CN1337944A - 作为TACE抑制剂的炔β-氨磺酰和次膦酸酰胺异羟肟酸 - Google Patents
作为TACE抑制剂的炔β-氨磺酰和次膦酸酰胺异羟肟酸 Download PDFInfo
- Publication number
- CN1337944A CN1337944A CN00803031A CN00803031A CN1337944A CN 1337944 A CN1337944 A CN 1337944A CN 00803031 A CN00803031 A CN 00803031A CN 00803031 A CN00803031 A CN 00803031A CN 1337944 A CN1337944 A CN 1337944A
- Authority
- CN
- China
- Prior art keywords
- carbon atom
- phenyl
- unit
- heteroatoms
- heteroaryl
- 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
- 239000002253 acid Substances 0.000 title claims abstract description 30
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title claims description 14
- 239000002447 tumor necrosis factor alpha converting enzyme inhibitor Substances 0.000 title description 9
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 title description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 148
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 100
- 150000001875 compounds Chemical class 0.000 claims description 89
- 229910052799 carbon Inorganic materials 0.000 claims description 88
- 238000000034 method Methods 0.000 claims description 56
- 229910052760 oxygen Inorganic materials 0.000 claims description 56
- 125000004432 carbon atom Chemical group C* 0.000 claims description 51
- 229910052717 sulfur Inorganic materials 0.000 claims description 49
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 31
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- 229920006395 saturated elastomer Polymers 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 15
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 230000000903 blocking effect Effects 0.000 claims description 11
- 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 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 150000002790 naphthalenes Chemical class 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 5
- 108010051210 beta-Fructofuranosidase Proteins 0.000 claims description 5
- 235000011073 invertase Nutrition 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 206010022489 Insulin Resistance Diseases 0.000 claims description 4
- 206010052779 Transplant rejections Diseases 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical group C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012964 benzotriazole Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 208000004232 Enteritis Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 210000003169 central nervous system Anatomy 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 206010040070 Septic Shock Diseases 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 2
- 230000036285 pathological change Effects 0.000 claims description 2
- 231100000915 pathological change Toxicity 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000036303 septic shock Effects 0.000 claims description 2
- 206010006895 Cachexia Diseases 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- 206010037660 Pyrexia Diseases 0.000 claims 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims 1
- 208000026500 emaciation Diseases 0.000 claims 1
- -1 rheumatoid arthritis Chemical compound 0.000 abstract description 18
- 210000000845 cartilage Anatomy 0.000 abstract description 3
- 230000003412 degenerative effect Effects 0.000 abstract description 3
- 230000001404 mediated effect Effects 0.000 abstract description 3
- 201000008482 osteoarthritis Diseases 0.000 abstract description 3
- 208000030507 AIDS Diseases 0.000 abstract description 2
- 206010009900 Colitis ulcerative Diseases 0.000 abstract description 2
- 208000011231 Crohn disease Diseases 0.000 abstract description 2
- 206010040047 Sepsis Diseases 0.000 abstract description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 abstract description 2
- 150000007513 acids Chemical class 0.000 abstract description 2
- 201000006417 multiple sclerosis Diseases 0.000 abstract description 2
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 abstract 1
- 239000002585 base Substances 0.000 description 100
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000007787 solid Substances 0.000 description 39
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 31
- 150000001721 carbon Chemical group 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Natural products OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 230000008569 process Effects 0.000 description 21
- 238000012360 testing method Methods 0.000 description 19
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 15
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 102100040247 Tumor necrosis factor Human genes 0.000 description 14
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000029936 alkylation Effects 0.000 description 12
- 238000005804 alkylation reaction Methods 0.000 description 12
- 230000008859 change Effects 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
- 102100033732 Tumor necrosis factor receptor superfamily member 1A Human genes 0.000 description 11
- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 10
- 229940124530 sulfonamide Drugs 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 9
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 9
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 9
- 239000013641 positive control Substances 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 150000001345 alkine derivatives Chemical class 0.000 description 8
- NKBWMBRPILTCRD-UHFFFAOYSA-N 2-Methylheptanoic acid Chemical class CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 description 7
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 150000003862 amino acid derivatives Chemical class 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 102000004890 Interleukin-8 Human genes 0.000 description 6
- 108090001007 Interleukin-8 Proteins 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 239000005864 Sulphur Substances 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 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 6
- 229940096397 interleukin-8 Drugs 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- FQJRZOYTUCCBQR-UHFFFAOYSA-N tert-butyl 2-methylheptanoate Chemical class CCCCCC(C)C(=O)OC(C)(C)C FQJRZOYTUCCBQR-UHFFFAOYSA-N 0.000 description 6
- JAELLLITIZHOGQ-UHFFFAOYSA-N tert-butyl propanoate Chemical compound CCC(=O)OC(C)(C)C JAELLLITIZHOGQ-UHFFFAOYSA-N 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- WOXWUZCRWJWTRT-UHFFFAOYSA-N 1-amino-1-cyclohexanecarboxylic acid Chemical compound OC(=O)C1(N)CCCCC1 WOXWUZCRWJWTRT-UHFFFAOYSA-N 0.000 description 5
- 102100027995 Collagenase 3 Human genes 0.000 description 5
- 108050005238 Collagenase 3 Proteins 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 5
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 5
- VAKKJWXZRREDEX-UHFFFAOYSA-N [O].CC#CC Chemical compound [O].CC#CC VAKKJWXZRREDEX-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 238000013016 damping Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 230000026731 phosphorylation Effects 0.000 description 5
- 238000006366 phosphorylation reaction Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000010998 test method Methods 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 101000801228 Homo sapiens Tumor necrosis factor receptor superfamily member 1A Proteins 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000003226 mitogen Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 208000031886 HIV Infections Diseases 0.000 description 3
- 208000037357 HIV infectious disease Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 229940124761 MMP inhibitor Drugs 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 102000018594 Tumour necrosis factor Human genes 0.000 description 3
- 108050007852 Tumour necrosis factor Proteins 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- 229940000635 beta-alanine Drugs 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- MJBPUQUGJNAPAZ-UHFFFAOYSA-N Butine Natural products O1C2=CC(O)=CC=C2C(=O)CC1C1=CC=C(O)C(O)=C1 MJBPUQUGJNAPAZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 210000000621 bronchi Anatomy 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 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 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- WFYWVWNFVSGLFT-UHFFFAOYSA-N tert-butyl cyclohexanecarboxylate Chemical compound CC(C)(C)OC(=O)C1CCCCC1 WFYWVWNFVSGLFT-UHFFFAOYSA-N 0.000 description 2
- WQNHTMOGCGLHIZ-UHFFFAOYSA-N tert-butyl cyclopentanecarboxylate Chemical compound CC(C)(C)OC(=O)C1CCCC1 WQNHTMOGCGLHIZ-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 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
- 231100000397 ulcer Toxicity 0.000 description 2
- USQHEVWOPJDAAX-RITPCOANSA-N (1r,2s)-2-aminocyclohexane-1-carboxylic acid Chemical compound N[C@H]1CCCC[C@H]1C(O)=O USQHEVWOPJDAAX-RITPCOANSA-N 0.000 description 1
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- LNNXOEHOXSYWLD-UHFFFAOYSA-N 1-bromobut-2-yne Chemical compound CC#CCBr LNNXOEHOXSYWLD-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- UMOCURSMAKCWOP-UHFFFAOYSA-N 2-methylpropan-2-ol;propanoic acid Chemical compound CCC(O)=O.CC(C)(C)O UMOCURSMAKCWOP-UHFFFAOYSA-N 0.000 description 1
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- ULUPAWKAWBVCAI-UHFFFAOYSA-N 4-hydroxybenzenesulfonic acid;sodium Chemical compound [Na].OC1=CC=C(S(O)(=O)=O)C=C1 ULUPAWKAWBVCAI-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical class C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 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
- 206010000871 Acute monocytic leukaemia Diseases 0.000 description 1
- 208000010266 Aggressive Periodontitis Diseases 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- 206010001580 Albuminuria Diseases 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 206010053555 Arthritis bacterial Diseases 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- YLMXBNACRIGGFX-UHFFFAOYSA-N C=1[C-]=NNN=1 Chemical compound C=1[C-]=NNN=1 YLMXBNACRIGGFX-UHFFFAOYSA-N 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 206010011017 Corneal graft rejection Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000013382 Gelatinases Human genes 0.000 description 1
- 108010026132 Gelatinases Proteins 0.000 description 1
- 208000022461 Glomerular disease Diseases 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- 208000004575 Infectious Arthritis Diseases 0.000 description 1
- 206010060820 Joint injury Diseases 0.000 description 1
- 201000002287 Keratoconus Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 101150014058 MMP1 gene Proteins 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 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
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 208000003107 Premature Rupture Fetal Membranes Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- VWPHVNHYMPWECW-UHFFFAOYSA-N SC(CO)CC(C)C Chemical compound SC(CO)CC(C)C VWPHVNHYMPWECW-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 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 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 108700004333 collagenase 1 Proteins 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 125000004407 fluoroaryl group Chemical group 0.000 description 1
- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 231100000852 glomerular disease Toxicity 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 150000002443 hydroxylamines Chemical class 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000002390 hyperplastic effect Effects 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000002780 macular degeneration Diseases 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
- 239000011976 maleic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000029052 metamorphosis Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 208000001491 myopia Diseases 0.000 description 1
- 230000004379 myopia Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000065 osmolyte Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 201000006727 periodontosis Diseases 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000012207 quantitative assay Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 230000006340 racemization Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Natural products CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- NBNBICNWNFQDDD-UHFFFAOYSA-N sulfuryl dibromide Chemical compound BrS(Br)(=O)=O NBNBICNWNFQDDD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- JGQSREKJPFNXQH-UHFFFAOYSA-N tert-butyl 1-aminocyclohexane-1-carboxylate Chemical compound CC(C)(C)OC(=O)C1(N)CCCCC1 JGQSREKJPFNXQH-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003527 tetrahydropyrans Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 230000005186 women's health Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/78—Halides of sulfonic acids
- C07C309/86—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/87—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P15/06—Antiabortive agents; Labour repressants
-
- 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
- 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
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- 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
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/41—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
- C07C309/42—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
本发明公开了一种式(B)的可用于治疗受TNF—α介导的疾病如类风湿性关节炎、骨关节炎、脓毒病、AIDS、溃疡性结肠炎、多发性硬化、局限性回肠炎和退化性软骨丧失的异羟肟酸。在该式中点线表示可任选的双键,R5、R6、R7、R8、R11、R12、X、Y和Z的定义见说明书。
Description
发明领域
本发明涉及作为TNF-α转化酶(TACE)的抑制剂的炔芳基氨磺酰和次膦酸酰胺异羟肟酸。本发明的化合物可用于治疗TNF-α介导的疾病,如类风湿性关节炎、骨性关节炎、脓毒病、AIDS、溃疡性结肠炎、多发性硬化症、局限性回肠炎和退化性软骨丧失。
发明背景
TNF-α转化酶(TACE)催化膜结合TNF-α前体蛋白形成TNF-α。TNF-α是一种促炎症细胞因子,据信在以下疾病中起作用:类风湿性关节炎(Shire,M.G.;Muller,G.W.Exp.Opin.Ther.Patents 1998,8(5),531;Grossman,J.M.;Brahn,E.J.Women’s Health 1997,6(6),627;Isomaki,P.;Punnonen,J.Ann.Med.1997,29,499;Camussi,G.;Lupia,E.Drugs,1998,55(5),613)、脓毒性休克(Mathison,等人,J.Clin.Invest.1988,81,1925;Miethke,等人,J.Exp.Med.1992,175,91)、移植排斥(Piguet,P.F.;Grau,G.E.;等人,J.Exp.Med.1987,166,1280.),恶质病(Beutler,B.;Cerami,A.Ann.Rev.Biochem.1988,57,505)、厌食、炎症(Ksontini,R,;MacKay,S.L.D.;Moldawer,L.L.Arch.Surg.1998,133,558.)、充血性心力衰竭(Packer,M.Circulation,1995,92(6),1973;Ferrari,R.;Bachetti,T.:等人.Circulation,1995,92(6),1479)、局部缺血后重复灌注(ischaemic)的损伤、中枢神经***炎性疾病、肠炎、胰岛素抗性(Hotamisligil,G.S.;Shargill,N.S.;Spiegelman,B.M.;等人.Science,1993,259,87.)和HIV感染(Peterson,P.K.;Gekker,G.;等人,J.Clin.Invest.1992,89,574;Pallares-Trujillo,J.;Lopez-Soriano,F.J.Argiles,J.M.Med.Res.Reviews,1995,15(6),553),及其熟知的抗肿瘤特性(Old,L.Science,1985,230,630)。例如,用抗TNF-α抗体和转基因动物作的研究表明阻断TNF-α的形成抑制了关节炎的发展(Rankin,E.C.;Choy,E.H.;Kassimos,D.;Kingsley,G.H.;Sopwith,A.M.;Isenberg,D.A.;Panayi,G.S.Br.J.Rheumatol.1995,34,334;Pharmaprojects,1996,Therapeutic Updates 17(10月)aul97-M2Z)。最近这个观察已扩展到人,如“人类疾病中的TNF-α”,CurrentPharmaceutical Design,1996,2,662所述。
预计TACE的小分子抑制剂具有治疗各种疾病症状的潜力。虽然已知有许多TACE抑制剂,但这些分子中的许多是肽类或类肽,存在生物可利用性和药物动力学问题。另外,这些分子中许多是非选择性的基质金属蛋白酶(尤其是MMP-1)的强抑制剂。已假设对MMP-1(胶原酶1)的抑制会造成MMP抑制剂临床实验中的关节疼痛(Scrip,1998,2349,20)。因此长效、选择性、口服生物可利用性的非肽类TACE抑制剂对治疗上述疾病是非常理想的。
WIPO国际出版物WO9816503、WO9816506、WO9816514和WO9816520和美国专利No.5,776,961公开了呈下式的异羟肟酸氨磺酰MMP/TACE抑制剂的例子,其中2碳链将异羟肟酸和氨磺酰氮分开。
美国专利N0.5,445,258、5,506,242、5,552,419、5,770,624、5,804,593和5,817,822以及欧洲专利EP606,046A1和WIPO国际出版物WO9600214和WO9722587公开了基质金属蛋白酶和/或TACE的非肽类抑制剂,即以下所示的异羟肟酸芳基氨磺酰,其中1碳将异羟肟酸和氨磺酰氮分开。其他出版物公开的氨磺酰为基础的MMP抑制剂,是以下所示的氨磺酰-异羟肟酸的变体或氨磺酰-异羟肟酸的类似物,公开于欧洲专利EP-757037-A1和EP-757984-A1和WIPO国际出版物WO9535275、WO9535276、WO9627583、WO9719068、WO9727174、WO9745402、WO9807697和WO9831664、WO9833768、WO9839313、WO9839329、WO9842659和WO9843963。MacPherson,等人在J.Med.Chem,(1997),40,2525和Tamura等人在J.Med.Chem.(1998),41,640中进一步详细公开了这种类型的MMP抑制剂。
公开MMP和/或TACE的β-氨磺酰-异羟肟酸抑制剂(其中异羟肟酸的α碳与氨磺酰的氮呈环状连接,如下所示)的出版物包括美国专利No.5,753,653、WIPO国际出版物WO9633172、WO9720824、WO9827069、WO9808815、WO9808822、WO9808823、WO9808825、WO9834918、WO9808827、Levin等人,Bioorg.&Med.Chem.Letters 1998,8,2657和Pikul等人,J.Med.Chem.1998,41,3568。
本发明的目的是公开芳基氨磺酰和次膦酸酰胺异羟肟酸MMP/TACE抑制剂,其中Y(磺酰基或氧膦基芳基)被取代的丁炔基部分或炔丙醚、炔丙胺或炔丙硫醚所对位取代。这些化合物在体外和细胞试验中提供TACE活性水平增强的抑制和/或优于MMP-1的选择性。所以这些化合物可用于治疗由TNF介导的疾病。
发明概述
可用下式代表本发明的抑制TACE和MMP的邻位亚磺酰氨基异羟肟酸或其药学上可接受的盐:其中C(=O)NHOH部分和-NR5-部分连接于相邻的碳原子;
X是SO2或-P(O)R10;
Y是5-10元杂芳基环,所述的杂芳基环的1-3个杂原子选自N、NR9、S和O、苯基或萘基;条件是X和Z不连接于Y的相邻原子;
Z是O、NH、CH2或S;
R5是氢或1-6个碳原子的烷基;
R6和R7各是氢或甲基;
R8是氢,1-6个碳原子的烷基,2-6个碳原子的链烯基,2-6个碳原子的炔基,3-6个碳原子的环烷基,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,或5-7元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、S或O,或苯基;
R9是氢,1-6个碳原子的烷基,3-6个碳原子的环烷基或苯基;
R10是1-6个碳原子的烷基,3-6个碳原子的环烷基,苯基,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O;
R11和R12各是氢,1-6个碳原子的烷基,3-6个碳原子的环烷基,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元杂环烷基,所述的杂环烷基的1-2个杂原子选自N、NR9、S或O,或苯基,并且存在点线表示的任选双键;或
R11和R12及连接它们的碳原子一起形成5-10元饱和的或不饱和的单环或双环烷基环,可任选地稠合于一5-7元饱和的或不饱和的环烷基环,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、S或O,苯环或萘环;或
R11和R12及连接它们的碳原子一起形成5-10元饱和的或不饱和的单环或双环杂环烷基,所述的双环杂环烷基的1-2个杂原子选自N、NR9、S或O,其任选地稠合于一5-7元单环或双环杂芳基,所述的双环杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元饱和的或不饱和的杂芳基环或苯环或萘环;
点线表示可任选的双键;
和n=0-2。
本发明的优选化合物包括结构为B的化合物,其中X是SO2。
本发明更优选的化合物包括结构为B的化合物,其中X是SO2,Y是在1-和4-位被X和Z分别取代的苯环。
本发明更优选的化合物包括结构为B的化合物,其中X是SO2,Y是在1-和4-位被X和Z分别取代的苯环,且Z是氧。
本发明更优选的化合物包括结构为B的化合物,其中X是SO2,Y是在1-和4-位被X和Z分别取代的苯环,Z是氧,R6和R7是氢。
本发明更优选的化合物包括结构为B的化合物,其中X是SO2,Y是在1-和4-位被X和Z分别取代的苯环,Z是氧,R6和R7是氢,R8是-CH2OH或甲基。
本发明的优选化合物是(1R,2R)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基环己烷甲酰胺;
(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-N-羟基环己烷甲酰胺;
3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基丙酰胺;
3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基丙酰胺;
(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基环戊烷甲酰胺;
(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基环戊烷甲酰胺;
(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基环己烷甲酰胺;
(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基环己烷甲酰胺;
(1R,2R,3S,4R)-(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基二环[2.2.1]庚烷-2-甲酰胺;和
(1R,2R,3S,4R)-(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基二环[2.2.1]庚烷-2-甲酰胺。
本文所用的杂芳基是5-10元单环或双环,其中1-3个杂原子选自N、NR9、S和O。杂芳基较佳的是 或
其中K是NR9、O或S,R9是氢、1-6个碳原子的烷基、3-6个碳原子的环烷基或苯基。优选的杂芳环包括吡咯、呋喃、噻吩、吡啶、嘧啶、哒嗪、吡嗪、***、吡唑、咪唑、异噻唑、噻唑、异噁唑、噁唑、吲哚、异吲哚、苯并呋喃、苯并噻吩、喹啉、异喹啉、喹噁啉、喹唑啉、苯并***、吲唑、苯并咪唑、苯并噻唑、苯并异噁唑和苯并噁唑。
本发明的杂芳基可任选地为单取代或双取代。
本文所用的杂环烷基是5-10元饱和的或不饱和单环或双环,其中1或2个杂原子选自N、NR9、S和O。本发明的杂环烷基较佳地选自 或
其中M是NR4、O或S,R4是氢、1-6个碳原子的烷基、3-6个碳原子的环烷基、苯基、萘基、杂芳基、-S(O)nR2、-COOR2、-CONR2R3、-SO2NR2R3或-COR2。优选的杂环烷基环包括哌啶、哌嗪、吗啉、四氢吡喃、四氢呋喃或吡咯烷。本发明的杂环烷基可任选地为单取代或双取代。
本文所用的芳基指苯基或萘基,可任选地单、双或三取代。
烷基、链烯基、炔基和全氟烷基包括直链和支链部分。烷基、链烯基、炔基和环烷基可以是未取代的(碳原子连接于氢、或链或环中的其他碳原子)或单或多取代的。环烷基可以是单环或双环。单环烷基的例子包括环戊基和环己基。双环烷基的例子包括双环庚烷和金刚烷基。
卤素指溴、氯、氟和碘。
芳基、杂芳基、烷基、链烯基、炔基、环烷基适合的取代基包括(但不限于)卤素、1-6个碳原子的烷基、2-6个碳原子的链烯基、2-6个碳原子的炔基、3-6个碳原子的环烷基、-OR2、-CN、-COR2、1-4个碳原子的全氟烷基、1-4个碳原子的-O-全氟烷基、-CONR2R3、-S(O)nR2、-OPO(OR2)OR3、-PO(OR2)R3、-OC(O)NR2R3、-C(O)NR2OR3、-COOR2、-SO3H、-NR2R3、-N[(CH2)2]2NR2、-NR2COR3、-NR2COOR3、-SO2NR2R3、-NO2、-N(R2)SO2R3、-NR2CONR2R3、-NR2C(=NR3)NR2R3、NR2C(=NR3)N(SO2R2)R3、NR2C(=NR3)N(C=O)R2R3、-SO2NHCOR4、-CONHSO2R4、-四唑-5-基、-SO2NHCN、-SO2NHCONR2R3、苯基、萘基、杂芳基或杂环烷基;
其中-NR2R3可形成吡咯烷、哌啶、吗啉、硫代吗啉、噁唑烷、噻唑烷、吡唑烷、哌嗪或氮杂环丁烷环;
R2和R3各是氢、1-6个碳原子的烷基、3-6个碳原子的环烷基、苯基、萘基、杂芳基或杂环烷基;
R4是氢、1-6个碳原子的烷基、3-6个碳原子的环烷基、苯基、萘基、杂芳基-S(O)nR2、-COOR2、-CONR2R3、-SO2NR2R3或-COR2;n是0-2。
本发明杂环烷基的合适的取代基包括(但不限于):1-6个碳原子的烷基、3-6个碳原子的环烷基、苯基、萘基、杂芳基和杂环烷基。
当某部分含有相同名称的一个以上的取代基时,这些取代基各自可以是相同的和不同的。
当本发明的化合物含有碱性部分时,可从以下无机和有机酸形成药学上可接受的盐,如醋酸、丙酸、乳酸、柠檬酸、酒石酸、丁二酸、反式丁烯二酸、顺式丁烯二酸、丙二酸、扁桃酸、羟基丁二酸、苯二甲酸、盐酸、氢溴酸、磷酸、硝酸、硫酸、甲磺酸、萘磺酸、苯磺酸、甲苯磺酸、樟脑磺酸和类似已知的可接受的酸。当本发明的化合物含有酸性部分时,也可从无机和有机碱形成盐,较佳地为碱金属盐如钠盐、锂盐或钾盐。
本发明的化合物可含有不对称碳原子,本发明的一些化合物可含有一个或多个不对称中心,且因此可能产生旋光异构体和非对映异构体。不考虑立体化学而言,本发明包括这种旋光异构体和非对映异构体;以及消旋和拆解的、对映体纯化的R和S立体异构体;以及R和S立体异构体的其他混合物和它们药学上可接受的盐。据信一种旋光异构体包括非对映异构体和对映体或立体异构体具有比其他有利的特性。所以当公开和说明本发明权利时,当公开一种消旋混合物时,显然考虑了公开和要求了这两种光学异构体的权利包括非对映异构体和对映异构体,或基本无其他物质的立体异构体。
本发明的化合物表现出能抑制酶MMP-1、MMP-9、MMP-13和TNF-α转化酶(TACE),并因此可用于治疗关节炎、肿瘤转移、组织溃烂、异常伤口的愈合、牙周病、移植排斥、胰岛素抗性、骨骼疾病和HIV感染。具体说,本发明的化合物在体外和细胞试验中提供增强的抑制TACE活性的水平和/或提高优于MMP-1的选择性,因此这些化合物可特别用于治疗TNF所介导的疾病。
本发明还提供制备如下定义的式I化合物的方法,所述的方法包括如下步骤之一:
b)将式VI的化合物去保护产生相应的式B的化合物:其中R5、R6、R7、R8、和R11R12、X、Y和Z及点线的定义如上,R30是合适的保护基团如叔丁基、苄基或三烷基甲硅烷基;
c)拆解式B化合物的旋光活性异构体的混合物(如外消旋物),从而分离出基本无其他对映异构体或非对映异构体的一种对映异构体或非对映异构体;
或
d)用药学上可接受的酸来酸化式B的碱性化合物,得到药学上可接受的盐。
对步骤a)而言,此反应可用本领域已知的方法进行,如通过酰基氯活性衍生物与羟胺的反应。
如步骤b)所示的除去保护基团的反应也可用本领域已知的方法进行,得到异羟肟酸。
对步骤c)而言,可用标准分离技术分离特定的对映体或非对映异构体形式。例如,通过与‘拆解试剂’的单对映体(如非对映异构体盐形式或共价键形式)反应,可将消旋混合物转化成旋光性非对映异构体的混合物。可用标准方法(如结晶或层析)分离得到的旋光性非对映异构体的混合物,然后处理各旋光性非对映异构体以除去‘拆解试剂’,从而释放出本发明化合物的单对映异构体。可用手性层析(用手性载体、洗脱液或离子配对剂)直接分离对映异构体混合物。
可以药学上可接受的盐的形式分离式B的化合物,如用上述酸处理的有机或无机酸。
本发明还涉及制备结构B化合物的方法,包括如下的一个或多个反应:
通过将该化合物与1,2,4-***、咪唑或苯并***反应,分别可进一步将得到的磺酰氯、磺酰氟或磺酰溴转化成酰***(triazolide)、酰咪唑(imidazolide)或酰苯并噻唑(benzothiazolide)衍生物,其中J为1,2,4-***基、苯并***基或咪唑基,R6、R7和R8的定义如上。
本发明还涉及制备结构B化合物的方法,包括如下一个或多个反应:
2)将上述式IV的化合物或其盐或溶剂合物与氯磺酸反应,制备上述式II的化合物。
特别优选的中间体是式II和III的化合物,条件是R6不是氢。
可用有机合成领域技术人员已知的常规方法制备本发明的化合物。用于制备本发明化合物的起始原料是已知的,或可用已知方法制备或可购得。
本领域技术人员将会认识到当分子上其他潜在的反应官能团受到屏蔽或保护,因而避免不利的副反应和/或增加反应的产量时,可最佳地进行某些反应。为此,本领域技术人员可以使用保护基团。这些保护基团的例子可见于T.W.Greene,P.G.M.Wuts“有机合成中的保护基团”,第二版,1991,Wiley&Sons,New York。较佳地,将氨基酸起始原料上反应性侧链的官能团保护起来。对特定反应保护基团的需要和选择是本领域技术人员已知的,这取决于被保护的官能团(羟基、氨基、羧基等)的性质、含该取代基的分子的结构和稳定性及反应条件。
当制备或加工本发明的含芳基、杂芳基或杂环化合物时,本领域技术人员知道可在构建该环的同时、之前或之后制备该环上的取代基。为清晰起见,以下从该流程中删去了这些环上的取代。
本领域技术人员会明白为了最佳制备本发明化合物,合成步骤的性质和顺序可作改变。
按流程1制备本发明的异羟肟酸化合物,通过将羧酸2(其中A=R11和R12)转化成相应的酰基氯或酸酐,或通过将它与适当的肽偶联剂反应,然后与羟胺反应形成1,或与被保护的羟胺衍生物反应,得到3。然后可用已知的方法保护化合物3得到异羟肟酸1,其中R30是叔丁基、苯基、三烷基甲硅烷基或其他合适的屏蔽基团。
可按流程2所示制备羧酸2。将氨基酸衍生物4通过与化合物5反应,磺酰基化或磷酸化,其中R40是氢或合适的羧酸保护基团,其中J是合适的离去基团包括(但不限于)氯。然后在极性质子惰性溶剂如丙酮、N,N-二甲基甲酰胺(DMF)或四氢呋喃(THF)中,用R3J和碱如碳酸钾或氢化钠将N-H化合物6烷基化得到氨磺酰7。化合物7也可通过5直接与N-取代的氨基酸衍生物8反应得到。用酸、碱水解或其他方法(包括选择保护基团R40和存在碳碳三键)将7转化成羧酸。
由流程3显示了制备磺酰剂5的方法。因此,用炔10(其中J是合适的离去基团如卤素、甲磺酸酯、甲苯磺酸酯或三氟甲烷磺酸酯(triflate))将磺酸盐9(其中ZR50是羟基、硫醇或取代的氨基部分)烷基化,得到11。炔10是可购得的或是已知的化合物,或它们可用本领域技术人员已知的方法合成。通过已知的方法如与草酰氯或其他与取代基R6、R7和R8和炔相容的试剂反应,将磺酸盐11转化成相应的磺酰氯或其他磺酰化试剂5。另外,通过与化合物10反应可将二硫化物12转化成二炔13,然后还原二硫键得到类似的硫醇,再可用已知的方法将其转化成5。用10将酚、硫酚、苯胺或被保护的苯胺14烷基化得15,然后与氯磺酸反应得到磺酸16,用草酰氯或类似的试剂不难将其转化成5。通过保护硫醇、ZH的烷基化(Z是O、N或S)和硫的去保护及随后磺酸16的氧化,硫酚17也是5的前体。
如流程5所示,在氨基酸衍生物的磺酰基化或磷酸化后还可再加上炔侧链。所以,可用化合物20(其中ZR50是羟基或被保护的羟基、硫醇或胺)将氨基酸衍生物4和8磺酰基化或磷酸化,若需要可用R7J(如流程2所示)烷基化,得到21。除去R50屏蔽基团得到22,随后用10烷基化得到的苯酚、硫醇或胺,得到7。在此情况中ZR50为OH,无需去保护步骤可得到22。
流程5:
如流程6所示,以氨基酸衍生物4和/或8为起始物可合成炔丙胺类似物7。在DMF中用对硝基芳基化合物23(如4-硝基苯磺酰氯)磺酰基化或磷酸化,然后在DMF中用碱如碳酸钾或氢化钠以R5J(对4)烷基化,得到24。用氢和钯碳、氯化锡或其他已知的方法还原硝基部分,得到苯胺25,随后用10烷基化得到7。可用合适的氮保护基团如叔丁氧基羰基,衍生化苯胺25,得到26然后用10烷基化,去保护。
如流程7所示,炔衍生物7还可通过氟化合物27制备,化合物27易通过氨基酸衍生物4和/或8与氟芳基26反应制得。在极性质子惰性溶剂如DMF中,存在碱如氢化钠时用屏蔽的羟基、硫醇或氨基(HZR70,其中R70是合适的保护基团)置换27的氟,随后去保护得到28,然后可用10将其烷基化得到7。可用Na2S、K2S、NaSH或KS(C=S)OEt,将27转化成28,其中Z是硫。还可在极性质子惰性溶剂中,存在碱如氢化钠时,用炔丙基衍生物29(其中Z是O、S或NH)置换27的氟,直接得到7。
如流程8所示,可通过30得到化合物7(其中Z是亚甲基)。在氯代烃溶剂中用N-溴琥珀酰亚胺将30苄基溴化,得到溴化物31。随后溴化物用合适的铜酸丙炔置换可得到氨磺酰8。
本发明的化合物还可通过以下方法制备:在磺酰基化或磷酸化起始氨基酸衍生物4或8后的任何一个阶段,修饰炔侧链上的取代基。可用标准方法操作官能团如卤素、羟基、氨基、醛、酯、酮等,形成化合物1的R1-R8所定义的部分。有机合成领域的技术人员懂得这些方法的成功使用取决于分子其他部分上取代基的相容性。本文的保护基团和/或反应步骤的顺序可能需要变化。
流程9显示了衍生结构为32的化合物(相当于化合物7,其中R12是氢)的一些方法。将末端炔烃32进行金属取代,然后以醛或烷基卤、磺酸酯或三氟甲烷磺酸酯加成,产生衍生物33和34。32与甲醛和胺反应产生Mannich加成产物35。溴化氰加成于35产生炔丙基溴化物36,它可用各种亲核试剂置换,生成如醚、硫醚和胺37。32的钯催化的偶联反应产生芳基或杂芳基炔38。有机合成领域技术人员懂得这些方法的成功使用取决于分子其他部分上取代基的相容性。本文所述的保护基团和/或反应步骤的顺序可能需要变化,和R35、R45、R55、R65和R75是烷基如甲基;
以下具体实施例说明了本发明代表性化合物的制备。起始原料、中间体和试剂可购得或可用有机合成领域技术人员已知的标准方法不难制备。
实施例1
(反式)-2-(4-甲氧基苯磺酰基)氨基环己烷羧酸
室温,在含有1.7ml(12.2mmol)三乙胺的50ml二噁烷∶H2O(1∶1)配制的1g(6.8mmol)反式-2-氨基-1-环己烷羧酸溶液中,加入1.54g(7.46mmol)4-甲氧基苯磺酰氯。25℃搅拌此混合物18小时。用戊烷稀释得到的混合物,生成1.119g(51%)呈白色固体的所需产物。1H NMR(DMSO-d6):7.7ppm(dd,2H,Ar),7.4ppm(d,1H,NH),7.0ppm(dd,2H,Ar),3.8ppm(s,3H,OMe),3.5ppm(m,1H,N-CH),1.0-1.7ppm(m,9H,烃类)。
实施例2
(顺式)-2-(4-甲氧基苯磺酰基)氨基环己烷羧酸
按实施例1所述相同的方法,用2.5g(17mmol)顺式-2-氨基-1-环己基羧酸生成了3.283g(60%)所需的羧酸。电喷雾质谱314.1(M+H)+。
实施例3
(反式)-2-(4-甲氧基苯磺酰基)氨基环己烷羧酸叔丁酯
在5.0ml甲苯配制的0.313g(1mmol)实施例1产物的溶液中加入1ml(4mmol)N,N-二甲基甲酰胺二叔丁基乙缩醛。氮气中在110加热得到的混合物4小时,然后冷却至室温。将溶液倾倒在硅胶柱的顶部。以10-20%乙酸乙酯/己烷洗脱,硅胶层析得到353mg(96%)呈白色固体的所需酯。1H NMR(CDCl3):7.8ppm(dd,2H,Ar),7.0ppm(dd,2H,Ar),5.7ppm(d,1H,NH),3.9ppm(s,3H,OMe),3.4ppm(m,1H,N-CH),2.5ppm(m,1H,CH-CO2-),1.0-2.0ppm(m,17H,烃类)。
实施例4
(顺式)-2-(4-甲氧基苯磺酰基氨基)-环己烷羧酸叔丁酯
按实施例3所述相同的方法,用1.438g(4.59mmol)实施例2的产物生成0.379g(44%)呈无色油状的所需叔丁酯。电喷雾质谱370.1(M+H)+。
实施例5
(反式)-2-[苄基-(4-甲氧基苯磺酰基)氨基]-环己烷羧酸叔丁酯
在31ml DMF配制的1.146g(3.1mmol)实施例3产物的溶液中加入0.137g(3.42mmol)60%氢化钠。在25℃搅拌得到的混合物30分钟,然后一次性加入0.42ml(3.50mmol)溴化苄。55℃搅拌得到的反应混合物10小时,然后倾倒入水中,用***提取。用水和盐水洗涤混合的有机物,MgSO4干燥,过滤并真空浓缩,得到白色固体,用乙酸乙酯/己烷重结晶后得到1.364g(95%)所需的产物。1HNMR(CDCl3):7.7ppm(dd,2H,Ar),7.1-7.4(m,5H,Ar),6.9ppm(dd,2H,Ar),4.5-4.7ppm(AB四,2H,CH-Ar),3.9ppm(s,3H,OMe),4.0ppm(m,1H,N-CH),2.9ppm(m,1H,CH-CO2-),1.0-2.3ppm(m,17H,烃类)。
实施例6
(顺式)-2-[苄基-(4-甲氧基苯磺酰基)氨基]-环己烷羧酸叔丁酯
按实施例5所述相同的方法,用0.600g(1.62mmol)实施例4的产物生成0.310g(42%)呈无色油状的所需苄酯。电喷雾质谱460.1(M+H)+。
实施例7
(反式)-2-[苄基-(4-甲氧基苯磺酰基)氨基]-环己烷羧酸
在10ml二氯甲烷配制的1.364g(2.97mmol)实施例5产物的溶液中加入10ml三氟乙酸,室温搅拌此混合物4小时。真空除去溶剂,以10-100%乙酸乙酯/己烷洗脱,硅胶层析残留物得到1.092g(73%)呈白色固体的所需产物。电喷雾质谱404.2(M+H)+。
实施例8
(反式)-2-[苄基-(4-甲氧基苯磺酰基)氨基]-环己烷羧酸
按实施例7所述相同的方法,用0.240g(0.522mmol)实施例6的产物生成0.207g(98%)呈白色固体的所需羧酸。电喷雾质谱404.0(M+H)+。
实施例9
4-丁-2-炔氧基-苯磺酰酸钠盐
在1L异丙醇和225ml 1.0N氢氧化钠溶液配制的52.35g(0.225mol)4-羟基苯磺酸钠溶液中加入59.96g(0.45mol)1-溴-2-丁炔。将得到的混合物加热至70℃15小时,然后真空蒸发除去异丙醇。过滤收集产生的白色沉淀,用异丙醇和***洗涤,真空干燥得到56.0g(100%)呈白色固体的丁炔醚。
实施例10
4-丁-2-炔氧基-苯磺酰氯
在29ml二氯甲烷配制的43.8ml(0.087mol)2M草酰氯/二氯甲烷的0℃溶液中逐滴加入6.77ml(0.087mol)DMF,随后加入7.24g(0.029mol)实施例9的产物。0°搅拌此反应混合物10分钟,然后让其升温至室温,搅拌2天。然后将反应物倾倒入冰中,用150ml己烷提取。用水和盐水洗涤有机物,Na2SO4干燥,过滤并真空浓缩,得到6.23g(88%)呈黄色固体的磺酰氯;m.p.63-65℃。电喷雾质谱为:243.9MH+
实施例11
丁-2-炔氧基-苯
在溶解于100ml苯和40ml THF的6.14g(0.023mol)三苯基膦的溶液中加入1.75ml(0.023mol)2-丁炔-1-醇。5分钟后,在反应物中加入溶解于10mlTHF的2.08(0.023mol)苯酚,然后再加入3.69ml(0.023mol)偶氮二羧酸二乙酯。室温搅拌得到的反应混合物18小时,真空浓缩。以乙酸乙酯/己烷(1∶10)洗脱,硅胶层析残留物,得到2.18g(70%)呈清澈液体的丁炔醚。EI质谱:146.0MH+。
实施例12
4-丁-炔氧基-苯磺酰氯
在丙酮/冰浴中N2下,逐滴将0.3ml二氯甲烷配制的0.073ml(1.1mmol)氯磺酸加到由0.3ml二氯甲烷配制的0.146g(1.0mmol)实施例11产物的溶液中。加完后,移去冰浴,室温搅拌反应物2小时。然后在反应物中逐滴加入0.113ml(1.3mmol)草酰氯,随后加入0.015ml DMF。加热反应物回流2小时,然后用己烷稀释,倾倒入冰水中。用盐水洗涤有机层,硫酸钠干燥,真空浓缩得到0.130g(53%)呈浅褐色固体的所需产物。
实施例13
(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-环己烷羧酸
在含有2.55ml(18.3mmol)三乙胺的75ml二噁烷∶H2O(1∶1)配制的1.5g(10.2mmol)反式-2-氨基-1-环己烷羧酸的室温溶液中,加入3.0g(11.2mmol)4-丁炔氧基苯磺酰氯。25℃搅拌此混合物18小时。用乙酸乙酯稀释得到的混合物,用1N盐酸水溶液(3X)洗涤。无水硫酸镁干燥有机相,真空浓缩得到呈白色固体的(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-环己烷羧酸。电喷雾质谱为:352.2(M+H)+
实施例14
叔-丁基(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-环己烷羧酸
在30ml甲苯配制的2.1g(6mmol)(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-环己烷羧酸溶液中加入6ml(24mmol)N,N-二甲基甲酰胺二叔丁基乙缩醛。氮气中110℃加热得到的混合物4小时,然后冷却至室温。将溶液倾倒入硅胶柱的顶部。以10-20%乙酸乙酯/己烷洗脱,硅胶层析得到1.7g呈白色固体的叔-丁基(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-环己烷羧酸。电喷雾质谱为:408.3(M+H)+
实施例15
(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-环己烷羧酸叔-丁酯
在20ml DMF配制的1.38g(3.4mmol)(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)环己烷羧酸叔丁醇的溶液中加入0.164g(4.1mmol)60%氢化钠。25℃搅拌得到的反应混合物30分钟,一次性加入0.26ml(4.1mmol)碘代甲烷。25℃搅拌此反应混合物0.5小时,然后加入水和乙酸乙酯。用水洗涤有机物,无水碳酸钾干燥,真空浓缩得到呈白色固体的(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-环己烷羧酸叔-丁酯。电喷雾质谱为:422.2(M+H)+
实施例16
(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-环己烷羧酸
在20ml二氯甲烷配制的(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-环己烷羧酸叔-丁酯溶液中加入5ml三氟乙酸,室温搅拌此混合物3小时。真空除去溶剂,以甲醇/二氯甲烷洗脱,硅胶层析残留物。用乙酸乙酯/己烷研磨得到1.04g呈白色固体的(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-环己烷羧酸。电喷雾质谱为:364.3(M+H)+
实施例17
(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-N-羟基环己烷甲酰胺
0℃,在二氯甲烷配制的草酰氯(1.42ml在二氯甲烷中为2M的溶液)的溶液中加入二甲基甲酰胺(0.22ml)。15分钟后,加入以二甲基甲酰胺配制的(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-环己烷羧酸溶液,室温搅拌得到的反应混合物1小时。
在分液瓶中,在7.6ml THF和3.2ml水配制的0.987g盐酸羟胺0℃混合物中加入3ml三乙胺。混合后0℃搅拌15分钟,一次性加入酰基氯溶液,然后让得到的溶液升温至室温,再搅拌18小时。然后在反应瓶中加入乙酸乙酯和重碳酸钠水溶液。用重碳酸钠水溶液洗涤有机相,无水碳酸钾干燥。真空浓缩,用二***研磨得到呈白色固体的(485mg)(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-N-羟基环己烷羧酸。电喷雾质谱为:381.2(M+H)+
实施例18
(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-N-羟基环己烷甲酰胺
如实施例17所述的相同方法,用0.50g(1.42mmol)(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)环己烷羧酸生成0.32g呈白色固体的(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-N-羟基环己烷甲酰胺。电喷雾质谱为:367.2(M+H)+
实施例19
3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)丙酸叔丁酯
0℃,在20ml二氯甲烷配制的叔-丁基-2-氨基丙酸(2.0g,11.0mmol)溶液中加入三乙胺(6.75ml,48.4mmol),然后加入4-(2-丁炔氧基)苯磺酰氯(2.94g,12.1mmol)。在此浓浆中加入10ml二氯甲烷。搅拌此混合物过夜,然后用二氯甲烷稀释,顺序用水、2N柠檬酸水溶液和盐水洗涤,无水硫酸钠干燥。过滤、真空浓缩得到固体,然后用己烷/乙酸乙酯研磨得到呈灰白色固体的3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)丙酸叔丁酯(3.88g),mp 63-65℃。分析C17H23NO5S:计算值:C,55.77;H,6.56;N,3.96,实测值:C,57.68;H,6.42;N,3.90。电喷雾质谱为:354.2(M+H)+
实施例20
N-{[4-(2-丁炔氧基)苯基]磺酰基}-β-丙氨酸
按实施例16所述相同的流程,用3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)丙酸叔丁醇(1.0g,2.83mmol)生成呈白色固体的N-{[4-(2-丁炔氧基)苯基]磺酰基}-β-丙氨酸(1.12g)。电喷雾质谱为:296.2(M-H)-
实施例21
3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-N-羟基丙酰胺
在二甲基甲酰胺(5ml)配制的N-{[4-(2-丁炔氧基)苯基]磺酰基}-β-丙氨酸(0.80g,2.69mmol)溶液中加入1-羟基苯并***(0.436g,3.23mmol)和1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺(0.67g,3.5mmol)。1小时后,加入50%羟胺水溶液(1.3ml)。搅拌此反应混合物过夜,真空浓缩。加入乙酸乙酯,用水(2X)和盐水洗涤有机相,然后无水硫酸钠干燥。过滤、真空浓缩得到的白色固体,用乙酸乙酯研磨后生成呈白色固体的3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-N-羟基丙酰胺(0.30g),mp118-128℃。电喷雾质谱为:313.3(M+H)+
实施例22
3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)丙酸叔丁酯
0℃,在二甲基甲酰胺(5ml)配制的3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)丙酸叔丁酯(1.0g,2.83mmol)溶液中加入氢化钠(3.39mmol),然后加入碘代甲烷(211μl,3.39mmol)。72小时后,用乙酸乙酯稀释反应混合物,用水和盐水洗涤,无水硫酸钠干燥。过滤并真空浓缩后得到呈无色油状的3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)丙酸叔丁酯(1.0g)。电喷雾质谱为:368.2(M+H)+
实施例23
N-{[4-(2-丁炔氧基)苯基]磺酰基}-N-甲基-β-丙氨酸
按实施例16所述相同的流程,用3-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]丙酸叔丁酯(0.863g,2.34mmol)生成呈白色固体的N-{[4-(2-丁炔氧基)苯基]磺酰基}-N-甲基-β-丙氨酸(0.760g),mp90-110℃。电喷雾质谱为:312.1(M+H)+
实施例24
3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-N-羟基丙酰胺
按实施例21所述,将N-{[4-(2-丁炔氧基)苯基]磺酰基)-N-甲基-β-丙氨酸(0.7g,2.25mmol)转化成3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-N-羟基丙酰胺(0.525g,白色固体)。分析C14H18N2O5S:计算值:C,51.52;H,5.56;N,8.58,实测值:C,51.38;H,5.16;N,8.28。电喷雾质谱为:327.2(M+H)+
实施例25
(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]环戊烷羧酸
0℃,在1∶1水∶二甲基甲酰胺(10ml)配制的顺式-2-氨基-1-环戊烷(1.0g,7.74mmol)溶液中加入碳酸钠(2.7g,25.5mmol),然后再加入4-(2-丁炔氧基)苯基磺酰氯(2.08g,8.5mmol)。让反应混合物升温至室温。搅拌过夜后,加入水和乙酸乙酯,用6N盐酸将混合物酸化至pH=1。用水和盐水洗涤有机相,无水硫酸钠干燥。过滤并真空浓缩得到呈白色固体的(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]环戊烷羧酸1.58g,mp105-135℃。电喷雾质谱为:336.4(M+H)+
实施例26
(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基环戊烷羧酸
按实施例21所述,将(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]环戊烷羧酸(0.506g,1.5mmol),转化成(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基环戊烷羧酸(0.28g),得到灰白色固体(0.185g),mp140-145℃。电喷雾质谱为:353.4(M+H)+
实施例27
(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]环戊烷羧酸叔丁酯
按实施例14所述,将(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]环戊烷羧酸(0.80g)转化成呈白色晶体的(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]环戊烷羧酸叔丁酯(0.60g),mp97-110℃。分析C20H27NO5:计算值:C,61.05;H,6.92;N,3.56,实测值:C,61.04;H,6.79;N,3.72。电喷雾质谱为:394.2(M+H)+
实施例28
(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基环戊烷羧酸叔丁酯
将二甲基甲酰胺(4ml)配制的(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基环戊烷羧酸叔丁酯(0.50g,1.27mmol)用碳酸钾(0.527g,3.81mmol)和碘代甲烷(95μl,1.53mmol)处理。18小时后,真空浓缩反应混合物,用乙酸乙酯稀释,用水和盐水洗涤,无水硫酸钠干燥。过滤和真空浓缩得到呈白色固体的(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基环戊烷羧酸叔丁酯(0.495g),mp131-133℃。电喷雾质谱为:408.2(M+H)+
实施例29
(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]环戊烷羧酸
按实施例16所述,将(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基环戊烷羧酸(0.44g)叔丁酯转化成呈白色固体的(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]环戊烷羧酸(0.375g)。电喷雾质谱为:352.2(M+H)+
实施例30
(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]N-羟基环戊烷甲酰胺
按实施例21所述,将(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]环戊烷羧酸(0.320g)转化成呈白色晶体的(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]N-羟基环戊烷甲酰胺(0.105g),mp160-164℃。分析C17H22N2O5S:计算值:C,55.72;H,6.05;N,7.64,实测值:C,55.40;H,6.15;N,7.50。电喷雾质谱为:367.25(M+H)+
实施例31
(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基环己烷羧酸
按实施例25所述,将顺式-2-氨基-1-环己烷(1.2g,8.38mmol)转化成呈白色固体的(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基环己烷羧酸(0.825g),mp172-175℃。分析C17H21NO5S:计算值:C,58.10;H,6.02;N,3.99,实测值:C,58.32;H,5.92;N,3.87。电喷雾质谱为:350.1(M-H)-
实施例32
(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基环己烷甲酰胺
按实施例21所述,将(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基环己烷羧酸(0.300g,0.854mmol)转化成呈灰白色泡沫状的(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基环己烷甲酰胺(0.210g)。电喷雾质谱:367.2(M+H)+
实施例33
(顺式)-叔-丁基-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]环己烷羧酸
按实施例14所述,将(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基环己烷羧酸(0.38g,1.08mmol)转化成呈白色固体的(顺式)-叔-丁基-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]环己烷羧酸(0.450g)。电喷雾质谱:408.2(M+H)+
实施例34
(顺式)-叔-丁基-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]环己烷羧酸
按实施例28所述所述,将(顺式)-叔-丁基-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]环己烷羧酸(0.390g,0.956mmol)转化成呈无色油状的(顺式)-叔-丁基-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]环己烷羧酸(0.260g)。电喷雾质谱:422.2(M+H)+
实施例35
(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]环己烷羧酸
按实施例16所述,将(顺式)-叔-丁基-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]环己烷羧酸(0.220g,0.522mmol)转化成呈白色固体的(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]环己烷羧酸(0.190g)。电喷雾质谱:366.2(M+H)+
实施例36
(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基环己烷甲酰胺
按实施例21所述,将(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]环己烷羧酸(0.165g,0.45mmol)转化成呈灰白色固体的(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基环己烷甲酰胺(0.50g)。电喷雾质谱:381.2(M+H)+
实施例37
(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)二环[2.2.1]庚烷-2-羧酸
按实施例25所述,将3-外-氨基二环[2.2.1]庚烷-2-外-羧酸(1.0g,6.44mmol)转化成呈白色固体的(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)二环[2.2.1]庚烷-2-羧酸(1.32g),mp195-215℃。电喷雾质谱:364.3(M+H)+
实施例38
(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-N-羟基二环[2.2.1]庚烷-2-甲酰胺
按实施例21所述,将(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)二环[2.2.1]庚烷-2-羧酸(0.363g,1mmol)转化成呈白色固体的(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-N-羟基二环[2.2.1]庚烷-2-甲酰胺(0.30g)。分析C18H22N2O5S:计算值:C,57.13;H,5.86;N,7.4,实测值:C,57.76;H,6.12;N,7.6。电喷雾质谱为:379.3(M+H)+
实施例39
(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)二环[2.2.1]庚烷-2-羧酸叔丁酯
按实施例14所述,将(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)二环[2.2.1]庚烷-2-羧酸(0.80g,2.2mmol)转化成呈白色固体的(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)二环[2.2.1]庚烷-2-羧酸叔丁酯(0.69g),mp94-99℃。分析C22H29NO5S:计算值:C,62.98;H,6.97;N,3.34,实测值:C,62.65;H,6.95;N,3.7。电喷雾质谱为:420.3(M+H)+
实施例40
(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)二环[2.2.1]庚烷-2-羧酸叔丁酯
按实施例28所述,将(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)二环[2.2.1]庚烷-2-羧酸叔丁酯(0.55g,1.31mmol)转化成呈白色固体的(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)二环[2.2.1]庚烷-2-羧酸叔丁酯(0.54g),mp120-125℃。分析C23H31NO5S:计算值:C,63.72;H,7.21;N,3.23,实测值:C,63.34;H,7.11;N,3.55。电喷雾质谱为:434.2(M+H)+
实施例41
(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)二环[2.2.1]庚烷-2-羧酸
按实施例16所述,将(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)二环[2.2.1]庚烷-2-羧酸叔丁酯(0.45g.1.04mmol)转化成呈白色固体的(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)二环[2.2.1]庚烷-2-羧酸(0.37g),mp153-158℃。分析C19H23NO5S:计算值:C,60.46;H,6.14;N,3.71,实测值:C,60.71;H,5.94;N,3.97。电喷雾质谱为:378.1(M+H)+
实施例42
(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-N-羟基二环[2.2.1]庚烷-2-甲酰胺
按实施例21所述,将(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)二环[2.2.1]庚烷-2-羧酸(0.30g,0.79mmol)转化成(1R,2R,3S,4R)-(顺式)-3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基)-N-羟基二环[2.2.1]庚烷-2-甲酰胺(0.137g)。电喷雾质谱为:393.2(M+H)+
药理学
以下的体外试验显示:本发明化合物及其药学上可接受的盐,具有抑制基质金属蛋白酶或TACE的能力,并由此证明它们对治疗受基质金属蛋白酶或TACE介导的疾病的效果。
测定MMP-1、MMP-9和MMP-13抑制的测试程序
这些标准药理测试程序是基于基质金属蛋白酶MMP-1、MMP-13(胶原酶)或MMP-9(明胶酶)切割硫肽(thiopeptide)底物如Ac-Pro-Leu-Gly(2-巯基-4-甲基-戊醇基)-Leu-Gly-OEt,导致释放出能与DTNB(5,5′-二硫二(2-硝基-苯甲酸)产生颜色反应的底物产物。用颜色增加的速率衡量酶的活性。用溶于100%DMSO的20mM硫肽底物的新配制原液,将DTNB溶解在100%DMSO中作为100mM原液,室温储存在暗处。使用前用底物缓冲液(50mM HEPES pH7.5,5mMCaCl2)将底物和DTNB一起稀释至1mM。用缓冲液(50mM HEPES,pH7.5,5mMCaCl2,0.02%Brij)将酶原液稀释至所需的最终浓度。按缓冲液、酶、运载体或抑制剂、和DTNB/底物的顺序将这些物质加到96孔板中(终反应体积为200μl),在405nm用分光光度议平板读数仪上监测颜色的增加5分钟,绘制随时间颜色增加的线性图。
另外,使用荧光肽底物。在该测试程序中,肽底物含有荧光基团和淬灭基团。一旦MMP切割底物,在荧光平板读数仪上定量测定产生的荧光。在HCBC试验缓冲液(50mM HEPES,pH7.0,5mM Ca+2,0.02%Brij,0.5%半胱氨酸)中用人重组MMP-1、MMP-9或MMP-13进行该试验。将底物溶解在甲醇中,以1mM等份冰冻储存。该试验中,用HCBC缓冲液将底物和酶稀释至所需的浓度。将化合物加到含酶的96孔板中,加入底物开始反应。读取(340nm激发,444nm发射)应10分钟,绘制随时间荧光增加的线性图。
对硫肽或荧光肽测试程序而言,计算直线的斜率,其代表反应速率。证实反应速率的线性(r2>0.85)。计算对照速率的平均值(x±sem),并用Dunnett多重比较检验与药物处理速率比较有统计学显著性(p<0.05)。用多种剂量的药物可得到剂量—反应关系,用线性回归估计95%CI的IC50值。
测定TACE抑制的试验程序
用96孔黑色微量滴定板,各孔加入由10μl TACE(终浓度为1μg/ml)、70μl Tris缓冲液、pH7.4含有10%甘油(终浓度为10mM)、和10μl以DMSO配制的测试化合物(终浓度为1μM,DMSO浓度<1%)组成的溶液,室温培育10分钟。各孔中加入荧光肽底物(终浓度为100μM)以引发反应,然后在摇床上振荡5秒。
读取反应10分钟(340nm激发,420nm发射),绘制随时间荧光增加的线性图。计算该线的斜率,其代表反应速率。
证实反应速率的线性(r2>0.85)。计算对照速率的平均值(x±sem),并用Dunnett多重比较检验与药物处理速率比较有统计学显著性(p<0.05)。用多种剂量的药物可得到剂量—反应关系,用线性回归估计95%CI的IC50值。
可溶性蛋白质的人单核THP-1细胞分化试验(THP可溶性蛋白质试验)
有丝***刺激THP-1细胞致使***成巨噬细胞样细胞,伴有除其他蛋白质外同时分泌肿瘤坏死因子(TNF-α)和TNF受体(TNF-R,p75/80和TNF-R p55/60)以及白细胞介素-8(IL-8)。另外,在该时间以后未受刺激的THP-1细胞分泌出p75/80和p55/60受体。称为TNF-a转化酶或TACE的酶介导了膜结合TNF-α的释放和可能的TNF-R p75/80和TNF-R p55/60的释放但无IL-8释放。可用该试验来证明抑制性或刺激性化合物对此TACE酶的作用和该化合物的细胞毒性结果。
THP-1细胞(由ATCC获得)是一种人单核细胞系,获自一个一岁的患急性单核细胞白血病男童的外周血液。它们可以在培养基中生长,且受促细胞***剂刺激后能***成巨噬细胞样细胞。
在该试验中,由上述生长的和以5×106ml/瓶冷冻保藏的ATCC原液中采集THP-1细胞。将一管接种到T25瓶中,其中含有16ml补充有Glutamax(Gibco)的RPMI-1640培养基(含10%胎牛血清、100单位/ml青霉素、100μg/ml链霉素和5×10-5M 2-巯基-乙醇(THP-1培养基))。在用于试验前,将各管细胞培养约2星期,然后再使用4-6周来筛选化合物。在星期一和星期四传代细胞至浓度1×105/ml。
为了进行试验,37℃在5%CO2中,将THP-1细胞以1.091×106个细胞/ml(1.1ml/孔)在24孔平板中,与每孔含有50ml 24mg/ml的脂多糖(LPS)(CalbiochemLot#B13189)原液共培养24小时。同时将50ml/孔的药物、运载体或THP-1培养液置于适当的孔中,终体积为1.2ml/孔。将标准化合物和测试化合物溶解在浓度为36mM的DMSO中,并从此浓度用THP-1培养基稀释至适当的浓度,在培养开始时加到诸孔中,使终浓度为100mM、30mM、10mM、3mM、1mM、300nM和100nM。将与DMSO接触的细胞限制在0.1%终浓度。试验中包括阳性对照孔,其中有促细胞***剂但无药物。还包括运载体对照孔,除加入终浓度为0.083%的DMSO外都与阳性对照相同。试验中还包括阴性对照孔,细胞中加入了运载体但不加促细胞***剂或药物。可通过用50ml/孔的THP-1培养基代替LPS评估化合物对受体基础性(无刺激)分泌的作用。将平板置于设置为5%CO2和37℃的培养箱中。培养4小时后,取出300ml/孔组织培养物上清液(TCS)用于TNF-a ELISA。培养24小时后,取出700ml/孔TCS,用于TNF-R p75/80、TNF-R p55/60和IL-8 ELISA分析。
另外在24小时时,将细胞重悬浮于500μl/孔的THP-1培养液中收集各处理组的细胞,并转移到FACS管中。加入2ml/管0.5mg/ml二碘化丙锭原液(PI)(Boerhinger Mannheim cat.#1348639)。将这些样品在Becton Dickinson FaxCaliberFLOW细胞记数仪上跑样,以红外线波长(FL3)测定各细胞摄取的染料量。只有膜受损的细胞(死或濒死)才吸收PI。通过计数未被PI染色的细胞除以样品中细胞的总量来计算活细胞百分比。将药物处理组的活力计算值与运载体处理的促细胞***剂刺激组(“载体阳性对照”)的活力计算值相比较,确定“相当于对照的变化百分比”。这个“相当于对照的变化百分比”是表明药物细胞毒性的一种指标。
采用从R&D Systems购得的ELISAs测得THP-1细胞培养物的TCS中可溶性TNF-a、TNF-R p75/80和TNF-R p55/60和IL-8的量,通过用试剂盒标准品所产生的标准曲线外推。用FLOW细胞记数仪测定了摄取或排斥PI的细胞数量,并用可购得的Cytologic软件绘制直方图直观化各处理组(包括所有对照)的数据。
THP-1细胞培养物的反应强度的生物学变化要求根据每种药物的“载体阳性对照”的变化百分比为基础对这些试验进行比较。按以下公式计算各化合物浓度的各可溶性蛋白质相当于“载体阳性对照”的变化百分比:
对于刺激条件下可溶性蛋白质(TNF-a、p75/80、p55/60、IL-8)的研究,测定了重复孔的平均值pg/ml,结果以相当于“载体阳性对照”的变化百分比表示。对于非刺激条件下可溶性蛋白质(p75/80和p55/60受体)的研究,测定了重复孔的平均值pg/ml,结果用以下公式表示成相当于“载体阳性对照”的变化百分比:
用定制的软件(使用JUMP统计软件包),由非线性的回归分析计算出各化合物的IC50值。
参考文献:
Bjornberg,F.,Lantz,M.,Olsson,I.,和Gullberg,U.“将p55和p75肿瘤坏死因子(TNF)受体加工成可溶性受体形式有关的机制”,Lymphokine Cytokine Res.13:203-211,1994。
Gatanaga,T.,Hwang.C.,Gatanaga,M.,Cappuccini,F.,Yamamoto,R.,和Granger,G.“体外PMA-和LPS刺激的人单核THP-1细胞对TNF mRNA合成、膜表达和释放的调节”,Cellular Immun.138:1-10,1991。
Tsuchiya,S.,Yamabe,M.,Yamagughi,Y.,Kobayashi,Y.,Konno,T.,和Tada,K.“人急性单核细胞白血病细胞系(THP-1)的建立和特性分析”,Int.J.Cancer.26:1711-176,1980。
下表I列出了上述体外基质金属蛋白酶抑制、TACE抑制和THP标准药理测试方法的结果。
表1:
实施例# | MMP-1a | MMP-9a | MMP-13a | TACEa | THPb |
17 | >10μM | >10μM | >10μM | 28 | 14 |
18 | >10μM | >10μM | >10μM | 61 | 1 |
21 | >10μM | >10μM | >10μM | 145 | 0 |
24 | >10μM | -10μM | -10μM | 73 | 9 |
26 | >1μM | 5056 | 672 | 15 | 23 |
30 | 2768 | 383 | 308 | 14 | 65 |
32 | >10μM | -10μM | 1738 | 36 | 29 |
36 | 4229 | 1319 | 1820 | 53 | 23 |
38 | >10μM | >10μM | ~10μM | 30 | 9 |
42 | ~10μM | - | 1142 | 62 | 77 |
aIC50(nM)
b在3μM时的抑制
根据上述标准药理测试方法,本发明的化合物可用于治疗病症如关节炎、肿瘤转移、组织溃疡、异常伤口愈合、牙周病、移植排斥、胰岛素抗性、骨骼病和HIV感染等疾病。
本发明的化合物还可用于治疗或抑制基质金属蛋白酶介导的病理变化如动脉粥样硬化、动脉粥样硬化斑形成、动脉粥样硬化斑破溃所致的冠脉血栓形成的复原、再狭窄、MMP-介导的骨质疏松、中枢神经***的炎性疾病、肌肤老化、新血管生成、肿瘤转移、肿瘤生长、骨关节炎、类风湿性关节炎、脓毒性关节炎、角膜溃疡、蛋白尿、动脉瘤病、创伤性关节损伤后的退化性软骨丢失、神经***的脱髓鞘病、肝硬化、肾小球疾病、胎膜早破、肠炎病、年龄相关的黄斑变性、糖尿病视网膜病、增生性玻璃体视网膜***、视网膜未熟病、眼部炎症、圆锥形角膜、斯耶格伦综合症、近视、眼部肿瘤、眼部血管生成/血管再生和角膜移植排斥。
本发明的化合物可单独给予或与药用载体一起给予需要其的患者。药用载体可以是固体或液体。
可采用的固体载体包括一种或多种物质,这些载体也可作为增香剂、润滑剂、稳定剂、悬浮剂、填充剂、助流剂、助压剂、粘合剂或药片崩解剂或封装材料。在粉状制剂中,载体是分散得很细的固体,可与分散得很细的活性组分相混合。在片剂中,活性组分与适当比例的具有必需的助压特性的载体相混合,被压制成所需的性状和尺寸。粉末制剂和片剂较佳地含有多至99%活性组分。合适的固体载体包括如磷酸钙、硬脂酸镁、滑石粉、糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠盐、聚乙烯吡咯烷酮、低熔点蜡和离子交换树脂。
液态载体可用于制备溶液、悬浮液、乳剂、糖浆和酏剂。可将本发明的活性组分溶解于或悬浮于药学上可接受的液态载体如水、有机溶剂、这两者的混合物或药学上可接受的油或脂肪中。液态载体可含有其他合适的药用添加剂如稳定剂、乳化剂、缓冲剂、防腐剂、甜味剂、增香剂、悬浮剂、增稠剂、色素、粘度调节剂、稳定剂或渗透调节剂。合适的用于口服和肠胃外给药的液态载体的例子包括水(尤其含有上述添加剂如纤维素衍生物,较佳地是羧甲基纤维素钠盐的溶液)、醇(包括一元醇和多元醇如甘油)和它们的衍生物,和油(如分级椰子油和花生油)。用于肠胃外给药的载体也可以是油酯,如油酸乙酯和肉豆蔻酸异丙酯。无菌液态载体可用于肠胃外给药的无菌液体形式的组合物中。
可将无菌溶液或悬浮液的液体药物组合物用于例如肌内、腹腔内或皮下注射。也可静脉内注射给予无菌溶液。口服给药可以是液体或固体组合物形式。
可以常规栓剂的形式直肠给予本发明的化合物。对于鼻内或支气管内吸入或吹入给药,可将本发明的化合物配制成水溶液或部分水溶液,然后以气雾剂形式使用。本发明的化合物还可以透皮给予,采用含有活性化合物和对该活性化合物为惰性、对皮肤无毒的载体的透皮贴片,通过皮肤让该药剂全身吸收送递入血流。运载体可以采取多种形式如乳剂、软膏、糊剂、凝胶和包藏装置。乳剂和软膏可以是粘性液体或水包油或油包水类型的半固体乳剂。由分散在含该活性组分的石油或亲水性石油中的吸收性粉末构成的糊膏。可用各种包藏装置将该活性组分释放到血流中,如覆盖含有该活性组分的有或无载体的储器、或含有该活性组分的基质的半透膜。其他包藏装置是本领域已知的。
必须由主治医生主观确定用于治疗患MMP或TACE依赖性病症的具体患者的剂量。所涉及的各种变化包括功能紊乱的严重程度、和患者的体形、年龄和反应模式。通常从低于该化合物最佳剂量的小剂量开始治疗。随后逐渐增加剂量直到在此情况下达到最佳效果。可由给药的医生依据治疗个体的经验和标准的用药原则,确定口服、肠胃外、鼻内或支气管内给药的精确剂量。
较佳地,此药用组合物以单位剂量形式如片剂或胶囊。在该形式中,将此组合物再分成含有适当量该活性组分的单位剂量;单位剂量形式可以是包装的组合物如包装的粉末、小瓶、安瓿、预先充满的针筒或含有液体的小袋。单位剂量形式可以是例如胶囊或片剂本身,或者也可是适当数量的包装形式的这些组合物。
Claims (13)
1.一种具有下式的异羟肟酸及其药学上可接受的盐:其中C(=O)NHOH部分和-NR5-部分连接于相邻的碳原子;
X是SO2或-P(O)R10;
Y是5-10元杂芳基环,所述的杂芳基环的1-3个杂原子选自N、NR9、S和O;苯基或萘基;条件是X和Z不连接于Y的相邻原子;
Z是O、NH、CH2或S;
R5是氢或1-6个碳原子的烷基;
R6和R7各是氢或甲基;
R8是氢,1-6个碳原子的烷基,2-6个碳原子的链烯基,2-6个碳原子的炔基,3-6个碳原子的环烷基,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,或5-7元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、S或O,或苯基;
R9是氢、1-6个碳原子的烷基、3-6个碳原子的环烷基或苯基;
R10是1-6个碳原子的烷基,3-6个碳原子的环烷基,苯基,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O;
R11和R12各是氢,1-6个碳原子的烷基,3-6个碳原子的环烷基,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元杂环烷基,所述的杂环烷基的1-2个杂原子选自N、NR9、S或O,或苯基,并且存在点线表示的任选双键;或
R11和R12及连接它们的碳原子一起形成5-10元饱和的或不饱和的单环或双环烷基环,可任选地稠合于一5-7元饱和的或不饱和的环烷基环,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、S或O,苯环或萘环;或
R11和R12及连接它们的碳原子一起形成5-10元饱和的或不饱和的单环或双环杂环烷基,所述的双环杂环烷基的1-2个杂原子选自N、NR9、S或O,其可任选地稠合于一5-7元单环或双环杂芳基,所述的双环杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元饱和的或不饱和的环烷环或苯环或萘环;
点线表示可任选的双键;
和n=0-2。
2.如权利要求1所述的化合物,其特征在于,所述的X是SO2。
3.如权利要求1或2所述的化合物,其特征在于,所述的Y是在1-或4-位被X和Z分别取代的苯环。
4.如权利要求1-3任一所述的化合物,其特征在于,所述的Z是氧。
5.如权利要求1-4任一所述的化合物,其特征在于,所述的R6和R7是氢。
6.如权利要求1-5任一所述的方法,其特征在于,所述的R8是CH2OH或甲基。
7.如权利要求1所述的化合物,其特征在于,所述的化合物选自:(1R,2R)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基环己烷甲酰胺;
(1R,2R)-2-({[4-(2-丁炔氧基)苯基]磺酰基}氨基)-N-羟基环己烷甲酰胺;
3-({[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基丙酰胺;
3-({[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基丙酰胺;
(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基环戊烷甲酰胺;
(1R,2S)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基环戊烷甲酰胺;
(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基环己烷甲酰胺;
(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基环己烷甲酰胺;
(1R,2R,3S,4R)-(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}氨基]-N-羟基二环[2.2.1]庚烷-2-甲酰胺;和
(1R,2R,3S,4R)-(顺式)-2-[{[4-(2-丁炔氧基)苯基]磺酰基}(甲基)氨基]-N-羟基二环[2.2.1]庚烷-2-甲酰胺。
8.一种制备权利要求1所述化合物的方法,其特征在于,所述的方法包括如下步骤之一:
b)将式VI的化合物去保护产生式B的相应化合物:其中R5、R6、R7、R8、和R11R12、X、Y和Z及点线的定义如权利要求1所述,R30是合适的保护基团;
c)拆解式B化合物的旋光活性异构体的混合物(如外消旋物),分离出基本无其他对映异构体或非对映异构体的一种对映异构体或非对映异构体;
或
d)用药学上可接受的酸来酸化式B的碱性化合物,得到药学上可接受的盐。
11.一种抑制需要抑制受TNF-α转化酶(TACE)介导的病理变化的哺乳动物的方法,其特征在于,所述的方法包括给予所述的哺乳动物治疗有效剂量的下式化合物或其药学上可接受的盐其中C(=O)NHOH部分和-NR5-部分连接于相邻的碳原子;
X是SO2或-P(O)R10;
Y是5-10元杂芳基环,所述的杂芳基环的1-3个杂原子选自N、NR9、S和O、苯基或萘基;条件是X和Z不连接于Y的相邻原子;
Z是O、NH、CH2或S;
R5是氢或1-6个碳原子的烷基;
R6和R7各是氢或甲基;
R8是氢,1-6个碳原子的烷基,2-6个碳原子的链烯基,2-6个碳原子的炔基,3-6个碳原子的环烷基,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,或5-7元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、S或O,或苯基;
R9是氢、1-6个碳原子的烷基、3-6个碳原子的环烷基或苯基;
R10是氢、1-6个碳原子的烷基、3-6个碳原子的环烷基、苯基、或L;
R11和R12各是氢,1-6个碳原子的烷基,3-6个碳原子的环烷基,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元杂环烷基,所述的杂环烷基的1-2个杂原子选自N、NR9、S或O,或苯基,并且存在点线表示的任选双键;或
R11和R12及连接它们的碳原子一起形成5-10元饱和的或不饱和的单环或双环烷基环,可任选地稠合于-5-7元饱和的或不饱和的环烷基环,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、S或O,苯环或萘环;或
R11和R12及连接它们的碳原子一起形成5-10元饱和的或不饱和的单环或双环杂环烷基,所述的双环杂环烷基的1-2个杂原子选自N、NR9、S或O,可任选地稠合于一5-7元单环或双环杂芳基,所述的双环杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元饱和的或不饱和的环烷基环或苯环或萘环;
点线表示的可任选的双键;
和n=0-2。
12.如权利要求11所述的方法,其特征在于,所述治疗的疾病是类风湿性关节炎、移植排斥、恶病质、炎症、发烧、胰岛素抗性、脓毒性休克、充血性心力衰竭、中枢神经***炎性疾病、肠炎病或HIV感染。
13.一种药物组合物,其特征在于,它包含下式的化合物或其药学上可接受的盐其中C(=0)NHOH部分和-NR5-部分连接于相邻的碳原子;
X是SO2或-P(O)R10;
Y是5-10元杂芳基环,所述的杂芳基环的1-3个杂原子选自N、NR9、S和O;苯基或萘基;条件是X和Z不连接于Y的相邻原子;
Z是O、NH、CH2或S;
R5是氢或1-6个碳原子的烷基;
R6和R7各是氢或甲基;
R8是氢,1-6个碳原子的烷基,2-6个碳原子的链烯基,2-6个碳原子的炔基,3-6个碳原子的环烷基,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,或5-7元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、S或O,或苯基;
R9是氢、1-6个碳原子的烷基、3-6个碳原子的环烷基或苯基;
R10是氢、1-6个碳原子的烷基、3-6个碳原子的环烷基、苯基、或L;
R11和R12各是氢,1-6个碳原子的烷基,3-6个碳原子的环烷基,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元杂环烷基,所述的杂环烷基的1-2个杂原子选自N、NR9、S或O,或苯基,并且存在点线表示的任选双键;或
R11和R12及连接它们的碳原子一起形成5-10元饱和的或不饱和的单环或双环烷基环,可任选地稠合于一5-7元饱和的或不饱和的环烷基环,5-7元杂芳基,所述的杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元杂环烷基,所述的杂环烷基的1或2个杂原子选自N、NR9、S或O,苯环或萘环;或
R11和R12及连接它们的碳原子一起形成5-10元饱和的或不饱和的单环或双环杂环烷基,所述的双环杂环烷基的1-2个杂原子选自N、NR9、S或O,可任选地稠合于一5-7元单环或双环杂芳基,所述的双环杂芳基的1-3个杂原子选自N、NR9、S或O,5-7元饱和的或不饱和的环烷基环或苯环或萘环;
点线表示可任选的双键;
和n=0-2;和药学上可接受的载体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US23908399A | 1999-01-27 | 1999-01-27 | |
US09/239,083 | 1999-01-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1337944A true CN1337944A (zh) | 2002-02-27 |
Family
ID=22900530
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN00803031A Pending CN1337944A (zh) | 1999-01-27 | 2000-01-27 | 作为TACE抑制剂的炔β-氨磺酰和次膦酸酰胺异羟肟酸 |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP1147078A1 (zh) |
JP (1) | JP2002535383A (zh) |
KR (1) | KR20010089617A (zh) |
CN (1) | CN1337944A (zh) |
AR (1) | AR035478A1 (zh) |
AU (1) | AU769410B2 (zh) |
BR (1) | BR0007754A (zh) |
CA (1) | CA2356345A1 (zh) |
CZ (1) | CZ20012709A3 (zh) |
EA (1) | EA200100808A1 (zh) |
HU (1) | HUP0200605A3 (zh) |
IL (1) | IL144321A0 (zh) |
NO (1) | NO20013639D0 (zh) |
NZ (1) | NZ512025A (zh) |
WO (1) | WO2000044711A1 (zh) |
ZA (1) | ZA200104508B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102471260A (zh) * | 2009-06-30 | 2012-05-23 | 盖尔德马研究及发展公司 | 新型苯磺酰胺化合物、其合成方法及其在药品以及美容用品中的用途 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7199155B2 (en) | 2002-12-23 | 2007-04-03 | Wyeth Holdings Corporation | Acetylenic aryl sulfonate hydroxamic acid TACE and matrix metalloproteinase inhibitors |
ATE449760T1 (de) | 2004-03-22 | 2009-12-15 | Southern Res Inst | Nichtpeptidinhibitoren von matrixmetalloproteinasen |
FR2950057B1 (fr) * | 2009-09-17 | 2011-08-26 | Galderma Res & Dev | Nouveaux composes benzene-carboxylamides, leur procede de synthese et leur utilisation en medecine ainsi qu'en cosmetique |
BR112021006407A8 (pt) | 2018-10-04 | 2022-12-06 | Inst Nat Sante Rech Med | uso de inibidores do egfr para ceratodermas |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5514716A (en) * | 1994-02-25 | 1996-05-07 | Sterling Winthrop, Inc. | Hydroxamic acid and carboxylic acid derivatives, process for their preparation and use thereof |
HRP970245B1 (en) * | 1996-05-15 | 2002-06-30 | Bayer Ag | Biaryl acetilenes as matrix metalloprotease inhibitors |
IL129147A0 (en) * | 1996-10-16 | 2000-02-17 | American Cyanamid Co | The preparation and use of ortho-sulfonamide aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
US5977408A (en) * | 1996-10-16 | 1999-11-02 | American Cyanamid Company | Preparation and use of β-sulfonamido hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
ES2200335T3 (es) * | 1997-10-06 | 2004-03-01 | Wyeth Holdings Corporation | Preparacion y utilizacion de acidos orto-sulfonamido(heteroarilo biciclico)hidroxamicos como inhibidores de las metaloproteinasas matriz y del tace. |
-
2000
- 2000-01-26 AR ARP000100325A patent/AR035478A1/es not_active Application Discontinuation
- 2000-01-27 KR KR1020017009153A patent/KR20010089617A/ko not_active Application Discontinuation
- 2000-01-27 EA EA200100808A patent/EA200100808A1/ru unknown
- 2000-01-27 JP JP2000595968A patent/JP2002535383A/ja active Pending
- 2000-01-27 BR BR0007754-2A patent/BR0007754A/pt not_active IP Right Cessation
- 2000-01-27 NZ NZ512025A patent/NZ512025A/en unknown
- 2000-01-27 WO PCT/US2000/001865 patent/WO2000044711A1/en not_active Application Discontinuation
- 2000-01-27 IL IL14432100A patent/IL144321A0/xx unknown
- 2000-01-27 AU AU26306/00A patent/AU769410B2/en not_active Ceased
- 2000-01-27 CA CA002356345A patent/CA2356345A1/en not_active Abandoned
- 2000-01-27 CZ CZ20012709A patent/CZ20012709A3/cs unknown
- 2000-01-27 CN CN00803031A patent/CN1337944A/zh active Pending
- 2000-01-27 EP EP00904570A patent/EP1147078A1/en not_active Withdrawn
- 2000-01-27 HU HU0200605A patent/HUP0200605A3/hu unknown
-
2001
- 2001-05-31 ZA ZA200104508A patent/ZA200104508B/xx unknown
- 2001-07-24 NO NO20013639A patent/NO20013639D0/no not_active Application Discontinuation
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102471260A (zh) * | 2009-06-30 | 2012-05-23 | 盖尔德马研究及发展公司 | 新型苯磺酰胺化合物、其合成方法及其在药品以及美容用品中的用途 |
US8633196B2 (en) | 2009-06-30 | 2014-01-21 | Galderma Research & Development | Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics |
CN102471260B (zh) * | 2009-06-30 | 2014-10-22 | 盖尔德马研究及发展公司 | 苯磺酰胺化合物、其合成方法及其在药品以及美容用品中的用途 |
US8980897B2 (en) | 2009-06-30 | 2015-03-17 | Galderma Research & Development | Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics |
US9365529B2 (en) | 2009-06-30 | 2016-06-14 | Galderma Research & Devlopment | Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics |
Also Published As
Publication number | Publication date |
---|---|
NZ512025A (en) | 2003-08-29 |
EP1147078A1 (en) | 2001-10-24 |
NO20013639L (no) | 2001-07-24 |
ZA200104508B (en) | 2002-09-02 |
CZ20012709A3 (cs) | 2002-04-17 |
HUP0200605A3 (en) | 2005-05-30 |
HUP0200605A2 (hu) | 2002-07-29 |
CA2356345A1 (en) | 2000-08-03 |
AR035478A1 (es) | 2004-06-02 |
NO20013639D0 (no) | 2001-07-24 |
AU769410B2 (en) | 2004-01-29 |
EA200100808A1 (ru) | 2001-12-24 |
JP2002535383A (ja) | 2002-10-22 |
KR20010089617A (ko) | 2001-10-06 |
BR0007754A (pt) | 2001-11-13 |
AU2630600A (en) | 2000-08-18 |
IL144321A0 (en) | 2002-05-23 |
WO2000044711A1 (en) | 2000-08-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1134439C (zh) | 吡咯并[2,3d]嘧啶类化合物及它们作为酪氨酸激酶抑制剂的用途 | |
CN1036920C (zh) | 含杂环碳酸衍生物 | |
JP4343690B2 (ja) | プロテアーゼ阻害薬としてのシアノアルキルアミノ誘導体 | |
CN1296488A (zh) | 双环异羟肟酸类衍生物 | |
CN1280267C (zh) | 磺酰氨基羧酸 | |
CN1172672C (zh) | α-酮酰胺多元催化蛋白酶抑制剂 | |
CN1304930A (zh) | 芳基磺酰基异羟肟酸衍生物 | |
CN1246792A (zh) | 杂环硫酯的n-键合氨磺酰 | |
CN1688548A (zh) | 喹啉抗生素中间体的制备方法 | |
CN1253474A (zh) | 磺酰基二价芳基或杂芳基异羟肟酸化合物 | |
CN1505625A (zh) | 用于治疗由过度细胞因子活性引起的疾病的***化合物 | |
CN1505628A (zh) | 用于治疗由有害细胞因子活性引起的疾病的***化合物 | |
CN1232398A (zh) | Il-8受体拮抗剂 | |
CN1378539A (zh) | 硫代氨基甲酸衍生物 | |
CN1331076A (zh) | 稠合的吡唑基化合物、包含该化合物的组合物及该化合物的应用 | |
CN1224612C (zh) | 炔基磺酰胺硫醇tace抑制剂 | |
CN1040025A (zh) | 新的四氢苯并吲哚丙酸磺酰胺的制备 | |
CN1032534C (zh) | 二氨基三氟甲基吡啶衍生物的制备方法 | |
CN1183107C (zh) | 作为tace抑制剂的含炔基的异羟肟酸化合物 | |
CN1284059A (zh) | 联苯基脒衍生物 | |
CN1301265A (zh) | 新的用作金属蛋白酶抑制剂的取代的芳基异羟肟酸 | |
CN1635979A (zh) | Il-8受体拮抗剂 | |
CN1337944A (zh) | 作为TACE抑制剂的炔β-氨磺酰和次膦酸酰胺异羟肟酸 | |
CN1332724A (zh) | N-芳基磺酰氨基酸ω-酰胺 | |
US6326516B1 (en) | Acetylenic β-sulfonamido and phosphinic acid amide hydroxamic acid TACE inhibitors |
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 |