CN1525956A - α-氨基-N-羟基-乙酰胺衍生物 - Google Patents
α-氨基-N-羟基-乙酰胺衍生物 Download PDFInfo
- Publication number
- CN1525956A CN1525956A CNA028047133A CN02804713A CN1525956A CN 1525956 A CN1525956 A CN 1525956A CN A028047133 A CNA028047133 A CN A028047133A CN 02804713 A CN02804713 A CN 02804713A CN 1525956 A CN1525956 A CN 1525956A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- base
- salt
- amino
- 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.)
- Granted
Links
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 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 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 122
- -1 carboxylic acid halides Chemical class 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 206010028980 Neoplasm Diseases 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 19
- 241001465754 Metazoa Species 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 239000000651 prodrug Substances 0.000 claims description 10
- 229940002612 prodrug Drugs 0.000 claims description 10
- 230000001225 therapeutic effect Effects 0.000 claims description 9
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 4
- 206010048962 Brain oedema Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 208000006752 brain edema Diseases 0.000 claims description 3
- 238000002512 chemotherapy Methods 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000011877 solvent mixture Substances 0.000 claims description 3
- RFHNRJMEXSXGFO-UHFFFAOYSA-N 2-[[2-(cyclopropylmethoxy)phenyl]sulfonyl-[[4-(diethylamino)phenyl]methyl]amino]-n-hydroxyacetamide Chemical compound C1=CC(N(CC)CC)=CC=C1CN(CC(=O)NO)S(=O)(=O)C1=CC=CC=C1OCC1CC1 RFHNRJMEXSXGFO-UHFFFAOYSA-N 0.000 claims description 2
- BHDRFUWOJAIXMU-UHFFFAOYSA-N 2-[[2-(cyclopropylmethoxy)phenyl]sulfonyl-[[4-(diethylamino)phenyl]methyl]amino]-n-hydroxyacetamide;hydrochloride Chemical compound Cl.C1=CC(N(CC)CC)=CC=C1CN(CC(=O)NO)S(=O)(=O)C1=CC=CC=C1OCC1CC1 BHDRFUWOJAIXMU-UHFFFAOYSA-N 0.000 claims description 2
- ZOVRVIVUIBBCAW-UHFFFAOYSA-N 2-[[2-(cyclopropylmethoxy)phenyl]sulfonyl-[[4-(dimethylamino)phenyl]methyl]amino]-n-hydroxyacetamide Chemical compound C1=CC(N(C)C)=CC=C1CN(CC(=O)NO)S(=O)(=O)C1=CC=CC=C1OCC1CC1 ZOVRVIVUIBBCAW-UHFFFAOYSA-N 0.000 claims description 2
- SECUOMRDOIZQHH-UHFFFAOYSA-N 2-[[2-(cyclopropylmethoxy)phenyl]sulfonyl-[[4-(dimethylamino)phenyl]methyl]amino]-n-hydroxyacetamide;hydrochloride Chemical compound Cl.C1=CC(N(C)C)=CC=C1CN(CC(=O)NO)S(=O)(=O)C1=CC=CC=C1OCC1CC1 SECUOMRDOIZQHH-UHFFFAOYSA-N 0.000 claims description 2
- KHUZQRKCIZHSEE-UHFFFAOYSA-N 2-[[2-(cyclopropylmethoxy)phenyl]sulfonyl-[[4-(triazol-1-yl)phenyl]methyl]amino]-n-hydroxyacetamide Chemical compound C=1C=CC=C(OCC2CC2)C=1S(=O)(=O)N(CC(=O)NO)CC(C=C1)=CC=C1N1C=CN=N1 KHUZQRKCIZHSEE-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 5
- 102000002274 Matrix Metalloproteinases Human genes 0.000 abstract description 4
- 108010000684 Matrix Metalloproteinases Proteins 0.000 abstract description 4
- 125000001401 1,2,4-triazol-4-yl group Chemical group N=1N=C([H])N([*])C=1[H] 0.000 abstract 1
- VDBCTDQYMZSQFQ-UHFFFAOYSA-N glycine hydroxamate Chemical class NCC(=O)NO VDBCTDQYMZSQFQ-UHFFFAOYSA-N 0.000 abstract 1
- 230000001404 mediated effect Effects 0.000 abstract 1
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 31
- 210000004027 cell Anatomy 0.000 description 30
- 238000012360 testing method Methods 0.000 description 30
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- 239000000460 chlorine Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 101000627872 Homo sapiens 72 kDa type IV collagenase Proteins 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 21
- 230000000694 effects Effects 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- 239000003112 inhibitor Substances 0.000 description 20
- 239000002585 base Substances 0.000 description 19
- 238000005406 washing Methods 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 239000003795 chemical substances by application Substances 0.000 description 17
- 230000005764 inhibitory process Effects 0.000 description 15
- 102000004190 Enzymes Human genes 0.000 description 14
- 108090000790 Enzymes Proteins 0.000 description 14
- 229940088598 enzyme Drugs 0.000 description 14
- 239000000284 extract Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 210000004072 lung Anatomy 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000002299 complementary DNA Substances 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 125000001309 chloro group Chemical group Cl* 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 101001013150 Homo sapiens Interstitial collagenase Proteins 0.000 description 8
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 238000001890 transfection Methods 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 229920000159 gelatin Polymers 0.000 description 7
- 235000019322 gelatine Nutrition 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000011159 matrix material Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 108091007196 stromelysin Proteins 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 102000005741 Metalloproteases Human genes 0.000 description 6
- 108010006035 Metalloproteases Proteins 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 239000008273 gelatin Substances 0.000 description 6
- 235000011852 gelatine desserts Nutrition 0.000 description 6
- 150000002466 imines Chemical class 0.000 description 6
- 206010061289 metastatic neoplasm Diseases 0.000 description 6
- 239000011550 stock solution Substances 0.000 description 6
- 102000016942 Elastin Human genes 0.000 description 5
- 108010014258 Elastin Proteins 0.000 description 5
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 5
- 206010027476 Metastases Diseases 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 229920002549 elastin Polymers 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- GUAQVFRUPZBRJQ-UHFFFAOYSA-N n-(3-aminopropyl)-2-methylprop-2-enamide Chemical compound CC(=C)C(=O)NCCCN GUAQVFRUPZBRJQ-UHFFFAOYSA-N 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 238000003752 polymerase chain reaction Methods 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 101150101095 Mmp12 gene Proteins 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 206010020718 hyperplasia Diseases 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 239000002516 radical scavenger Substances 0.000 description 4
- 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 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 241000701447 unidentified baculovirus Species 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- WLNDWROIFARIFO-UHFFFAOYSA-N COClS(C1=CC=C(C2CC2)C=C1)(=O)=O Chemical compound COClS(C1=CC=C(C2CC2)C=C1)(=O)=O WLNDWROIFARIFO-UHFFFAOYSA-N 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- 102000029816 Collagenase Human genes 0.000 description 3
- 108060005980 Collagenase Proteins 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 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 3
- 101150014058 MMP1 gene Proteins 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229960002424 collagenase Drugs 0.000 description 3
- 108700004333 collagenase 1 Proteins 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 3
- 210000003000 inclusion body Anatomy 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 2
- IGHRDAXEBOVVSF-UHFFFAOYSA-N 2-[[4-(cyclopropylmethoxy)phenyl]sulfonyl-[[4-(dimethylamino)phenyl]methyl]amino]acetic acid Chemical compound C1=CC(N(C)C)=CC=C1CN(CC(O)=O)S(=O)(=O)C(C=C1)=CC=C1OCC1CC1 IGHRDAXEBOVVSF-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 206010002329 Aneurysm Diseases 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 208000016192 Demyelinating disease Diseases 0.000 description 2
- 206010012305 Demyelination Diseases 0.000 description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 206010014561 Emphysema Diseases 0.000 description 2
- 108010062466 Enzyme Precursors Proteins 0.000 description 2
- 102000010911 Enzyme Precursors Human genes 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 102000013382 Gelatinases Human genes 0.000 description 2
- 108010026132 Gelatinases Proteins 0.000 description 2
- 101001074035 Homo sapiens Zinc finger protein GLI2 Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000009151 Luteinizing Hormone Human genes 0.000 description 2
- 108010073521 Luteinizing Hormone Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 102000001776 Matrix metalloproteinase-9 Human genes 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 208000010191 Osteitis Deformans Diseases 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 208000027868 Paget disease Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000012614 Q-Sepharose Substances 0.000 description 2
- 206010039361 Sacroiliitis Diseases 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 239000012505 Superdex™ Substances 0.000 description 2
- 102000018594 Tumour necrosis factor Human genes 0.000 description 2
- 108050007852 Tumour necrosis factor Proteins 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 102100035558 Zinc finger protein GLI2 Human genes 0.000 description 2
- QMFYUQNBKYHUKJ-UHFFFAOYSA-M [Na+].C1(CC1)C1=CC(=C(C=C1)S(=O)(=O)[O-])OC Chemical compound [Na+].C1(CC1)C1=CC(=C(C=C1)S(=O)(=O)[O-])OC QMFYUQNBKYHUKJ-UHFFFAOYSA-M 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 2
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 208000027202 mammary Paget disease Diseases 0.000 description 2
- 210000005075 mammary gland Anatomy 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- VATYWCRQDJIRAI-UHFFFAOYSA-N p-aminobenzaldehyde Chemical compound NC1=CC=C(C=O)C=C1 VATYWCRQDJIRAI-UHFFFAOYSA-N 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 208000028169 periodontal disease Diseases 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000011533 pre-incubation Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- GUEHESDOJBMSSE-UHFFFAOYSA-M (2-aminophenyl)mercury(1+);acetate Chemical compound CC(=O)O[Hg]C1=CC=CC=C1N GUEHESDOJBMSSE-UHFFFAOYSA-M 0.000 description 1
- BRZYSWJRSDMWLG-DJWUNRQOSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-[(1r)-1-hydroxyethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H]([C@@H](C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-DJWUNRQOSA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 1
- ISPMNMMLLQDSDT-UHFFFAOYSA-N 2-[4-(chloromethyl)phenyl]triazole Chemical compound C1=CC(CCl)=CC=C1N1N=CC=N1 ISPMNMMLLQDSDT-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102000013918 Apolipoproteins E Human genes 0.000 description 1
- 108010025628 Apolipoproteins E Proteins 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- UTMZWVBRFCNVGS-UHFFFAOYSA-N C(C)(=O)OCN(CC1=CC=C(C=C1)N(C)C)S(=O)(=O)C1=CC=C(C=C1)OCC1CC1 Chemical compound C(C)(=O)OCN(CC1=CC=C(C=C1)N(C)C)S(=O)(=O)C1=CC=C(C=C1)OCC1CC1 UTMZWVBRFCNVGS-UHFFFAOYSA-N 0.000 description 1
- WHRYHXNNLQWZTD-UHFFFAOYSA-N C(C)(=O)OCNCC1=CC=C(C=C1)N(C)C Chemical compound C(C)(=O)OCNCC1=CC=C(C=C1)N(C)C WHRYHXNNLQWZTD-UHFFFAOYSA-N 0.000 description 1
- VNNYBWYBTMSOOZ-UHFFFAOYSA-N C(C)(=O)OCNS(=O)(=O)C1=CC=C(C=C1)OCC1CC1 Chemical compound C(C)(=O)OCNS(=O)(=O)C1=CC=C(C=C1)OCC1CC1 VNNYBWYBTMSOOZ-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 229920004449 Halon® Polymers 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 1
- 101000990915 Homo sapiens Stromelysin-1 Proteins 0.000 description 1
- 101000577874 Homo sapiens Stromelysin-2 Proteins 0.000 description 1
- 101000577877 Homo sapiens Stromelysin-3 Proteins 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102100026720 Interferon beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 201000002287 Keratoconus Diseases 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 101000577882 Mus musculus Macrophage metalloelastase Proteins 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 108010064696 N,O-diacetylmuramidase Proteins 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 208000003788 Neoplasm Micrometastasis Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- 208000003435 Optic Neuritis Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108010051611 Signal Recognition Particle Proteins 0.000 description 1
- 102000013598 Signal recognition particle Human genes 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 102100030416 Stromelysin-1 Human genes 0.000 description 1
- 102100028848 Stromelysin-2 Human genes 0.000 description 1
- 102100028847 Stromelysin-3 Human genes 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 108020005038 Terminator Codon Proteins 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002001 anti-metastasis Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000008366 buffered solution 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
- 239000004202 carbamide Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 102000057593 human F8 Human genes 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000011177 media preparation Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- LLYKPZOWCPVRPD-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine;n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=CC=N1 LLYKPZOWCPVRPD-UHFFFAOYSA-N 0.000 description 1
- VZUGBLTVBZJZOE-KRWDZBQOSA-N n-[3-[(4s)-2-amino-1,4-dimethyl-6-oxo-5h-pyrimidin-4-yl]phenyl]-5-chloropyrimidine-2-carboxamide Chemical compound N1=C(N)N(C)C(=O)C[C@@]1(C)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CN=2)=C1 VZUGBLTVBZJZOE-KRWDZBQOSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000008795 neuromyelitis optica Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 108091005981 phosphorylated proteins Proteins 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000012207 quantitative assay Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940047431 recombinate Drugs 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000004153 renaturation Methods 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- BYMHXIQVEAYSJD-UHFFFAOYSA-M sodium;4-sulfophenolate Chemical compound [Na+].OC1=CC=C(S([O-])(=O)=O)C=C1 BYMHXIQVEAYSJD-UHFFFAOYSA-M 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000009923 sugaring Methods 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 238000004454 trace mineral analysis Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 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
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- 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
- A61P7/10—Antioedematous agents; Diuretics
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Cardiology (AREA)
- Pulmonology (AREA)
- Virology (AREA)
- Hematology (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- Vascular Medicine (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
本发明涉及式I的α-氨基-N-羟基-乙酰胺衍生物或其盐,其中R是二-低级烷基氨基、1,2,3-三唑-1-基、1,2,3-三唑-2-基或1,2,4-三唑-4-基,m表示1至10且包括10的整数并且n表示0至10且包括10的整数;本发明还涉及其制备方法、含有所说异羟肟酸衍生物的药物组合物、这种异羟肟酸衍生物作为药物的用途以及单独使用所说的衍生物或者将其与一种或多种其它治疗剂联用来治疗由降解基质的金属蛋白酶(MMP)介导的病况或疾病的方法。
Description
本发明涉及α-氨基乙酰异羟肟酸衍生物、其制备方法、含有所说衍生物的药物组合物、这种异羟肟酸衍生物作为药剂的用途以及通过单独使用或与一种或多种其它治疗剂联合使用所说的衍生物来治疗由降解基质的金属蛋白酶(MMP)介导的病况或疾病、特别是过度增生性疾病的方法。
本发明具体说涉及下式I的α-氨基-N-羟基-乙酰胺衍生物或其盐,
其中
R是二-低级烷基氨基、1,2,3-三唑-1-基、1,2,3-三唑-2-基或1,2,4-三唑-4-基,m表示1至10且包括10的整数,并且n表示0至10且包括10的整数。
优选,基团R或环丙基甲氧基位于各自相应苯环的第4位。更优选,这两个基团都位于各自相应苯环的第4位。
本发明的一个优选实施方案中,R是二甲基氨基或[1,2,3]三唑-2-基。
n优选是1至4之间的整数,更优选n是1。
m优选是1至5之间的整数。更优选m是1、2或3并且首选m是1。
除非另有说明,在本发明的公开内容中,命名为“低级”的有机基团含有不超过7个、优选不超过4个的碳原子。
低级烷基是支链或直链的并且含有1至7个碳原子,优选1至4个碳原子,更优选一个或两个碳原子,并且例如,表示甲基或乙基。
盐主要是酸加成盐,例如,无机酸如盐酸的加成盐。
式I化合物具有有价值的药理学特性。具体说,它们是MMP,特别是MT1-MMP、MMP-2和MMP-9的选择性抑制剂,并且可用于治疗MMP所介导的病况、特别是上述所列的病况。
降解基质的金属蛋白酶(MMP)这一酶家族中的各个成员,例如,明胶酶、基质溶素和胶原酶涉及各种生物学过程,例如组织基质降解(例如,胶原萎陷)和很多病理学病况,包括异常结缔组织和基底膜基质代谢,例如,关节炎(例如,骨关节炎和类风湿关节炎)、组织溃疡(例如,角膜、表皮和胃溃疡)、异常伤口愈合、牙周疾病、骨疾病(例如,佩吉特氏疾病和骨质疏松症)、肿瘤转移或侵入、牛皮癣以及HIV-感染(J.Leuk.Biol.52(2):244-248,1992)、动脉粥样硬化、血管成形术中的心室扩张和再狭窄。
巨噬细胞金属弹性蛋白酶是另一种降解基质的金属蛋白酶,其参与弹性蛋白的降解并且与诸如肺病,例如肺气肿和COPD(慢性阻塞性肺病)等病理学病况有牵连。
选择性通常是药理活性化合物的一个有利特点,因为含有选择性化合物的药物比含具较小选择性的化合物的药物,其副作用要小。由于MMP家族由数种参与不同生物学过程的不同酶组成,因而可能期望具有针对单独MMP或MMP酶家族的单个亚组的选择性抑制剂。
式I化合物及其可药用盐特别适合用作MT1-MMP(1膜型基质金属蛋白酶)、MMP2(明胶酶A)和MMP9(明胶酶B)的抑制剂。
据报道,很多肽可以与病理学过程或疾病中所牵涉的生物物质,诸如酶、细胞或受体相互作用。肽的缺陷是在生理学条件下、特别是在温血动物血液或胃部的生理学条件下容易水解。式I化合物的优点是它不是肽。
有益效果可以在本领域通常已知的药理学测试中进行评价,并且在本文中作举例说明。
上述特性可以在体外和体内测试中得到验证,有利的是,在这些测试中使用哺乳动物,例如,大鼠、豚鼠、狗、兔或分离的器官和组织以及哺乳动物的酶制品。体外剂量的范围可以是约10-5摩尔至10-10摩尔浓度。体内剂量范围,取决于给药途径,可以是约0.1至100mg/kg。
抗炎活性可以在本领域公知的标准炎性和关节炎动物模型中测定,例如,大鼠的佐剂性关节炎模型和胶原II诱导的小鼠关节炎模型(Mediatorsof Inflam.
1,273-279(1992))。
测定对基质溶素活性的抑制效果的一种测试方法是基于基质溶素对P物质的水解,其使用了Harrison等,Anal.Biochem.
180,110-113(1989)的改良方法。在此试验中,将P物质通过重组人基质溶素水解,产生片段P物质7-11,其可以通过HPLC来定量。在一个典型的试验中,将待测化合物的10mM储备溶液在试验用缓冲剂中稀释至50mM,与8mg重组人基质溶素(摩尔重量45-47kDa,2单位;其中1单位在30分钟内产生20毫摩尔的P物质7-11)1∶1混合,并且与0.5mM P物质一起以0.125mL的最终体积于37℃下保温30分钟。通过添加10mM EDTA将反应停止,并且在RP-8 HPLC上定量测定P物质7-11。从不含抑制剂的对照反应中计算基质溶素活性抑制的IC50和Ki。
巨噬细胞金属弹性蛋白酶(MME)抑制活性可以通过测定截短的重组小鼠巨噬细胞金属弹性蛋白酶对[3H]-弹性蛋白降解时所受到的抑制来确定,具体如下所述:
将约2ng通过Q-Sepharose柱色谱法纯化的重组截短小鼠巨噬细胞金属弹性蛋白酶(FASEB杂志,Vol.8,A151,1994),与期望浓度的测试化合物在5nMCaCl2、400nM NaCl、[3H]弹性蛋白(60,000cpm/管)和20m0MTris(pH 8.0)的存在下于37℃下保温过夜。将样品在微量离心机中于12,000rpm下旋转15分钟。将上清液的一份等分试样在闪烁计数器中计数,以便测定被降解的[3H]弹性蛋白的量。从一系列浓度的测试化合物和获得的酶活性的抑制百分比确定IC50。
式I化合物对MT1-MMP、MMP1(胶原酶1)和MMP2(明胶酶A)的抑制活性可以如下测定:
在100%DMSO中,制备底物(MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2,C.G.Knight等,FEBS lett.,
296,263-266,(1992))的浓度为1.0mM的储备溶液。在100%DMSO中制备抑制剂的储备溶液。将抑制剂从在100%DMSO中的溶液稀释成试样,而对照用等体积的DMSO替代,使所有试验中来自抑制剂和底物稀释液的最终DMSO浓度是6.0%。在含6.0%DMSO的试验用缓冲剂(150mM NaCl,10mM CaCl2,50mMTris-ClpH7.5,0.05%Brij-35)中,在将底物和抑制剂稀释于其中之后,进行试验。试验中所用的底物浓度是10μM。测试在37℃下进行。使用320nm的激发波长和340nm的发射波长来监测荧光变化。将反应混合物一式两份地添加到96孔microfluor平板的适宜孔中。将反应混合物与抑制剂一起预保温30min,通过添加MMP酶来使反应开始,并且测定荧光强度10min。选择位于曲线线性部分上的时间点来测定活性。抑制结果按对对照(未抑制的)反应中的活性产生50%抑制(IC50)时的抑制剂浓度来表示。在此测试中,式I化合物及其可药用盐对MMP2的IC50抑制浓度[μmol/升]为0.0001-0.030,通常是0.0002-0.010,并且对MT1-MMP的IC50抑制浓度[μmol/升]为0.0005-0.125,通常是0.001-0.05。式I化合物对MMP1(胶原酶1)的IC50抑制浓度比对MT1-MMP的IC50高最多1000倍,通常是高约40-倍至400-倍。式I化合物对MMP1的IC50抑制浓度比对MMP2的IC50高最多2000倍,对大部分的式I化合物来说,高约100倍至1000倍。
上述测试中所用的酶如下制备:
MT1-MMP:
质粒:将编码全长人MT1-MMP基因的cDNA片段的催化域[H.Sato等Nature(伦敦),370:61-65,1994]]通过聚合酶链反应(PCR)扩增,使用如下的引物:CTCCATATGTACGCCATCCAGGGTCTCAA用作有义引物,该引物在ATG起始密码子的5′-末端处包括一NdeI位点;以及CTCGGATCCTCACCCAT AAAGTTGCTGGAT-GCC用作反义引物,其具有BamHI位点和一个TGA终止密码子(1)。将所得的519-bp片段的PCR产物亚克隆在pET11a(Stratagene)的NdeI和BamHI独特位点之间。通过ABI PRISMTM染料终止循环测序试剂盒,用ABI PRISMTM 377DNA测序仪(Perkin Elmer),验证MT1-MMP的催化域(CD-MT1-MMP)的序列。
表达和纯化:使用此亚克隆化的CD-MT1-MMP转染大肠杆菌(E.coli)菌株BL21[DE3](Hanahan,D.J.Mol.Biol.1983;166(4):557-80)并且以不溶性包含体物质的形式表达。将转染子在37℃下于50mlLuria-Bertani(LB)培养基中在50g/ml氨苄青霉素的存在下生长至细胞密度为OD600=0.6-1.0,并且用1mM异丙基-1-D-吡喃半乳糖苷(IPTG)诱导CD-MT1-MMP产生。用5mg/ml溶菌酶和10μg/ml DNase I处理后,通过使用含0.2M NaCl、1%w/v脱氧胆酸和1%v/v Nonidet P-40的去污剂缓冲液,从收获的细胞中制备包含体。将此包含体再悬浮于由6M尿素、100mM 2-巯基乙醇和20mM Tris-Cl组成的pH8.5的增溶缓冲剂中,以达到溶解。使用10ml Q-Sepharose(Amersham Pharmacia Biotech)柱将酶纯化和复性,其中所说的柱用20mM Tris-Cl(pH7.5)中的5mM CaCl2、0.02%v/v NaN3已平衡过。用三体积的相同缓冲剂洗涤之后,用两体积线性梯度的0.5-1.0M NaCl洗脱结合蛋白。将收集的级分(各自为1ml)在平衡缓冲液中透析6h。将Superdex G200柱(1×15cm)(AmershamPharmacia)用20mM Tris-Cl(pH 7.5)、5mM CaCl2、0.02%NaN3平衡。将脱盐样品上Superdex G200柱并且以0.5ml/min的流速进行色谱分析。收集1ml的级分并且通过免疫印迹法分析30ml等分试样。将显出最高纯度的级分汇集在一起,在Amicon搅拌池中用YM2膜浓缩并且在-80℃下储存。
将洗脱的蛋白质对5mM CaCl2、0.5mM ZnSO4、20mMTris-Cl(pH7.5)的5L缓冲剂透析两次,然后在Amicon搅拌池中用YM2膜浓缩。在这些条件下,重组蛋白保持可溶性并且正确地折叠。
MMP1(胶原酶1)
质粒:通过cDNA(得自从人U937细胞(ATCC#CRL-2367)中分离的RNA)的PCR,产生人胶原酶的cDNA。用来产生此cDNA的引物是AAGAAGCTTAAGGCCAGTATGCACAGCTTTCCT和AAGGCGGCCGCA CACCTTCTTTGGACTCACACCA,对应于报道的cDNA序列的第58-1526位核苷酸(GenBank登记号X05231)。将所得的cDNA片段亚克隆至哺乳动物表达载体pBPV-MMT的Not I位点中(Matthias,P.等,J.Mol.Biol.1986,187(4):557-68)。
将C127细胞(ATCC-小鼠乳腺肿瘤细胞系)在补充有10%热灭活的胎牛血清和1X抗生素-抗真菌溶液的Dulbecco改良基本培养基中,于37℃下在湿润CO2保温箱中生长。使用磷酸钙沉淀法,对以8×105接种在100mm皿中的细胞进行转染。转染前5h,将培养基替换成新鲜的培养基。用15μg的表达载体转染各皿。转染后16-18h将细胞用PBS洗涤两次,并且在生长培养基中保温培养另外48h。然后通过与浓度为400μg/ml的新霉素相关抗生素G418一起保温培养来选择克隆。通过酶试验,在来自被选克隆的培养基中分析胶原酶表达。
表达和纯化:将16升的培养基浓缩至1.6升并且通过Wilhelm等描述的方法(Proc.Natl.Acad.Sci.(USA).1987;84:6725-29)分离酶。将最终的产物在Superose G-75(Pharmacia/LKB,Piscataway,NJ)凝胶过滤柱上进一步纯化,其中所说的柱已在含0.15M NaCl的试验缓冲剂中平衡过。将酶汇集在一起并且按等分试样在-70℃下储存。用1mM APMA(
氨基苯 基乙酸汞,ICN Pharmaceuticals)在37℃下将重组胶原酶原(43-45kDa)活化,通过对含0.15M NaCl的试验缓冲剂进行大量透析来除去APMA。将活化的酶(~36-kDa)在-70℃下冻存至使用前。
MMP2(明胶酶A)
质粒:由Motoharu Seiki教授(Institute of Medical Science,东京大学)提供人MMP2原的cDNA。通过cDNA(得自从人HT1080细胞(ATCC#CCL121)中分离的RNA)的PCR,产生编码全长人MMP2原的cDNA。产生此cDNA的引物是GAATTCGATGGAGGCG CTAATGGCCCGG和CTCGAGT CAGCAGCCTAGCCAGTCGGATTTGAT,对应于报道的全长人MMP2原的cDNA序列(GenBank登记号J03210)。将所得的2.0KbPCR片段克隆至pFAST BAC 1载体(pBAC-MMP2)的EcoR1/Xho 1位点中(I.E.Collier等,J.Biol.Chem.,263:6579-6587,1988)。
表达和纯化:对于r-MMP2原的杆状病毒表达,将pBAC-MMP2转化至DH10BAC感受态细胞中,以产生r-MMP2原杆粒DNA。将重组杆粒DNA用Cellfectin试剂(Gibco BRL)转染至培养的昆虫细胞(Tn细胞)中。将重组杆状病毒进行噬斑纯化至同质,并且用来产生高滴度重组杆状病毒原种。通过明胶信号识别蛋白体的受体,证实r-MMP2原的表达。
将感染杆状病毒的Tn细胞的培养液离心并且通过0.22mm孔径滤器过滤除去细胞碎片。将重组MMP2原于4℃下吸附至在25mM Tris-HCl(pH 7.5)、1M NaCl、10mM CaCl2、0.05%Briji 35的平衡缓冲剂中的明胶Sepharose 4B(Pharmacia Biotech)上。用平衡缓冲剂洗涤珠粒后,用含10%DMSO的平衡缓冲剂洗脱r-MMP2原。将酶在4℃下储存直至活化前。为进行试验,将此纯化的MMP2原用1mM APMA在37℃下活化1hr。
MMP9(明胶酶-B)
由TPA处理过的THP1人单核细胞白血病细胞的培养基制备MMP9。将THP1细胞维持在含10%FCS的DMEM/F-12培养基中,并且在不含血清的培养基中用TPA(1nM)刺激48h以产生MMP9原。所有的纯化过程在4℃下进行。通过Centricon(Amicon)将1升的培养基浓缩至100ml并且上明胶-sepharose(Pharmacia)柱(1×8cm),其中所说的柱用50mMTris-Cl(pH=8.0)、300mM NaCl平衡过。将含MMP-9原的级分用存在于50mM Tris-Cl(pH=8.0)、300mM NaCl中的10%DMSO洗脱,然后对50mM Tris-Cl(pH 7.5)、150mM NaCl透析。将级分通过Centricon浓缩并且上Sephadex G200(2×20cm)柱进行色谱,其中所说的柱用含150mMNaCl的50mM Tris-Cl(pH=7.5)平衡过。将纯化的MMP9原以原液的形式在-80℃下储存,并且使用必需量的酶原用于活化。将MMP9原用1mM氨基苯基乙酸汞(APMA,ICN Pharmaceuticals)在含150mM NaCl、10mM CaCl2和0.05%Brij-35的50mM Tris-Cl(pH=7.5)(MMP试验缓冲剂)中于37℃下活化18h,并且通过对MMP试验缓冲剂作大量透析来除去APMA。将活化的MMP9在-80℃下冻存至使用前。
MMP9的试验
然后,将活化的MMP-9(82kDa)用于筛选化合物。在此研究的所有MMP试验中,使用25μM的荧光肽,2-N-甲基氨基苯甲酸(Nma)-Gly-Pro-Gln-Gly-Leu-Ala-Gly-Gln-Lys-Nε-(2,4-二硝基-苯基)(Dnp)-NH2(Peptide Institute,Osaka,日本)作为唯一的底物。在100%DMSO中制备底物的浓度为1.0mM的储备溶液。试验在MMP试验缓冲剂中进行。将反应混合物一式两份地添加到96孔microfluor平板的适宜孔中并且在37℃下预保温30min。通过添加0.5nM活化的MMP9来使反应开始。通过溶解在100%DMSO中,制备各抑制剂的储备溶液。将抑制剂从具有100%DMSO的稀释溶液(由储备溶液制备)添加到试验混合物中。向对照添加等体积的DMSO。来自抑制剂和底物溶液的DMSO最终浓度为5.0%。在460nm下监测荧光的增加(在355nm下激发)。选择曲线线性部分上的时间点来测定活性。抑制结果按对对照反应中的活性产生50%抑制(IC50)时的抑制剂浓度来表示。
式I化合物的抗肿瘤效果也可以在例如体内转移模型中得到证实,在所述模型中使用EGFP转染的HT1080细胞并测定转移至裸鼠肺部中的肿瘤细胞的荧光强度(其中给所说的裸鼠静脉内注射肿瘤细胞)或者使用B16-F10黑素瘤细胞并在将肿瘤细胞静脉内注射至BDF1小鼠中后测定肺部肿瘤结节。
EGFP转染的HT1080:在裸鼠的尾静脉内注射肿瘤细胞的混悬液[2×106个细胞/0.1ml PBS(磷酸盐缓冲的盐水)]。在头一天(0天)中相对于细胞注射时间的-1hr和+5hrs时,给动物口服施用化合物。之后,给动物每天给药两次,第一次在上午9-10:30而第二次在下午5:30-7:00。化合物以在1%羧甲基纤维素(Wako,日本)中的混悬液的形式以60mg/kg每天两次的剂量施用。给对照组只施用赋形剂。第17天时,将动物处死后从小鼠中取出肺。将取出的肺部组织分成直径大约为2-3mm的块,然后在微量离心管中将大约100mg的组织悬浮于0.2ml PBS中,随后温和匀化并且离心。室温下,将细胞用1ml溶胞试剂(150mM NH4Cl,0.1mMEDTA-4 Na,10mM KHCO3 pH7.4)洗涤3次以便将红细胞裂解,然后用1ml PBS洗涤2次。在最后的洗涤之后,将细胞用0.5ml的存在于PBS中的1%Triton溶胞。在15000rpm下离心5min后,将0.23ml的各上清液转移至96孔多孔板的孔中。通过使用荧光平板读出器(Cytoflour II),在分别为485nm和530nm的激发和发射波长下测定荧光强度。使用湿肺重量将所获得的每个肺的荧光标准化。
按照Fidler的方法研究B16-F10黑素瘤实验性转移模型。通过胰蛋白酶消化收获细胞,并且用含血清的培养基洗涤一次并且用冷PBS洗涤三次,然后保持在冰上。在小鼠的尾静脉中注射肿瘤细胞的混悬液(2×105个细胞/0.1ml PBS)。在头两天(0、1天)中相对于细胞注射时间的-1小时、+5小时、23小时和29小时时,给动物口服施用化合物。之后,给动物每天上午给药一次。化合物以在1%羧甲基纤维素(Wako,日本)中的混悬液的形式以120mg/kg的剂量施用。给对照组只施用赋形剂。第14天时,将动物处死后从小鼠中取出肺,并且用布安氏溶液(存在于蒸馏水中的2%苦味酸∶10%甲醛中性缓冲溶液∶乙酸=15∶5∶1)固定后,人工计算肿瘤结节的数目。
本发明化合物的抗肿瘤效果可以如下测定,例如按照本领域公知的方法测定在处理的Balb/c裸鼠中皮下植入的人肿瘤的生长,并与安慰剂处理的小鼠进行比较。示例性的肿瘤为例如,雌激素依赖性人乳腺癌BT20和MCF7、人膀胱癌T24,人结肠癌Colo 205、人肺腺癌A549和人卵巢癌NIH-OVCAR3。
对肿瘤血管生成的作用可以例如在植入了丸粒状Walker 256癌(以刺激从异组织边缘(limbus)的血管实现血管发生)的大鼠中测定,如Galardy等,Cancer Res.
54,4715(1994)中所述。
此外,式I化合物的抗肿瘤、特别是抗转移活性还可以在自发转移瘤模型中得到证实,其中大鼠乳腺肿瘤BN472被同位移植到受体大鼠中,并且转移至肺部和局部淋巴结的瘤清晰可见。
将大约25mm3的肿瘤碎片移植在雌性Brown-Norwegian(BN)大鼠乳房的脂肪垫的下面。将式I化合物悬浮于无菌水中的1%羧甲基纤维素(CMC)中。将此制剂以30mg/kg每天一次或15mg/kg每天两次的剂量口服施用。在带有肿瘤的对照组和不带肿瘤的对照组(健康大鼠)中,动物只接受赋形剂。随机选择后开始治疗,并且持续4周。治疗4周后,通过计算用布安氏固定液固定后肺部表面上的可见病灶的数量,确定肺的转移。在此模型中,剂量为30mg/kg每天一次或15mg/kg每天两次的式I化合物可使肺部和局部淋巴结中转移瘤的发生率和/或程度都有所降低。肺部转移瘤中数或局部淋巴结重量的降低为大约25%和70%。例如,对实施例3的化合物而言,肺部病灶的中数对两种剂量来说都是约105个,而赋形剂对照组中肺部病灶的中数为约230个。基于体重和一般健康状况的增加,化合物表现出很好的耐受性。这些结果清楚地表明,式I化合物能够降低转移瘤,例如,由BN472大鼠乳腺癌产生的转移瘤的转移程度和/或数量。
式I化合物可以抑制基质降解,因此非常适合用于治疗对MT1-MMP、MMP2和/或MMP9酶活性的抑制有响应的疾病。尤其可以提及的是骨质疏松症,以及在其过程中破骨细胞对骨的重吸收起一定作用的其它疾病,例如,肿瘤诱发的高血钙、佩吉特氏疾病或骨转移瘤的治疗,还有关节和骨的炎症过程及软骨组织中的退化过程。尤其是,式I化合物可通过抑制肿瘤生长、肿瘤转移、肿瘤增进或侵入和/或肿瘤的血管生成,用于治疗对MT1-MMP、MMP2和/或MMP9酶活性的抑制有响应的良性或恶性肿瘤,例如乳腺、肺、膀胱、结肠、卵巢、脑和皮肤的癌。它们能够引起肿瘤的消退和防止微转移瘤的生长。
可以用本发明化合物治疗的其它病况包括类风湿关节炎,骨关节炎,支气管病症(例如,哮喘,通过抑制弹性蛋白的降解),动脉粥样硬化病(例如,通过抑制动脉粥样斑块的破裂)以及急性冠心病综合征,心脏病发作(心脏局部缺血),休克(脑局部缺血),血管成形术后的再狭窄,还有血管溃疡形成、扩张和动脉瘤。其它可用本发明化合物治疗的病况是神经系统的炎性脱髓鞘病状(其中涉及髓磷脂的破坏或损失(例如,多发性硬化)),视神经炎,视神经脊髓炎(德维克氏病),弥漫性和过渡性硬化(希尔德病)和急性传播性脑脊髓炎,还有导致脱髓鞘的外周神经病,例如运动缺损的Landry-Guillain-Barre-Strohl综合征;还有组织溃疡(例如,表皮和胃溃疡),异常伤口愈合和牙周疾病。式I化合物还可以治疗子宫内膜异位,脓毒性休克,炎性肠疾病,局限性回肠炎,特别是脑水肿。
本发明化合物的眼部应用包括治疗眼部发炎,角膜溃疡,翼状胬肉,角膜炎,圆锥角膜,开角型青光眼,视网膜病,并且它们还可以与屈光手术(激光或切开)联合使用以最大程度地减少不利效果。
某些金属蛋白酶抑制剂据报导还可抑制肿瘤坏死因子(TNF)的产生和释放,例如,TNF-α,其是炎症的重要介体。由此,本发明的化合物是潜在的哺乳动物的抗炎剂。
本发明化合物对动脉粥样硬化病况的效果可以通过使用来自胆固醇喂养的兔子的动脉粥样斑块(其含有活化的基质金属蛋白酶)来评价,如Sukhova等,Circulation
90,I 404(1994)中所述。对兔子动脉粥样斑块中的基质金属蛋白酶活性的抑制效果可以通过原位信号识别蛋白体的受体来测定,如Galis等,J.Clin.Invest.
94,2493(1994)中所述,并以斑块破裂作为指示。
对血管动脉瘤的效果,例如,对动脉瘤形成的抑制,可以在诸如Apo-E转基因小鼠和/或LDL受体剔除小鼠等实验性模型中测定。式I化合物可以抑制动脉瘤的发展。
式I化合物可以单独给药,或者与一种或多种其它治疗剂联合给药,联合治疗可以采用的形式有固定联合或本发明化合物和一种或多种其它治疗剂交错给药或彼此独立地给药,或者是将一种或多种其它治疗剂和固定联合一起组合给药。此外,式I化合物特别是还可以与化学疗法、放射疗法、免疫疗法、手术干预或其组合相联合用于肿瘤治疗。如上所述,可以在其它治疗策略的背景中作为辅助疗法,而长期治疗同样是可能的。其它可能的治疗有治疗以维持肿瘤消退后的患者状态,或甚至作为化学预防治疗,例如,对易感患者。
可以联合的治疗剂特别是一种或多种细胞抑制化合物或细胞毒性化合物,例如,化疗剂或选自以下的一些治疗剂,包括但不限于:聚胺生物合成抑制剂;蛋白质激酶抑制剂,特别是丝氨酸/苏氨酸蛋白质激酶,例如,蛋白质激酶C,或者酪氨酸蛋白质激酶,例如,EGF受体酪氨酸激酶、VEGF受体酪氨酸激酶或PDGF受体酪氨酸激酶的抑制剂;细胞因子;负生长调节剂,例如,TGF-β或IFN-β;芳香酶抑制剂;SH2结构域与磷酸化蛋白质相互作用的抑制剂;抗雌激素;拓扑异构酶I抑制剂;拓扑异构酶II抑制剂;微管活性剂;烷基化剂;抗肿瘤剂;抗代谢物;铂化合物;抗血管生成化合物;促黄体生成素释放素激动剂;抗雄激素;二膦酸类化合物和trastuzumab。
本发明的一个实施方案尤其涉及式I的化合物及其盐,其中R是二-低级烷基氨基、1,2,3-三唑-1-基、1,2,3-三唑-2-基或1,2,4-三唑-4-基,m是1、2、3、4或5并且n是0。
本发明的另一个实施方案尤其涉及式I的化合物及其盐,其中R是二-低级烷基氨基、1,2,3-三唑-1-基、1,2,3-三唑-2-基或1,2,4-三唑-4-基,m是1、2、3、4或5并且n是1、2、3或4。
本发明特别涉及式I的化合物,其中R是二甲基氨基或1,2,3-三唑-2-基,及其可药用的前药衍生物和盐。
具体说,以下化合物是优选的:
2-[(环丙基甲氧基-苯磺酰基)-(4-[1,2,3]三唑-2-基-苄基)-氨基]-N-羟基-乙酰胺,
2-[(环丙基甲氧基-苯磺酰基)-(4-[1,2,3 ]三唑-2-基-苄基)-氨基]-N-羟基-乙酰胺-盐酸盐,
2-[(环丙基甲氧基-苯磺酰基)-(4-二甲基氨基苄基)-氨基]-N-羟基-乙酰胺,
2-[(环丙基甲氧基-苯磺酰基)-(4-二甲基氨基苄基)-氨基]-N-羟基-乙酰胺-盐酸盐,
2-[(环丙基甲氧基-苯磺酰基)-(4-[1,2,3]三唑-1-基-苄基)-氨基]-N-羟基-乙酰胺,
2-[(环丙基甲氧基-苯磺酰基)-(4-[1,2,4]三唑-4-基-苄基)-氨基]-N-羟基-乙酰胺,
2-[(环丙基甲氧基-苯磺酰基)-(4-二乙基氨基苄基)-氨基]-N-羟基-乙酰胺,和
2-[(环丙基甲氧基-苯磺酰基)-(4-二乙基氨基苄基)-氨基]-N-羟基-乙酰胺-盐酸盐。
式I化合物及其盐可以通过本领域已知的方法来制备,例如,通过将下式II的碳酸或其盐
其中R是二-低级烷基氨基、1,2,3-三唑-1-基、1,2,3-三唑-2-基或1,2,4-三唑-4-基,m表示1至10且包括10的整数并且n表示0至10且包括10的整数,首先与能够将此碳酸转化成相应酰卤的试剂,任选地在适宜的催化剂的存在下在适宜的溶剂存在下反应;之后在适宜溶剂或溶剂混合物中、特别是在水和四氢呋喃的混合物中与NH2OH反应;并且任选地,为制备盐,将所得的游离式I化合物转化成盐,或者如果必要的话为制备游离化合物,将所得的式I的化合物的盐转化成游离化合物。
下面将更详细描述上述方法:
式II的碳酸与能够将此碳酸转化成相应酰卤的试剂之间的反应,可以在适宜的溶剂中进行,如氯仿或者优选二氯甲烷。能够将此碳酸转化成相应酰卤的适宜的试剂是,例如,(COCl)2,还有COCl2、SOCl2、POCl3或POBr3。适宜的催化剂是,例如,二甲基甲酰胺。反应在振荡或搅拌的条件下进行。取决于具体反应物的性质,反应在-10℃至+50℃、优选0℃至+30℃下进行30分钟至10小时,优选1至3小时。酰卤(优选是新鲜制备的)与NH2OH在水和第二种溶剂的混合物中的进一步反应,优选在约-35℃至-5℃下、例如-20℃至-10℃下进行约1或2小时,其中所说的第二种溶剂可与其它组分形成均相溶液,例如是四氢呋喃。然后,优选通过将反应混合物倾入冰水中,使反应猝灭。
式II的起始物料可以按如下获得:
将下式III的α-氨基酸衍生物
其中R具有如式I化合物中所规义的含义并且R1是低级烷基或苄基,与下式IV的化合物
其中Hal是氟、溴或者优选是氯,并且m和n具有如式I化合物中所规义的含义,在适宜的溶剂如二氯甲烷中,在碱的存在下,特别是在叔胺的存在下,并且任选地在催化剂(优选二甲基氨基吡啶)的存在下,于0℃至50℃例如室温反应约30分钟至24小时,例如10、12或15小时,得到下式V的碳酸酯
其中R、m和n具有如式I化合物所规义的含义并且R1是低级烷基或苄基。然后,可以通过本领域已知的方法将所获得的碳酸酯水解,得到游离的碳酸。适宜的反应条件是,例如,将式V的碳酸酯溶解在四氢呋喃中并且在-10℃至+10℃、优选0至+5℃下相继添加氢氧化锂一水合物和水。然后,将反应混合物加温至室温并且搅拌约2至12小时,例如,4、6或8小时。
下式III的α-氨基酸衍生物
其中R具有如式I化合物中所规义的含义并且R1是低级烷基或苄基,其可以例如按如下方式获得,将下式VIII的醛
其中R具有如式I化合物中所规义的含义,在第一步中与下式IX的α-氨基酸酯的盐酸盐反应
其中R1是低级烷基或苄基,此反应优选通过将式IX的酯与叔胺例如三乙胺和MgSO4一起添加到溶解在适宜溶剂如二氯甲烷中的式VIII的醛中进行,以便制得相应的亚胺。然后,可以将亚胺进一步与NaBH4在低于0℃、优选-30℃至-5℃、更优选-20℃至-10℃下反应约30至240分钟,例如,60或90分钟,其中优选将NaBH4溶解在四氢呋喃和甲醇或乙醇的混合物中。
式VIII的醛,其中R是1,2,3-三唑-1-基、1,2,3-三唑-2-基或1,2,4-三唑-4-基,可以通过将溶解在二甲基甲酰胺中的式VIII的醛(其中R是氯或者非常优选地氟),与1,2,3-三唑或1,2,4-三唑在碳酸钾的存在下于大约溶剂的回流温度下反应约2至10小时,例如4或6小时来获得。
式IV的化合物,其中Hal是氟、溴或优选是氯,可以通过将悬浮于二氯甲烷或另一种适宜溶剂或溶剂混合物中的下式VI的磺酸钠盐,
与例如COCl2、SOCl2、POCl3或POBr3,在催化量的二甲基甲酰胺的存在下于约室温下反应约12至24小时来获得。
式VI的磺酸钠盐可以通过将悬浮于二甲基甲酰胺中并且用氢化钠在室温下预处理过的下式VII的化合物,
与溴烷基-环烷烃在催化量的碘化四丁基铵的存在下于约50℃至70℃下反应12至36小时,例如24小时来制备。
通用方法条件:
可通过本方法获得的并且具有成盐特性的游离式I化合物可以按本领域已知的方式转化成盐,例如,可以用酸或其适宜的衍生物处理,例如,将所述的酸添加到溶解在适宜溶剂如醚(例如,环醚,尤其是二噁烷并且特别是四氢呋喃)中的式I化合物中。
可以按本领域已知的方式例如,借助于分级结晶将可根据本发明获得的异构体混合物分成单个的异构体。
上述反应可以在本领域已知的反应条件下,在没有或者通常地有溶剂或稀释剂的存在下(这些溶剂或稀释剂优选对所用的试剂来说是惰性的并且能够溶解它们),在没有或者有催化剂、缩合剂(例如,五氧化二磷)或中和剂(例如碱,特别是含氮碱,例如三乙胺)的存在下,根据反应的性质和/或反应的参与者,在低温、正常温度或高温下,例如,约-80℃至约200℃,优选约-20℃至约150℃,例如,在所用溶剂的沸点或在室温下,在大气压下或在密闭容器中,如果适宜的话,在压力下和/或在惰性气氛中,例如,在氮气气氛下进行。
在各自情形中所具体规定的反应条件是优选的。
溶剂和稀释剂是,例如,水;醇,例如,低级烷基氢氧化物,例如,甲醇、乙醇、丙醇或者特别是丁醇;二醇,例如,乙二醇;三醇,例如,甘油或芳基醇,例如,苯酚;酰胺,例如,羧酸酰胺,例如,二甲基甲酰胺、二甲基乙酰胺或1,3-二甲基-3,4,5,6-四氢-2(1H)-嘧啶酮(DMPU);羧酸,特别是甲酸或乙酸;无机酸的酰胺,例如,六甲替磷酰三胺;醚,例如,环醚,例如,四氢呋喃或二噁烷,或无环醚,例如,二乙醚或乙二醇二甲基醚;卤化烃,例如,卤代-低级链烷烃,例如,二氯甲烷或氯仿;酮,例如,丙酮;腈,例如,乙腈;酸酐,例如,乙酸酐;酯,例如,乙酸乙酯;双链烷基锍化物(bisalkanesulfine),例如,二甲基亚砜;含氮杂环化合物,例如,吡啶;烃,例如,低级链烷烃,例如,庚烷;或者芳族化合物,例如,苯、甲苯或二甲苯或者这些溶剂的混合物,对于上述反应可以在各自的情形中选择适宜的溶剂。
可以使用常规的工艺来后处理可以获得的式I化合物或其盐,例如,过量试剂的溶剂分解;再结晶;色谱法,例如,分配,离子或凝胶色谱,特别是制备型高压液相色谱法;在无机和有机溶剂相之间分配;一次或数次萃取,特别是在酸化或增加碱度或盐含量之后;经过吸湿性盐干燥;消化;过滤;洗涤;溶解;蒸发(如果必要的话,在真空或高度真空条件下);蒸馏;结晶,例如,油形式的所得化合物的结晶或从母液中结晶,对产品来说还可以用终产品的晶体作为晶种;或者这些后处理步骤中的两步或多步的组合,这些步骤还可以重复使用。
起始物料和中间体可以以纯的形式使用,例如,在如紧上面所述的后处理之后,或以部分纯化的形式或者,例如,直接以粗产物的形式使用。
鉴于游离形式和盐形式的式I化合物之间有密切关系,如果化合物中含有成盐基团,则在适当时应当适当和为方便着想地将上述和下述的游离化合物及其盐理解为也指相应的盐或游离化合物。
化合物,包括其盐,还可以以水合物的形式获得,或其晶体中可以含有例如,用于结晶的溶剂。
本发明还涉及本方法的如下实施方案形式:其中使用在任一加工阶段中可获得的中间体化合物作为起始物质并且实施所缺少的加工步骤;或者其中起始物质在反应条件下形成或以衍生物的形式,例如,以盐的形式使用。
此外,本发明涉及下式II的化合物及其盐,
其中R是二-低级烷基氨基、1,2,3-三唑-1-基、1,2,3-三唑-2-基或1,2,4-三唑-4-基,m表示1至10且包括10的整数,且n表示0至10且包括10的整数。
本发明还涉及使用本发明化合物及其可药用盐或者其药物组合物的方法,用于在哺乳动物中抑制降解基质的金属蛋白酶,例如,基质溶素(MMP3,MMP10,MMP11);巨噬细胞金属弹性蛋白酶(MMP12)且特别是明胶酶(MMP2,MMP9)和MT1-MMP,从而抑制组织基质降解及治疗如本文所述的依赖于降解基质的金属蛋白酶的病况,例如,炎症、类风湿关节炎、骨关节炎及肿瘤(肿瘤生长、转移、增进或侵入),肺病(例如,肺气肿)及本文所述的其它病况。肿瘤(癌)包括哺乳动物的乳腺、肺部、膀胱、结肠、前列腺和卵巢的癌以及皮肤癌,包括黑素瘤和卡波西肉瘤。
此外,本发明涉及治疗与MMP,特别是MT1-MMP、MMP2和/或MMP9相关的病况或疾病,特别是本文所述的病况或疾病的方法,所说的方法包括给需要治疗的温血动物,包括人,施用治疗有效量的式I化合物或者这种化合物的可药用盐或可药用前体药物衍生物。
本发明尤其涉及治疗患有过度增生性疾病、特别是肿瘤疾病并且具体地说对MT1-MMP、MMP2和/或MMP9抑制有响应的过度增生性疾病的温血动物(包括人)的方法,该方法包括施用能有效抗过度增生的量的式I化合物或其可药用盐或可药用前体药物衍生物,或者涉及式I的化合物在这种治疗中的用途。
本文中所用的术语“选择性MMP2抑制剂”和“选择性MMP9抑制剂”是指,尤其通过本文所述的方法测定,化合物对酶MMP1所显出的抑制浓度IC50比对酶MMP2或MMP9所显出的抑制浓度IC50高至少100倍。优选,选择性MMP2或MMP9抑制剂对酶MMP1所显出的抑制浓度IC50比对酶MMP2或MMP9所显出的IC50高至少1000倍。更优选,选择性MMP2或MMP9抑制剂对酶MMP1所显出的抑制浓度IC50比对酶MMP2或MMP9所显出的IC50高至少2000倍。
本文所用的术语“非-肽”是指化合物不具有在脂族胺和羧酸之间含有化学键的亚结构。
本发明还涉及式I化合物或其可药用盐在抑制温血动物包括人的MT1-MMP、MMP2和/或MMP9中的用途,或者在制备用于治疗人或动物、特别是化学治疗肿瘤、COPD、脑水肿或哮喘的药物组合物中的用途。
根据种族、年龄、个体状况、给药模式和具体的临床表现,可以给大约70kg体重的温血动物施用有效剂量的本发明化合物,例如,大约0.05至约5g、优选约0.25至约2g的每日剂量。
本发明还涉及药物组合物,其含有有效量、特别是治疗上述一种病状时有效的量的活性成分以及适宜于局部、经肠例如口服或直肠或者非肠道给药的可药用载体,并且这些载体可以是无机或有机的、固态或液态的。用于口服给药时,可以使用特别是片剂或明胶胶囊,其中含有活性成分以及稀释剂,例如,乳糖、葡萄糖、甘露糖醇和/或甘油;和/或润滑剂和/或聚乙二醇。片剂中还可以含有粘合剂,例如,硅酸铝镁、淀粉例如玉米、小麦或水稻淀粉、明胶,甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮,并且如果需要的话,可以含有崩解剂,例如,淀粉、琼脂、藻酸或其盐,例如,藻酸钠;和/或泡腾剂混合物或吸附剂,色素,调味剂和甜味剂。还可以以可非肠道给药的组合物形式或以输注溶液的形式来使用本发明的药理学活性化合物。药物组合物可以是经过灭菌的和/或可以含有赋形剂,例如,防腐剂、稳定剂、润湿剂和/或乳化剂、增溶剂、调节渗透压用的盐和/或缓冲剂。本发明的药物组合物中如果需要的话可以含有其它药理学活性物质,其可以按本领域已知的方式制备,例如,借助于常规的混合、造粒、制糖膏、溶解或冻干工艺制备,并且含有大约1%至95%、特别是大约1%至20%的活性成分。
此外,本发明涉及用于治疗温血动物(包括人)肿瘤的药物组合物,其含有抗肿瘤有效剂量的上述式I化合物或这种化合物的可药用盐或可药用前体药物衍生物以及药物载体。
对于异羟肟酸化合物的前体药物衍生物,例如,式I的异羟肟酸化合物的前体药物衍生物,其制备是本领域技术人员已知的。
以下实施例起举例说明本发明的作用而不是限制本发明范围。温度以摄氏度给出。如果没有其它的说明,所有的蒸发都在减压条件下,优选地在约15-100mmHg(=20-133毫巴)之间进行。终产品、中间体和起始物料的结构通过标准分析方法来验证,例如,微量分析和光谱特征(例如,MS,IR,NMR)。所用的简写是本领域常规知道的。
所用的简短名称和简写具有以下含义:
简写:
AcOEt 乙酸乙酯
CC 柱色谱法
DMAP 二甲基氨基吡啶
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
Et 乙基
h 小时
Me 甲基
min. 分钟
NMR 核磁共振
r.t. 室温
sat. 饱和的
THF 四氢呋喃
NMR光谱数据中的简写
br 宽峰
d 双峰
J 耦合常数
m 多重峰
q 四重峰
s 单峰
t 三重峰
ppm 百万分之一
实施例1:2-[(4-环丙基甲氧基-苯磺酰基)-(4-二甲基氨基-苄基)-氨基]-N-羟
基-乙酰胺
向36g(85.2mmol)[(4-环丙基甲氧基-苯磺酰基)-(4-二甲基氨基-苄基)-氨基]-乙酸在500ml CH2Cl2中的溶液中,逐滴添加14.8ml(169.7mmol)草酰氯,接着逐滴添加1ml(12.9mmol)DMF(注意!-有大量的气体产生)并且在0至5℃下搅拌1h。在室温下搅拌另外1h后,通过使用聚四氟乙烯树脂管,在N2压力条件下,将所获得的酰基氯溶液于-20至-10℃下缓慢加到157ml(2379mmol)50%含水NH2OH在400ml THF中的溶液中。在-10℃下搅拌1.5h后,将反应混合物用冰水猝灭并且滤掉沉淀的粉末。将滤液用CH2Cl2萃取,经MgSO4干燥并且减压浓缩,用二乙醚洗涤后得到无色固体状的标题化合物;1H-NMR(400MHz,DMSO-d6):0.30-0.40(m,2H),0.55-0.65(m,2H),1.20-1.30(m,1H),2.85(s,6H),3.54(s,2H),3.91(d,2H,J=6.56Hz),4.23(s,2H),6.64(d,2H,J=8.04Hz),7.00(d,2H,J=7.56Hz),7.06(d,2H,J=8.04Hz),7.76(d,2H,J=7.56Hz),8.82(brs,1H),10.42(brs,1H).
步骤1.1:(4-二甲基氨基-苄基氨基)-乙酸甲酯
向50g(335mmol)4-氨基苯甲醛在1000ml CH2Cl2中的溶液中,在0至5℃下相继添加67.3g(536mmol)甘氨酸甲酯盐酸盐、182ml(1305mmol)三乙胺和70g MgSO4。将混合物在室温下搅拌18h并且通过celite过滤。将滤液减压浓缩并且将残余物用AcOEt稀释。将Et3N-盐酸盐滤掉,并且使用甲苯按共沸的方式将滤液减压浓缩,得到粗亚胺。向此粗制亚胺在500ml THF和500ml MeOH中的溶液中,在-20至-10℃下逐份添加18g(475mmol)NaBH4,并且将混合物搅拌1h。将反应混合物用饱和含水NH4Cl缓慢猝灭,然后用CH2Cl2萃取。将合并的萃取物用H2O、盐水洗涤,经MgSO4干燥并且减压浓缩。将残余物通过CC在硅胶上纯化(正己烷∶AcOEt=5∶1~1∶1),得到淡黄色油状的标题化合物。
步骤1.2:4-环丙基甲氧基-苯磺酸钠盐
向75g(323mmol)4-羟基苯磺酸钠盐在1350ml DMF中的悬浮液中,室温下小心地逐份添加20.67g(517mmol)的60%油悬浮的NaH。向混合物中,相继添加11.93g(32.3mmol)碘化四丁基铵和50.13ml(517mmol)(溴甲基)-环丙烷。在60℃下搅拌25h后,将反应混合物冷却至室温。收集沉淀并且用CH2Cl2洗涤数次,然后用混合溶剂(EtOH∶H2O=2∶1)再结晶,得到无色固体状的标题化合物。
步骤1.3:4-环丙基甲氧基-苯磺酰基氯
向100g(399.6mmol)4-环丙基甲氧基-苯磺酸钠盐的混悬液中,室温下逐滴添加186.55ml(2557.5mmol)亚硫酰氯和6.19ml(80mmol)DMF。搅拌15h后,将混合物倾入冰水中并且用CH2Cl2萃取。将合并的萃取物用H2O洗涤,经MgSO4干燥并且减压浓缩,得到无色固体状的标题化合物;1H-NMR(400MHz,CDCl3):0.35-0.45(m,2H),0.65-0.75(m,2H),1.25-1.35(m,1H),3.91(d,2H,J=7.04Hz),7.02(d,2H,J=9.04Hz),7.96(d,2H,J=9.04Hz)。
步骤1.4:[(4-环丙基甲氧基-苯磺酰基)-(4-二甲基氨基-苄基)-氨基]-乙酸甲酯
向49.4g(222mmol)[(4-二甲基氨基-苄基氨基)-乙酸甲酯]、41.4ml(244mmol)二异丙基乙胺和0.271g(2.2mmol)DMAP在600ml CH2Cl2中的溶液中,在0至5℃下添加存在于100ml CH2Cl2中的54.8g(222mmol)4-环丙基甲氧基-苯磺酰基氯。室温下搅拌15h后,将反应混合物用冰水和饱和含水NH4CO3猝灭。将混合物用AcOEt萃取并且将合并的萃取物用饱和含水NH4CO3和盐水洗涤,经MgSO4干燥并且减压浓缩。将残余物通过CC在硅胶上纯化(正己烷∶AcOEt=4∶1),得到无色固体状的标题化合物。
步骤1.5:[(4-环丙基甲氧基-苯磺酰基)-(4-二甲基氨基-苄基)-氨基]-乙酸
向74.6g(172.4mmol)步骤1.4的化合物在800ml THF中的溶液中,在0至5℃下相继添加14.5g(345.6mmol)氢氧化锂一水合物和400mlH2O。在室温下搅拌4h后,将混合物用含水2mol HCl在0至5℃下中和并且用CH2Cl2萃取数次。将合并的萃取物用MgSO4干燥并且减压浓缩,得到标题化合物。
实施例2:2-[(4-环丙基甲氧基-苯磺酰基)-(4-二甲基氨基-苄基)-氨基]-N-羟 基-乙酰胺HCl盐
向50g(114.3mmol)实施例1的化合物在500ml含水90%CH3CN中的溶液中,室温下相继添加137ml(137mmol)含水1mol HCl和另外的500ml H2O。将混合物冻干,得到无色固体状的标题化合物;1H-NMR(400MHz,DMSO-d6):0.30-0.40(m,2H),0.55-0.65(m,2H),1.20-1.30(m,1H),3.02(s,6H),3.61(s,2H),3.91(d,2H,J=7.08Hz),4.0(brs,1H),4.33(s,2H),7.07(d,2H,J=8.56Hz),7.30(brs,4H),7.76(d,2H,J=9.08Hz),10.53(brs,1H)。
实施例3:[(4-环丙基甲氧基-苯磺酰基)-(4-[1,2,3]三唑-2-基-苄基)氨基]-N-
羟基-乙酰胺
按照实施例1的类似方式,由[(4-环丙基甲氧基-苯磺酰基)-(4-[1,2,3]三唑-2-基-苄基)氨基]-乙酸开始,制备标题化合物;1H-NMR(400MHz,CDCl3):0.32-0.45(m,2H),0.55-0.65(m,2H),1.15-1.30(m,1H),3.66(s,3H),3.90(d,2H,J=7.04Hz),4.41(s,2H),7.07(d,2H,J=8.56Hz),7.45(d,2H,J=8.56Hz),7.79(d,2H,J=8.04Hz),7.96(d,2H,J=8.04Hz),8.12(s,2H),8.84(brs,1H),10.49(brs,1H).
步骤3.1:4-[1,2,3]-三唑-2-基-苯甲醛(A)和4-[1,2,3]-三唑-1-基-苯甲醛(B)
向100g(803mmol)对-氟苯甲醛在400ml DMF中的溶液中,相继添加95g(1377mmol)1-H-1,2,3-三唑和200g(1449mmol)K2CO3并且将混合物在100℃下搅拌4h。将混合物冷却至室温并且通过celite过滤。将滤液减压浓缩,得到粗制的晶体,将其用AcOEt洗涤数次。将未完全溶解在AcOEt中的固体用水洗涤,并且真空干燥,得到4-[1,2,3]-三唑-1-基-苯甲醛(B)。将滤液减压浓缩,将所获得的固体溶解于CH2Cl2中然后吸附在硅胶上进行干CC(正己烷∶AcOEt=2∶1~1∶2),得到淡黄色固体状的4-[1,2,3]-三唑-2-基-苯甲醛(A)和另一种化合物(B);1H-NMR(400MHz,CDCl3):化合物A,7.88(s,2H),8.01(d,2H,J=8.56Hz),8.29(d,2H,J=8.56Hz),10.06(s,1H);化合物B:7.90(s,1H),7.98(d,2H,J=8.56Hz),8.07(d,2H,J=8.56Hz),8.13(s,1H),10.09(s,1H).
步骤3.2:(4-[1,2,3]-三唑-2-基-苄基氨基)乙酸甲酯
向60g(347mmol)4-[1,2,3]-三唑-2-基-苯甲醛在1000ml CH2Cl2中的溶液中,在0至5℃下相继添加78.9g(629mmol)甘氨酸甲酯盐酸盐、104.2ml(749mmol)三乙胺和150g MgSO4。将混合物在室温下搅拌18h并且通过celite过滤。将滤液减压浓缩并且将残余物用AcOEt稀释。滤掉Et3N盐酸盐,并且使用甲苯按共沸的方式将滤液减压浓缩,得到粗制的亚胺。向此粗制亚胺在600ml THF和600ml MeOH中的溶液中,在-20至-10℃下逐份添加20g(526mmol)NaBH4并且将混合物搅拌1h。将反应混合物用饱和含水NH4Cl缓慢猝灭,然后用CH2Cl2萃取。将合并的萃取物用H2O、盐水洗涤,经MgSO4干燥并且减压浓缩。将残余物通过CC在硅胶上纯化(正己烷∶AcOEt=2∶1~1∶1),得到标题化合物。
步骤3.3:[(4-环丙基甲氧基-苯磺酰基)-(4-[1,2,3]-三唑-2-基-苄基)氨基]-乙酸甲酯
向79.5g(323.2mmol)步骤3.2的化合物、80.9ml(581.6mmol)Et3N和1.97g(16.1mmol)DMAP在1000ml CH2Cl2中的溶液中,添加99.6g(404mmol)4-环丙基甲氧基-苯磺酰基氯在150ml CH2Cl2中的溶液并且在0至5℃下搅拌60min.。在室温下搅拌另外18h后,将反应混合物用冰水猝灭并且用CH2Cl2萃取。将合并的萃取物用H2O、盐水洗涤,经MgSO4干燥并且减压浓缩。将残余物通过CC在硅胶上纯化(正己烷∶AcOEt=4:1~2∶1),得到无色固体状的标题化合物;1H-NMR(400MHz,CDCl3):0.35-0.45(m,2H),0.65-0.75(m,2H),1.25-1.35(m,1H),3.58(s,3H),3.87(d,2H,J=7.04Hz),3.94(s,2H),4.52(s,2H),6.99(d,2H,J=7.04Hz),7.37(d,2H,J=8.56Hz),7.81(s,2H),7.82(d,2H,J=7.04Hz),8.02(d,2H,J=8.56Hz)。
步骤3.4:[(4-环丙基甲氧基-苯磺酰基)-(4-[1,2,3]-三唑-2-基-苄基)氨基]-乙酸
按照类似于步骤1.5的方式,获得标题化合物;1H-NMR(400MHz,CDCl3):0.35-0.45(m,2H),0.65-0.75(m,2H),1.25-1.35(m,1H),3.86(d,2H,J=7.04Hz),3.95(s,2H),4.51(s,2H),6.97(d,2H,J=8.56Hz),7.34(d,2H,J=8.56Hz),7.80(s,2H),7.83(d,2H,J=8.56Hz),8.01(d,2H,J=8.56Hz)。
或者可以通过如下顺序获得步骤3.3的化合物:
步骤3.5:(4-[1,2,3]-三唑-2-基-苯基)-甲醇
向42.26g(244mmol)4-[1,2,3]-三唑-2-基-苯甲醛在140ml THF和420ml MeOH中的溶液中,在0至5℃下逐份添加9.23g(244mmol)NaBH4并且将混合物在相同温度下搅拌30min。用饱和NH4Cl在0至5℃下猝灭反应并且用AcOEt萃取混合物。将合并的萃取物用盐水洗涤,经MgSO4干燥并且减压浓缩,得到无色固体状的标题化合物。
步骤3.6:2-(4-氯甲基-苯基)-2H-[1,2,3]-三唑
向50.58g(289mmol)(4-[1,2,3]三唑-2-基-苯基)-甲醇在2000mlCH2Cl2中的溶液中,在0至5℃下逐滴添加31.59ml(433mmol)亚硫酰氯并且让反应混合物升温至室温。搅拌16h后,将反应混合物用饱和NaHCO3在0至5℃下碱化并且用CH2Cl2萃取。将合并的萃取物用盐水洗涤,经MgSO4干燥并且减压浓缩,得到标题化合物。
步骤3.7:(4-环丙基甲氧基-苯磺酰基氨基)-乙酸甲酯
向7.125g(56.75mmol)甘氨酸甲酯盐酸盐在60ml二噁烷和24mlH2O中的溶液中,在0至5℃下逐滴添加15ml(107.8mmol)Et3N,然后逐滴添加10g(40.53mmol)4-环丙基甲氧基-苯磺酰基氯在10ml二噁烷中的溶液。室温下搅拌3h后,将反应用冰水猝灭并且将混合物用AcOEt萃取。将合并的萃取物用H2O、盐水洗涤,经MgSO4干燥并且减压浓缩,得到无色固体状的标题化合物1H-NMR(400MHz,CDCl3)0.3-0.40(m,2H),0.65-0.72(m,2H),1.20-1.35(m,1H),3.65(m,3H),3.77(d,2H,J=5.04Hz),3.86(d,2H,J=7.08Hz),4.98(brs,1H),6.96(d,2H,J=8.52Hz),7.77(d,2H,J=8.52Hz)。
步骤3.8:[(4-环丙基甲氧基-苯磺酰基)-(4-[1,2,3]三唑-2-基-苄基)氨基]-乙酸甲酯
向1g(3.3mmol)步骤3.7的化合物在10ml DMF中的溶液中,室温下相继添加0.8086g(4.175mmol)2-(4-氯甲基-苯基)-2H-[1,2,3]三唑、0.0555g(0.33mmol)KI和0.646g(4.68mmol)K2CO3。搅拌18h后,将反应用冰水猝灭并且将混合物用AcOEt萃取。将合并的萃取物用H2O、盐水洗涤,经MgSO4干燥并且减压浓缩,得到固体,将其用二乙醚和MeOH洗涤,得到标题化合物。
实施例4:
按照实施例1和3中所描述的方法,可以获得如下化合物:
表1
实施例5:无水胶囊
如下制备3000个胶囊,每个含有0.25g前述实施例中提到的式I化合物的一种作为活性成分:
组成
活性成分 75.00g
乳糖 750.00g
Avicel PH 102 300.00g
(微晶纤维素)
Polyplasdone XL 30.00g
(聚乙烯吡咯烷酮)
硬脂酸镁 9.00g
制备方法:让活性成分通过30号手动筛(hand screen)。将活性成分、乳糖、Avicel PH 102和Polyplasdone XL在混合器中共混15分钟。将共混物用足量的水(约500mL)造粒,在35℃烘箱中干燥过夜并且通过20号筛。让硬脂酸镁通过20号筛,添加到制粒混合物中,并且将混合物在混合器中共混5分钟。将共混物装入0号硬明胶胶囊中,每个胶囊含有相当于25mg活性成分的共混物。
实施例6:体外活性
在本申请所描述的体外测试中,测定实施例2化合物的抑制活性,结果示于下表2。
表2
实施例 | MT1-MMPIC50[nM] | MMP1IC50[nM] | MMP2IC50[nM] | MMP9IC50[nM] |
2 | 4.67±0.17 | 1770±144 | 3.29±0.49 | 2.57±0.27 |
IC50值是三次独立实验的平均值±SEM。
Claims (12)
2.权利要求1的式I化合物或其盐,其中
R是二甲基氨基或1,2,3-三唑-2-基,
m表示1至10且包括10的整数,并且
n表示0至10且包括10的整数。
3.权利要求1或2的式I化合物或其盐,其中
m是1,2,3,4或5,并且
n是0。
4.权利要求1或2的式I化合物或其盐,其中
m是1、2、3、4或5,并且
n是1、2、3或4。
5.权利要求1的式I化合物或其盐,
其中
R是二-低级烷基氨基、1,2,3-三唑-1-基、1,2,3-三唑-2-基或1,2,4-三唑-4-基,
n是1并且
m是1。
6.权利要求1的式I化合物或其盐,选自以下化合物:
2-[(环丙基甲氧基-苯磺酰基)-(4-[1,2,3]三唑-2-基-苄基)-氨基]-N-羟基-乙酰胺,
2-[(环丙基甲氧基-苯磺酰基)-(4-[1,2,3]三唑-2-基-苄基)-氨基]-N-羟基-乙酰胺-盐酸盐,
2-[(环丙基甲氧基-苯磺酰基)-(4-二甲基氨基苄基)-氨基]-N-羟基-乙酰胺,
2-[(环丙基甲氧基-苯磺酰基)-(4-二甲基氨基苄基)-氨基]-N-羟基-乙酰胺-盐酸盐,
2-[(环丙基甲氧基-苯磺酰基)-(4-[1,2,3]三唑-1-基-苄基)-氨基]-N-羟基-乙酰胺,
2-[(环丙基甲氧基-苯磺酰基)-(4-[1,2,4]三唑-4-基-苄基)-氨基]-N-羟基-乙酰胺,
2-[(环丙基甲氧基-苯磺酰基)-(4-二乙基氨基苄基)-氨基]-N-羟基-乙酰胺,和
2-[(环丙基甲氧基-苯磺酰基)-(4-二乙基氨基苄基)-氨基]-N-羟基-乙酰胺-盐酸盐。
7.药物组合物,其含有权利要求1-6任一项的式I化合物或这种化合物的可药用盐或可药用前体药物衍生物以及药用载体。
8.治疗由MMP介导的病况或疾病的方法,包括给需要治疗的温血动物,包括人,施用治疗有效量的权利要求1-6任一项的式I化合物或这种化合物的可药用盐或可药用前体药物衍生物。
9.用于治疗人或动物体的权利要求1-6任一项的式I化合物或这种化合物的可药用盐或可药用前体药物衍生物。
10.权利要求1-6任一项的式I化合物或这种化合物的可药用盐或可药用前体药物衍生物在制备用于化学治疗肿瘤、COPD、脑水肿或哮喘的药物组合物中的用途。
11.下式I的α-氨基乙酰异羟肟酸衍生物或其盐的制备方法
其中R是二-低级烷基氨基、1,2,3-三唑-1-基、1,2,3-三唑-2-基或1,2,4-三唑-4-基,m表示1至10且包括10的整数,并且n表示0至10且包括10的整数,所说的方法包括将下式II的碳酸
其中R、m和n具有如式I化合物中所定义的含义,首先与能够将此碳酸转化成相应酰卤的试剂反应,此反应任选地在适宜的催化剂的存在下进行;之后在适宜溶剂或溶剂混合物中与NH2OH反应;并且任选地,为制备盐,将所得的游离式I化合物转化成盐,或者如果必要的话为制备游离化合物,将所得的式I化合物的盐转化成游离化合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0103303.4 | 2001-02-09 | ||
GBGB0103303.4A GB0103303D0 (en) | 2001-02-09 | 2001-02-09 | Organic compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1525956A true CN1525956A (zh) | 2004-09-01 |
CN100509773C CN100509773C (zh) | 2009-07-08 |
Family
ID=9908475
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB028047133A Expired - Fee Related CN100509773C (zh) | 2001-02-09 | 2002-02-08 | α-氨基-N-羟基-乙酰胺衍生物 |
Country Status (10)
Country | Link |
---|---|
US (3) | US7112611B2 (zh) |
EP (1) | EP1360175A1 (zh) |
JP (1) | JP4262982B2 (zh) |
CN (1) | CN100509773C (zh) |
AR (1) | AR032553A1 (zh) |
AU (1) | AU2002249197A1 (zh) |
CA (1) | CA2435611C (zh) |
GB (1) | GB0103303D0 (zh) |
PE (1) | PE20020845A1 (zh) |
WO (1) | WO2002064552A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101410370B (zh) * | 2006-03-29 | 2013-06-12 | 诺瓦提斯公司 | 基于异羟肟酸酯的选择性mmp抑制剂 |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9918684D0 (en) | 1999-08-09 | 1999-10-13 | Novartis Ag | Organic compounds |
GB0103303D0 (en) * | 2001-02-09 | 2001-03-28 | Novartis Ag | Organic compounds |
WO2005090297A1 (en) * | 2004-03-19 | 2005-09-29 | Biotie Therapies Corporation | Sulphonamide derivatives |
US20100234378A1 (en) * | 2006-08-22 | 2010-09-16 | Array Biopharma Inc. | Alkylsulfonamide-substituted triazoles as matrix metalloprotease inhibitors |
WO2008147764A1 (en) * | 2007-05-23 | 2008-12-04 | Array Biopharma, Inc. | Mmp inhibitors and methods of use thereof |
EP2934555B1 (en) | 2012-12-21 | 2021-09-22 | Astellas Institute for Regenerative Medicine | Methods for production of platelets from pluripotent stem cells |
US11058804B2 (en) | 2017-06-13 | 2021-07-13 | Ethicon Llc | Surgical fastener device for the prevention of ECM degradation |
JP2020523132A (ja) * | 2017-06-13 | 2020-08-06 | エシコン エルエルシーEthicon LLC | 広域スペクトルmmp阻害剤を有する手術用締結具 |
US10939911B2 (en) | 2017-06-13 | 2021-03-09 | Ethicon Llc | Surgical stapler with end effector coating |
CN110769866B (zh) * | 2017-06-13 | 2022-07-29 | 爱惜康有限责任公司 | 具有可控愈合的外科缝合器 |
US20180353174A1 (en) * | 2017-06-13 | 2018-12-13 | Ethicon Llc | Surgical Stapler with Controlled Healing |
Family Cites Families (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2513826A (en) | 1946-12-05 | 1950-07-04 | Gen Aniline & Film Corp | Aromatic sulfonhydrazides |
US4772733A (en) | 1986-07-17 | 1988-09-20 | Hercules Incorporated | Epoxy-azides |
US4806528A (en) | 1987-09-04 | 1989-02-21 | Hanreich Reinhard G | Process for the preparation of 2-(2-chloroethoxy)-benzenesulfonamide |
US5338755A (en) | 1990-07-31 | 1994-08-16 | Elf Sanofi | N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present |
FR2682498A1 (fr) | 1991-10-15 | 1993-04-16 | Kodak Pathe | Colorants comprenant des macrocycles thioethers. |
US5663431A (en) | 1992-01-30 | 1997-09-02 | Sanofi | 1-benzenesulfonyl-1,3-dihydro-indol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present |
US5455258A (en) | 1993-01-06 | 1995-10-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
US5646167A (en) | 1993-01-06 | 1997-07-08 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamix acids |
US5552419A (en) * | 1993-01-06 | 1996-09-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
US5506242A (en) | 1993-01-06 | 1996-04-09 | Ciba-Geigy Corporation | Arylsufonamido-substituted hydroxamic acids |
GB9503749D0 (en) | 1995-02-24 | 1995-04-12 | British Biotech Pharm | Synthesis of hydroxamic acid derivatives |
DE69737605T2 (de) * | 1996-01-23 | 2008-04-03 | Shionogi & Co., Ltd. | Sulfonierte aminosäurederivate und metalloproteinase-inhibitoren, die diese enthalten |
CA2242416C (en) * | 1996-01-23 | 2006-03-21 | Shionogi & Co., Ltd. | Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same |
DK0901466T3 (da) | 1996-05-17 | 2002-02-18 | Warner Lambert Co | Biphenylsulfonamid-matriksmetalloproteinase-inhibitorer |
JPH10265452A (ja) | 1996-05-24 | 1998-10-06 | Ono Pharmaceut Co Ltd | フェニルスルホンアミド誘導体 |
WO1998018754A1 (en) | 1996-10-28 | 1998-05-07 | Versicor, Inc. | Methods for solid-phase synthesis of hydroxylamine compounds and derivatives, and combinatorial libraries thereof |
CA2263886A1 (en) | 1996-12-09 | 1998-06-18 | Warner-Lambert Company | Method for treating and preventing heart failure and ventricular dilatation |
EA002594B1 (ru) | 1997-02-03 | 2002-06-27 | Пфайзер Продактс Инк. | Производные арилсульфониламиногидроксамовой кислоты |
GB9708133D0 (en) | 1997-04-22 | 1997-06-11 | British Biotech Pharm | Novel use of matrix metalloproteinase inhibitors |
PT877019E (pt) | 1997-05-09 | 2002-05-31 | Hoechst Ag | Acidos diaminocarboxilicos substituidos |
DE19719621A1 (de) | 1997-05-09 | 1998-11-12 | Hoechst Ag | Sulfonylaminocarbonsäuren |
KR100352316B1 (ko) | 1997-07-31 | 2002-09-12 | 더 프록터 앤드 갬블 캄파니 | 메탈로프로테아제억제제로서사용되는술포닐아미노치환히드록삼산유도체 |
IL127496A0 (en) | 1997-12-19 | 1999-10-28 | Pfizer Prod Inc | The use of MMP inhibitors for the treatment of ocular angiogenesis |
PL342009A1 (en) | 1998-02-04 | 2001-05-07 | Novartis Ag | Sulphonylamine derivatives capable to inhibit extracellular substance degrading metaloproteinases |
JPH11236369A (ja) * | 1998-02-23 | 1999-08-31 | Kotobuki Seiyaku Kk | スルホンアミド誘導体及びその製造法並びにこれを含有する医薬組成物 |
PA8469301A1 (es) | 1998-04-10 | 2000-09-29 | Pfizer Prod Inc | Procedimientos para la preparacion de acidos hidroxamicos. |
HUP0104658A3 (en) | 1998-12-22 | 2005-12-28 | Hoffmann La Roche | Sulfonamide hydroxamates |
AR035311A1 (es) | 1999-01-27 | 2004-05-12 | Wyeth Corp | Derivados de acido hidroxamico que contienen alquinilo, como inhibidores de las metalloproteinasas de matriz y de la tace, composicion farmaceutica y el uso de los mismos para la manufactura de un medicamento |
AR035313A1 (es) | 1999-01-27 | 2004-05-12 | Wyeth Corp | Inhibidores de tace acetilenicos de acido hidroxamico de sulfonamida a base de alfa-aminoacidos, composiciones farmaceuticas y el uso de los mismos para la manufactura de medicamentos. |
GB9918684D0 (en) * | 1999-08-09 | 1999-10-13 | Novartis Ag | Organic compounds |
GB0103303D0 (en) * | 2001-02-09 | 2001-03-28 | Novartis Ag | Organic compounds |
-
2001
- 2001-02-09 GB GBGB0103303.4A patent/GB0103303D0/en not_active Ceased
-
2002
- 2002-02-07 AR ARP020100398A patent/AR032553A1/es unknown
- 2002-02-07 PE PE2002000088A patent/PE20020845A1/es not_active Application Discontinuation
- 2002-02-08 CA CA2435611A patent/CA2435611C/en not_active Expired - Fee Related
- 2002-02-08 CN CNB028047133A patent/CN100509773C/zh not_active Expired - Fee Related
- 2002-02-08 JP JP2002564485A patent/JP4262982B2/ja not_active Expired - Fee Related
- 2002-02-08 WO PCT/EP2002/001345 patent/WO2002064552A1/en active Application Filing
- 2002-02-08 AU AU2002249197A patent/AU2002249197A1/en not_active Abandoned
- 2002-02-08 EP EP02718115A patent/EP1360175A1/en not_active Withdrawn
- 2002-02-08 US US10/467,611 patent/US7112611B2/en not_active Expired - Fee Related
-
2006
- 2006-08-07 US US11/500,138 patent/US7291634B2/en not_active Expired - Fee Related
-
2007
- 2007-10-05 US US11/868,032 patent/US7659293B2/en not_active Expired - Fee Related
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101410370B (zh) * | 2006-03-29 | 2013-06-12 | 诺瓦提斯公司 | 基于异羟肟酸酯的选择性mmp抑制剂 |
Also Published As
Publication number | Publication date |
---|---|
CA2435611C (en) | 2011-07-12 |
CN100509773C (zh) | 2009-07-08 |
US20060270719A1 (en) | 2006-11-30 |
WO2002064552A1 (en) | 2002-08-22 |
AU2002249197A1 (en) | 2002-08-28 |
JP2004523545A (ja) | 2004-08-05 |
PE20020845A1 (es) | 2002-10-30 |
US7291634B2 (en) | 2007-11-06 |
US20080176916A1 (en) | 2008-07-24 |
US20040082630A1 (en) | 2004-04-29 |
GB0103303D0 (en) | 2001-03-28 |
WO2002064552A8 (en) | 2002-12-12 |
US7112611B2 (en) | 2006-09-26 |
CA2435611A1 (en) | 2002-08-22 |
EP1360175A1 (en) | 2003-11-12 |
US7659293B2 (en) | 2010-02-09 |
AR032553A1 (es) | 2003-11-12 |
JP4262982B2 (ja) | 2009-05-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1281590C (zh) | 具有抑制血管生成活性的六员氨基酰胺类衍生物 | |
CN1116288C (zh) | 用作肌苷-5'-一磷酸脱氢酶抑制剂的脲衍生物 | |
CN1057085C (zh) | 杂环取代的苯基-环己烷羧酸衍生物 | |
CN1723197A (zh) | 作为纤溶酶原激活物抑制剂-1(pai-1)的抑制剂的取代3-烷基和3-芳基烷基1h-吲哚-1-基乙酸衍生物 | |
US7291634B2 (en) | α-amino-N-hydroxy-acetamide derivatives | |
CN1239949A (zh) | 新的杂环取代的苯甲酰胺及其控制疾病的用途 | |
CN1950359A (zh) | 作为IkB激酶抑制剂的基本纯净的2-{ [2-(2-甲基氨基-嘧啶-4-基)-1H-吲哚-5-羰基]-氨基}-3-(苯基吡啶-2-基-氨基)-丙酸 | |
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 | |
CN1265098A (zh) | 抑制因子xa的杂环衍生物 | |
JP2007506760A (ja) | 置換ヘテロアリールベンゾフラン酸 | |
CN1368958A (zh) | 芳基磺酰氨基取代的异羟肟酸衍生物 | |
CN1048239C (zh) | 萘衍生物 | |
CN1966506A (zh) | 吡唑并嘧啶酮衍生物及其制备方法和用途 | |
CN1305465A (zh) | 芳基链烷酰基哒嗪化合物 | |
CN1662490A (zh) | 环氧酶2-抑制剂的硝酰氧基衍生物 | |
CN1842529A (zh) | 用作蛋白激酶抑制剂的化合物和组合物 | |
CN1976903A (zh) | 因子VⅡa抑制剂 | |
CN1216872C (zh) | 喹唑啉衍生物及其药物用途 | |
CN1914169A (zh) | 作为环氧合酶-2抑制剂的二芳基-2-(5h)-呋喃酮的氧化氮释放前药 | |
CN1126737C (zh) | 新型吡咯化合物和其制备方法及含其的药物组合物 | |
CN1404467A (zh) | 氨基磺酰基联苯基衍生物 | |
CN1889949A (zh) | PDK-1/Akt信号传导抑制剂 | |
RU2675854C2 (ru) | Кристаллическая форма азолбензольного производного | |
CN1610679A (zh) | 制备因子xa抑制剂的有效方法 | |
CN1378538A (zh) | 二氮芳辛-二酮衍生物及其作为类胰蛋白酶抑制剂的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C56 | Change in the name or address of the patentee |
Owner name: NOVARTIS CO., LTD. Free format text: FORMER NAME: NOVARTIS AG |
|
CP01 | Change in the name or title of a patent holder |
Address after: Basel Patentee after: Novartis Ag Address before: Basel Patentee before: Novartis AG |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090708 Termination date: 20150208 |
|
EXPY | Termination of patent right or utility model |