CC([N+]([O-])=O)=C1 RTZZCYNQPHTPPL-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- TYNLGDBUJLVSMA-UHFFFAOYSA-N 4,5-diacetyloxy-9,10-dioxo-2-anthracenecarboxylic acid Chemical compound O=C1C2=CC(C(O)=O)=CC(OC(C)=O)=C2C(=O)C2=C1C=CC=C2OC(=O)C TYNLGDBUJLVSMA-UHFFFAOYSA-N 0.000 description 1
- MBLJFKQACMILLC-UHFFFAOYSA-N 4-[[3-[[4-[2-(4-hydroxyphenyl)propan-2-yl]phenoxy]methyl]phenyl]methoxy]benzenecarboximidamide Chemical compound C=1C=C(OCC=2C=C(COC=3C=CC(=CC=3)C(N)=N)C=CC=2)C=CC=1C(C)(C)C1=CC=C(O)C=C1 MBLJFKQACMILLC-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- KJQIWHNCILXLMV-UHFFFAOYSA-N 4-chloro-2-ethyl-1-fluorobenzene Chemical compound CCC1=CC(Cl)=CC=C1F KJQIWHNCILXLMV-UHFFFAOYSA-N 0.000 description 1
- NWSIFTLPLKCTSX-UHFFFAOYSA-N 4-chloro-2-nitrophenol Chemical class OC1=CC=C(Cl)C=C1[N+]([O-])=O NWSIFTLPLKCTSX-UHFFFAOYSA-N 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- IXJCHVMUTFCRBH-SDUHDBOFSA-N 7-[(1r,2s,3e,5z)-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]deca-3,5-dien-2-yl]sulfanyl-4-oxochromene-2-carboxylic acid Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1OCCCC\C=C/C=C/[C@@H]([C@H](O)C=1C=C(C=CC=1)C(F)(F)F)SC1=CC=C2C(=O)C=C(C(O)=O)OC2=C1 IXJCHVMUTFCRBH-SDUHDBOFSA-N 0.000 description 1
- PFWLFWPASULGAN-UHFFFAOYSA-N 7-methylxanthine Chemical compound N1C(=O)NC(=O)C2=C1N=CN2C PFWLFWPASULGAN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 102400000069 Activation peptide Human genes 0.000 description 1
- 101800001401 Activation peptide Proteins 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 102100028116 Amine oxidase [flavin-containing] B Human genes 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical group CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 description 1
- 102000036365 BRCA1 Human genes 0.000 description 1
- 108700020463 BRCA1 Proteins 0.000 description 1
- 101150072950 BRCA1 gene Proteins 0.000 description 1
- 102000052609 BRCA2 Human genes 0.000 description 1
- 108700020462 BRCA2 Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone 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)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 101150008921 Brca2 gene Proteins 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- 102100031092 C-C motif chemokine 3 Human genes 0.000 description 1
- 101710155856 C-C motif chemokine 3 Proteins 0.000 description 1
- 102100031102 C-C motif chemokine 4 Human genes 0.000 description 1
- 102100032366 C-C motif chemokine 7 Human genes 0.000 description 1
- 101710155834 C-C motif chemokine 7 Proteins 0.000 description 1
- 102100034871 C-C motif chemokine 8 Human genes 0.000 description 1
- 101710155833 C-C motif chemokine 8 Proteins 0.000 description 1
- 102000001902 CC Chemokines Human genes 0.000 description 1
- 108010040471 CC Chemokines Proteins 0.000 description 1
- 108010059108 CD18 Antigens Proteins 0.000 description 1
- 229940124003 CRTH2 antagonist Drugs 0.000 description 1
- 108090000835 CX3C Chemokine Receptor 1 Proteins 0.000 description 1
- 102100039196 CX3C chemokine receptor 1 Human genes 0.000 description 1
- 108050006947 CXC Chemokine Proteins 0.000 description 1
- 102000019388 CXC chemokine Human genes 0.000 description 1
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 235000002566 Capsicum Nutrition 0.000 description 1
- 240000008574 Capsicum frutescens Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 108010055165 Chemokine CCL4 Proteins 0.000 description 1
- 208000000094 Chronic Pain Diseases 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
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-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
- 108060005980 Collagenase Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108050005238 Collagenase 3 Proteins 0.000 description 1
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 1
- 101150065984 Comp gene Proteins 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 1
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- OABOXRPGTFRBFZ-IMJSIDKUSA-N Cys-Cys Chemical compound SC[C@H](N)C(=O)N[C@@H](CS)C(O)=O OABOXRPGTFRBFZ-IMJSIDKUSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 241000238557 Decapoda Species 0.000 description 1
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 1
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 102100031111 Disintegrin and metalloproteinase domain-containing protein 17 Human genes 0.000 description 1
- 229940094659 Dopamine reuptake inhibitor Drugs 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 229940122858 Elastase inhibitor Drugs 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- 229940124226 Farnesyltransferase inhibitor Drugs 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 102100037362 Fibronectin Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- OZLGRUXZXMRXGP-UHFFFAOYSA-N Fluo-3 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(Cl)C(=O)C=C3OC3=CC(O)=C(Cl)C=C32)N(CC(O)=O)CC(O)=O)=C1 OZLGRUXZXMRXGP-UHFFFAOYSA-N 0.000 description 1
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 1
- 102000011652 Formyl peptide receptors Human genes 0.000 description 1
- 108010076288 Formyl peptide receptors Proteins 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010026132 Gelatinases Proteins 0.000 description 1
- 102000013382 Gelatinases Human genes 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- 101000768078 Homo sapiens Amine oxidase [flavin-containing] B Proteins 0.000 description 1
- 101000798902 Homo sapiens Atypical chemokine receptor 4 Proteins 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 101000988419 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4D Proteins 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
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 101710200424 Inosine-5'-monophosphate dehydrogenase Proteins 0.000 description 1
- 102100022337 Integrin alpha-V Human genes 0.000 description 1
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 1
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 1
- 102100030703 Interleukin-22 Human genes 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 241000764238 Isis Species 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- 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 1
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 102000019145 JUN kinase activity proteins Human genes 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 1
- 229940122696 MAP kinase inhibitor Drugs 0.000 description 1
- 108700041567 MDR Genes Proteins 0.000 description 1
- 101150014058 MMP1 gene Proteins 0.000 description 1
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 1
- 101710187853 Macrophage metalloelastase Proteins 0.000 description 1
- 108010076503 Matrix Metalloproteinase 13 Proteins 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 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
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- PVLJETXTTWAYEW-UHFFFAOYSA-N Mizolastine Chemical compound N=1C=CC(=O)NC=1N(C)C(CC1)CCN1C1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 PVLJETXTTWAYEW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- OPVCHBZGQYEKTG-UHFFFAOYSA-N N1C=CC=C1.OCC(O)CO Chemical class N1C=CC=C1.OCC(O)CO OPVCHBZGQYEKTG-UHFFFAOYSA-N 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
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100030411 Neutrophil collagenase Human genes 0.000 description 1
- 101710118230 Neutrophil collagenase Proteins 0.000 description 1
- 108030001564 Neutrophil collagenases Proteins 0.000 description 1
- 102000056189 Neutrophil collagenases Human genes 0.000 description 1
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical class O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 1
- 102000004459 Nitroreductase Human genes 0.000 description 1
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 101710189965 P2X purinoceptor 7 Proteins 0.000 description 1
- 101150098694 PDE5A gene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100025358 Probable G-protein coupled receptor 162 Human genes 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- RBQOQRRFDPXAGN-UHFFFAOYSA-N Propentofylline Chemical compound CN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CCC RBQOQRRFDPXAGN-UHFFFAOYSA-N 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 108091008611 Protein Kinase B Proteins 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 102000005765 Proto-Oncogene Proteins c-akt Human genes 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 108010080192 Purinergic Receptors Proteins 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 101100545004 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) YSP2 gene Proteins 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 102100030416 Stromelysin-1 Human genes 0.000 description 1
- 101710108790 Stromelysin-1 Proteins 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 230000017274 T cell anergy Effects 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102000003141 Tachykinin Human genes 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- RZOXEODOFNEZRS-UHFFFAOYSA-N Tramazoline hydrochloride Chemical compound [Cl-].N1CCN=C1[NH2+]C1=CC=CC2=C1CCCC2 RZOXEODOFNEZRS-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 229940116731 Uricosuric agent Drugs 0.000 description 1
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- 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 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- LHLMOSXCXGLMMN-CLTUNHJMSA-M [(1s,5r)-8-methyl-8-propan-2-yl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate;bromide Chemical compound [Br-].C([C@H]1CC[C@@H](C2)[N+]1(C)C(C)C)C2OC(=O)C(CO)C1=CC=CC=C1 LHLMOSXCXGLMMN-CLTUNHJMSA-M 0.000 description 1
- MKFFGUZYVNDHIH-UHFFFAOYSA-N [2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]-propan-2-ylazanium;sulfate Chemical compound OS(O)(=O)=O.CC(C)NCC(O)C1=CC(O)=CC(O)=C1.CC(C)NCC(O)C1=CC(O)=CC(O)=C1 MKFFGUZYVNDHIH-UHFFFAOYSA-N 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- VSJVHFFAEGLOBH-UHFFFAOYSA-N [F].C1=CN=CN=C1 Chemical compound [F].C1=CN=CN=C1 VSJVHFFAEGLOBH-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- FGGYJWZYDAROFF-UHFFFAOYSA-N ablukast Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1OCCCCCOC(C(=C1)C(C)=O)=CC2=C1CCC(C(O)=O)O2 FGGYJWZYDAROFF-UHFFFAOYSA-N 0.000 description 1
- PTPUOMXKXCCSEN-UHFFFAOYSA-N acetyloxymethyl 2-[2-[2-[5-[3-(acetyloxymethoxy)-2,7-dichloro-6-oxoxanthen-9-yl]-2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]-n-[2-(acetyloxymethoxy)-2-oxoethyl]-4-methylanilino]acetate Chemical compound CC(=O)OCOC(=O)CN(CC(=O)OCOC(C)=O)C1=CC=C(C)C=C1OCCOC1=CC(C2=C3C=C(Cl)C(=O)C=C3OC3=CC(OCOC(C)=O)=C(Cl)C=C32)=CC=C1N(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O PTPUOMXKXCCSEN-UHFFFAOYSA-N 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 229960003792 acrivastine Drugs 0.000 description 1
- PWACSDKDOHSSQD-IUTFFREVSA-N acrivastine Chemical compound C1=CC(C)=CC=C1C(\C=1N=C(\C=C\C(O)=O)C=CC=1)=C/CN1CCCC1 PWACSDKDOHSSQD-IUTFFREVSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 108010003059 aggrecanase Proteins 0.000 description 1
- 210000001552 airway epithelial cell Anatomy 0.000 description 1
- VFRROHXSMXFLSN-SLPGGIOYSA-N aldehydo-D-glucose 6-phosphate Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O VFRROHXSMXFLSN-SLPGGIOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 102000030619 alpha-1 Adrenergic Receptor Human genes 0.000 description 1
- 108020004102 alpha-1 Adrenergic Receptor Proteins 0.000 description 1
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 1
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- PECIYKGSSMCNHN-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=NC=N[C]21.O=C1N(C)C(=O)N(C)C2=NC=N[C]21 PECIYKGSSMCNHN-UHFFFAOYSA-N 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- 229940113720 aminosalicylate Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 239000000584 angiotensin II type 2 receptor blocker Substances 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229960002708 antigout preparations Drugs 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 description 1
- 229960005207 auranofin 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
- 229960001671 azapropazone Drugs 0.000 description 1
- 229960004574 azelastine Drugs 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- DQHILPAWOOYSNZ-UHFFFAOYSA-N azetidine Chemical compound N1CCC1.N1CCC1 DQHILPAWOOYSNZ-UHFFFAOYSA-N 0.000 description 1
- 229960004168 balsalazide Drugs 0.000 description 1
- IPOKCKJONYRRHP-FMQUCBEESA-N balsalazide Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1\N=N\C1=CC=C(O)C(C(O)=O)=C1 IPOKCKJONYRRHP-FMQUCBEESA-N 0.000 description 1
- 229950000210 beclometasone dipropionate Drugs 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical class NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 1
- 229960002529 benzbromarone Drugs 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical group [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- HODFCFXCOMKRCG-UHFFFAOYSA-N bitolterol mesylate Chemical compound CS([O-])(=O)=O.C1=CC(C)=CC=C1C(=O)OC1=CC=C(C(O)C[NH2+]C(C)(C)C)C=C1OC(=O)C1=CC=C(C)C=C1 HODFCFXCOMKRCG-UHFFFAOYSA-N 0.000 description 1
- 229960000585 bitolterol mesylate Drugs 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 102100029170 cAMP-specific 3',5'-cyclic phosphodiesterase 4D Human genes 0.000 description 1
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229950002826 canertinib Drugs 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
- 229960002504 capsaicin Drugs 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 239000001390 capsicum minimum Substances 0.000 description 1
- 239000002775 capsule Substances 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
- 229960000623 carbamazepine Drugs 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000845 cartilage Anatomy 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
- 239000006285 cell suspension Substances 0.000 description 1
- 229960003115 certolizumab pegol 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
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960003728 ciclesonide Drugs 0.000 description 1
- 229960000724 cidofovir Drugs 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 108700004333 collagenase 1 Proteins 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229960005537 combretastatin A-4 Drugs 0.000 description 1
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- 230000001186 cumulative effect Effects 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
- 239000003260 cyclooxygenase 1 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
- 229960000978 cyproterone acetate Drugs 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- 108010004073 cysteinylcysteine Proteins 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 229960001271 desloratadine Drugs 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 229960004590 diacerein Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 1
- DGODWNOPHMXOTR-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium;dihydrate Chemical compound O.O.[K+].[K+].[O-][Os]([O-])(=O)=O DGODWNOPHMXOTR-UHFFFAOYSA-N 0.000 description 1
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000000221 dopamine uptake inhibitor Substances 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003602 elastase inhibitor Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- SBVYURPQULDJTI-UHFFFAOYSA-N ethyl n-[amino-[4-[[3-[[4-[2-(4-hydroxyphenyl)propan-2-yl]phenoxy]methyl]phenyl]methoxy]phenyl]methylidene]carbamate Chemical compound C1=CC(C(=N)NC(=O)OCC)=CC=C1OCC1=CC=CC(COC=2C=CC(=CC=2)C(C)(C)C=2C=CC(O)=CC=2)=C1 SBVYURPQULDJTI-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 229950002170 fenleuton Drugs 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- 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 1
- 229940125753 fibrate Drugs 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 229960000676 flunisolide Drugs 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate 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)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 229960000289 fluticasone propionate Drugs 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-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
- 229940001490 fosamax Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 239000002474 gonadorelin antagonist Substances 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 230000018981 granulocyte chemotaxis Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000012739 integrated shape imaging system Methods 0.000 description 1
- 108010074109 interleukin-22 Proteins 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 229950000831 iralukast Drugs 0.000 description 1
- ZRKSVHFXTRFQFL-UHFFFAOYSA-N isocyanomethane Chemical compound C[N+]#[C-] ZRKSVHFXTRFQFL-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 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
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229940054136 kineret Drugs 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- GWNVDXQDILPJIG-NXOLIXFESA-N leukotriene C4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-NXOLIXFESA-N 0.000 description 1
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 1
- OTZRAYGBFWZKMX-JUDRUQEKSA-N leukotriene E4 Chemical compound CCCCCC=CCC=C\C=C\C=C\[C@@H](SC[C@H](N)C(O)=O)[C@@H](O)CCCC(O)=O OTZRAYGBFWZKMX-JUDRUQEKSA-N 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 229960001120 levocabastine Drugs 0.000 description 1
- ZCGOMHNNNFPNMX-KYTRFIICSA-N levocabastine Chemical compound C1([C@@]2(C(O)=O)CCN(C[C@H]2C)[C@@H]2CC[C@@](CC2)(C#N)C=2C=CC(F)=CC=2)=CC=CC=C1 ZCGOMHNNNFPNMX-KYTRFIICSA-N 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000003589 local anesthetic agent Substances 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
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- AEUKDPKXTPNBNY-XEYRWQBLSA-N mcp 2 Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)C1=CC=CC=C1 AEUKDPKXTPNBNY-XEYRWQBLSA-N 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 1
- 229960004963 mesalazine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- LPEKGGXMPWTOCB-VKHMYHEASA-N methyl (S)-lactate Chemical class COC(=O)[C@H](C)O LPEKGGXMPWTOCB-VKHMYHEASA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 229960001952 metrifonate Drugs 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960001144 mizolastine Drugs 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- RVXKHAITGKBBAC-SFHVURJKSA-N n-[(1s)-2-cyclohexyl-1-pyridin-2-ylethyl]-5-methyl-1,3-benzoxazol-2-amine Chemical compound C([C@H](NC=1OC2=CC=C(C=C2N=1)C)C=1N=CC=CC=1)C1CCCCC1 RVXKHAITGKBBAC-SFHVURJKSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940099751 naphcon Drugs 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-M naproxen(1-) Chemical compound C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-M 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 229960004398 nedocromil Drugs 0.000 description 1
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 239000000181 nicotinic agonist Substances 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 239000002840 nitric oxide donor Substances 0.000 description 1
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 108020001162 nitroreductase Proteins 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 108091008685 nuclear receptors type I Proteins 0.000 description 1
- 229960004110 olsalazine Drugs 0.000 description 1
- QQBDLJCYGRGAKP-FOCLMDBBSA-N olsalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=C(C(O)=CC=2)C(O)=O)=C1 QQBDLJCYGRGAKP-FOCLMDBBSA-N 0.000 description 1
- SBQLYHNEIUGQKH-UHFFFAOYSA-N omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 229950010666 ontazolast Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960001609 oxitropium bromide Drugs 0.000 description 1
- LCELQERNWLBPSY-KHSTUMNDSA-M oxitropium bromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CC)=CC=CC=C1 LCELQERNWLBPSY-KHSTUMNDSA-M 0.000 description 1
- BEEDODBODQVSIM-UHFFFAOYSA-N oxymetazoline hydrochloride Chemical compound Cl.CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 BEEDODBODQVSIM-UHFFFAOYSA-N 0.000 description 1
- 229960005162 oxymetazoline hydrochloride Drugs 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical group O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 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
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 1
- 229960004633 pirenzepine 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
- 230000010118 platelet activation Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 229960003089 pramipexole Drugs 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
- 238000001556 precipitation Methods 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 229960002934 propentofylline Drugs 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000000197 pyrolysis Methods 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
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 1
- 229960000245 rasagiline Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940061969 rheumatrex Drugs 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 1
- 229960001879 ropinirole Drugs 0.000 description 1
- 229960003522 roquinimex 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
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 description 1
- YPURUCMVRRNPHJ-UHFFFAOYSA-M sodium;3-[3-tert-butylsulfanyl-1-[(4-chlorophenyl)methyl]-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate Chemical compound [Na+].C12=CC=C(OCC=3N=C4C=CC=CC4=CC=3)C=C2C(SC(C)(C)C)=C(CC(C)(C)C([O-])=O)N1CC1=CC=C(Cl)C=C1 YPURUCMVRRNPHJ-UHFFFAOYSA-M 0.000 description 1
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical class [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 108091007196 stromelysin Proteins 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- GECHUMIMRBOMGK-UHFFFAOYSA-N sulfapyridine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=CC=N1 GECHUMIMRBOMGK-UHFFFAOYSA-N 0.000 description 1
- 229960002211 sulfapyridine Drugs 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 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
- 229960000894 sulindac Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229950011332 talnetant Drugs 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940000238 tasmar Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- 229950004351 telenzepine Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- XYKWNRUXCOIMFZ-UHFFFAOYSA-N tepoxalin Chemical compound C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(CCC(=O)N(C)O)=N1 XYKWNRUXCOIMFZ-UHFFFAOYSA-N 0.000 description 1
- 229950009638 tepoxalin Drugs 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 1
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 229960004603 tolcapone Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960001262 tramazoline Drugs 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- NFACJZMKEDPNKN-UHFFFAOYSA-N trichlorfon Chemical compound COP(=O)(OC)C(O)C(Cl)(Cl)Cl NFACJZMKEDPNKN-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 239000002750 tryptase inhibitor Substances 0.000 description 1
- 239000002447 tumor necrosis factor alpha converting enzyme inhibitor Substances 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 239000003383 uricosuric agent Substances 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 229940093257 valacyclovir Drugs 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
- 229950003905 verlukast Drugs 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940023080 viracept Drugs 0.000 description 1
- 229940100050 virazole Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
- 229960001095 xylometazoline hydrochloride Drugs 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- 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
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- 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
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Pulmonology (AREA)
- Virology (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Rheumatology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Reproductive Health (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Molecular Biology (AREA)
- Transplantation (AREA)
- Otolaryngology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Obesity (AREA)
Abstract
本发明提供了式(I)化合物,其中变量如本文所定义;涉及制备这种化合物的方法;涉及这种化合物在治疗趋化因子(例如CCR3)或H1介导的疾病状态中的用途。
Description
本发明涉及具有药物活性的哌啶衍生物,制备这种衍生物的方法,包括这种衍生物的药物组合物和这种衍生物作为活性治疗剂的用途。
药学活性的哌啶衍生物公开于WO99/38514,WO99/04794和WO00/35877中。
组胺为一种碱性胺,2-(4-咪唑基)-乙胺,利用组氨酸脱羧酶由组氨酸形成。在身体的绝大多数组织中存在,但以高浓度存在于肺、皮肤和胃肠道中。在细胞水平的炎性细胞如肥大细胞和嗜碱性粒细胞中存储大量的组胺。目前已经认识到肥大细胞和嗜碱性粒细胞的脱粒以及随后的组胺释放是产生过敏过程临床表现的基本机理。组胺通过对特定组胺G-蛋白偶联受体的影响而发挥其作用,所述受体有3种主要类型-H1、H2和H3。组胺H1拮抗剂包括用于治疗患过敏性疾病尤其是鼻炎和荨麻疹病人的大多数药物种类。H1拮抗剂可用于控制过敏反应,通过例如阻断组胺对后毛细管小静脉平滑肌的作用,导致降低脉管渗透性、渗出和水肿。该拮抗剂也阻断组胺对H1受体对c型痛觉神经纤维的作用,使发痒和打喷嚏减轻。
趋化因子是趋化细胞因子,其由多种细胞释放,以将巨噬细胞、T细胞、嗜酸性粒细胞、嗜碱性粒细胞以及嗜中性粒细胞吸引到炎症部位,并且还在免疫系统细胞的成熟中发挥作用。趋化因子在多种疾病和失调的免疫和炎性反应中发挥中重要作用,这些疾病和失调包括哮喘和过敏性疾病,以及自身免疫性病变如类风湿性关节炎和动脉粥样硬化。这些小的分泌分子属于不断增加的8-14kDa蛋白超家族,该家族特征为保守的4个半光氨酸基序。趋化因子超家族可分成显示出特征性结构基序的两类主要家族Cys-X-Cys(C-X-C,或α)和Cys-Cys(C-C,或β)。根据NH-附近的半光氨酸残基对之间插入的单个氨基酸和序列相似性来区分这两个家族。
C-X-C趋化因子包括嗜中性粒细胞的几种强效的化学引诱物和活化剂,如白介素-8(IL-8)和嗜中性粒细胞活化肽2(NAP-2)。
C-C趋化因子包括单核细胞和淋巴细胞(但不包括嗜中性粒细胞)的强效化学引诱物,如人单核细胞趋化蛋白1-3(MCP-1,MCP-2和MCP-3),RANTES(调节活化、正常T表达和分泌)、嗜酸细胞活化趋化因子(eotaxin)以及巨噬细胞炎性蛋白1α和1β(MIP-1α和MIP-1β)。
研究表明趋化因子的作用是通过G蛋白-偶联受体亚族介导的,其中这些受体被称为CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CXCR1、CXCR2、CXCR3和CXCR4。由于调节这些受体的药物可用于治疗上述提及的那些疾病和失调,因此这些受体表现了较好的药物开发目标。
已知病毒感染会引起肺炎。实验表明普通感冒会增加气道中嗜酸细胞活化趋化因子粘膜分泌。将嗜酸细胞活化趋化因子滴注到鼻腔会产生类似于普通感冒的一些征兆和症状(参见Greiff L等人,Allergy(1999)54(11)1204-8[Experimental common cold increase mucosal output of eotaxin inatopic individuals]和Kawaguchi M等人,Int.Arch.Allergy Immunol.(2000)
122 S1 44[Expression of eotaxin by normal airway epithelial cells aftervirus A infection])。
本发明提供了式(I)化合物;或其N-氧化物;或其药学可接受的盐:
其中:
A、B、D、E和G中之一是CXYCO2R5,另一个是CH或N,其它的是CR2、CR3和CR4;
Q是氢或羟基;
W是CH2,O,NH或N(C1-4烷基);
X是O或键;
Y是CR10R11,CR10R11CR12R13,CR10R11CR12R13CR14R15;
R1是苯基,其任选被下列基团取代:卤素,氰基,C1-4烷基,C1-4卤代烷基,C1-4烷氧基或C1-4卤代烷氧基;
R2、R3和R4独立地是氢、卤素、氰基、硝基、羟基、NR6R7、C1-6烷基(任选被卤素取代)、C1-6烷氧基(任选被卤素取代)、S(O)p(C1-6烷基)、S(O)qCF3或S(O)2NR8R9;
R5是氢,C1-6烷基或苄基;
p和q独立地是0、1或2;
R6、R7、R8和R9独立地是氢;C1-6烷基(任选被卤素,羟基或C3-6环烷基取代);CH2(C2-5烯基);苯基(本身任选被下列取代:卤素,羟基,硝基,NH2,NH(C1-4烷基),N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),S(O)2(C1-4烷基),S(O)2NH2,S(O)2NH(C1-4烷基),S(O)2N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),氰基,C1-4烷基,C1-4烷氧基,C(O)NH2,C(O)NH(C1-4烷基),C(O)N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),CO2H,CO2(C1-4烷基),NHC(O)(C1-4烷基),NHS(O)2(C1-4烷基),C(O)(C1-4烷基),CF3或OCF3);或杂环基(本身任选被下列取代:卤素,羟基,硝基,NH2,NH(C1-4烷基),N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),S(O)2(C1-4烷基),S(O)2NH2,S(O)2NH(C1-4烷基),S(O)2N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),氰基,C1-4烷基,C1-4烷氧基,C(O)NH2,C(O)NH(C1-4烷基),C(O)N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),CO2H,CO2(C1-4烷基),NHC(O)(C1-4烷基),NHS(O)2(C1-4烷基),C(O)(C1-4烷基),CF3或OCF3);
或者NR6R7或NR8R9可以独立地形成4-7元杂环、氮杂环丁烷(azetidine)、比咯烷、哌啶、氮杂卓(azepine)、吗啉或哌嗪,后者在末端氮上任选被C1-4烷基取代;
R10,R11,R12,R13,R14和R15独立地是氢或C1-4烷基;或R10和R11与它们两个都连接的碳一起形成C3-6环烷基环,对于C4-6环烷基环,所述环任选具有被O、S(O)或S(O)2替代的环碳(ring carbon),但不是R10和R11两个都连接的环碳。
本发明的某些化合物可以以不同的异构形式存在(比如对映体,非对映体,几何异构体或互变异构体)。本发明包括所有这类异构体和其按各种比例的混合物。
合适的盐包括酸加成盐,比如盐酸盐,二盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,乙酸盐,双乙酸盐,富马酸盐,马来酸盐,酒石酸酯,柠檬酸盐,草酸盐,甲磺酸盐或对-甲苯磺酸盐。合适的盐的另一个例子是苯磺酸盐。在本发明的一方面,合适的盐是盐酸盐或乙酸盐。
本发明的化合物可以以溶剂化物(比如水合物)的形式存在,并且本发明包括所有这类溶剂化物。
卤素包括氟,氯,溴和碘。卤素是,例如氟或氯。
烷基基团和烷基部分是直链或支链的,并包括,例如1至6个(比如1至4个)碳原子。烷基的例子是甲基,乙基,正丙基,异丙基或叔丁基。
卤代烷基基团和部分包括如以上所定义的烷基部分,和一个或多个(例如1至6个)相同或不同的卤素原子。卤代烷基是,例如,CH2F,CHF2或CF3。
链烯基包括,例如2至6个(比如2至4个)碳原子。链烯基的例子是乙烯基或烯丙基。
在一个实施方案中,环烷基包括3至6个碳原子,并且是单环。环烷基是,例如环丙基,环戊基或环己基。
杂环基(heterocyclyl)是芳香或非芳香的5或6元环,任选与一个或多个其它环稠合,包括至少一个选自氮,氧和硫的杂原子;或其N-氧化物,或其S-氧化物或S-二氧化物。杂环基,例如是呋喃基,噻吩基(又名thiophenyl),吡咯基,2,5-二氢吡咯基,噻唑基,吡唑基,噁唑基,异噁唑基,咪唑基,哌啶基,吗啉基,吡啶基,二氢吡啶基(例如在6-氧代-1,6-二氢-吡啶基部分中),嘧啶基,吲哚基,2,3-二氢吲哚基,苯并[b]呋喃基(又名苯并呋喃基),苯并[b]噻吩基(又名苯并噻吩基),2,3-二氢苯并[b]噻吩基(例如在1-二氧代-2,3-二氢苯并[b]噻吩基部分中),吲唑基,苯并咪唑基,苯并三唑基,苯并噁唑基,苯并噻唑基(例如在1H-苯并噻唑-2-酮-基部分中),2,3-二氢苯并噻唑基(例如在2,3-二氢苯并噻唑-2-酮-基部分中),1,2,3-苯并噻二唑基,咪唑并吡啶基(例如咪唑并[1,2-a]吡啶基),噻吩并[3,2-b]吡啶-6-基,1,2,3-苯并噁二唑基,苯并[1,2,3]噻二唑基,2,1,3-苯并噻二唑基,苯并呋咱(又名2,1,3-苯并噁二唑基),喹喔啉基,二氢-1-苯并吡喃鎓基(dihydro-1-benzopyryliumyl)(例如在香豆素基或色酮基部分中),3,4-二氢-1H-2,1-苯并噻嗪基(例如在2-二氧代-3,4-二氢-1H-2,1-苯并噻嗪基部分中),吡唑并吡啶(例如1H-吡唑并[3,4-b]吡啶基),嘌呤(例如在3,7-二氢-嘌呤-2,6-二酮-8-基部分中),喹啉基,异喹啉基,二氢异喹啉基(例如在2H-异喹啉-1-酮-基部分中),萘啶基(例如[1,6]萘啶基或[1,8]萘啶基),二氢[1,8]萘啶基(例如在1H-[1,8]萘啶-4-酮-基部分中),苯并噻嗪基,二氢苯并噻嗪基(例如在4H-苯并[1,4]噻嗪-3-酮-基部分中),苯并[d]咪唑并[2,1-b]噻唑-2-基或二苯并噻吩基(又名二苯并噻吩基);或其N-氧化物,或其S-氧化物或S-二氧化物。
式(I)化合物的N-氧化物是,例如,1-氧基-[1,4′]联哌啶基-1′-基化合物。
在一个具体的方面,本发明提供了其中W是O的式(I)化合物。
在另一个方面,R1是任选被卤素(例如氯或氟)、C1-4烷基(例如甲基或乙基)、氰基或C1-4烷氧基(例如甲氧基)取代的苯基(例如独立地单、二-或三取代的)。在进一步的方面,R1是任选被卤素(例如氯或氟)、C1-4烷基(例如甲基或乙基)或氰基取代的苯基(例如独立地单、二-或三取代的)。
在又一个方面,R1是任选被卤素(例如氯或氟)、1-4烷基(例如甲基)或C1-4烷氧基(例如甲氧基)取代的苯基(例如独立地单或二取代的)。
在进一步的方面,R1是任选被氟、氯、氰基、1-4烷基(例如甲基)或C1-4烷氧基(例如甲氧基)取代(例如一个、两个或三个相同或不同的取代基)的苯基。在更进一步的方面,R1是被一个、两个或三个(例如两个或三个)独立选自下列的取代基取代的苯基:氟,氯,氰基和甲基。在另一个方面,R1是3,4-二氯苯基,2,4-二氯-3-甲基苯基,3,4-二氯-2-甲基苯基,2,4-二氯苯基,4-氯-2-甲基苯基,2-氯-4-氟苯基,4-氟苯基,3-氯-4-氰基苯基,3-氯-4-氰基-2-甲基苯基或3,4-二氯-2-乙基苯基。例如R1是3,4-二氯苯基,2,4-二氯-3-甲基苯基,3,4-二氯-2-甲基苯基,2,4-二氯苯基,4-氯-2-甲基苯基,2-氯-4-氟苯基,4-氟苯基或3-氯-4-氰基苯基。在又一个方面,R1是3,4-二氯苯基,2,4-二氯-3-甲基苯基,3,4-二氯-2-甲基苯基,3-氯-4-氰基-2-甲基苯基或3,4-二氯-2-乙基苯基。
在本发明的更进一步方面,Q是氢。
在本发明的另一个方面,R5是氢或C1-6烷基(例如甲基或叔丁基)。在本发明的进一步方面,R5是氢。
在本发明的又一个方面,R10,R11,R12,R13,R14和R15独立地是H或C1-4烷基(例如甲基)。
在本发明的另一个方面,X是氧或键;Y是CR10R11或CR10R11CR12R13。
在本发明的又一个方面,A、B、D、E和G中之一是CXYCO2R5,其它的全部是CH。
在本发明的进一步方面,XY是CH2,CH2CH2,OCH2,OC(CH3)2或OCHCH3。
在本发明的更进一步方面,当XY是CR10R11、CR10R11CR12R13或CR10R11CR12R13CR14R15时,则A、B或D是CXYCO2R5。
在本发明的另一个方面,当XY是OCR10R11、OCR10R11CR12R13或OCR10R11CR12R13CR14R15时,则A、B或D是CXYCO2R5。
在本发明的又一个方面,R2、R3和R4独立地是氢,卤素,氰基,C1-4烷基(例如甲基或乙基),C1-4烷氧基(例如甲氧基或乙氧基),CF3,OCF3,S(O)2(C1-4(例如S(O)2CH3)或S(O)2NH2{例如R2,R3和R4独立地是氢,卤素,氰基,硝基,C1-4烷基(例如甲基或乙基),C1-4烷氧基(例如甲氧基或乙氧基),CF3或OCF3}。
在本发明的进一步方面,R2、R3和R4中之一是氢或C1-4烷氧基(例如甲氧基)。
在更进一步方面,本发明提供了式(I)化合物,其中:Q是氢;W是O;A、B、D、E和G中之一是CXYCO2R5,另三个是CH,一个是CR2;R1是被下列取代的苯基:卤素,氰基或C1-4烷基(例如任选被氯、氰基、甲基或乙基取代);R2是氢,卤素(例如氯)或C1-4烷氧基(例如甲氧基);R5是氢或C1-4烷基(例如甲基或叔丁基);和XY是CH2,CH2CH2,OCH2,OC(CH3)2或OCHCH3。
在另一个方面,本发明提供了式(I)化合物,其中:Q是氢;W是O;E是CH;A、B、D和G中之一是CXYCO2H,其它是CR2、CR3和CR4(其中R2,R3和R4独立地是氢或C1-4烷氧基(例如甲氧基));R1是被卤素取代(例如一或两个氯原子)的苯基;和XY是CH2,CH2CH2,OCH2,OC(CH3)2或OCHCH3。
本发明的化合物可以按照如下所述进行制备。
其中R5是H的式(I)化合物,可以通过水解由其中R5是烷基的式(I)化合物来制备,例如用合适的氢氧化物(例如碱金属氢氧化物,例如氢氧化锂),在合适的溶剂(例如C1-6脂族醇例如甲醇)中,一般在室温下(例如10-30℃)。
其中R5是H的式(I)化合物,可以通过水解由其中R5是烷基的式(I)化合物来制备,例如用酸(例如盐酸或三氟乙酸),在合适的溶剂(例如水或二氯甲烷)中,一般在室温至回流温度下(例如10-100℃)。
其中R5是烷基的式(I)化合物,可以通过本领域熟知的方法(例如酯化)由其中R5是H的式(I)化合物形成。
其中R5是H的式(I)化合物,可以由式(II)化合物在本领域熟知的条件下通过水解来形成,
其中A、B、D、E或G中之一表示CXYCN。
式(I)或(II)的化合物,可以在碘化亚铜、脯氨酸和碱(例如碳酸钾)的存在下、在合适的溶剂(例如DMSO)中、在合适高温(例如60-100℃,例如约80℃)下,通过使式(III)的化合物与式(IV)的化合物(其中A、B、D、E、G如以上式(I)或(II)中所定义,Z是Br、I)反应来制备。
或者,式(I)化合物可以在钯盐(例如乙酸钯)、膦(例如BINAP或二环己基-(2′,4′,6′-三异丙基-联苯-2-基)膦)和碱(例如碳酸铯)的存在下、在合适的溶剂(例如甲苯)中、在合适高温(例如80-100℃)下,通过使式(III)的化合物与式(IV)的化合物(其中A、B、D、E、G如以上式(I)或(II)中所定义,Z是Br、I)反应来制备。
可对式(V)的化合物进行脱保护来制备式(III)的化合物:
例如在合适的溶剂中(比如二氯甲烷)使用三氟乙酸;或在合适的溶剂中(比如二噁烷)使用氯化氢源。
式(V)的化合物(其中Q是氢),可以通过式(VI)的化合物与式(VII)的化合物在NaBH(OAc)3和乙酸的存在下、在合适的溶剂(比如四氢呋喃或二氯甲烷)中反应来制备,
式(V)的化合物(其中Q是羟基),可以通过式(VI)的化合物与式(VIII)的化合物在合适的溶剂(比如C1-6脂族醇,例如乙醇)中及室温下反应来制备
式(I)化合物(其中A是CXYCO2R5),可以通过式(IX)的化合物与甲基甲硫基甲基亚砜(methyl methylthiomethyl sulfoxide)或乙基乙硫基甲基亚砜(ethyl ethylthiomethyl sulfoxide)在碱(例如氢化钠)的存在下、在合适的溶剂(例如THF)中、在适宜的温度下(例如在10至-20℃范围,例如0℃)反应来制备,
并且在R5OH中用HCl处理从其中得到的产物。
式(II)的化合物(其中A是CXYCN),可以在碱(例如叔丁醇钾)的存在下、在合适的溶剂(例如二甲氧基乙烷)中、在-78℃和0℃之间的温度下,通过使式(IX)的化合物与甲苯磺酰甲胩(toluenesulfonylmethyl isocyanide)反应来制备。
式(IX)的化合物可以通过式(III)的化合物与式(X)的化合物在碱(例如碳酸钾)的存在下、在合适的溶剂(比如二甲基乙酰胺)中、在80-100℃温度下反应来制备
式(I)化合物(其中XY是OCR10R11、OCR10R11CR12R13或OCR10R11CR12R13CR14R15),可以通过使式(XI)的化合物(其中A、B、D、E或G中之一表示COH),与式(XII)的化合物(其中L是卤素或磺酸酯(例如甲苯磺酸酯),n和m独立地是0或1),在碱(例如碳酸钾)的存在下、在合适的溶剂(例如DMF)中、在室温(例如10-30℃)下反应来制备。
LC(R10R11)[C(R12R13)]n[C(R14R15)]mCOOR5 (XII)
式(XI)的化合物可以通过使式(III)的化合物与式(XIII)的化合物在碘化亚铜、脯氨酸和碱(例如碳酸钾)的存在下、在合适的溶剂(例如DMSO)中、在合适的高温(例如60-100℃范围,例如约80℃)下反应来制备
其中M是溴或碘,A、B、D、E或G中之一是COH。(注释:在本发明方法的一个实施方案中,使用如下所述的保护和脱保护方法、以醚(例如甲醚)的形式保护酚)。
或者,可以在相似条件下,对于式(XIV)的化合物进行使用式(III)化合物的任何方法:
(其中该羟基例如是被保护的)。然后将得到的产物氧化为醛(例如在Swern条件下),而后在NaBH(OAc)3和乙酸的存在下、在合适的溶剂(例如四氢呋喃或二氯甲烷)中与式(VI)的化合物缩合,得到式(I)、(II)或(XI)的化合物。或者,这些步骤可以以不同的顺序进行;例如通过式(IX)的化合物进行,条件是在Swern氧化产生还原胺化的醛以前发生芳族醛的反应。
或者,其中Q表示H的式(I)化合物,可以在合适的还原剂例如三(十六烷氧基)硼氢化钠(tricetoxyborohydride)或氰基硼氢化钠和乙酸的存在下、在合适的溶剂(例如四氢呋喃或二氯甲烷)中,通过使式(XV)的化合物与式(XVI)的化合物(其中A、B、D、E G如以上式(I)或(II)所定义)反应来制备。
类似地,式(XI)的化合物可以通过使式(XV)的化合物与式(XVII)的化合物(其中A、B、D、E和G如式(XIII)中所定义)反应来制备。
式(XV)的化合物可以通过使式(XVIII)的化合物在碳酸钠的存在下、在二氯甲烷中与四乙酸铅或在水中与高碘酸钠反应来制备。
式(XVIII)的化合物,可以在N-甲基吗啉N-氧化物(NMMO)的存在下、在含水丙酮中、在环境(10-30℃)温度下,用四氧化锇将式(XIX)的化合物氧化来制备。或者式(XVIII)的化合物可以如WO2004029041中所述进行制备。
式(XIX)的化合物,可以在合适的还原剂例如三(十六烷氧基)硼氢化钠或氰基硼氢化钠和乙酸的存在下、在合适的溶剂(例如四氢呋喃或二氯甲烷)中,通过使式(VI)的化合物与式(XX)的化合物反应来制备。
可以在WO 00/66559和WO 01/77101中找到各种中间体的制备方法;或者使用或采用文献方法来制备它们。
进一步的式(I)化合物可以通过修改上面描述的路径、本领域描述的方法或下面列举的实施例来制备。
可使用或采用本领域所描述的方法来制备式(III)至(XX)的化合物。各种苯氧基哌啶的制备方法在WO 01/77101中作出了描述。
在上述方法中,可能需要或必须保护酸基或羟基或其它潜在的反应基团。合适的保护基和添加与除去这种基团的详细方法,可以在Greene和Wuts的“Protective Groups in Organic Synthesis”第三版(1999)中得到。
在另一个方面,本发明提供了式(I)化合物的制备方法。
式(I)化合物具有药物的活性,尤其可作为趋化因子受体(例如CCR3)活性的调节剂,并且可用于治疗自身免疫性疾病、炎症性、增殖性或高度增殖性疾病,或免疫介导的疾病(包括移植器官或组织的排斥以及获得性免疫缺陷综合征(AIDS))。
这些疾病的实例为:
(1)(呼吸道)气道阻塞性疾病包括:慢性阻塞性肺病(COPD)(如不可逆COPD);哮喘{如支气管、过敏性、内源性、外源性或粉尘性哮喘,特别是慢性或成癖哮喘(如迟发性哮喘或气道高反应性)};支气管炎{如嗜酸性支气管炎);急性、过敏性、萎缩性鼻炎或慢性鼻炎包括干酪性鼻炎、肥厚性鼻炎、化脓性鼻炎、干燥性鼻炎或药物性鼻炎;膜性鼻炎包括格鲁布性鼻炎、纤维蛋白性鼻炎或假膜性鼻炎或腺病性鼻炎;季节性鼻炎包括神经性鼻炎(枯草热)或血管运动性鼻炎;肉样瘤病;农夫肺以及相关疾病;鼻息肉病;纤维化肺,特发性间质性肺炎;镇咳药活性,气道炎性疾病相关的慢性咳嗽或医源性咳嗽的治疗;
(2)(骨和关节)关节炎包括风湿性关节炎、感染性关节炎、自身免疫性关节炎,血清反应阴性脊椎关节病(如强直性脊柱炎、牛皮癣性关节炎和莱特氏病),贝切特(氏)病,斯耶格伦(氏)综合征以及全身性硬化症;
(3)(由于损伤[例如运动创伤]或疾病引起的疼痛和结缔组织再造的肌骨胳病症),关节炎(例如类风湿性关节炎,骨关节炎,痛风或晶体关节病),其它关节病(例如椎间盘退化或颞下颌的关节退化),骨再造疾病(例如骨质疏松症,变形性骨炎或骨坏死),多软骨炎,硬皮病,混合结缔组织病症,脊椎关节病或牙周病(例如牙周炎);
(4)(皮肤和眼睛)牛皮癣、特应性皮炎、接触性皮炎或其他湿疹性皮炎、脂溢性皮炎、扁平苔癣、天疱疮、大疱性天疱疮、大疱性表皮松解、荨麻疹、血管性水肿、血管炎红斑、皮肤酸性细胞过多、葡萄膜炎、斑秃、角膜溃疡以及春季结膜炎;
(5)(胃肠道)腹部疾病、直肠炎、嗜酸性肠胃炎、肥大细胞病、节段性回肠炎、溃疡性结肠炎、过敏性肠疾病或具有远离肠的效应的食物相关的过敏症(例如,偏头痛、鼻炎以及湿疹);
(6)(同种异体移植物排斥)慢性和急性的下列移植,例如,肾、心脏、肝、肺、骨髓、皮肤或角膜的移植;或慢性移植物抗宿主病;和/或
(7)(其他组织和疾病)阿耳茨海默(氏)病、多发性硬化症、动脉粥样硬化、获得性免疫缺陷综合征(AIDS)、狼疮病(如红斑狼疮或全身性狼疮)、全身性红斑狼疮、桥本(氏)甲状腺炎、重症肌无力、I型糖尿病、肾病综合征、嗜酸性细胞增多筋膜炎、高IgE综合征、麻风病(如瘤型麻风)、牙周病、塞泽里综合征、先天性血小板减少紫癜或月经周期失调。
式(I)化合物或其药学可接受的盐,也是H1拮抗剂(并可因此用于变应性紊乱的治疗);并可以用来控制通常称为感冒的迹象和/或病征(例如普通感冒或流行性感冒或其它有关的呼吸病毒症感染的迹象和/或病征)。
按照本发明的进一步的特征,提供了一种在患有或处在所述疾病状态危险中的哺乳动物例如人类中治疗趋化因子介导的疾病状态(比如CCR3介导的疾病状态)的方法,包括对需要这种治疗的哺乳动物给药治疗有效量的式(I)化合物或其药学可接受的盐。
按照本发明的另一个特征,提供了一种在患有或处于H1介导疾病状态危险中的哺乳动物中拮抗H1的方法,包括对需要这种治疗的哺乳动物给药治疗有效量的式(I)化合物或其药学可接受的盐。
按照本发明的另一个特征,本发明提供了一种在患有或处于所述疾病状态危险之中的哺乳动物例如人类中用于治疗通常称为感冒的迹象和/或病征的方法,包括对需要这种治疗的哺乳动物给药治疗有效量的式(I)化合物或其药学可接受的盐。
本发明也提供了用于治疗的式(I)化合物,或其药学可接受的盐。
在另一个方面,本发明提供了式(I)化合物、或其药学可接受的盐在制备用于治疗的药剂中的用途(例如调节趋化因子受体活性(比如CCR3受体活性),拮抗H1或治疗通常称为感冒的迹象和/或病征)。
本发明进一步提供了式(I)化合物、或其药学可接受的盐在制备用于治疗哺乳动物(例如人类)的下列疾病的药物中的用途:
(1)(呼吸道)气道阻塞性疾病包括:慢性阻塞性肺病(COPD)(如不可逆COPD);哮喘{如支气管、过敏性、内源性、外源性或粉尘性哮喘,特别是慢性或成癖哮喘(如迟发性哮喘或气道高反应性)};支气管炎{如嗜酸性支气管炎);急性、过敏性、萎缩性鼻炎或慢性鼻炎包括干酪性鼻炎、肥厚性鼻炎、化脓性鼻炎、干燥性鼻炎或药物性鼻炎;膜性鼻炎包括格鲁布性鼻炎、纤维蛋白性鼻炎或假膜性鼻炎或腺病性鼻炎;季节性鼻炎包括神经性鼻炎(枯草热)或血管运动性鼻炎;肉样瘤病;农夫肺以及相关疾病;鼻息肉病;纤维化肺,特发性间质性肺炎;镇咳药活性,气道炎性疾病相关的慢性咳嗽或医源性咳嗽的治疗;
(2)(骨和关节)关节炎包括风湿性关节炎、感染性关节炎、自身免疫性关节炎,血清反应阴性脊椎关节病(如强直性脊柱炎、牛皮癣性关节炎和莱特氏病),贝切特(氏)病,斯耶格伦(氏)综合征以及全身性硬化症;
(3)(由于损伤[例如运动创伤]或疾病引起的疼痛和结缔组织再造的肌骨胳病症),关节炎(例如类风湿性关节炎,骨关节炎,痛风或晶体关节病),其它关节病(例如椎间盘退化或颞下颌的关节退化),骨再造疾病(例如骨质疏松症,变形性骨炎或骨坏死),多软骨炎,硬皮病,混合结缔组织病症,脊椎关节病或牙周病(例如牙周炎);
(4)(皮肤和眼睛)牛皮癣、特应性皮炎、接触性皮炎或其他湿疹性皮炎、脂溢性皮炎、扁平苔癣、天疱疮、大疱性天疱疮、大疱性表皮松解、荨麻疹、血管性水肿、血管炎红斑、皮肤酸性细胞过多、葡萄膜炎、斑秃、角膜溃疡以及春季结膜炎;
(5)(胃肠道)腹部疾病、直肠炎、嗜酸性肠胃炎、肥大细胞病、节段性回肠炎、溃疡性结肠炎、过敏性肠疾病或具有远离肠的效应的食物相关的过敏症(例如,偏头痛、鼻炎以及湿疹);
(6)(同种异体移植物排斥)慢性和急性的下列移植,例如,肾、心脏、肝、肺、骨髓、皮肤或角膜的移植;或慢性移植物抗宿主病;和/或
(7)(其他组织和疾病)阿耳茨海默(氏)病、多发性硬化症、动脉粥样硬化、获得性免疫缺陷综合征(AIDS)、狼疮病(如红斑狼疮或全身性狼疮)、全身性红斑狼疮、桥本(氏)甲状腺炎、重症肌无力、I型糖尿病、肾病综合征、嗜酸性细胞增多筋膜炎、高IgE综合征、麻风病(如瘤型麻风)、牙周病、塞泽里综合征、先天性血小板减少紫癜或月经周期失调。
另一方面,本发明提供了式(I)化合物或其可药用盐,可用于治疗哮喘{如支气管、过敏性、内源性、外源性或粉尘性哮喘,特别是慢性或成癖哮喘(如迟发性哮喘或气道高反应性)};或鼻炎{包括急性、过敏性、萎缩性或慢性鼻炎,如干酪性鼻炎、肥厚性鼻炎、化脓性鼻炎、干燥性鼻炎或药物性鼻炎;膜性鼻炎包括格鲁布性鼻炎、纤维蛋白性鼻炎或假膜性鼻炎或腺病性鼻炎;季节性鼻炎包括神经性鼻炎(枯草热)或血管运动性鼻炎}。
在更进一步的方面,式(I)化合物,或其药学可接受的盐,可有效用于治疗哮喘。
本发明还提供了式(I)化合物、或其药学可接受的盐在制备用于治疗下列疾病的药剂中的用途:哮喘{如支气管、过敏性、内源性、外源性或粉尘性哮喘,特别是慢性或成癖哮喘(如迟发性哮喘或气道高反应性)};或鼻炎{包括急性、过敏性、萎缩性或慢性鼻炎,如干酪性鼻炎、肥厚性鼻炎、化脓性鼻炎、干燥性鼻炎或药物性鼻炎;膜性鼻炎包括格鲁布性鼻炎、纤维蛋白性鼻炎或假膜性鼻炎或腺病性鼻炎;季节性鼻炎包括神经性鼻炎(枯草热)或血管运动性鼻炎}。
为了使用本发明的化合物或其药学可接受的盐治疗哺乳动物比如人类,通常将所述组分按照标准药物实际应用配制为药物组合物。因此在另一个方面,本发明提供了药物组合物,包括式(I)化合物、或其药学可接受的盐(活性组分)和药学可接受的助剂、稀释剂或载体。
在进一步的方面,本发明提供了所述组合物的制备方法,包括将活性组分与药学可接受的助剂、稀释剂或载体的混合。根据给药方式,药物组合物包含例如0.05至99%w(重量百分率),比如0.05至80%w,例如0.10至70%w,比如0.10至50%w的活性组分,所有的重量百分率以全部组合物为基准。
本发明的药物组合物可以以标准方式对需要治疗的疾病病症进行给药,例如通过局部(比如给药至肺和/或气道或至皮肤),口服,直肠或肠胃外给药。为了达到上述目的,通过本领域已知的方法将本发明的化合物进行配制。本发明的合适的药物组合物是适于口服的单位剂型,例如含有0.1毫克-1g活性组分的片剂或胶囊。
每个患者可以接受,例如,0.01mgkg-1至100mgkg-1的剂量,比如在0.1mgkg-1至20mgkg-1范围内的剂量给药的活性组分,例如,1至4次每日。
本发明进一步涉及组合治疗,其中式(I)化合物或其药学可接受的盐、溶剂化物或体内可水解的酯或包括式(I)化合物的药物组合物或制剂,可以同时或顺序给予,或以与另一种治疗剂或药剂的组合制剂形式给予,用于治疗所列举的一或多种病症。
尤其用于该治疗炎症性的疾病例如(但不局限于):类风湿性关节炎,骨关节炎,哮喘,过敏性鼻炎,慢性阻塞性肺病(慢性阻塞性肺病),牛皮癣,和炎症性肠病,本发明的化合物可以与例如下列药剂组合:-非甾族的消炎药(下文的NSAIDs),包括非选择性的环加氧酶COX-1/COX-2抑制剂,不论局部或系统施用(例如吡罗昔康,双氯芬酸,丙酸酸例如萘普生,氟比洛芬,非诺洛芬,酮洛芬和布洛芬,芬那酸例如扑湿痛,消炎痛(Indomethacin),舒林酸,阿扎丙酮,吡唑啉酮例如苯基保泰松,水杨酸盐例如阿斯匹林);选择性COX-2抑制剂(例如美洛昔康,西乐葆,罗非考昔,伐地考昔,lumarocoxib,帕瑞考营和默沙东);环加氧酶抑制一氧化氮供体(CINODs);糖皮质类固醇(不论通过局部、口服、肌肉内、静脉内或关节内的路径给药);氨甲喋呤,来氟米特;羟氯奎,d-青霉胺,金诺芬或其它肠胃外的或口服的黄金制剂;镇痛药;双醋瑞因;关节内的治疗例如透明质酸衍生物;和营养增补剂例如葡糖胺。
本发明更进一步涉及本发明的化合物与细胞因子或细胞因子功能的激动剂或拮抗剂一起联用,(包括作用于细胞因子信号路径例如SOCS系统的调节剂的药剂)包括α-、β-和γ-干扰素;胰岛素类生长因子I型(IGF-1);白介素(IL)包括IL1至17,和白介素拮抗剂或抑制剂例如阿那白滞素;肿瘤坏死因子α(TNF-α)抑制剂例如抗肿瘤坏死因子单克隆抗体(例如英夫利昔单抗(infliximab);阿达木单抗(adalimumab),和CDP-870)和TNF受体拮抗剂包括免疫球蛋白分子(例如依那西普)和低分子量药剂例如配妥西菲林(pentoxyfylline)。
本发明更进一步涉及本发明的化合物与趋化因子受体功能调节剂例如下列的拮抗剂一起联用:CCR1,CCR2,CCR2A,CCR2B,CCR4,CCR5,CCR6,CCR7,CCR8,CCR9,CCR10和CCR11(C-C家族);CXCR1,CXCR2,CXCR3,CXCR4和CXCR5(C-X-C家族)和C-X3-C家族的CX3CR1。
本发明更进一步涉及本发明化合物与下列抑制剂的一起联用:基质金属蛋白酶抑制剂,即溶基质蛋白酶(stromelysins)、胶原酶和明胶酶以及蛋白聚糖酶(aggrecanase)的抑制剂;例如胶原酶-1(MMP-),胶原酶-2(MMP-8),胶原酶-3(MMP-13),溶基质蛋白酶-1(MMP-3),溶基质蛋白酶-2(MMP-10)和溶基质蛋白酶-3(MMP-11)和MMP-9和MMP-12,包括药剂例如强力霉素。
本发明更进一步涉及本发明的化合物与下列的一起联用:白细胞三烯生物合成抑制剂,5-脂肪氧合酶(5-LO)抑制剂或5-脂肪氧合酶活化蛋白(FLAP)拮抗剂例如;弃留通;ABT-761;芬留顿;替泊沙林;Abbott-79175;Abbott-85761;N-(5-取代的)-噻吩-2-烷基磺酰胺;2,6-二-叔丁基酚腙;甲氧基四氢吡喃例如Zeneca ZD-2138;化合物SB-210661;吡啶基-取代的2-氰基萘化合物例如L-739,010;2-氰基喹啉化合物例如L-746,530;吲哚和喹啉化合物例如MK-591,MK-886,和B AYx1005。
本发明更进一步涉及本发明化合物与选自下列的白细胞三烯(LT)B4、LTC4、LTD4、和LTE4的受体拮抗剂一起联用:吩噻嗪-3-酮例如L-651,392;脒基化合物例如CGS-25019c;苯并噁胺(benzoxalamine)例如昂唑司特;苯甲酰亚胺酰胺(benzenecarboximidamides)例如BIIL 284/260;化合物例如扎鲁司特、阿鲁司特、孟鲁司特、普仑司特、维鲁司特(MK-679)、RG-12525、Ro-245913、伊拉司特(CGP 45715A)和B AYx7195。
本发明更进一步涉及本发明化合物与下列的一起联用:磷酸二酯酶(PDE)抑制剂例如甲基黄嘌呤(methylxanthanines)包括茶碱和氨茶碱;和选择性的PDE同功酶抑制剂,包括PDE4抑制剂和异构型PDE4D的抑制剂,和PDE5的抑制剂。
本发明更进一步涉及本发明化合物与下列的一起联用:组胺类型1受体拮抗剂,例如西替立嗪,氯雷他定,地氯雷他定,非索非那定,阿伐斯丁,特非那定,阿司咪唑,氮卓斯汀,左卡巴斯汀,扑尔敏,普鲁米近,赛克力嗪(cyclizine),和咪唑斯汀,口服、局部或胃肠外施用。
本发明更进一步涉及本发明化合物与质子泵抑制剂(例如奥美拉唑)或胃保护组胺II型受体拮抗剂一起联用。
本发明更进一步涉及本发明的化合物与组胺类型4受体的拮抗剂的拮抗剂一起联用:
本发明更进一步涉及与下列一起联用:α-1/α-2肾上腺素受体肾上腺素受体激动剂,血管收缩剂,拟交感神经药剂,例如丙己君(propylhexedrine),苯肾上腺素,苯丙醇胺,麻黄碱,假麻黄碱,盐酸萘甲唑啉,盐酸氧甲唑啉,盐酸四氢唑啉,盐酸木甲唑啉,盐酸曲马唑啉和盐酸乙基去甲肾上腺素。
本发明更进一步涉及与下列一起联用:抗胆碱能药剂,包括胆碱受体(M1,M2和M3)拮抗剂,例如阿托品,东莨菪碱(hyoscine),甘油吡咯酸酯(glycopyrrrolate),异丙托溴胺,噻托溴铵,氧托溴铵,哌仑西平,和替仑西平。
本发明更进一步涉及本发明化合物与下列一起联用:β-肾上腺素受体肾上腺素受体激动剂(包括β受体亚型1-4)例如异丙肾上腺素,柳丁氨醇(salbutamol),福莫特罗,沙美特罗,特布他林(terbutaline),间羟异丙肾上腺素,双甲苯喘定甲磺酸盐,和比布特罗,包括其手性对映体。
本发明更进一步涉及本发明的化合物与色酮包括色甘酸二钠和萘多罗米钠一起联用。
本发明更进一步涉及该本发明的化合物与下列一起联用:糖皮质激素,例如氟尼缩松,曲安奈德,二丙酸氯地米松,布地奈德,丙酸氟替卡松,环索奈德,和糠酸莫美松。
本发明更进一步涉及本发明的化合物与调节核激素受体例如PPARs的药剂一起联用。
本发明更进一步涉及本发明的化合物与下列一起联用:免疫球蛋白(Ig)或Ig制剂或拮抗剂或抗体调节Ig功能例如抗IgE(例如奥马珠单抗)。
本发明更进一步涉及本发明的化合物与其它系统的或局部施用的消炎药包括沙利度胺(thalidomide)和衍生物、类视黄醇、地蒽酚(dithranol)和卡泊三醇(calcipotriol)一起联用。
本发明更进一步涉及本发明的化合物与下列一起联用:氨基水杨酸盐和磺胺吡啶例如柳氮磺吡啶,美沙拉嗪,巴柳氮,和奥沙拉秦;和免疫调节药剂例如硫代嘌呤(thiopurines),和皮质甾类例如布地奈德。
本发明更进一步涉及本发明的化合物与下列一起联用:抗菌剂,包括青霉素衍生物,四环素,大环内酯,β-内酰胺,氟喹诺酮,甲硝哒唑,和吸入氨基糖苷类;和抗病毒药,包括无环鸟苷,泛昔洛韦,伐昔洛韦,更昔洛韦,西多福韦;金刚烷胺,金刚乙胺;病毒唑;扎那米韦(zanamavir)和特敏服(oseltamavir);蛋白酶抑制剂,例如茚地那韦,奈非那韦,利托那韦,和沙奎那维;核苷逆转录酶抑制剂,例如去羟肌苷,拉夫米定,司他夫定(stavudine),扎西他滨,叠氮胸苷;非核苷逆转录酶抑制剂,例如奈韦拉平(nevirapine),依法韦仑(efavirenz)。
本发明更进一步涉及本发明的化合物与下列一起联用:心血管药剂,例如钙通道阻断剂,β-肾上腺素受体阻断剂,血管紧张素-转化酶(ACE)抑制剂,血管紧张素-2受体拮抗剂;脂类降低药剂,例如抑制素,和贝特类(fibrates);血细胞形态调节剂,例如配妥西菲林;溶栓剂,和抗凝血剂,包括血小板聚集抑制剂。
本发明更进一步涉及本发明的化合物与下列一起联用:CNS药剂,例如抗抑郁药(例如舍曲林),抗帕金森氏病的药物(例如丙炔苯丙胺,左旋多巴,罗匹尼罗,普拉克索,MAOB抑制剂例如selegine和雷沙吉兰,comP抑制剂例如托卡朋(tasmar),A-2抑制剂,多巴胺再摄取抑制剂,NMDA拮抗剂,烟碱激动剂,多巴胺激动剂和神经元一氧化氮合酶的抑制剂(inhibitorsof neuronal nitric oxide synthase)),和抗阿尔茨海默药物例如多奈哌齐(donepezil),利凡斯的明,他克林,COX-2抑制剂,丙戊茶碱或美曲膦酯。
本发明更进一步涉及与治疗急性和慢性疼痛的药剂一起联用,包括中枢和外周作用止痛剂,例如阿片样物质类似物和衍生物,酰胺咪嗪,苯妥英,丙戊酸钠,阿米替林(amitryptiline)及其它抗抑郁药,扑热息痛和非甾族消炎药。
本发明更进一步涉及本发明的化合物与胃肠外或局部施用(包括吸入)的局部麻醉剂例如利诺卡因(lignocaine)和类似物一起联用。
本发明的化合物也可以与抗骨质疏松症药剂包括激素药剂例如雷诺昔芬和双膦酸盐(biphosphonate)例如阿伦膦酸盐(alendronate)的组合中使用。
本发明更进一步涉及本发明的化合物与下列一起联用:(i)类胰蛋白酶抑制剂;(ii)血小板活化因子(PAF)拮抗剂;(iii)白介素转换酶(ICE)抑制剂;(iv)IMPDH抑制剂;(v)粘附分子抑制剂包括VLA-4拮抗剂;(vi)组织蛋白酶;(vii)激酶抑制剂,包括但不局限于酪氨酸激酶抑制剂(例如Btk,Itk,Jak3MAP,抑制剂的例子可以包括吉非替尼(Gefitinib),伊马替尼甲磺酸盐),丝氨酸/苏氨酸激酶抑制剂(包括但不局限于MAP激酶例如p38、JNK、蛋白激酶A、B和C和IKK的抑制剂),和涉及细胞周期调节的激酶(例如但不局限于细胞周期蛋白依赖激酶)抑制剂;(viii)葡萄糖-6磷酸脱氢酶抑制剂;(ix)细胞分裂素-B1-和B2-受体拮抗体;(x)抗痛风试剂,例如,秋水仙碱;(xi)黄嘌呤氧化酶抑制剂,例如,别嘌呤醇;(xii)排尿酸剂,例如丙磺舒或磺砒酮,和苯溴马隆;(xiii)生长激素促分泌剂;(xiv)转化生长因子(TGF);(xv)血小板衍生生长因子(PDGF);(xvi)成纤维细胞生长因子,例如基本成纤维细胞生长因子(bFGF);(xvii)粒细胞巨噬细胞集落刺激因子(GM-CSF);(xviii)辣椒素油(capsaicin cream);(xix)速激肽NK1和NK3受体拮抗剂,例如选自NKP-608C、SB-233412(他奈坦)、和D-4418;(xx)弹性蛋白酶抑制剂,选自UT-77和ZD-0892;(xxi)TNFα转化酶抑制剂(TACE);(xxii)诱导的一氧化氮合酶抑制剂(iNOS)或(xxiii)TH2细胞上表达的化学引诱物受体同源分子(CRTH2拮抗剂);(xxiv)P38的抑制剂(xxv)调节Toll类受体(TLR)功能的药剂,和(xxvi)调节嘌呤能受体例如P2X7活性的药剂;(xxvii)转录因子活化例如NFkB、API和STATS的抑制剂,。
本发明的化合物还可以在与治疗癌症的现有治疗剂的组合中使用。在组合中使用的合适药剂包括:
(i)如用于医学肿瘤学的抗增殖/抗肿瘤药及其组合,例如烷化剂(如顺铂、碳铂、环磷酰胺、氮芥、美法仓、苯丁酸氮芥、白消安和亚硝基脲);抗代谢物(例如抗叶酸剂,如氟嘧啶如5-氟尿嘧啶和替加氟、雷替曲塞、甲氨喋呤、阿糖胞苷、羟基脲、吉西他滨和紫杉醇;抗肿瘤抗生素(例如蒽环类抗生素,如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素-C、更生霉素和光辉霉素);抗有丝分裂剂(例如长春花生物碱类,如长春新碱、长春碱、长春地辛和长春瑞滨,以及紫杉烷类,如紫杉醇和多西紫杉醇);和拓扑异构酶抑制剂(例如表鬼臼毒素类,如依托泊苷和替尼泊苷、安沙可林、托泊替康和喜树碱类);
(ii)细胞生长抑制剂如抗雌激素药(例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬和iodoxyfene)、雌激素受体下调药(如氟维司群)、抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特和醋酸环丙氯地孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕激素类(如醋酸甲地孕酮)、芳香酶抑制剂(例如阿纳托唑、来曲唑、vorazole和依西美坦)和5α-还原酶抑制剂如非那司提;
(iii)抑制癌细胞入侵的药物(例如金属蛋白酶抑制剂如马立马司他和尿激酶纤维蛋白溶酶原激活剂受体功能的抑制剂);
(iv)生长因子功能抑制剂,例如诸如下述的抑制剂,包括生长因子抗体、生长因子受体抗体(例如抗-erbb2抗体曲妥单抗和抗-erbb1抗体西妥昔单抗[C225])、法尼基转移酶抑制剂、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂,例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,如
N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉基丙氧基)喹唑啉-4-胺(吉非替尼,AZD 1839)、
N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺(erlotinib,OSI-774)和6-丙烯酰基氨基-
N-(3-氯-4-氟苯基)-7-(3-吗啉基丙氧基)喹唑啉-4-胺(CI 1033)),例如血小板衍生的生长因子家族的抑制剂和例如肝细胞生长因子家族的抑制剂;
(v)抗血管生成剂,例如那些抑制血管内皮生长因子作用的药物,(例如抗-血管内皮生长因子抗体贝伐单抗,例如在国际专利申请WO 97/22596、WO 97/30035、WO 97/32856和WO 98/13354中公开的那些化合物)和以其它机制起作用的化合物(例如利诺胺、整联蛋白αvβ3功能的抑制剂和血管他丁);
(vi)脉管损坏剂如考布他汀A4和国际专利申请WO 99/02166、WO00/40529、WO 00/41669、WO 01/92224、WO 02/04434和WO 02/08213中公开的化合物;
(vii)反义治疗剂,例如定向于上面列出靶点的那些物质如ISIS 2503、抗-ras反义物;
(viii)基因治疗方法,包括例如替换异常基因如异常p53或异常BRCA1或BRCA2的方法、GDEPT(基因定向的酶前药治疗)方法例如那些使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的方法和增加病人对化学治疗或放射治疗耐受性的方法例如多元抗药性基因治疗;和
(ix)免疫治疗方法,包括例如在体外和体内增加病人肿瘤细胞免疫原性的方法,如用细胞因子如白介素2、白介素4或粒细胞巨噬细胞集落刺激因子转染、减少T-细胞无反应性的方法、使用转染的免疫细胞如转染了细胞因子的树突细胞的方法、使用转染了细胞因子的肿瘤细胞系的方法和使用抗独特型抗体的方法。
本发明将由下列非限制的实施例举例说明,其中,除非另有说明:
(i)当得到时,引用1H NMR数据,并且以主要特征质子的δ值形式,以相对于作为内标的四甲基硅烷(TMS)的百万分之一(ppm)的形式表示,使用全氘DMSO-D6(CD3SOCD3)或CDCl3作为溶剂,在300MHz或400MHz测定,除非另有说明;
(ii)使用直接暴露的探针以化学电离(CI)的方式用70电子伏特的电子能量运行质谱(MS);其中所表示的电离是通过电子轰击(EI)或快原子轰击(FAB)实现的;如果给出m/z值,通常只报道表示母体质量的离子,且除非另有说明,引用的质量离子是带正电质量离子-(M+H)+;
(iii)实施例和方法的标题和副标题化合物是使用Advanced ChemistryDevelopment Inc,6.00版本的ACD/名称程序命名的;
(iv)除非另有说明,反相HPLC是使用反相SymmetryTM、NovaPakTM或XerraTM反相硅胶柱进行的;
(v)对于分析HPLC,使用下面的条件:
反相分析HPLC(Hewlett Packard Series 1100),使用Waters“对称”C8柱,3.5m;4.6×50mm柱,使用0.1%乙酸铵/乙腈梯度,2mL/min,以%含水形式给予
标准75%至5%,3分钟
快速45%至5%,2.5分钟
中等快速65%至5%,2.5分钟
慢速95%至50%,2.5分钟
非常慢速100%至80%,2.5分钟;
以水溶液/起始%aq/最终%aq/有机/时间(分钟)的形式记录其它梯度,其中NH4表示0.1%乙酸铵,A表示乙腈;
和
(vi)使用下面的缩写:
RPHPLC | 反相HPLC | DMSO | 二甲亚砜 |
HPLC | 高压液相色谱法 | aq | 水溶液 |
TFA | 三氟乙酸 | RT | 室温 |
DMF | N,N-二甲基甲酰胺 | TBME | 叔丁基甲醚 |
Ret | 保留时间 |
中间体1
这说明了4-(3,4-二氯-2-乙基苯氧基)哌啶的制备
a)1,2-二氯-3-乙基-4-氟苯
将1,2-二氯-4-氟苯(1.3毫升)溶于THF(10毫升)中,并将得到的溶液冷却至-78℃。历时5分钟逐滴加入正丁基锂(10m,1.2毫升)。将得到的溶液在-78℃搅拌5分钟,然后升温至大约-40℃,并在此温度下保持15分钟。将冷却至-78℃,而后加入碘乙烷(1.24mL)。将得到的溶液升温至10℃。加入pH7缓冲液,而后加入乙酸乙酯和乙醚。分离各相,用乙醚提取水相两次。合并有机物,用盐水洗涤,干燥,过滤并浓缩,得到标题化合物,其被乙醚和乙酸乙酯污染。(2.37g)。
GCMS 97.75%保留时间4.61min(M+(EI)192/194/196;bp 177)(Agilent6890/5973 GC/MSD HP5-MS柱,30m×0.25mm,膜厚0.25μm,90-310℃,30℃/分钟)。
1H NMRδ(CDCl3)1.18(3H,t),2.84(2H,qd),6.92(1H,t),7.27(1H,dd)。
b)4-(3,4-二氯-2-乙基苯氧基)哌啶
将1,2-二氯-3-乙基-4-氟-苯(2.37克)、4-羟基哌啶(1.24克)和叔丁醇钾(1.47克)加入到烧瓶中。加入1-甲基-2-吡咯烷酮(12毫升),搅拌混合物、并加热到65℃,保持6小时。
加入2M HCl aq,并将混合物用乙酸乙酯提取两次。将水相用碳酸钠水溶液中和,用乙酸乙酯提取三次,干燥,过滤并浓缩。
将残余物溶于醚中,用氢氧化钠溶液(2M)、水(三次)和盐水洗涤。将有机相干燥,过滤并蒸发,得到标题化合物(1.22g)黄色油。
LCMS(标准梯度)RT 1.91(ES+274/276/278)。
1H NMRδ(CDCL3)1.10(3H,t),2.01-2.10(2H,m),2.20-2.29(2H,m),2.39(3H,s),2.81(2H,q),3.28-3.38(4H,m),4.53-4.58(1H,m),6.62(1H,d),7.20-7.25(3H,m),7.77(2H,d),8.84-8.95(1H,m),9.01-9.12(1H,m)
中间体2
此实施例说明了4-(3,4-二氯苯氧基)-1-(4-哌啶基甲基)-哌啶的制备
a)1,1-二甲基乙基4-[[4-(3,4-二氯苯氧基)-1-哌啶基]甲基]-1-哌啶羧酸酯
将4-(3,4-二氯苯氧基)哌啶(1.27克)溶于四氢呋喃(20毫升)中;将乙酸(0.5毫升)和4-甲酰哌啶-1-羧酸叔丁基酯(1.43克)加入到该溶液中。将反应混合物在室温下搅拌30分钟,然后加入三乙酰氧基硼氢化钠(1.53克),混合物在室温下搅拌过夜。将反应混合物倾倒在2M氢氧化钠溶液(50mL)中,用乙醚提取产物。将合并的乙醚提取物用盐水洗涤,干燥,过滤并蒸发。将粗品用快速色谱法纯化,(用979∶20∶1的二氯甲烷∶甲醇∶氨水洗脱),得到副标题化合物(2.15g)。
MS 443/445[M+H]+(ES+)。
1H NMRδ(CDCl3)1.06(2H,ddd),1.45(9H,s),1.61-1.82(5H,m),1.92-1.98(2H,m),2.1 6-2.27(4H,m),2.65-2.73(4H,m),4.08(2H,d),4.25(1H,dq),6.75(1H,dd),6.99(1H,d),7.30(1H,d)。
b)4-(3,4-二氯苯氧基)-1-(4-哌啶基甲基)-哌啶
将1,1-二甲基乙基4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基)}哌啶-1-羧酸酯(1.0克)加入到20%三氟乙酸的二氯甲烷(20毫升)混合物中,并将该混合物在室温下搅拌1小时。通过蒸发除去溶剂,将2M氢氧化钠溶液(25毫升)加入到残余物中。将产物用乙酸乙酯提取,用盐水洗涤有机相,干燥,过滤并蒸发,得到标题化合物(0.5g)。
MS 343/345[M+H]+(ES+).
1H NMRδ(CDCl3)1.10(2H,qd),1.60(1H,qquintet),1.73-1.83(4H,m),1.90-2.01(2H,m),2.16-2.26(4H,m),2.55-2.70(4H,m),3.09(2H,d),4.24(1H,dquintet),6.75(1H,dd),6.99(1H,d),7.27(1H,d).
下列中间体是由合适的芳氧基哌啶类似制备的:
中间体 | 名称(M+H) | 1H NMRδ(CDCl3) |
3 | 4-(2,4-二氯-3-甲基苯氧基)-1-(4-哌啶基甲基)-哌啶(357/359) | 1.13-1.27(2H,m),1.57-1.70(1H,m),1.76-2.00(2H,m),2.16-2.32(4H,m),2.46(3H,s),2.60-2.99(8H,m),3.16(2H,d),4.31(1H,五重 |
峰),6.75(1H,d),7.18(1H,d) | ||
4 | 4-(4-氯-2-甲基苯氧基)-1-(4-哌啶基甲基)-哌啶(322/324) | 1.08-1.21(2H,m),1.56-1.68(1H,m),1.73-1.86(4H,m),1.90-1.99(2H,m),2.16-2.31(7H,m),2.57-2.69(4H,m),3.12(2H,d),4.23-4.31(1H,m),6.74(1H,d),7.06(1H,dd),7.11(1H,d) |
中间体5
此实施例说明了2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯酚的制备
4-(3,4-二氯苯氧基)-1-{[1-(2-甲氧基苯基)哌啶-4-基]甲基}哌啶
将4-(3,4-二氯苯氧基)-1-(哌啶-4-基甲基)哌啶(1.0克)、1-碘代-2-甲氧基苯(0.68克)、碘化亚铜(55毫克)、L-脯氨酸(66毫克)和K2CO3(0.8克)悬浮在DMSO中,并加热到80℃,保持16小时。将混合物用水稀释,而后使用EtOAc提取(3×100mL)。将有机层合并,用盐水洗涤,干燥,蒸发溶剂。将残余物通过色谱(EtOAc)纯化,得到副标题化合物(0.20克)。
HPLC保留时间标准2.9。
MS(ES+ve)449/451(M+H)+。
2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基)甲基}哌啶-1-基)苯酚
将4-(3,4-二氯苯氧基)-1-{[1-(2-甲氧基苯基)哌啶-4-基]甲基}哌啶(0.15克)溶于二氯甲烷(2毫升)中,并将该溶液在冰浴(干冰/乙腈)中冷却至-30℃。加入三溴甲硼烷(1M二氯甲烷溶液,2.6毫升)。历时4小时使反应混合物升温至0℃。小心地加入甲醇(2毫升),同时使反应混合物保持0℃。蒸发溶剂,并将残余物溶于MeOH中,而后通过RPHPLC纯化(梯度75%-5%乙酸铵水溶液,25%-95%乙腈),得到副标题化合物(100毫克)。
HPLC保留时间快速2.02
MS(ES+ve)435/437(M+H)+
使用合适的碘苯酚、以类似于中间体5的方式制备下面的中间体:
中间体 | 名称 | MS(ES+ve)(M+H)+ | 保留时间梯度 |
6 | 2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基] | 435/437 | 2.75标准 |
甲基}哌啶-1-基)苯酚 |
中间体7
此实施例说明了2-氯-4-({1-[(3,4-二羟基环戊基)-甲基]哌啶-4-基}氧基)-3-甲基苄腈的制备
a)2-氯-4-{[1-(环戊-3-烯-1-基甲基)哌啶-4-基]氧基}-3-甲基苄腈
在氮气氛围下,将2-氯-3-甲基-4-(哌啶-4-基氧基)苄腈(1.3克)(WO2004099144)、乙酸(0.32毫升)、三乙酰氧基硼氢化钠(1.4克)和四氢呋喃(20毫升)合并并搅拌。加入环戊-3-烯-1-甲醛(0.5克),并继续搅拌1小时。将反应混合物减压浓缩,并将残余物分配在碳酸氢钠饱和水溶液和二氯甲烷之间。用盐水洗涤二氯甲烷,干燥(MgSO4),过滤并减压浓缩。将粗产品通过快速色谱法纯化,得到副标题化合物无色油(1.5克)。
1H NMRδ(CDCL3)1.78-1.90(2H,m),1.93-2.14(4H,m),2.28-2.39(7H,m),2.41-2.53(3H,m),2.63-2.72(2H,m),4.38-4.48(1H,m),5.64(2H,s),6.79(1H,d),7.46(1H,d);MS:331/333[M+H]+;保留时间:2.66分钟,标准梯度。
b)2-氯-4-({1-[(3,4-二羟基环戊基)甲基]哌啶-4-基}氧基)-3-甲基苄腈
将2-氯-4-{[1-(环戊-3-烯-1-基甲基)哌啶-4-基]氧基}-3-甲基苄腈(1.5克)、锇酸钾二水合物(0~042克)和N-甲基吗啉-N-氧化物(50%水溶液,3.2毫升)在丙酮(40毫升)和水(5毫升)的混合物中搅拌,然后回流加热1小时。使反应混合物冷却到室温,加入焦亚硫酸钠的饱和水溶液。用二氯甲烷提取产物。通过加入碳酸氢钠的饱和水溶液将含水馏份碱化,将其也用二氯甲烷提取。将二氯甲烷馏份合并,减压浓缩。使用SCX树脂纯化粗品。用甲醇和二氯甲烷的1∶1混合物将非碱性的杂质从柱中洗掉,然后用10%氨水/甲醇洗脱产物。减压除去溶剂,得到副标题化合物(1.3g)固体。
1H NMRδ(CDCL3)1.42-1.64(2H,m),1.78-2.14(4H,m),2.23-2.47(9H,m),2.51-2.86(4H,m),3.72(1H,t),3.92-4.18(2H,m),4.38-4.50(1H,m),6.78(1H,d),7.46(1H,d);MS:365/367[M+H]+;保留时间:1.53分钟,标准梯度。
中间体8
此实施例说明了4-[4-(3,4-二氯-苯氧基)-哌啶-1-基甲基]-环戊烷-1,2二醇的制备,其是按照WO2004029041的方法、使用4-(3,4-二氯-2-乙基苯氧基)哌啶制备的。
MS 360/362 ES+
保留时间,标准,1.95
中间体9
此实施例说明了(2R)-2-(3-硝基苯氧基)丙酸甲酯的制备
将3-硝基苯酚(3.7克)、三苯基膦(7.7克)和(2S)-2-羟基丙酸甲酯(2.5毫升)加入到四氢呋喃(30毫升)中,和并在室温下搅拌该混合物,直至形成溶液。将反应混合物是冷却至0℃,加入二异丙基偶氮二羧酸酯(5.8毫升)。0.5小时之后,使反应混合物达到室温,并在氮气氛围下继续搅拌过夜。减压浓缩反应混合物,并将得到的黄色油在乙醚和异己烷的1∶1混合物中搅拌。沉淀出白色固体三苯基氧膦,过滤除去。将滤液减压浓缩,通过快速色谱法纯化粗品残余物,用10%乙酸乙酯/异己烷洗脱。由此得到标题化合物固体(5.7克)。
1H NMRδ(CDCL3)1.67(3H,dd),3.79(3H,d),4.86(1H,q),7.21(1H,dd),7.44(1H,td),7.70(1H,t),7.84-7.87(1H,m);保留时间:1.92分钟,标准梯度。
中间体10
此实施例说明了(2R)-2-(3-硝基苯氧基)丙酸甲酯的制备
将(2R)-2-(3-硝基苯氧基)丙酸甲酯(2.5克)溶于乙醇(25毫升)中,加入铁粉(3.1克)。将氯化铵(3克)溶于最低量的合适水中,并将该溶液加入到反应混合物中。在回流下加热混合物,过夜,然后冷却至室温。过滤除去固体物质,并将滤液减压浓缩。使用SCX树脂纯化粗品。用甲醇将非碱性杂质从柱中洗掉,然后用10%氨水/甲醇洗脱产物。减压除去溶剂,得到浅棕色油(1.58g),通过LC/MS显示其是所需要的甲酯和一些乙酯的混合物。
1H NMRδ(CDCL3)甲酯1.59(3H,dd),3.48(2H,s),3.78(3H,s),4.68-4.76(1H,m),6.22-6.34(3H,m),7.03(1H,t);MS甲酯:196[M+H]+。
保留时间:1.25分钟,标准梯度(甲酯);1.53分钟,标准梯度(乙酯)
中间体11
此实施例说明了(4-氯-2-硝基-苯氧基)-乙酸叔丁基酯的制备
向4-氯-2-硝基苯酚(2克)的DMF(10毫升)溶液中加入碳酸钾(1.59克)和溴乙酸叔丁基酯(2.25克)。将混合物加热至70℃。1小时之后,将反应物分配在醚和水之间,用盐水洗涤有机物,用硫酸钠干燥,真空浓缩,得到标题化合物金色油(3.1克)。
1H NMRδ(DMSO)8.04(d,1H),7.71(dd,1H),7.31(d,1H),4.92(s,2H),1.40(s,9H)。
中间体12
此实施例说明了2-氨基-4-氯-苯氧基)-乙酸叔丁基酯的制备
在3 Bar氢气压力下,将(4-氯-2-硝基-苯氧基)-乙酸叔丁基酯(1.9克)溶液在含有5%铂/碳(0.2克)的乙醇(20毫升)中搅拌3小时。过滤溶液,真空浓缩,得到标题化合物(1.4g)澄清油。
1H NMRδ(DMSO)6.68(d,1H),6.67(d,2H),6.48(dd,1H),4.60(s,2H),1.43(s,9H)。
实施例1
此实施例说明了[3-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸甲酯的制备
将4-(3,4-二氯苯氧基)-1-(哌啶-4-基甲基)哌啶(0.7克)、(3-溴苯基)乙酸甲酯(0.5克)、碘化亚铜(38毫克)、L-脯氨酸(23毫克)和K2CO3(0.8克)悬浮在DMSO中,并加热到85℃,保持16小时。将混合物用水稀释,而后使用EtOAc提取(3×100mL)。将有机层合并,用盐水洗涤,干燥,蒸发溶剂。将残余物通过色谱(EtOAc)纯化,得到标题化合物(0.19克)。HPLC保留时间标准2.98,MS(ES+)491/493(M+H)+。
通过与实施例1相同的方法、使用合适的芳基溴或碘化物,制备实施例2至8和13(下面表I)。
实施例9
本实施例举例说明了(2R)-2-[2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]丙酸甲酯的制备
将2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯酚(100毫克)和K2CO3(44毫克)悬浮在DMF(3毫升)中,并搅拌15分钟。加入(2S)-2-{[(4-甲基苯基)磺酰基]氧基}丙酸甲酯(65毫克),并加热反应混合物至65℃,保持18小时。将混合物用水稀释,而后使用TBME提取(3×20mL)。将有机层合并,用碳酸氢盐溶液洗涤,干燥,蒸发溶剂。通过RPHPLC纯化(梯度75%-5%乙酸铵水溶液,25%-95%乙腈)残余物,得到副标题化合物(100毫克)。HPLC保留时间标准3.28,MS(ES+ve)521/523(M+H)+。
利用与实施例9相同的方法、使用合适的酚和甲苯磺酸酯,制备实施例10至12(下面表I)。
实施例14
此实施例说明了[4-(4-{[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸甲酯的制备
将4-(3,4-二氯-2-甲基苯氧基)-1-(哌啶-4-基甲基)哌啶(200毫克)、(4-溴苯基)乙酸甲酯(128毫克)、Cs2CO3(273毫克)、乙酸钯(5毫克)和二环己基(2′,4′,6′-三异丙基联苯-2-基)膦(12毫克)合并,并用氮气吹扫3分钟。将反应混合物悬浮在甲苯(3ml)中,并加热至100℃,保持16小时。将混合物用水稀释,而后使用EtOAc提取(3×100mL)。将有机层合并,用H2O洗涤,干燥,蒸发溶剂。将残余物通过色谱(异己烷/EtOAc,1/1至纯EtOAc)纯化,得到标题化合物(210mg)。HPLC保留时间标准3.04,MS(ES+ve)505/507(M+H)+。
利用与实施例14相同的方法、使用合适的芳基溴和胺,制备实施例15&16(下面表I)。
实施例17
此实施例说明了[4-(4-{[4-(3-氯-4-氰基-2-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸甲酯的制备
将2-氯-4-({1-[(3,4-二羟基环戊基)甲基]哌啶-4-基}氧基)-3-甲基苄腈(0.4克)在乙酸(0.06毫升)和水(15毫升)的混合物中搅拌,直至它溶解。加入高碘酸钠(0.24克),并继续搅拌15分钟。通过加入碳酸钾(0.2克)将反应混合物中和,并用二氯甲烷提取中间体二醛。用盐水洗涤二氯甲烷,干燥(MgSO4),并过滤到含有下列物质的烧瓶中:(4-氨基苯基)乙酸甲酯盐酸盐(0.22克),三乙胺(0.15毫升),三乙酰氧基硼氢化钠(0.53克)和乙酸(0.06毫升)/二氯甲烷(10毫升)。将混合物在氮气氛围中搅拌1小时。加入饱和碳酸氢水溶液,用二氯甲烷提取产物。用盐水洗涤二氯甲烷,干燥(MgSO4),过滤并减压浓缩。通过快速色谱法纯化粗品,用乙酸乙酯洗脱。得到标题化合物油(0.24克)。
1H NMRδ(CD3OD)1.27-1.45(2H,m),1.65-1.79(1H,m),1.81-1.96(4H,m),2.01-2.13(2H,m),2.29-2.36(5H,m),2.39-2.50(2H,m),2.63-2.78(4H,m),3.56(2H,s),3.62-3.70(5H,m),4.58-4.68(1H,m),6.96(2H,d),7.07-7.18(3H,m),7.62(1H,d);MS:496/498[M+H]+,保留时间:2.65分钟,标准梯度。
由合适的二醇(中间体7或WO2004029041)和合适的胺制备下面的实施例18-19
表I
实施例 | 名称 | MS[M+H]+(ES+) | 保留时间梯度 |
2 | [2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸甲酯 | 491/493 | 2.95标准 |
3 | [4-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸甲酯 | 491/493 | 1.21快速 |
4 | [3-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)-4-甲氧基苯基]乙酸甲酯 | 521/523 | 2.77标准 |
5 | [2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]乙酸叔丁基酯 | 549/551 | 2.66快速 |
6 | [3-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]乙酸叔丁基酯 | 549/551 | 2.48快速 |
7 | [4-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]乙酸叔丁基酯 | 549/551 | 1.95快速 |
8 | 2-[2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]-2-甲基丙酸叔丁基酯 | 577/579 | 3.01快速 |
10 | (2S)-2-[2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]丙酸甲酯 | 521/523 | 3.17标准 |
11 | (2R)-2-[3-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]丙酸甲酯 | 521/523 | 3.15标准 |
12 | (2S)-2-[3-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]丙酸甲酯 | 521/523 | 3.10标准 |
13 | 3-[2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]丙酸甲酯 | 505/507 | 3.01标准 |
15 | [4-(4-{[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸甲酯 | 505/507 | 2.98标准 |
16 | [3-(4-{[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸甲酯 | 505/507 | 3.03标准 |
18 | (2R)-2-[3-(4-{[4-(3-氯-4-氰基-2-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]丙酸甲酯以及乙酯1H NMR(甲酯)δ(CD3OD)1.23-1.43(2H,m),1.56(3H,d),1.65-1.80(1H,m),1.82-1.94(4H,m),2.02-2.13(3H,m),2.29-2.36(5H,m),2.39-2.51(2H,m),2.64-2.78(4H,m),3.67(2H,d),3.75(3H,s),4.59-4.68(1H,m),6.34(1H,dd),6.52(1H,t),6.63(1H,dd),7.07-7.16(2H,m),7.61(1H,d) | 526/528 | 1.55快速(甲酯)1.78(乙酯) |
19 | (3-{4-[4-(3 ,4-二氯-2-乙基-苯氧基)-哌啶-1-基甲基]-哌啶-1-基}-苯基)-乙酸甲酯 | 519/521 | 2.39快速 |
实施例20
此实施例说明了[3-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸的制备
将[3-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸甲酯(0.19克)悬浮在MeOH/水(4/1,5ml)中,并加入LiOH(25mg)。将混合物加热至85℃,保持2小时。将反应混合物冷却,蒸发溶剂。将残余物溶于MeOH中,用乙酸酸化,而后通过RPHPLC纯化(梯度95%-50%乙酸铵水溶液,5%-50%乙腈),得到标题化合物(76毫克)。HPLC保留时间快速0.42,MS(ES+)477/479(M+H)+。
1H NMRδ(CD3OD+NaOD)1.28-1.40(2H,m),1.63-1.82(3H,m),1.82-1.91(2H,m),1.96-2.05(2H,m),2.25-2.37(4H,m),2.62-2.78(4H,m),3.42(2H,s),3.62-3.68(2H,m),4.35-4.43(1H,m),6.79-6.84(2H,m),6.89(1H,dd),6.98-7.01(1H,m),7.08-7.14(2H,m),7.37(1H,d)。
利用与实施例16相同的方法制备实施例21至23和27至38(下面表II)。
实施例24
此实施例说明了[2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]乙酸的制备
将[2-(4-[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]乙酸叔丁基酯(0.11克)溶于二氯甲烷(5毫升)中,并加入三氟乙酸(5毫升)。将溶液在室温下搅拌16小时。蒸发溶剂。将残余物溶于MeOH中,而后通过RPHPLC纯化(梯度95%-50%乙酸铵水溶液,5%-50%乙腈),得到标题化合物(64毫克)。HPLC Ret.快速0.50,MS(ES+ve)493/495(M+H)+。
1H NMRδ(CD3OD+NaOD)1.38-1.50(2H,m),1.63-1.88(5H,m),1.96-2.04(2H,m),2.26-2.37(4H,m),2.53-2.62(2H,m),2.70-2.78(2H,m),3.50-3.57(2H,m),4.35-4.43(1H,m),4.45(2H,s),6.83-6.94(4H,m),6.95-6.99(1H,m),7.09(1H,d),7.37(1H,d).
利用与实施例20相同的方法制备实施例25和26(下面表II)。利用实施例20的方法、由实施例17的方法所制备的酯来制备实施例39。
实施例40
此实施例说明了(2-氯-6-{4-[4-(3,4-二氯-苯氧基)-哌啶-1-基甲基]-哌啶-1-基}-苯氧基)-乙酸的制备
向4-[4-(3,4-二氯-苯氧基)-哌啶-1-基甲基]-环戊烷-1,2二醇(0.54克)的二氯甲烷(20毫升)溶液中加入四乙酸铅(0.99克)和碳酸钾(0.25克)。将混合物在室温下搅拌1.5小时,然后加入3-氯-2-甲氧基-苯胺(0.26克)和三乙酰氧基硼氢化钠(0.64克)。进一步的2小时之后,将混合物分配在二氯甲烷和饱和碳酸氢钠溶液之间,用硫酸钠干燥有机物。真空浓缩,得到褐色胶质,将其溶解在二氯甲烷(20mL)中,并用三溴化硼(1.0 M二氯甲烷溶液,12.4mL)逐滴处理,在室温搅拌1小时。用甲醇(100mL)稀释反应,真空浓缩。将残余物分配在乙酸乙酯和饱和碳酸氢钠溶液之间,用硫酸钠干燥有机物,真空浓缩。对残余物进行反相HPLC(Xterra柱,50%至95%乙腈/氨水(0.2%)洗脱),得到2-氯-6-{4-[4-(3,4-二氯-苯氧基)-哌啶-1-基甲基]-哌啶-1-基]-苯酚(0.12克)。将酚溶于DMF(5毫升)中;加入碳酸钾(0.03克)和溴乙酸甲酯(0.15克)。将反应在70℃加热加热2小时,而后在饱和碳酸氢钠溶液和二乙醚之间分配。用硫酸钠干燥有机物,并真空浓缩。将残余物溶于THF∶水(1∶1,5mL)中,并加入氢氧化锂(0.02g)。将反应在室温下搅拌1小时,而后真空浓缩。将残余物溶于水(5mL)中,逐滴加入HCl(1M)进行中和,沉淀出标题化合物(0.03g)白色固体,通过过滤将其收集。
1H NMRδ(DMSO)7.50(d,1H),7.26(d,1H),7.14-6.95(m,4H),4.57(s,2H),4.49-4.39(m,1H),2.75-2.55(m,2H),2.49-2.36(m,2H),2.29-2.16(m,4H),2.00-1.87(m,2H),1.86-1.73(m,2H),1.67-1.54(m,2H),1.32-1.14(m, 2H),3.57-3.13(m,3H);MS[M-H]-=525/527(APCI-)。
利用与实施例40相同的方法制备实施例41-43(下面表II)。利用与上述化合物类似的方法制备实施例44 & 45。
表II
实施例 | 名称 | MS[M+H]+(ES+) | 保留时间梯度 | 1H NMR |
21 | [2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸 | 477/479 | 0.59快速 | δ(CD3OD+NaOD)1.37-1.50(2H,m),1.55-1.69(1H,m),1.71-1.86(4H,m),1.97-2.06(2H,m),2.28-2.38(4H,m),2.60-2.68(2H,m),2.70-2.80(2H,m),3.07-3.14(2H,m),3.62(2H,s),4.35-4.43(1H,m),6.89(1H,dd),6.94-6.99(1H,m),7.04-7.07(1H,m),7.09-7.14(2H,m),7.25-7.29(1H,m),7.37(1H,d) |
22 | [4-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸 | 477/479 | 1.82标准 | δ(CD3OD+NaOD)1.30-1.45(2H,m),1.60-1.94(5H,m),1.97-2.08(2H,m),2.27-2.41(4H,m),2.61-2.82(4H,m),3.40(2H,s),3.57-3.65(2H,m),4.37-4.46(1H,m),6.88-6.97(3H,m),7.11-7.14(1H,m),7.19-7.24(2H,m),7.37-7.42(1H,m) |
23 | [3-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)-4-甲氧基苯基]乙酸 | 507/509 | 2.40NH4/85/30/A/5 | δ(CD3OD+NaOD)1.27-1.48(2H,m),1.61-1.89(5H,m),1.96-2.06(2H,m),2.26-2.39(4H,m),2.53-2.62(2H,m),2.70-2.79(2H,m),3.36-3.44(4H,m),3.83(3H,s),4.36-4.43(1H,m),6.83(1H,d),6.89(1H,dd),6.93-6.96(1H,m),7.01(1H,d),7.10(1H,d),7.37(1H,d) |
25 | [3-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]乙酸 | 493/495 | 1.66标准 | δ(CD3OD+NaOD)1.28-1.44(2H,m),1.60-1.93(5H,m),1.98-2.10(2H,m),2.26-2.41(4H,m),2.63-2.81(4H,m),3.64-3.71(2H,m),4.36(2H,s),4.37-4.46(1H,m),6.41-6.46(1H,m),6.56-6.63(2H,m),6.91(1H,dd),7.04-7.19(2H,m),7.40(1H,d) |
26 | [4-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]乙酸 | 493/495 | 0.60快速 | δ(CD3OD+NaOD)1.31-1.46(2H,m),1.59-1.95(5H,m),1.97-2.08(2H,m),2.28-2.40(4H,m),2.57-2.68(2H,m),2.71-2.81(2H,m),3.44-3.52(2H,m),4.33(2H,s),4.37-4.46(1H,m),6.86-6.93(3H,m),6.95-7.01(2H,m),7.12(1H,d),7.40(1H,d) |
27 | 2-[2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]-2-甲基丙酸 | 521/523 | 0.61快速 | δ(CD3OD+NaOD)1.38-1.48(2H,m),1.54(6H,s),1.64-1.88(5H,m),1.97-2.05(2H,m),2.28-2.38(4H,m),2.51-2.59(2H,m),2.70-2.79(2H,m),3.51-3.58(2H,m),4.36-4.43(1H,m),6.78-6.84(2H,m),6.87-6.96(3H,m),7.10(1H,d),7.38(1H,d) |
28 | (2R)-2-[2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]丙酸 | 507/509 | 1.66标准 | δ(CD3OD+NaOD)1.28-1.50(2H,m),1.56(3H,s),1.59-1.90(5H,m),1.97-2.06(2H,m),2.28-2.38(4H,m),2.42-2.51(1H,m),2.62-2.70(1H,m),2.71-2.79(2H,m),3.35-3.42(1H,m),3.76-3.83(1H,m),4.36-4.43(1H,m),4.53(1H,q),6.80-6.96(5H,m),7.10(1H,d),7.37(1H,d) |
29 | (2S)-2-[2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]丙酸 | 507/509 | 1.60标准 | δ(CD3OD+NaOD)1.27-1.48(2H,m),1.56(3H,d),1.60-1.90(5H,m),1.96-2.05(2H,m),2.27-2.38(4H,m),2.43-2.51(1H,m),2.62-2.71(1H,m),2.71-2.79(2H,m),3.35-3.42(1H,m),3.76-3.83(1H,m),4.36-4.43(1H,m),4.53(1H,q),6.80-6.91(4H,m),6.92-6.95(1H,m),7.10(1H,d),7.37(1H,d) |
30 | (2R)-2-[3-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]丙酸 | 507/509 | 1.51标准 | δ(CD3OD+NaOD)1.26-1.40(2H,m),1.50(3H,d),1.63-1.90(5H,m),1.96-2.05(2H,m),2.24-2.38(4H,m),2.60-2.78(4H,m),3.59-3.67(2H,m),4.35-4.43(1H,m),4.47(1H,q),6.37-6.41(1H,m),6.51-6.56(2H,m),6.89(1H,dd),7.06(1H,t),7.09(1H,d),7.37(1H,d) |
31 | (2S)-2-[3-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]丙酸 | 507/509 | 1.50标准 | δ(CD3OD)1.26-1.40(3H,m),1.50(3H,d),1.63-1.90(5H,m),1.96-2.05(2H,m),2.24-2.37(4H,m),2.61-2.69(2H,m),2.70-2.77(2H,m),3.60-3.66(2H,m),4.35-4.42(1H,m),6.37-6.41(1H,m),6.51-6.56(2H,m),6.89(1H,dd),7.05(1H,t),7.09(1H,d),7.37(1H,d) |
32 | 3-[2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]丙酸 | 491/493 | 1.95标准 | δ(CD3OD+NaOD)1.26-1.50(2H,m),1.59-1.87(5H,m),1.96-2.06(2H,m),2.27-2.40(4H,m),2.42-2.50(2H,m),2.61-2.79(4H,m),2.93-3.00(2H,m),3.01-3.07(2H,m),4.36-4.44(1H,m),6.89(1H,dd),6.93-6.98(1H,m),7.06-7.11(3H,m),7.21(1H,d),7.38(1H,d) |
33 | [4-(4-{[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸 | 491/493 | 1.71标准 | δ(CD3OD+NaOD)1.28-1.46(2H,m),1.61-1.96(5H,m),1.97-2.11(2H,m),2.23-2.47(4H,m),2.34(3H,s),2.60-2.78(4H,m),3.40(2H,s),3.56-3.65(2H,m),4.41-4.50(1H,m),6.89-7.00(3H,m),7.18-7.34(3H,m) |
34 | [4-(4-{[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸 | 491/493 | 1.65标准 | δ(CD3OD+NaOD)1.29-1.46(2H,m),1.63-1.78(1H,m),1.80-1.95(4H,m),1.96-2.09(2H,m),2.26-2.34(2H,m),2.36-2.45(2H,m),2.47(3H,s),2.59-2.81(4H,m),3.40(2H,s),3.52-3.70(2H,m),4.43-4.56(1H,m),6.89-7.03(3H,m),7.16-7.33(3H,m) |
35 | [3-(4-{[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸 | 491/493 | 1.65标准 | δ(CD3OD+NaOD)1.29-1.44(2H,m),1.63-1.78(1H,m),1.80-1.95(4H,m),1.96-2.09(2H,m),2.28-2.33(2H,m),2.34-2.45(2H,m),2.47(3H,s),2.63-2.81(4H,m),3.44(2H,s),3.63-3.72(2H,m),4.44-4.53(1H,m),6.81-6.87(2H,m),6.97(1H,d),7.00-7.03(1H,m),7.14(1H,t),7.28(1H,d) |
36 | [4-(4-{[4-(3-氯-4-氰基-2-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸 | 482/484 | δ(CD3OD)1.29-1.41(2H,m),1.62-1.75(1H,m),1.80-1.90(4H,m),2.01-2.09(2H,m),2.28(2H,d),2.31(3H,s),2.37-2.46(2H,m),2.60-2.72(4H,m),3.38(2H,s),3.58(2H,d),4.57-4.64(1H,m),6.92(2H,d),7.08(1H,d),7.19(2H,d),7.60(1H,d) |
37 | (2R)-2-[3-(4-{[4-(3-氯-4-氰基-2-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]丙酸 | 512/514 | 1.33标准 | δ(CD3OD)1.28-1.43(2H,m),1.53(3H,d),1.64-1.77(1H,m),1.82-1.94(4H,m),2.02-2.13(2H,m),2.30(2H,d),2.34(3H,s),2.39-2.49(2H,m),2.63-2.77(4H,m),3.66(2H,d),4.49(1H,q),4.59-4.67(1H,m),6.40-6.43(1H,m),6.54-6.59(2H,m),7.08(2H,t),7.62(1H,d) |
38 | (3-{4-[4-(3,4-二氯-2-乙基-苯氧基)-哌啶-1-基甲基]-哌啶-1-基}-苯基)-乙酸 | 505/507 | 1.92标准 | δ(CD3OD)1.12(3H,t),1.27-1.41(2H,m),1.62-1.74(1H,m),1.77-1.91(4H,m),1.98-2.07(2H,m),2.25-2.29(2H,m),2.34-2.43(2H,m),2.62-2.75(4H,m),2.87(2H,q),3.41(2H,s),3.61-3.68(2H,m),4.42-4.48(1H,m),6.78-6.83(2H,m),6.91(1H,d),6.98-7.00(1H,m),7.11(1H,t),7.26(1H,d) |
39 | (4-氯-2-{4-[4-(3,4-二氯-苯氧基)-哌啶-1-基甲基]-哌啶-1-基}-苯氧基)-乙酸盐酸盐 | 529/531 | δ(DMSO)7.59-7.52(m,1 H),7.40-7.33(m,1 H),7.11-7.00(m,1 H),6.97-6.91(m,1H),6.90-6.81(m,2H),4.69(s,2H),4.66-4.58(m,3H),3.64-2.99(m,7H),2.72-1.82(m,8H),1.49-1.32(m,2H) | |
41 | [2-(4-{[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)-4-甲基苯氧基]乙酸 | 525/527(ACPI-) | δ(DMSO)7.50(d,1H),7.26(d,1H),6.98(dd,1H),6.94-6.86(m,2H),6.83(s,1H),4.65(s,2H),4.45(s,1H),3.45-3.35(m,2H),2.72-2.63(m,2H),2.58-2.50(m,2H),2.25-2.19(m,4H),1.97-1.88(m,2H),1.80-1.71(m,2H),1.68-1.53(m,3H),1.33-1.17(m,2H) |
42 | [2-(4-{[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)-4-甲基苯氧基]乙酸 | 522/524 | δ(DMSO)1.2-1.4(m,2H),1.55-1.8(m,5H),1.8-2.0(m,2H),2.21(s,3H),2.40(s,3H),2.1-2.8(m,7H),3.08(s,H),3.3-3.5(m,2H),4.4-4.6(m,H),4.57(s,2H),6.85-6.60(m,3H),7.12(d,H),7.34(d,H) | |
43 | [2-(4-{[4-(3,4-二氯苯氧基)哌啶-1-基]甲基}哌啶-1-基)-4-甲基苯氧基]乙酸乙酸盐 | 522/524 | δ(DMSO)1.2-1.3(m,3H),1.36(d,3H),1.5-1.7(m,4H),1.7-1.8(m,2H),1.91(s,3H),1.9-2.0(m,2H),2.18(s,3H,AcOH),2.1-2.22(s,2H),2.40(dd,2H),2.6-2.7(m,2H),3.35(d,H),3.62(d,H),4.25(q,H),4.4-4.5(m,H),6.58(s,2H),6.61(s,H),6.98(dd,H),7.26(d,H),7.50(d,H) | |
44 | (2S)-2-[3-(4-{[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯氧基]丙酸 | (M-H)-519/521/523(APCI-) | δ(CD3OD)1.30-1.42(2H,m),1.54(3H,d),1.67-1.79(1H,m),1.80-1.95(4H,m),2.06(2H,d),2.31(2H,d),2,35(3H,s),2.41(2H,s),2.69(4H,t),2.67(2H,d),4.43-4.55(2H,m),6.41-6.45(1H,m),6.56-6.61(2H,m),6.96(1H,d),7.10(1H,t),7.31(1H,d) | |
45 | [3-(4-{[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]甲基}哌啶-1-基)苯基]乙酸 | (M-H)-489/491/493(APCI-) | δ(CD3OD)1.35(1H,ddd),1.62-1.75(1H,m),1.76-1.91(4H,m),1.97-2.06(2H,m),2.27(2H,d),2.31(3H,s),2.33-2.42(2H,m),2.61-2.75(4H,m),3.42(2H,s),3.65(2H,d),4.39-4.47(1H,m),6.80(1H,s),6.82(1H,s),6.91(1H,d),6.98(1H,s),7.12(1H,t),7.27(1H,d) |
实施例46
药理分析:钙流量[Ca2+]i测定
人嗜酸性粒细胞
按照前述方法(Hansel等,J.Immunol.Methods,1991,145,105-110)从EDTA抗凝的外周血中分离出人嗜酸性粒细胞。室温下将细胞悬浮(5×106ml-1)并负载5μM FLUO-3/AM+Pluronic F127 2.2μl/ml(Molecular Probes)的低钾溶液(LKS;NaCl 118mM,MgSO4 0.8mM,葡萄糖5.5mM,Na2CO38.5mM,KCl 5mM,HEPES 20mM,CaCl2 1.8mM,BSA 0.1%,pH7.4)一小时。负载后,将细胞在200g离心5分钟并以2.5×106ml-1的密度再悬浮于LKS中。然后将细胞以25μl/孔转移至96孔FLIPr板(Becton Dickinson的Poly-D-Lysine板,用5μM纤连蛋白预孵育2小时)中。将板在200g离心5分钟并将细胞用LKS(200μl;室温)洗涤两次。
将实施例化合物预溶于DMSO中,并加入至0.1%(v/v)DMSO的终浓度。加入A50浓度的嗜酸细胞活化趋化因子启动测定,并利用FLIPR(FluorometricImaging Plate Reader,Molecular Devices,Sunnyvale,U.S.A.)检测fluo-3荧光(lEx=490nm和lEm=520nm)的瞬时增加。
如果嗜酸细胞活化趋化因子(选择性CCR3激动剂)诱导的荧光增加受到浓度依赖的方式的抑制,就认为实施例化合物为拮抗剂。抑制50%荧光所需要的拮抗剂的浓度可用来定义为CCR3受体拮抗剂的IC50。
实施例47
人嗜酸性粒细胞趋化性
按照前述方法(Hansel等,J.Immunol.Methods,1991,145,105-110)从EDTA抗凝的外周血终分离得到人嗜酸性粒细胞。室温下,将细胞以10×106ml-1的密度悬浮在RPMI中,该培养基包含200IU/ml青霉素、200μg/ml硫酸链霉素并补加10%HIFCS。
将嗜酸性粒细胞(700μl)与7μl载体或化合物(100×需要的终浓度的10%DMSO溶液)在37℃预孵育15分钟。趋化性板(ChemoTx,3μm孔,Neuroprobe)通过下述方式进行负载:将28μl包含各种浓度的实施例化合物或溶剂的0.1~100nM浓度的嗜酸细胞活化趋化因子(在此浓度范围的选择性CCR3激动剂)加入到趋化性板下层孔中。然后将滤器放置在孔上,并将25μl嗜酸性粒细胞悬浮液加入到滤器的上部。将板在湿度培养箱中与95%空气/5%CO2氛在37℃培养1小时使之发生趋化性。
从滤器上部小心地吸出包含没有迁移细胞的培养基并弃去。将滤器用包含5mM EDTA的磷酸缓冲盐(PBS)洗涤一次以去除任何粘附的细胞。离心(在室温300×g离心5分钟)沉淀迁移通过滤器的细胞并去除滤器,并将上清液转移至96-孔板(Costar)的各孔中。加入28μl包含0.5%Triton×100的PBS然后通过两轮冻/融裂解沉淀的细胞。然后将细胞裂解液加入到上清液中。根据Strath等,J.Immunol.Methods,1985,
83,209的方法通过测定上清液中的嗜酸性粒细胞过氧化物酶活性定量迁移的嗜酸性粒细胞数。
如果响应嗜酸细胞活化趋化因子的浓度移到对照曲线的右侧,就认为实施例化合物为嗜酸细胞活化趋化因子介导的人嗜酸性粒细胞趋化性的拮抗剂。在有或无化合物存在的条件下测量给出50%趋化性所需要的嗜酸细胞活化趋化因子的浓度,从而计算出化合物对CCR3的表观亲和力。
实施例48
分离的豚鼠气道
(参见例如,Harrison,R.W.S.,Carswell,H.。& Young,J.M.(1984)EuropeanJ.Pharmacol.,106,405-409.)
将雄性白化Dunkin-Hartley豚鼠(250g)经颈脱位法处死并取出整个气道。清除粘附的结缔组织后,将气道切成6个环形片段,各有3根软骨带宽,然后悬浮在20ml器官培养液中,所述溶液包含下述成分的Krebs-Henseleit溶液(mM):NaCl 117.6,NaH2PO4 0.9,NaHCO3 25.0,MgSO41.2,KCl 5.4,CaCl2 2.6和葡萄糖11.1。将缓冲液保持在37℃并通入5%CO2的氧气。将消炎痛(2.8μM)加入到Krebs溶液中,以防止由于环-加氧酶产物的合成而导致的平滑肌紧张。将气道环悬挂在两个平行的钨丝钩之间,一端连接Ormed杆等力传感器并且另一端连接在器官培养液固定的支持物。在2-道Sekonic平床制图记录仪上记录等力(isometric force)的变化。
实验方案
在每次实验的开始,对组织施用1g的力,历时60分钟平衡时间进行恢复直到实现稳定不动的反应。随后,在各组织中以0.5 log10单位增量建立累积的组胺浓度效果(E/[A])曲线。然后清洗组织并且约30分钟后,加入受试化合物或溶媒(20%DMSO)。孵育60分钟后进行组胺的第二个E/[A]曲线。
浓度响应记录为第一曲线最大值的百分比。
数据分析
分析实验E/[A]曲线数据以评价有和无受试化合物存在下的组胺活性(p[A50]值)。随后用下述等式计算出受试化合物的亲和力(pA2)值:
log(r-1)=log[B]+pA2
其中r=测试化合物存在下的[A]50/无拮抗剂下的[A]50,并且[B]为受试化合物的浓度。发现实施例化合物为H1拮抗剂。
实施例49
在室温虾,在测定缓冲液(50mM Tris pH7.4,含有2mM MgCl2,250mM蔗糖和100mM NaCl)中,通过1nM[3H]-吡拉明(Amersham,Bucks,product code TRK608,比活性30Ci/mmol)与由表达人H1受体的重组细胞CHO-K1制备的2μg膜(Euroscreen SA,Brussels,Belgium,product codeES-390-M)进行竞争置换1小时,来评价本发明化合物的组胺H1受体结合活性。
下述本发明的化合物显示出对[3H]吡拉明(pyrilimine)结合的抑制性:
实施例 | H1 pKi/[1328_S] |
20 | 8.3 |
21 | 7.8 |
22 | 7.8 |
23 | 7.9 |
24 | 7.8 |
25 | 8.3 |
26 | 7.4 |
27 | 7.5 |
28 | 8.0 |
29 | 7.9 |
30 | 7.9 |
33 | 7.9 |
37 | 6.4 |
39 | 8.7 |
40 | 8.5 |
43 | 7.8 |
44 | 7.7 |
Claims (13)
1.式(I)化合物或其N-氧化物;或其药学可接受的盐,
其中:
A、B、D、E和G中之一是CXYCO2R5,另一个是CH或N,其它的是CR2、CR3和CR4;
Q是氢或羟基;
W是CH2,O,NH或N(C1-4烷基);
X是O或键;
Y是CR10R11,CR10R11CR12R13,CR10R11CR12R13CR14R15;
R1是苯基,其任选被下列基团取代:卤素,氰基,C1-4烷基,C1-4卤代烷基,C1-4烷氧基或C1-4卤代烷氧基;
R2、R3和R4独立地是氢、卤素、氰基、硝基、羟基、NR6R7、C1-6烷基(任选被卤素取代)、C1-6烷氧基(任选被卤素取代)、S(O)p(C1-6烷基)、S(O)qCF3或S(O)2NR8R9;
R5是氢,C1-6烷基或苄基;
p和q独立地是0、1或2;
R6、R7、R8和R9独立地是氢;C1-6烷基(任选被卤素,羟基或C3-6环烷基取代);CH2(C2-5烯基);苯基(本身任选被下列取代:卤素,羟基,硝基,NH2,NH(C1-4烷基),N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),S(O)2(C1-4烷基),S(O)2NH2,S(O)2NH(C1-4烷基),S(O)2N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),氰基,C1-4烷基,C1-4烷氧基,C(O)NH2,C(O)NH(C1-4烷基),C(O)N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),CO2H,CO2(C1-4烷基),NHC(O)(C1-4烷基),NHS(O)2(C1-4烷基),C(O)(C1-4烷基),CF3或OCF3);或杂环基(本身任选被下列取代:卤素,羟基,硝基,NH2,NH(C1-4烷基),N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),S(O)2(C1-4烷基),S(O)2NH2,S(O)2NH(C1-4烷基),S(O)2N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),氰基,C1-4烷基,C1-4烷氧基,C(O)NH2,C(O)NH(C1-4烷基),C(O)N(C1-4烷基)2(并且这些烷基可以连接形成下面对R6和R7所描述的环),CO2H,CO2(C1-4烷基),NHC(O)(C1-4烷基),NHS(O)2(C1-4烷基),C(O)(C1-4烷基),CF3或OCF3);
或者NR6R7或NR8R9可以独立地形成4-7元杂环、氮杂环丁烷、吡咯烷、哌啶、氮杂卓、吗啉或哌嗪,后者在末端氮上任选被C1-4烷基取代;
R10,R11,R12,R13,R14和R15独立地是氢或C1-4烷基;或R10和R11与它们两个都连接的碳一起形成C3-6环烷基环,对于C4-6环烷基环,所述环任选具有被O、S(O)或S(O)2替代的环碳,但不是R10和R11两个都连接的环碳。
2.权利要求1所要求的式(I)化合物或其N-氧化物;或其药学可接受的盐,其中W是O。
3.权利要求1或2所要求的式(I)化合物或其N-氧化物;或其药学可接受的盐,其中R1是任选被卤素、C1-4烷基或氰基取代的苯基。
4.权利要求1、2或3所要求的式(I)化合物或其N-氧化物;或其药学可接受的盐,其中R2、R3和R4独立地是氢,卤素,氰基,C1-4烷基,C1-4烷氧基,CF3,OCF3,S(O)2(C1-4烷基)或S(O)2NH2。
5.按照前述权利要求的任一项所要求的式(I)化合物或其N-氧化物;或其药学可接受的盐,其中Q是氢。
6.按照前述权利要求的任一项所要求的式(I)化合物或其N-氧化物;或其药学可接受的盐,其中A、B、D、E和G中之一是CXYCO2R5,其它的全部是CH。
7.按照前述权利要求的任一项所要求的式(I)化合物或其N-氧化物;或其药学可接受的盐,其中XY是CH2,CH2CH2,OCH2,OC(CH3)2或OCHCH3。
8.按照前述权利要求的任一项所要求的式(I)化合物或其N-氧化物;或其药学可接受的盐,其中R5是氢或C1-6烷基。
9.一种制备权利要求1所要求的式(I)化合物的方法,方法包括:
a.当R5是烷基或苄基时,酯化其中R5是H的式(I)化合物;
b.当R5是H时,将其中A、B、D、E或G中之一是CXYCN的式(I)化合物水解;
c.使式(III)的化合物与式(IV)的化合物在碘化亚铜、脯氨酸和碱的存在下、在合适的溶剂中、在合适的高温下反应,
其中Z是Br、I;
d.使式(III)的化合物与其中Z是Br或I的式(IV)化合物在钯盐、膦和碱的存在下、在合适的溶剂中、在合适的高温下反应;
e.当A是CXYCO2R5时,使式(IX)的化合物与甲基甲硫基甲基亚砜或乙基乙硫基甲基亚砜在碱的存在下、在合适的溶剂中、在适宜的温度下反应
并且在R5OH中用HCl处理从其中得到的产物;
f.当XY是OCR10R11、OCR10R11CR12R13或OCR10R11CR12R13CR14R15时,使其中A、B、D、E或G中之一表示C(O)H的式(XI)化合物,与其中L是卤素或磺酸酯且n和m独立地是0或1的式(XII)化合物在碱的存在下、在合适的溶剂中、在室温下反应
g.当Q是H时,使式(XV)的化合物与式(XVI)的化合物在合适还原剂和乙酸的存在下、在合适的溶剂中反应
10.一种药物组合物,包括权利要求1所要求的式(I)化合物、或其药学可接受的盐和药学可接受的助剂、稀释剂或载体。
11.权利要求1所要求的式(I)化合物、或其药学可接受的盐在治疗中的用途。
12.权利要求1所要求的式(I)化合物、或其药学可接受的盐在制备用于治疗的药剂中的用途。
13.一种在患有或处在所述疾病危险中的哺乳动物中治疗趋化因子介导的疾病状态的方法,包括对需要这种治疗的哺乳动物给药治疗有效量的权利要求1所要求的式(I)化合物、或其药学可接受的盐。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE0400925A SE0400925D0 (sv) | 2004-04-06 | 2004-04-06 | Chemical compounds |
SE04009254 | 2004-04-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1964964A true CN1964964A (zh) | 2007-05-16 |
Family
ID=32173699
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2005800184589A Pending CN1964964A (zh) | 2004-04-06 | 2005-04-05 | 用于治疗趋化因子介导的疾病的哌啶衍生物 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20080262037A1 (zh) |
EP (1) | EP1735298A1 (zh) |
JP (1) | JP2007532535A (zh) |
CN (1) | CN1964964A (zh) |
SE (1) | SE0400925D0 (zh) |
WO (1) | WO2005097775A1 (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE0200844D0 (sv) | 2002-03-19 | 2002-03-19 | Astrazeneca Ab | Chemical compounds |
SE0200843D0 (sv) | 2002-03-19 | 2002-03-19 | Astrazeneca Ab | Chemical compounds |
SE0300957D0 (sv) | 2003-04-01 | 2003-04-01 | Astrazeneca Ab | Chemical compounds |
SE0403003D0 (sv) * | 2004-12-09 | 2004-12-09 | Astrazeneca Ab | Chemical compound 1 |
EP2402316A1 (en) | 2005-07-21 | 2012-01-04 | AstraZeneca AB (Publ) | Piperidine derivatives |
KR20100135711A (ko) | 2007-12-20 | 2010-12-27 | 엔비보 파마슈티칼즈, 인코퍼레이티드 | 사중치환된 벤젠 |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4588722A (en) * | 1984-01-09 | 1986-05-13 | Janssen Pharmaceutica N.V. | N-(4-piperidinyl) bicyclic condensed 2-imidazolamine derivatives |
US4695575A (en) * | 1984-11-13 | 1987-09-22 | Janssen Pharmaceutica, N.V. | 4-[(bicycle heterocyclyl)-methyl and -hetero]-piperidines |
US5889006A (en) * | 1995-02-23 | 1999-03-30 | Schering Corporation | Muscarinic antagonists |
IL117149A0 (en) * | 1995-02-23 | 1996-06-18 | Schering Corp | Muscarinic antagonists |
US5952349A (en) * | 1996-07-10 | 1999-09-14 | Schering Corporation | Muscarinic antagonists for treating memory loss |
US5977138A (en) * | 1996-08-15 | 1999-11-02 | Schering Corporation | Ether muscarinic antagonists |
AU2654399A (en) * | 1998-02-02 | 1999-08-16 | Merck & Co., Inc. | Cyclic amine modulators of chemokine receptor activity |
TWI245763B (en) * | 1998-04-02 | 2005-12-21 | Janssen Pharmaceutica Nv | Biocidal benzylbiphenyl derivatives |
US6066636A (en) * | 1998-06-30 | 2000-05-23 | Schering Corporation | Muscarinic antagonists |
CA2347912A1 (en) * | 1998-12-18 | 2000-06-22 | Soo S. Ko | Heterocyclic piperidines as modulators of chemokine receptor activity |
ES2246233T3 (es) * | 1999-05-04 | 2006-02-16 | Schering Corporation | Derivados de piperidina utiles como antagonistas de ccr5. |
US6387930B1 (en) * | 1999-05-04 | 2002-05-14 | Schering Corporation | Piperidine derivatives useful as CCR5 antagonists |
US6294554B1 (en) * | 1999-09-22 | 2001-09-25 | Schering Corporation | Muscarinic antagonists |
AR033517A1 (es) * | 2000-04-08 | 2003-12-26 | Astrazeneca Ab | Derivados de piperidina, proceso para su preparacion y uso de estos derivados en la fabricacion de medicamentos |
JP4248251B2 (ja) * | 2001-03-29 | 2009-04-02 | シェーリング コーポレイション | Aidsの処置に有用なccr5アンタゴニスト |
DE60209736T2 (de) * | 2001-07-02 | 2006-11-02 | Astrazeneca Ab | Piperidinverbindungen, die sich als modulatoren der chemokinrezeptoraktivität eignen |
GB0117899D0 (en) * | 2001-07-23 | 2001-09-12 | Astrazeneca Ab | Chemical compounds |
GB0120461D0 (en) * | 2001-08-22 | 2001-10-17 | Astrazeneca Ab | Novel compounds |
GB0122503D0 (en) * | 2001-09-18 | 2001-11-07 | Astrazeneca Ab | Chemical compounds |
SE0200843D0 (sv) * | 2002-03-19 | 2002-03-19 | Astrazeneca Ab | Chemical compounds |
SE0200844D0 (sv) * | 2002-03-19 | 2002-03-19 | Astrazeneca Ab | Chemical compounds |
SE0202838D0 (sv) * | 2002-09-24 | 2002-09-24 | Astrazeneca Ab | Chemical compounds |
SE0300850D0 (sv) * | 2003-03-25 | 2003-03-25 | Astrazeneca Ab | Chemical compounds |
SE0300957D0 (sv) * | 2003-04-01 | 2003-04-01 | Astrazeneca Ab | Chemical compounds |
SE0301368D0 (sv) * | 2003-05-09 | 2003-05-09 | Astrazeneca Ab | Chemical compounds |
US20050020605A1 (en) * | 2003-06-13 | 2005-01-27 | Schering Aktiengesellschaft | Quinolyl amide derivatives as CCR-5 antagonists |
-
2004
- 2004-04-06 SE SE0400925A patent/SE0400925D0/xx unknown
-
2005
- 2005-04-05 CN CNA2005800184589A patent/CN1964964A/zh active Pending
- 2005-04-05 JP JP2007507274A patent/JP2007532535A/ja active Pending
- 2005-04-05 WO PCT/SE2005/000495 patent/WO2005097775A1/en active Application Filing
- 2005-04-05 EP EP05722310A patent/EP1735298A1/en not_active Withdrawn
- 2005-04-05 US US10/599,700 patent/US20080262037A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
JP2007532535A (ja) | 2007-11-15 |
WO2005097775A1 (en) | 2005-10-20 |
US20080262037A1 (en) | 2008-10-23 |
EP1735298A1 (en) | 2006-12-27 |
SE0400925D0 (sv) | 2004-04-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2311153T3 (es) | Derivados de piperidina para el tratamiento de enfermedades mediadas por quimioquina o h1. | |
CN101437795A (zh) | 哌啶衍生物,制备它们的方法,它们作为治疗剂的用途和含有它们的药物组合物 | |
US20090118513A1 (en) | Chemical Compounds | |
JP2008503573A (ja) | ケモカイン・レセプターccr5のモジュレーターとしての新規ピペリジン/8−アザビシクロ[3.2.1]オクタン誘導体 | |
CN1938274A (zh) | 用作趋化因子调节剂(ccr)的新哌啶化合物 | |
JP5147393B2 (ja) | 化学化合物i | |
ES2366807T3 (es) | Nuevos n-(fluoro-pirazinil)- fenilfulfonamidas como modulares del receptor de la guimiocina ccr4. | |
JP2006521374A (ja) | ケモカインまたはh1介在疾病状態の処置のためのピペリジン誘導体 | |
CN1964964A (zh) | 用于治疗趋化因子介导的疾病的哌啶衍生物 | |
JP2009514853A (ja) | Copdおよび喘息の処置に有用な新規1−ベンジル−4−ピペリジンアミン | |
ES2397418T3 (es) | Derivados de piperidina | |
JP2009501792A (ja) | ケモカイン受容体のモジュレーターとしてのn−ベンジル−モルホリン誘導体 | |
CN101268049A (zh) | 新哌啶衍生物 | |
SA04250056B1 (ar) | مشتقات ببريدين وعملية لتحضيره هذه المشتقات وتركيب صيدلاني يعتمد عليها | |
KR20070031951A (ko) | 화합물 i |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20070516 |