CN1309660A - 用作药物的次膦酸和膦酸衍生物 - Google Patents
用作药物的次膦酸和膦酸衍生物 Download PDFInfo
- Publication number
- CN1309660A CN1309660A CN99808668A CN99808668A CN1309660A CN 1309660 A CN1309660 A CN 1309660A CN 99808668 A CN99808668 A CN 99808668A CN 99808668 A CN99808668 A CN 99808668A CN 1309660 A CN1309660 A CN 1309660A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- phenyl
- formula
- compound
- integer
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 11
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title description 2
- RYIOLWQRQXDECZ-UHFFFAOYSA-N phosphinous acid Chemical compound PO RYIOLWQRQXDECZ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 78
- 230000000694 effects Effects 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 42
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
- -1 methylene-dioxy Chemical group 0.000 claims description 37
- 239000002253 acid Substances 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 150000001413 amino acids Chemical class 0.000 claims description 13
- 150000003009 phosphonic acids Chemical class 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 7
- 206010003246 arthritis Diseases 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 201000008482 osteoarthritis Diseases 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 102000035195 Peptidases Human genes 0.000 claims description 4
- 108091005804 Peptidases Proteins 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 150000002390 heteroarenes Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 208000018631 connective tissue disease Diseases 0.000 claims description 3
- 230000002101 lytic effect Effects 0.000 claims description 3
- 230000004060 metabolic process Effects 0.000 claims description 3
- 150000003217 pyrazoles Chemical class 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 150000003233 pyrroles Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 208000018083 Bone metabolism disease Diseases 0.000 claims description 2
- 206010058112 Chondrolysis Diseases 0.000 claims description 2
- 208000017667 Chronic Disease Diseases 0.000 claims description 2
- 208000027932 Collagen disease Diseases 0.000 claims description 2
- 230000005526 G1 to G0 transition Effects 0.000 claims description 2
- 208000012659 Joint disease Diseases 0.000 claims description 2
- 208000034693 Laceration Diseases 0.000 claims description 2
- 208000000112 Myalgia Diseases 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 2
- 206010040070 Septic Shock Diseases 0.000 claims description 2
- 206010041591 Spinal osteoarthritis Diseases 0.000 claims description 2
- 208000025865 Ulcer Diseases 0.000 claims description 2
- 208000026816 acute arthritis Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 230000006378 damage Effects 0.000 claims description 2
- YLFBFPXKTIQSSY-UHFFFAOYSA-N dimethoxy(oxo)phosphanium Chemical compound CO[P+](=O)OC YLFBFPXKTIQSSY-UHFFFAOYSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 230000036039 immunity Effects 0.000 claims description 2
- 150000002475 indoles Chemical class 0.000 claims description 2
- 208000014674 injury Diseases 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 210000003041 ligament Anatomy 0.000 claims description 2
- 230000003137 locomotive effect Effects 0.000 claims description 2
- 230000005499 meniscus Effects 0.000 claims description 2
- 210000000056 organ Anatomy 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 210000004417 patella Anatomy 0.000 claims description 2
- 208000028169 periodontal disease Diseases 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 2
- 230000036303 septic shock Effects 0.000 claims description 2
- 208000005801 spondylosis Diseases 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 230000008733 trauma Effects 0.000 claims description 2
- 231100000397 ulcer Toxicity 0.000 claims description 2
- 230000029663 wound healing Effects 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 235000019833 protease Nutrition 0.000 claims 1
- 102000036444 extracellular matrix enzymes Human genes 0.000 abstract description 2
- 108091007167 extracellular matrix enzymes Proteins 0.000 abstract description 2
- 238000011321 prophylaxis Methods 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 102000004190 Enzymes Human genes 0.000 description 20
- 108090000790 Enzymes Proteins 0.000 description 20
- 229940088598 enzyme Drugs 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 102000016284 Aggrecans Human genes 0.000 description 15
- 108010067219 Aggrecans Proteins 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 102000005741 Metalloproteases Human genes 0.000 description 5
- 108010006035 Metalloproteases Proteins 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102000029816 Collagenase Human genes 0.000 description 3
- 108060005980 Collagenase Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 206010029379 Neutrophilia Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 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
- 238000004113 cell culture Methods 0.000 description 3
- 229960002424 collagenase Drugs 0.000 description 3
- 238000005336 cracking Methods 0.000 description 3
- 239000012228 culture supernatant Substances 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 108091007196 stromelysin Proteins 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 229960004799 tryptophan Drugs 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 2
- SNDPXSYFESPGGJ-UHFFFAOYSA-N 2-aminopentanoic acid Chemical compound CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000005243 Chondrosarcoma Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 2
- KSPIYJQBLVDRRI-UHFFFAOYSA-N N-methylisoleucine Chemical compound CCC(C)C(NC)C(O)=O KSPIYJQBLVDRRI-UHFFFAOYSA-N 0.000 description 2
- 102100030411 Neutrophil collagenase Human genes 0.000 description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000016611 Proteoglycans Human genes 0.000 description 2
- 108010067787 Proteoglycans Proteins 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 241000219061 Rheum Species 0.000 description 2
- 102100030416 Stromelysin-1 Human genes 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000006035 Tryptophane Substances 0.000 description 2
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 229960000846 camphor Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- XVOYSCVBGLVSOL-UHFFFAOYSA-N cysteic acid Chemical compound OC(=O)C(N)CS(O)(=O)=O XVOYSCVBGLVSOL-UHFFFAOYSA-N 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 229960003104 ornithine Drugs 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- OXFGRWIKQDSSLY-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-2-ium-1-carboxylate Chemical compound C1=CC=C2C(C(=O)O)NCCC2=C1 OXFGRWIKQDSSLY-UHFFFAOYSA-N 0.000 description 1
- BWKMGYQJPOAASG-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CNC(C(=O)O)CC2=C1 BWKMGYQJPOAASG-UHFFFAOYSA-N 0.000 description 1
- RJXNZBKNKLNXLX-UHFFFAOYSA-N 1,2-oxazole;1,3-oxazole Chemical compound C=1C=NOC=1.C1=COC=N1 RJXNZBKNKLNXLX-UHFFFAOYSA-N 0.000 description 1
- UIQSKEDQPSEGAU-UHFFFAOYSA-N 1-Aminoethylphosphonic Acid Chemical class CC(N)P(O)(O)=O UIQSKEDQPSEGAU-UHFFFAOYSA-N 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- QLPZEDHKVHQPAD-UHFFFAOYSA-N 2,2,2-trifluoro-n-trimethylsilylacetamide Chemical compound C[Si](C)(C)NC(=O)C(F)(F)F QLPZEDHKVHQPAD-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 1
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 1
- XLMSKXASROPJNG-UHFFFAOYSA-N 2-azaniumyl-2-thiophen-2-ylacetate Chemical compound OC(=O)C(N)C1=CC=CS1 XLMSKXASROPJNG-UHFFFAOYSA-N 0.000 description 1
- NYCRCTMDYITATC-UHFFFAOYSA-N 2-fluorophenylalanine Chemical compound OC(=O)C(N)CC1=CC=CC=C1F NYCRCTMDYITATC-UHFFFAOYSA-N 0.000 description 1
- HAEFDDOAYBQRGK-UHFFFAOYSA-N 2-methylpropylphosphonic acid Chemical class CC(C)CP(O)(O)=O HAEFDDOAYBQRGK-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- XWHHYOYVRVGJJY-QMMMGPOBSA-N 4-fluoro-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(F)C=C1 XWHHYOYVRVGJJY-QMMMGPOBSA-N 0.000 description 1
- INPQIVHQSQUEAJ-UHFFFAOYSA-N 5-fluorotryptophan Chemical compound C1=C(F)C=C2C(CC(N)C(O)=O)=CNC2=C1 INPQIVHQSQUEAJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- 229940118148 Aldose reductase inhibitor Drugs 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 description 1
- 101100472050 Caenorhabditis elegans rpl-2 gene Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical compound [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- NIGWMJHCCYYCSF-UHFFFAOYSA-N Fenclonine Chemical compound OC(=O)C(N)CC1=CC=C(Cl)C=C1 NIGWMJHCCYYCSF-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000648097 Genetta pardina Species 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 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 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-UHNVWZDZSA-N L-allo-Isoleucine Chemical compound CC[C@@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-UHNVWZDZSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical compound C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 description 1
- QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Natural products CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108010016160 Matrix Metalloproteinase 3 Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102000014171 Milk Proteins Human genes 0.000 description 1
- 108010011756 Milk Proteins Proteins 0.000 description 1
- XCOBLONWWXQEBS-KPKJPENVSA-N N,O-bis(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)O\C(C(F)(F)F)=N\[Si](C)(C)C XCOBLONWWXQEBS-KPKJPENVSA-N 0.000 description 1
- AKCRVYNORCOYQT-YFKPBYRVSA-N N-methyl-L-valine Chemical compound CN[C@@H](C(C)C)C(O)=O AKCRVYNORCOYQT-YFKPBYRVSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 101710118230 Neutrophil collagenase Proteins 0.000 description 1
- 108030001564 Neutrophil collagenases Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- IAJOBQBIJHVGMQ-UHFFFAOYSA-N Phosphinothricin Natural products CP(O)(=O)CCC(N)C(O)=O IAJOBQBIJHVGMQ-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 101710108790 Stromelysin-1 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
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 241000863032 Trieres Species 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 108010003059 aggrecanase Proteins 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000003277 amino acid sequence analysis Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- IXMFOVOQHOSHDW-UHFFFAOYSA-N diazinan-3-ylphosphonic acid Chemical class OP(O)(=O)C1CCCNN1 IXMFOVOQHOSHDW-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- IAJOBQBIJHVGMQ-BYPYZUCNSA-N glufosinate-P Chemical compound CP(O)(=O)CC[C@H](N)C(O)=O IAJOBQBIJHVGMQ-BYPYZUCNSA-N 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VWHRYODZTDMVSS-QMMMGPOBSA-N m-fluoro-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC(F)=C1 VWHRYODZTDMVSS-QMMMGPOBSA-N 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 235000021239 milk protein Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 1
- FGFDBUYNZJGBSO-UHFFFAOYSA-N piperazin-2-ylphosphonic acid Chemical class OP(O)(=O)C1CNCCN1 FGFDBUYNZJGBSO-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- WZHRJGWXUCLILI-UHFFFAOYSA-N sulfonylcarbamic acid Chemical class OC(=O)N=S(=O)=O WZHRJGWXUCLILI-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 235000020238 sunflower seed Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- YSMODUONRAFBET-WHFBIAKZSA-N threo-5-hydroxy-L-lysine Chemical compound NC[C@@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-WHFBIAKZSA-N 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229960004418 trolamine Drugs 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
- 229960004441 tyrosine Drugs 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
-
- 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
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Cardiology (AREA)
- Communicable Diseases (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Diabetes (AREA)
- Dermatology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
式Ⅰ的化合物适合于制备用于预防和治疗与基质－降解酶活性增加有关的所有病症药物。
Description
本发明涉及新的磺酰基氨基次膦酸和-膦酸衍生物，其制备方法和其作为药物的用途。
专利申请EP0606046,WO95/35276和WO96/27583描述了芳基磺酰基氨基羟肟酸和其作为基质金属蛋白酶抑制剂的作用。特定的芳基磺酰基氨基羧酸被用作制备凝血酶抑制剂(EP0468231)和醛糖还原酶抑制剂(EP0305947)的中间体。专利申请EP0757037也描述了磺酰基氨基羧酸衍生物作为金属蛋白酶抑制剂的作用。芳基磺酰基已经被证明是α-氨基羧酸的氨基官能团的有效保护基(R.Roemmele,H.Rapoport,J.Org.Chem.53(1988)2367-2371)。为了寻找治疗结缔组织疾病的有效化合物，现已发现本发明的磺酰基氨基次膦酸和-膦酸衍生物是强的金属蛋白酶抑制剂。其特殊价值在于对溶基质素(基质金属蛋白酶3)，嗜中性白细胞胶原酶(MMP-8)和聚集蛋白聚糖酶的抑制作用，因为这些酶被认为在很大程度上与作为软骨组织重要组成的蛋白聚糖的降解有关(A.J.Fosang et al.,J.Clin.Invest.98(1996)2292-2299)。
聚集蛋白聚糖，软骨的主要蛋白聚糖的病理损失，包括在其球间区的蛋白酶裂解。从患关节痛，骨关节炎或关节炎的患者的滑液分离的蛋白聚糖代谢物的氨基酸序列分析显示，蛋白酶裂解优选地在人的聚集蛋白聚糖的球间区的氨基酸Glu373和Ala374之间发生(Lohmanderet al.,Arthritis Rheum.36,(1993),1214-1222)。直到现在，仍然不能确定响应该裂解的蛋白酶活性。它被标示为“聚集蛋白聚糖酶”，并可以归结到金属蛋白酶族。
人软骨组织MT1-MMP表达的第一次检测(Buttner et al.，Arthritis Rheum.、40,1997,704-709)，与该酶在重组聚集蛋白聚糖融合蛋白rAgglmut中在“聚集蛋白聚糖酶”裂解位点裂解的催化区的证据相结合，导致了本文所述的强基质金属蛋白酶抑制剂在其对“聚集蛋白聚糖酶”活性作用方面的试验。用各种分析体系可以显示，磺酰基氨基次膦酸和-膦酸衍生物是“聚集蛋白聚糖酶”活性的强抑制剂。
本发明还涉及式Ⅰ化合物
和/或式Ⅰ化合物的立体异构形式和/或式Ⅰ化合物的药用盐，其中R1是1．苯基，
2．被下列基团一-或二取代的苯基
2.1直链，环状或支链(C1-C6)-烷基，
2.2羟基，
2.3(C1-C6)-烷基-C(O)-O-，
2.4(C1-C6)-烷基-O-，
2.5(C1-C6)-烷基-O-(C1-C4)-烷基-O-，
2.6卤素，
2.7-CF3，
2.8-CN，
2.9-NO2，
2.10.HO-C(O)-，
2.11.(C1-C6)-烷基-O-C(O)-，
2.12.亚甲二氧基
2.13.R4-(R5)N-C(O)-，
2.14.R4-(R5)N-或
2.15.组3.1.至3.16.的杂芳族化合物，
3．3.1.至3.16.的杂芳族化合物，它们是未取代的或如2.1.至2.15.所述取代的，
3.1.吡咯，
3.2.吡唑，
3.3.咪唑，
3.4三唑，
3.5.噻吩，
3.6.噻唑
3.7.噁唑，
3.8异噁唑，
3.9.吡啶，
3.10.嘧啶，
3.11.吡咯烷，
3.12.吲哚，
3.13.苯并噻吩，
3.14.苯并咪唑，
3.15.苯并噁唑，或
3.16.苯并噻唑，或
4．-O-(C1-C6)-烷基，R2,R4和R5相同或不同，并且是
1．氢原子，
2．(C1-C6)-烷基-，
3．HO-C(O)-(C1-C6)-烷基-，
4．苯基-(CH2)n-，其中苯基是未取代的或如2.1.至2.15.所述的一-或二-取代的，或被-NH-C(O)-(C1-C3)-烷基取代，n是整数0,1或2，或
5．吡啶甲基或
6．R4和R5与环的氨基一起形成4-至7-元环，其中一个碳原子被-O-,-S-或-NH-非强制性代替或者4-至7-元环的两个相邻碳原子是苄基的一部分，R和R3相同或不同，并且是
1．氢原子，
2．(C1-C10)-烷基-，其中烷基是未取代的，和/或烷基的一个氢原子被-OH代替，
3．(C2-C10)-烯基-，其中烯基是直链或支链的，
4．R2-O-(C1-C6)-烷基-，
5．R2-S(O)n-(C1-C6)-烷基-，其中n具有前述意义，
6．R2-S(O)(=NH)-(C1-C6)-烷基-，
7．式Ⅱo的基团
其中n是整数0,1或2，而W是氮，氧或硫原子，
8．苯基-(CH2)m-，其中m是整数0,1,2,4,5或6和/或-(CH2)m-链的一个氢原子被-OH代替，而苯基是未取代的或被下列基团一-或二-取代
8.1.如2.1.至2.15.所述，
8.2.-O-(CH2)m-苯基，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，和
m是整数0,1,2,4,5或6，
8.3.-C(O)-(CH2)m-苯基，其中苯基如8.2定义，
9．杂芳基-(CH2)m-，其中杂芳基如3.1.至3.16.定义，m如上定义和/或-(CH2)m-链的一个氢原子被-OH代替，而杂芳基是未取代的或被如下基团一-或二-取代
9.1.如2.1.至2.15.所述，
9.2.-CH(O)，
9.3.-SO2-苯基，其中苯基是未取代的或如8.2.至8.3.定义，
9.4.-O-(CH2)m-苯基，
10．-(CH2)m-P(O)(OH)-(C1-C3)-烷基-，其中m如上定义
11．氨基酸的特征性残基或
12．R6-C(O)-(C0-C6)-烷基-，其中R6是
1．氢原子，
2．(C1-C6)-烷基，其中烷基是直链，支链或环状的，
3．苯基，其中苯基是未取代的或如2.1.至2.15.所述被取代，
4．杂芳基，其中杂芳基如3.1.至3.16.定义，和/或如2.1.至2.15.所述被取代，或被-(C1-C4)-烷基-COOH取代，
5．-OH，
6．-OR2，其中R2具有上述意义，
7．-NR4-(R5)，其中R4和R5如上定义，
8．杂芳基-(CH2)m-NH-，其中杂芳基如3.1.至3.16.定义，和/或如2.1.至2.15.所述被取代，m如上定义，
9．R4-(R5)N-NH-，其中R4和R5如上定义，
10．HO-C(O)-CH(R3)-NH-，其中R3如上定义，
13．-(CH2)p-N(R9)(R10)，其中p是整数1,2,3或4，其中R9和R10相同或不同，并且是
1．氢原子，
2．苯基-(CH2)m-，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，m是整数0,1,2或3，
3．RX-C(O)-，其中Rx是
3.1(C1-C6)-烷基-，
3.2.(C2-C6)-烯基-，
3.3.苯基-(CH2)m-，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，m是整数0,1,2或3，或
3.4.杂芳基-(CH2)m，其中杂芳基如3.1.至3.16.定义，和/或如2.1.至2.15.所述被取代，m是整数0,1,2或3，
4．RX-O-C(O)-，其中RX如上定义，
5．RX-CH(NH2)-C(O)-，其中RX如上定义，
6．R8-N(R7)-C(O)-，其中R8是
6.1.氢原子，
6.2.(C1-C6)-烷基-，
6.3.苯基-(CH2)m-，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，m是整数0,1,2或3，或
6.4.杂芳基-(CH2)m，其中杂芳基如3.1.至3.16.定义，和/或如2.1.至2.15.所述被取代，m是整数0,1,2或3，且其中R7是氢原子或(C1-C6)-烷基-或其中R7和R8与它们所连接的氮原子一起形成4-至7-元环，该环是未取代的，或者环中的一个碳原子被-O-,-S-或-NH-代替，
7．RX-SO2，其中RX如上定义，
8．RX-NH-C(=NR7)-，其中RX和R7如上定义，或者是
8.1.(C1-C6)-烷基-C(O)-，
8.2.-NO2或
8.3.-SO2-(CH2)q-苯基，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，q是整数0,1,2或3，
9．-SO2-(CH2)q-苯基-苯基，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，q是整数0,1,2或3，
10．式Ⅱp的基团
其中m是整数O,1,2或3，而W是氮原子，或R9和R10与它们所连接的氮原子一起形成式Ⅱa至Ⅱn的环
其中r是整数1或2,R11是如2.1.至2.15.所述的基团，R7和m具有上述意义，
14．-OH，
15．=O或
16．(C1-C6)-烷基-，或
-C(R)(R3)-基团是-NH-或-NR2-，其中R2如上定义，和
t是整数1,2,3或4，或R2和R3一起形成式Ⅱ的带外环次膦酸或膦酸的环
其中r是整数0,1,2或3，和/或环中的一个碳原子被-O-,-S-或-(R7)N-代替，其中
R7是1．氢原子，
2．(C1-C6)-烷基，
3．苯基，其中苯基是未取代的或如2.1.至2.15.所述取代
4．苄基，其中苄基是未取代的或如2.1.至2.15.所述被取代，或
5．R2N-C(=NH)-，其中R2具有上述意义，
和/或式Ⅱ环中的碳原子被(C1-C6)-烷基-，苯基-，苯基-(CH2)m-或HO-一-或多取代，U是-SO2-或CO-，Y1和Y2相同或不同，并且相互独立地是
a)氢原子，
b)-OH，
c)(C1-C4)-烷基，其中烷基是直链或支链的，
d)-(CH2)u-苯基，其中u是0或1，
e)-O-(C1-C4)-烷基，其中烷基是直链或支链的，
f)-O-(CH2)s-苯基，其中s是0或1，A是 a)共价键，
b)-O-，
c)-CH=CH-或
d)-C≡C-，B是 a)-(CH2)m-，其中m具有前述意义，
b)-O-(CH2)p-苯基，其中p是1至5的整数，或
c)-CH=CH-，和X是-CH=CH-，氧原子或硫原子。优选的是如下定义的式Ⅰ化合物，其中R1是1．苯基或
2．被下列基团一取代的苯基
2.1直链，环状或支链(C1-C6)-烷基，
2.2-OH，
2.3-C(O)-OH，
2.4-O-(C1-C6)-烷基，
2.5吡咯烷酮，
2.6卤素或
2.7-CF3，或
3．-O-(C1-C6)-烷基，R2、R4和R5相同或不同，是氢原子或C1-C6烷基，R是氢原子，R3是1．(C1-C6)-烷基-，其中烷基是直链，支链或环状的，和/或烷基的一个氢原子被-OH代替，
2．R2-S(O)n-(C1-C6)-烷基-，其中R2是(C1-C6)-烷基或苯基-(CH2)n-，而n是整数0或1，
3．-(CH2)m-苯基，其中苯基是未取代的或如2.1.至2.15.所述被一-或二-取代，和/或-(CH2)m-链的一个氢原子被-OH代替，而m是整数0,1,2,4或5，
4．-(CH2)m-杂芳基，其中杂芳基如3.3.,3.5.,3.6.,3.9.或3.11.定义，和/或2.1.至2.15.所述被取代，和/或-(CH2)m-链的一个氢原子被-OH代替，而m是整数0,1,2,3或4，
5．氨基酸的特征性残基或
6．-(CH2)p-N(R9)(R10)，其中p是整数0,1或2，其中R9和R10相同或不同，并且是氢原子，或-SO2-(CH2)q-苯基-苯基，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，q是整数0,1,2或3，或
7．R6-C(O)-，其中R6是
7.1-OH，
7.2.R2O-，其中R2如上定义，或
7.3.R4-(R5)N-，其中R4和R5如上定义，
8．氢原子，
9．-OH，
10．=O或
11．(C1-C6)-烷基-，或
-C(R)(R3)-基团是-NH-或-NR2-，其中R2如上定义，和
t是整数1,2,3或4，U是-SO2-，Y1是-OH，Y2是a)-O-(C1-C4)-烷基，其中烷基是直链或支链的，
b)-OH，
c)(C1-C4)-烷基，其中烷基是直链或支链的，A是共价键或-O-，B是共价键或(C1-C4)-烷基而X是-CH=CH。特别优选的是如下定义的式Ⅰ化合物，其中R1是1．被卤素一取代的苯基，R2是氢原子，R是氢原子，R3是1．(C1-C4)-烷基-，
2．-苯基，其中苯基是未取代的或被-CF3或-COOH一-或二-取代，
3．氢原子，
4．-OH或
5．-NH-SO2-苯基-苯基，其中苯基是未取代的或被卤素取代，
t是整数1,2,3或4，U是-SO2-，Y1和Y2是-OH或-OCH3，A是共价键，B是共价键或-(CH2)o-，其中o是1,2或3而X是-CH=CH-。
特别优选的化合物是(R)-[1-(4’-氯联苯-4-磺酰基氨基)-2-甲基丙基]膦酸，[3-(4’-氯联苯-4-磺酰基氨基)-1-羟基-3-(4-三氟甲基苯基)丙基]膦酸二甲酯或[1-(4’-氯联苯-4-磺酰基氨基)-3-甲基丁基]膦酸。
“R4和R5与环的氨基一起形成4-至7-元环和/或一个碳原子被-O-,-S-或-NH-非强制性代替”的表达被理解为该基团从，例如，氮杂环丁烷，吡咯，二氢吡咯，吡啶，氮杂，哌啶，噁唑，异噁唑，咪唑，二氢吲哚，吡唑，噻唑，异噻唑，二氮杂_，硫代吗啉，嘧啶或吡嗪衍生的。术语“卤素”被理解为氟，氯，溴或碘。术语“烷基”或“烯基”被理解为其烃链是直链或支链的烃基。环状烷基是，例如，3-至6-元单环化合物如环丙基，环丁基，环戊基或环己基。烯基可以还含有多个双键。
α-氨基酸的通式结构如下：α-氨基酸的R互相不同，它在本申请的文本中被称为氨基酸的“特征性基团”。
用于化学反应的起始物是已知的，或可以通过文献的已知方法容易制备的。用作合成本发明化合物起始物质的氨基-次膦酸和-膦酸，如果不能在各种情况下购买到，则可以根据已知的方法合成(R.S.Rogers,M.K.Stern,Sylett 1992,708;P.P.Giannousis,P.A.Bartlett,J.Med.Chem.,30,1603(1987)；J.P.Genet,M.Uziel,A.M.Touzin,S.Roland,S.Thorimbert,S.Tanier,Tetrahedron Lett.33,77(1992)；E.K.Baylis,C.D.Campbell,J.G.Dingwall,J.Chem.Soc.Perkin Trans.1,1984,2845)。
本发明还涉及制备式Ⅰ化合物和/或式Ⅰ化合物的立体异构形式和/或式Ⅰ化合物的药用盐的方法，该方法包括a)式Ⅲ的氨基次膦酸或-膦酸其中R2,Y1,Y2,R和R3如式Ⅰ中定义，与式Ⅳ的磺酸或羰基衍生物在碱或可有可无的脱水剂存在下反应，
其中R1,A,X,U和B如式Ⅰ中定义，而Z是卤原子，咪唑基或-OR8，其中R8是氢原子，(C1-C6)-烷基，苯基或苄基，如果需要，是被取代的，给出式Ⅰ化合物，或者b)式(Ⅴ)的氨基次膦酸或-膦酸酯
其中R2,R3,t,Y2和R8具有上述意义，与式Ⅳ的磺酸或羰基衍生物反应，给出式Ⅵ化合物
并优选地在碱或酸存在下除去基团R8使式Ⅵ化合物转化为式Ⅰ化合物，或者c)式Ⅶ化合物
其中n是整数0,1或2，与保护基E反应，给出式Ⅷ化合物
并用式Ⅳ化合物使式Ⅷ化合物转化为式Ⅸ化合物然后在合适的裂解试剂帮助下，除去保护基E和基团R8，使式Ⅸ化合物转化为式Ⅰ化合物，或者d)因为其化学结构为对映体形式，通过与对映体纯的酸或碱形成盐，在手性固定相上层析，或者通过手性对映体纯的化合物如氨基酸的手段衍生，分开所得的非对映体，除去手性辅基，将方法a)，b)或c)之一制备的式Ⅰ化合物分开为纯的对映体，或者e)将方法a),b),c)或d)之一制备的式Ⅰ化合物以游离形式分离，或者在酸性或碱性基团存在下转化为其药用盐。
这里所用的合适的保护基E优选地是常用于肽化学的N-保护基，例如脲烷型保护基，苄氧羰基(Z)，叔丁氧羰基(Boc),9-芴氧羰基(Fmoc)，烯丙氧羰基(Aloc)或酰胺型保护基，尤其是甲酰基，乙酰基或三氟乙酰基，和烷基型，例如苄基。
所用的其中R2是氢原子，而R3是氨基酸特征性基团的式Ⅲ化合物优选地是下列天然α-氨基酸的特征性基团：甘氨酸，丙氨酸，缬氨酸，亮氨酸，异亮氨酸，苯丙氨酸，酪氨酸，色氨酸，丝氨酸，苏氨酸，半胱氨酸，甲硫氨酸，天冬酰胺，谷氨酰胺，赖氨酸，组氨酸，精氨酸，谷氨酸和天冬氨酸。所用的其中R2是氢原子，而R3是氨基酸特征性基团的式Ⅲ化合物优选地是例如下列非天然氨基酸的特征性基团：2-氨基戊酸，2-氨基丁酸，2,4-二氨基丁酸，2-氨基异丁酸，2,3-而氨基丙酸，1,2,3,4-四氢异喹啉-1-羧酸，1,2,3,4-四氢异喹啉-3-羧酸，2-氨基庚二酸，苯基甘氨酸，3-(2-噻吩基)丙氨酸，3-(3-噻吩基)丙氨酸，2-(2-噻吩基)甘氨酸，2-氨基庚酸，2-哌啶酸，羟基赖氨酸，肌氨酸，N-甲基异亮氨酸，6-N-甲基赖氨酸，N-甲基缬氨酸，正缬氨酸，正亮氨酸，鸟氨酸，别异亮氨酸，4-羟基脯氨酸，3-羟基脯氨酸，别羟基赖氨酸，3-(2-萘基)丙氨酸，3-(1-萘基丙氨酸)，高苯丙氨酸，高半胱氨酸，高磺基丙氨酸，高色氨酸，磺基丙氨酸，3-(2-吡啶基)丙氨酸，3-(3-吡啶基)丙氨酸，3-(4-吡啶基)丙氨酸，瓜氨酸，phosphinothricin,4-氟苯基丙氨酸，3-氟苯基丙氨酸，2-氟苯基丙氨酸，4-氯苯基丙氨酸，4-硝基苯基丙氨酸，4-氨基苯基丙氨酸，环己基丙氨酸，5-氟色氨酸，5-甲氧基色氨酸，甲硫氨酸砜，甲硫氨酸亚砜，或NH2-NH-CONH2，如果需要，是被取代的。在侧链R3上具有诸如氨基，羟基，羧基，巯基，胍基，咪唑基或吲哚基的官能团的天然以及非天然氨基酸的情况下，该基团也可以被保护。
如果在R3中有咪唑基，用于磺酰胺形成的式Ⅳ磺酸衍生物，例如，作为咪唑氮的保护基，它可以被再除去，尤其是在诸如氢氧化钠水溶液的碱存在下。
为了制备其中R2和R3一起形成结构Ⅱ的环的式Ⅰ化合物，所用的式Ⅲ原料是，例如，2-甲基丙基膦酸，哌啶-2-膦酸，哌嗪-2-膦酸，六氢哒嗪-3-膦酸，特别是可以在哌嗪-2-膦酸的4-位氮上被保护基Z，例如在方法c)中所述的苄氧羰基或叔丁氧羰基或基团R7取代。
用于制备式Ⅳ的磺酸衍生物的原料优选地是式Ⅹ的磺酸或其盐，例如
其中R9是如2.1.至2.15.所述的基团。
对于式Xa和Xb的芳基磺酸的制备，优选地使用在Houben-Weyl“Methoden der Organischen Chemie”[有机化学方法]Volume 9，pp.450-546中所述的用浓硫酸的磺化法，如果需要，在催化剂，三氧化硫和其加成化合物或卤代磺酸，如氯磺酸存在下。尤其是在式Xb的二苯基醚的情况下，使用浓硫酸和乙酸酐作为溶剂(参见C.M.Suter,J.Am.Chem.Soc.53(1931)1114)，或者与过量的氯磺酸反应(J.P.Bassin,R.Cremlyn and F.Swinbourne；Phosphorus,Sulfur andSilicon 72(1992)157)已经被证明是合适的。式Xc,Xd或Xe磺酸的制备可以以类似的方法，通过相应的芳烷基卤化物与亚硫酸盐如亚硫酸钠或亚硫酸铵在水溶液或水/醇溶液中反应而制备，在四有机铵盐如氯化四丁基铵存在下，可以加速反应。
所用的式Ⅳ磺酸衍生物特别是磺酰氯。对于其制备，相应的磺酸，以及其盐所形式，如钠，铵或吡啶鎓盐，以已知的方式与五氯化磷或亚硫酰氯在有或没有溶剂如三氯氧磷或惰性溶剂如二氯甲烷，环己烷或氯仿存在下，一般在20℃至高达所用的反应介质沸点的温度下反应。
根据方法a),b)，或c)的方法，式Ⅳ的磺酸衍生物与式Ⅲ,Ⅴ或Ⅶ的氨基膦酸的反应优选地以Schotten-Baumann反应的方式进行。其中所用的合适的碱特别是碱金属氢氧化物如氢氧化钠，但也用碱金属乙酸盐，碳酸氢盐，碳酸盐和胺。反应在水和/或水混溶或不混溶溶剂如四氢呋喃(THF)，丙酮，二噁烷或乙腈中进行，反应一般保持在-10℃至50℃。如果反应在无水介质中进行，四氢呋喃或二氯甲烷，乙腈或二噁烷在碱如三乙胺，N-甲基吗啉，N-乙基-或二异丙基乙胺存在下，特别被使用，可能在作为催化剂的N,N-二甲基氨基吡啶存在下。
在另一种情况下，式Ⅲ,Ⅳ或Ⅶ的氨基羧酸首先可以用硅烷基化试剂如双三甲基甲硅烷基三氟乙酰胺(BSTFA)转化为其硅烷基化形式，然后它们可以与磺酸衍生物反应，给出式Ⅰ化合物。
可以形成盐的式Ⅰ化合物生理上可接受盐，包括其立体异构体形式的制备以已知的方式进行。膦酸或次膦酸与碱性试剂如氢氧化物，碳酸盐，碳酸氢盐，醇盐以及氨或有机碱，例如三甲胺或三乙胺，乙醇胺或三乙醇胺或碱性氨基酸，例如赖氨酸，鸟氨酸或精氨酸形成稳定的碱金属，碱土金属或非强制性取代的铵盐。如果式Ⅰ化合物具有碱性基团，也可以用强酸制备稳定的酸加成盐。无机和有机酸如盐酸，氢溴酸，硫酸，磷酸，甲磺酸，苯磺酸，对甲苯磺酸，4-溴苯磺酸，环己基酰氨基磺酸，三氟甲磺酸，乙酸，草酸，酒石酸，琥珀酸或三氟乙酸是适用的。
本发明也涉及包含有效量的至少一种式Ⅰ化合物和/或式Ⅰ化合物的药用盐和/或式Ⅰ化合物可有可无的立体异构体形式，与药学上适合的和生理上可接受的赋形剂，添加剂和/或其它活性化合物和辅助剂一起的药物。
由于其药理性质，本发明的化合物适合于预防和治疗与基质-降解酶如金属蛋白酶或聚集蛋白聚糖酶活性增加有关的所有病症。这些包括变性关节病如骨关节炎，椎关节强硬，关节创伤后的软骨溶解，或半月板或膑骨损伤或韧带撕裂后较长时间的关节制动术。这些也包括结缔组织疾病如胶原疾病，牙周疾病，创伤愈合疾病和运动器官慢性疾病如炎症，免疫或代谢相关的急性和慢性关节炎，关节病，肌痛和骨代谢疾病。式Ⅰ化合物还适合于治疗溃疡，动脉粥样硬化和狭窄。式Ⅰ化合物还适合于治疗发炎，癌症，肿瘤形成，噁病质，厌食和脓毒性休克。
一般说来，本发明的药物被口服或肠胃外给药。也可以直肠或经皮给药。
本发明也涉及生产药物的方法，该方法包括用药用的和生理上可接受的赋形剂，如果需要，还有其它合适的活性化合物，添加剂或辅助剂使至少一种式Ⅰ化合物成为适合于给药的形式。
合适的固体或药物制剂形式有，例如，颗粒剂，粉剂，包衣片剂，片剂，(微)胶囊，栓剂，糖浆，果汁，悬浮液，乳剂，滴剂或注射液，和缓释活性化合物的制剂，在其生产中，使用了常规辅助剂如赋形剂，崩解剂，黏合剂，包衣剂，膨胀剂，滑动剂或润滑剂，调味剂，甜味剂和增溶剂。要提到的常用辅助剂有碳酸镁，二氧化钛，乳糖，甘露醇和其它糖，滑石，乳蛋白，明胶，淀粉，纤维素和其衍生物，动物和植物油如鱼肝油，葵花籽油，花生油或蓖麻油，聚乙二醇和溶剂如，蒸馏水和一-多羟基醇如甘油。
药物制剂优选地以单位剂量制备和给药，各单位含有作为活性成分的特定剂量的本发明式Ⅰ化合物。在固体剂量单位如片剂，胶囊，包衣片剂或栓剂的情况下，该剂量可以高达大约1000mg，但优选地大约50至300mg，而在安瓿注射液的情况下，最高大约300mg，但优选地大约10至100mg。
为了治疗体重约70kg的成年患者，根据式Ⅰ化合物的效力，日剂量约20mg至1000mg活性化合物，优选地，例如100mg至500mg。但是，在某些情况下，更高或更低的日剂量也是允许的。日剂量可以通过以单个剂量单位或者许多更小的剂量单位的形式单给药，和在特定的间隔多给药。
1H-NMR谱在Bruker 400MHz或Varian 200MHz仪器上，用四甲基甲硅烷作内标，室温下测定。所用的溶剂在各种情况下指定。通常，最终产物都通过质谱法(FAB-,ESI-MS)测定；在各种情况下标出主峰。温度为摄氏度，RT表示室温(22℃至26℃)。所用的缩写要么是解释过的，或者是常用的。
实施例1(R)-[1-(4’-氯联苯-4-磺酰基氨基)-2-甲基丙基]膦酸
将250mg(1.6mmol)(R)-(1-氨基-2-甲基丙基)膦酸溶于6ML 1M氢氧化钠和6ML四氢呋喃。然后加入560mg(1.96mmol)4-氯联苯-4'-磺酰氯，并将混合物在22℃搅拌过夜。将反应混合物浓缩，用2M盐酸酸化，并用乙酸乙酯萃取。4-氯联苯-4'-磺酸以副产物的形式沉淀出来，并被分出。将乙酸乙酯相干燥并浓缩后，得到一固体。
产率：136mg(21％)；分子量：403.831H-NMR:in DMSO-d6；10.8(s,br,2H)；7.91；7.82；7.76；7.63 7.56(5d,9H)；3.06(m,1H)；1.98(m,1H)；0.87;0.80(dd,6H)；MS(ES1；M+Na+):425.9实施例2(R,S)-[1-(4’-氯联苯-4-磺酰基氨基)-1-苯基甲基]膦酸一乙酯
将830mg(3.85mmol)(R,S)-(氨基苯基甲基)膦酸一乙酯溶于6ML1M氢氧化钠和10ML四氢呋喃。然后加入1.44g(5.01mmol)4-氯联苯-4’-磺酰氯，并将混合物在22℃搅拌过夜。分出产生的沉淀并分散于热的水/乙酸乙酯中。用盐酸酸化至pH1至2后，将乙酸乙酯相分出并浓缩。留下一固体。
产率：610mg(34％)；分子量：4651H-NMR:in DMSO-d6；8.66(s,br,1H)；7.57(m,9H)；7.16(m,2H)；7.01(m,3H)；4.58(dd,1H)3.85(m,2H)；1.11(m,3H)；MS(FAB；M+,M+Na+):466.0；488.0实施例3(R,S)-[(4’-氯联苯-4-磺酰基氨基)-1-苯基甲基]膦酸
将320mg(0.69mmol)实施例2的一乙酯溶于6ML二氯甲烷，并在0℃用0.36ml(2.75mmol)三甲基甲硅烷基溴处理。RT4小时后，在旋转蒸发仪上浓缩至干，将残留物溶于水。除去固体，水相被冻干。
产率：257mg(80％)；分子量：436.8g/mol1H-NMR:DMSO-d6；7.6(m,8H)；7.2(m,2H)；7.0(m,3H)；4.2(m,1H)MS(ES1-):436.0实施例4(R,S)-[1-(4’-氯联苯-4-磺酰基氨基)-2-(1H-吲哚-3-基)乙基]膦酸
将150mg(0.274mmol)相应的二乙酯溶于4ML二氯甲烷，并在室温用0.11ml(0.82mmol)三甲基甲硅烷基溴处理。3小时后，在旋转蒸发仪上浓缩至干，将残留物用二异丙基醚处理，并滤除固体。
产率：42mg(33％)；分子量：490.921H-NMR:DMSO-d6；10.4(s,2H)；7.9；7.68；7.55(3d,5H)；7.3；6.9(2m,8 H)；3.7(m,1H)；3.2-2.6(2m,4H)；MS(ES1+):491.0实施例5(R,S)-[1-(4’-氯联苯-4-磺酰基氨基)乙基]膦酸
在氮气氛中，将733mg(2.8mmol)N,0-双三甲基甲硅烷基三氟乙酰胺加入178mg(1.4mmol)(R,S)-1-氨基乙基膦酸在30ML乙腈中的溶液中，混合物被加热回流2小时。冷却至15℃后，加入490mg(1.7mmol)4’-氯联苯-4-磺酰氯在15ML乙腈中的溶液。混合物在RT搅拌3小时，浓缩，用甲醇处理，并再次浓缩。残余物被用二氯甲烷/甲醇75∶25和1％乙酸硅胶层析。
产率：60mg(11％)；分子量：375.771H-NMR:DMSO-d6；1.0-1.2(m,3H),3.35-3.55(m,1H),7.5(d,2H),7.68(d,2H),7.8(d,2H),8.0(d,2H);MS(ES1-):374.1实施例6(R,S)-[1-(4’-氯联苯-4-磺酰基氨基)-3-甲基丁基]膦酸
在氮气氛中，将516mg(2mmol)N,0-双三甲基甲硅烷基三氟乙酰胺加入222mg(1mmol)(R,S)-1-氨基-3-甲基丁基膦酸盐酸盐在30ML乙腈中的溶液中，混合物被加热回流2小时。冷却至15℃后，加入345mg(1.2mmol)4’-氯联苯-4-磺酰氯在15ML乙腈中的溶液。混合物在RT搅拌3.5小时，浓缩，用甲醇处理，并再次浓缩。残余物被用乙腈/水(含0.1％三氟乙酸)，10％至100％梯度的乙腈经RPl8层析。产率：75mg(18％)，分子量：417.85；MS(ESI-):416.1类似于实施例1至6制备在下表1中定义的化合物。
表1 
药理实施例制备并测定人溶基质素和嗜中性胶原酶催化区的活性根据Ye等人(Biochemistry；31(1992)pp.11231-11235)的方法制备两种酶-溶基质素(MMP-3)和嗜中性胶原酶(NMP-8)。为了测定酶活性或酶抑制作用，将70μl缓冲溶液和10μl酶溶液用10μl非强制性地含有酶抑制剂的10％(v/v)二甲亚砜水溶液温育15分钟。加入10μl含有1mmol/l底物的10％(v/v)二甲亚砜水溶液后，该酶催化反应通过荧光光谱(328nm(ex)/-393nm(em))监测。
酶活性以消光增加/分钟给出。在表2中列出的IC50值作为在各种情况下导致50％酶抑制的抑制剂浓度。
该缓冲溶液含有0.05％Brij(Sigma,Deisenhofen,Germany)和0.1mol/lTris/HCl,0.1mol/l氯化钠，0.01mol/l氯化钙和0.1mol/l哌嗪-N,N'-双[2-乙磺酸](pH=6.5)。
酶溶液含有5μg/ml根据Ye等人的方法制备的酶域的一种。底物溶液含有1mmol/l发荧光底物(7-甲氧基香豆素-4-基)乙酰基-Pro-Leu-Gly-Leu-3-(2’,4’-二硝基苯基-L-2,3-二氨基丙酰基-Ala-Arg-NH2(Bachem,Heidelberg,Germany)。表2
用大鼠软骨肉瘤细胞制备和测定聚集蛋白聚糖酶催化域的酶催化活性
| 实施例 | 溶基质素IC50(M) | 嗜中性胶原酶IC50(M) |
| 1 | 6×10-9 | 1×10-9 |
| 2 | 5×10-6 | 2×10-7 |
| 3 | 1×10-7 | 7×10-9 |
| 4 | 5×10-7 | 6×10-8 |
| 5 | 1×10-7 | 5×10-9 |
| 6 | 3×10-8 | 3×10-9 |
| 18 | 10×10-6 | 1×10-6 |
| 19 | 5×10-9 | 2×10-9 |
| 20 | 8×10-9 | 2×10-9 |
| 22 | 2×10-8 | 2×10-8 |
| 24 | 4×10-7 | 3×10-8 |
| 25 | 3×10-9 | 2×10-9 |
为了产生尚未鉴定的“聚集蛋白聚糖酶”活性，使用了大鼠软骨肉瘤细胞(RCS)(Lark et al.；J.Biol.Chem.,270；(1995)，2550-2556)。这些细胞被接种到用聚L-赖氨酸预包的96-孔细胞培养板(80000细胞/孔)。用视黄酸(0.67μM)刺激RCS细胞，在37℃和5％CO2中温育时间为47小时后，这些细胞产生“聚集蛋白聚糖酶”活性。试验物化合物1然后在含有“聚集蛋白聚糖酶”的细胞培养上清液中预温育1小时，然后加入5μg真核rAgg 1 mut(Buttner et al.,Biochem.J.333；(1998),159-165和Hughes et al.,J.Biol.Chem.272；(1997),20269-20274)，检测在RCS细胞的细胞培养上清液中的“聚集蛋白聚糖酶”裂解活性。温育4小时后，除去细胞培养上清液，由“聚集蛋白聚糖酶”活性产生的rAgg 1 mut融合蛋白的裂解产物通过SDS-聚丙烯酰胺凝胶电泳和用单克隆抗体BC-3的Western Blot分析检测(Hughes et al.,Biochem.J.305,799-804,1995)。化合物1的作用在在降低BC-3反应活性裂解产物方面被看出。较少裂解的rAgg1 mut被检测到，更有效的是被试验的式Ⅰ化合物。
在表3中列出的IC50值作为在各种情况下导致50％酶聚集蛋白聚糖酶抑制的抑制剂浓度。表3
| 实施例 | 聚集蛋白聚糖酶IC50 |
| 1 | 0.6μM |
| 2 | 79μM |
| 3 | 22μM |
| 4 | 12μM |
| 5 | 25μM |
| 6 | 2.4μM |
| 7 | 29μM |
| 8 | 15μM |
| 10 | 2.1μM |
| 12 | 50μM |
| 13 | 50μM |
| 14 | 55μM |
| 15 | 67μM |
| 16 | 28μM |
| 17 | 69μM |
| 18 | 60μM |
| 20 | 4.7μM |
| 21 | 0.52μM |
| 22 | 8.3μM |
Claims (10)
1．式Ⅰ化合物
和/或式Ⅰ化合物的立体异构形式和/或式Ⅰ化合物的药用盐，其中R1是1．苯基，
2．被下列基团一-或二取代的苯基
2.1直链，环状或支链(C1-C6)-烷基，
2.2羟基，
2.3(C1-C6)-烷基-C(O)-O-，
2.4(C1-C6)-烷基-O-,
2.5(C1-C6)-烷基-O-(C1-C4)-烷基-O-，
2.6卤素，
2.7-CF3，
2.8-CN，
2.9-NO2，
2.10.HO-C(O)-，
2.11.(C1-C6)-烷基-O-C(O)-，
2.12.亚甲二氧基
2.13.R4-(R5)N-C(O)-，
2.14.R4-(R5)N-或
2.15．组3.1.至3.16.的杂芳族化合物，
3．3.1．至3.16．的杂芳族化合物，它们是未取代的或如2.1．至2.15．所述取代的，
3.1．吡咯，
3.2．吡唑，
3.3．咪唑，
3.4 三唑，
3.5．噻吩，
3.6．噻唑
3.7．噁唑，
3.8 异噁唑，
3.9．吡啶，
3.10．嘧啶，
3.11．吡咯烷，
3.12．吲哚，
3.13．苯并噻吩，
3.14．苯并咪唑，
3.15．苯并噁唑，或
3.16．苯并噻唑，或
4．-O-(C1-C6)-烷基，R2,R4和R5相同或不同，并且是
1．氢原子，
2．(C1-C6)-烷基-，
3．HO-C(O)-(C1-C6)-烷基-，
4．苯基-(CH2)N-，其中苯基是未取代的或如2.1.至2.15,所述的一-或二-取代的，或被-NH-C(O)-(C1-C3)-烷基取代，n是整数0，1或2，或
5．吡啶甲基或
6．R4和R5与环的氨基一起形成4-至7-元环，其中一个碳原子被-O-，-S-或-NH-非强制性代替或者4-至7-元环的两个相邻碳原子是苄基的一部分，R和R3相同或不同，并且是
1．氢原子，
2．(C1-C10)-烷基-，其中烷基是未取代的，和/或烷基的一个氢原子被-OH代替，
3．(C2-C10)-烯基-，其中烯基是直链或支链的，
4．R2-O-(C1-C6)-烷基-，
5．R2-S(O)n-(C1-C6)-烷基-，其中n具有前述意义，
6．R2-S(O)(=NH)-(C1-C6)-烷基-，
7．式Ⅱo的基团
其中n是整数0,1或2，而W是氮，氧或硫原子，
8．苯基-(CH2)m-，其中m是整数0,1,2,4,5或6和/或-(CH2)m-链的一个氢原子被-OH代替，而苯基是未取代的或被下列基团一-或二-取代
8.1．如2.1.至2.15.所述，
8.2.-O-(CH2)m-苯基，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，和
m是整数0,1,2,4,5或6，
8.3.-C(O)-(CH2)m-苯基，其中苯基如8.2定义，
9．杂芳基-(CH2)m-，其中杂芳基如3.1.至3.16.定义，m如上定义和/或-(CH2)m-链的一个氢原子被-OH代替，而杂芳基是未取代的或被如下基团一-或二-取代
9.1．如2.1.至2.15.所述，
9.2.-CH(O)，
9.3.-SO2-苯基，其中苯基是未取代的或如8.2.或8.3.定义，
9.4.-O-(CH2)m-苯基，
10.-(CH2)m-P(O)(OH)-(C1-C3)-烷基-，其中m如上定义
11．氨基酸的特征性残基或
12．R6-C(O)-(C0-C6)-烷基-，其中R6是
1．氢原子，
2．(C1-C6)-烷基，其中烷基是直链，支链或环状的，
3．苯基，其中苯基是未取代的或如2.1.至2.15.所述被取代，
4．杂芳基，其中杂芳基如3.1.至3.16.定义，和/或如2.1.至2.15.所述被取代，或被-(C1-C4)-烷基-COOH取代，
5．-OH，
6．-OR2，其中R2具有上述意义，
7．-NR4-(R5)，其中R4和R5如上定义，
8．杂芳基-(CH2)m-NH-，其中杂芳基如3.1.至3.16.定义，和/或如2.1.至2.15.所述被取代，m如上定义，
9．R4-(R5)N-NH-，其中R4和R5如上定义，
10．HO-C(O)-CH(R3)-NH-，其中R3如上定义，
13．-(CH2)p-N(R9)(R10)，其中p是整数1,2,3或4，其中R9和R10相同或不同，并且是
1．氢原子，
2．苯基-(CH2)m-,其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，m是整数0,1,2或3，
3．RX-C(O)-，其中RX是
3.1(C1-C6)-烷基-，
3.2.(C2-C6)-烯基-，
3.3.苯基-(CH2)m-，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，m是整数0,1,2或3，或
3.4.杂芳基-(CH2)m，其中杂芳基如3.1.至3.16.定义，和/或如2.1.至2.15.所述被取代，m是整数0,1,2或3，
4．RX-O-C(O)-，其中RX如上定义，
5．RX-CH(NH2)-C(O)-，其中RX如上定义，
6．R8-N(R7)-C(O)-，其中R8是
6.1.氢原子，
6.2.(C1-C6)-烷基-，
6.3.苯基-(CH2)m-，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，m是整数0,1,2或3，或
6.4.杂芳基-(CH2)m，其中杂芳基如3.1.至3.16.定义，和/或如2.1.至2.15.所述被取代，m是整数0,1,2或3，且其中R7是氢原子或(C1-C6)-烷基-或其中R7和R8与它们所连接的氮原子一起形成4-至7-元环，该环是未取代的，或者环中的一个碳原子被-O-,-S-或-NH-代替，
7．RX-SO2，其中RX如上定义，
8．RX-NH-C(=NR7)-，其中RX和R7如上定义，或者是
8.1.(C1-C6)-烷基-C(O)-，
8.2.-NO2或
8.3.-SO2-(CH2)q-苯基，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，q是整数0,1,2或3，
9．-SO2-(CH2)q-苯基-苯基，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，q是整数0,1,2或3，
10．式Ⅱp的基团
其中m是整数0,1,2或3，而W是氮原子，或R9和R10与它们所连接的氮原子一起形成式Ⅱa至Ⅱn的环
其中r是整数1或2,R11是如2.1.至2.15.所述的基团，R7和m具有上述意义，
14．-OH，
15．=O或
16．(C1-C6)-烷基-，或
-C(R)(R3)-基团是-NH-或-NR2-，其中R2如上定义，和
t是整数1,2,3或4，或R2和R3一起形成式Ⅱ的带外环次膦酸或膦酸的环
其中r是整数0,1,2或3，和/或环中的一个碳原子被-O-,-S-或-(R7)N-代替，其中
R7是1．氢原子，
2．(C1-C6)-烷基，
3．苯基，其中苯基是未取代的或如2.1.至2.15.所述取代
4．苄基，其中苄基是未取代的或如2.1.至2.15.所述被取代，或
5．R2N-C(=NH)-，其中R2具有上述意义，
和/或式Ⅱ环中的碳原子被(C1-C6)-烷基-，苯基-，苯基-(CH2)m-或HO-一-或多取代，U是-SO2-或CO-，Y1和Y2相同或不同，并且相互独立地是
a)氢原子，
b)-OH，
c)(C1-C4)-烷基，其中烷基是直链或支链的，
d)-(CH2)u-苯基，其中u是0或1，
e)-O-(C1-C4)-烷基，其中烷基是直链或支链的，
f)-O-(CH2)s-苯基，其中s是0或1，A是a)共价键，
b)-O-，
c)-CH=CH-或
d)-C≡C-，B是 a)-(CH2)m-，其中m具有前述意义，
b)-O-(CH2)p-苯基，其中p是1至5的整数，或
c)-CH=CH-，和X是-CH=CH-，氧原子或硫原子。
2．如权利要求1的式Ⅰ化合物，其中R1是1．苯基或
2．被下列基团一取代的苯基
2.1直链，环状或支链(C1-C6)-烷基，
2.2-OH，
2.3-C(O)-OH，
2.4-O-(C1-C6)-烷基，
2.5吡咯烷酮，
2.6卤素或
2.7-CF3，或
3．-O-(C1-C6)-烷基，R2、R4和R5相同或不同，是氢原子或C1-C6烷基，R为氢原子，R3是1．(C1-C6)-烷基-，其中烷基是直链，支链或环状的，和/或烷基的一个氢原子被-OH代替，
2．R2-S(O)n-(C1-C6)-烷基-，其中R2是(C1-C6)-烷基或苯基-(CH2)n-，而n是整数0或1，
3．-(CH2)m-苯基，其中苯基是未取代的或如2.1.至2.15.所述被一-或二-取代，和/或-(CH2)m-链的一个氢原子被-OH代替，而m是整数0,1,2,4或5，
4．-(CH2)m-杂芳基，其中杂芳基如3.3.,3.5.,3.6.,3.9.或3.11.定义，和/或2.1.至2.15.所述被取代，和/或-(CH2)m-链的一个氢原子被-OH代替，而m是整数0,1,2,3或4，
5．氨基酸的特征性残基或
6．-(CH2)p-N(R9)(R10)，其中p是整数0,1或2，其中R9和R10相同或不同，并且是氢原子，或-SO2-(CH2)q-苯基-苯基，其中苯基是未取代的或如2.1.至2.15.所述被一-或二取代，q是整数0,1,2或3，或
7．R6-C(O)-，其中R6是
7.1-OH，
7.2.R2O-，其中R2如上定义，或
7.3.R4-(R5)N-，其中R4和R5如上定义，
8．氢原子，
9．-OH，
10．=O或
11．(C1-C6)-烷基-，或
-C(R)(R3)-基团是-NH-或-NR2-，其中R2如上定义，和
t是整数1,2,3或4，U是-SO2-，Y1是-OH，Y2是a)-O-(C1-C4)-烷基，其中烷基是直链或支链的，
b)-OH，
c)(C1-C4)-烷基，其中烷基是直链或支链的，A是共价键或-O-，B是共价键或(C1-C4)-烷基而X是-CH=CH。
3．如权利要求1或2的式Ⅰ化合物，其中R1是1．被卤素一取代的苯基，R2是氢原子，R是氢原子，R3是1．(C1-C4)-烷基-，
2．-苯基，其中苯基是未取代的或被-CF3或-COOH一-或二-取代，
3．氢原子，
4．-OH或
5．-NH-SO2-苯基-苯基，其中苯基是未取代的或被卤素取代，
t是整数1,2,3或4，U是-SO2-，Y1和Y2是-OH或-OCH3，A是共价键，B是共价键或-(CH2)o-，其中o是1,2或3而X是-CH=CH-。
4．化合物(R)-[1-(4’-氯联苯-4-磺酰基氨基)-2-甲基丙基]膦酸，[3-(4’-氯联苯-4-磺酰基氨基)-1-羟基-3-(4-三氟甲基苯基)丙基]膦酸二甲酯或[1-(4’-氯联苯-4-磺酰基氨基)-3-甲基丁基]膦酸或(R,S)-[1-(4’-氯联苯-4-磺酰基氨基)-1-苯基甲基]膦酸-甲酯。
5．式Ⅵ化合物
和/或式Ⅵ化合物的立体异构体形式和/或式Ⅵ化合物的药用盐，其中R1,A,X,B,U,Y2,t,R2和R2具有权利要求1的式Ⅰ化合物中给出的意义，而R8具有如权利要求6的式Ⅳ化合物中给出的意义。
6．制备如权利要求1至5的一项或多项的式Ⅰ化合物的方法，该方法包括a)式Ⅲ的氨基次膦酸或-膦酸其中R2,Y1,Y2,R和R3如式Ⅰ中定义，与式Ⅳ的磺酸或羰基衍生物在碱或可有可无的脱水剂存在下反应，
其中R1,A,X,U和B如式Ⅰ中定义，而Z是卤原子，咪唑基或-OR8，其中R8是氢原子，(C1-C6)-烷基，苯基或苄基，如果需要，是被取代的，给出式Ⅰ化合物，或者b)式(Ⅴ)的氨基次膦酸或-膦酸酯
其中R2,R3,t,Y2和R8具有上述意义，与式Ⅳ的磺酸-或羰基衍生物反应，给出式Ⅵ化合物并优选地在碱或酸存在下除去基团R8，使式Ⅵ化合物转化为式Ⅰ化合物，或者c)式Ⅶ化合物
其中n是整数0,1或2，与保护基E反应，给出式Ⅷ化合物
并用式Ⅳ化合物使式Ⅷ化合物转化为式Ⅸ化合物
然后在合适的裂解试剂帮助下，除去保护基E和基团R8，使式Ⅸ化合物转化为式Ⅰ化合物，或者d)因为其化学结构为对映体形式，通过与对映体纯的酸或碱形成盐，在手性固定相上层析，或者通过手性对映体纯的化合物如氨基酸的手段衍生，分开所得的非对映体，除去手性辅基，将方法a),b)或c)之一制备的式Ⅰ化合物分开为纯的对映体，或者e)将方法a),b),c)或d)之一制备的式Ⅰ化合物以游离形式分离，或者在酸性或碱性基团存在下转化为其药用盐。
7．包含有效量的至少一种如权利要求1至5的一项或多项的式Ⅰ化合物，与药学上适合的和生理上可接受的赋形剂，添加剂和/或其它活性化合物和辅助剂一起的药物。
8．至少一种如权利要求1至5的一项或多项的式Ⅰ化合物在生产用于预防和治疗与基质-降解金属蛋白酶活性增加有关的所有病症药物中的用途。
9．如权利要求8的用途，用于治疗变性关节病如骨关节炎，椎关节强硬，关节创伤后的软骨溶解，或半月板或膑骨损伤或韧带撕裂后较长时间的关节制动术，结缔组织疾病如胶原疾病，牙周疾病，创伤愈合疾病和运动器官慢性疾病如炎症，免疫或代谢相关的急性和慢性关节炎，关节病，肌痛和骨代谢疾病，溃疡，动脉粥样硬化和狭窄，以及用于治疗发炎，癌症，肿瘤形成，噁病质，厌食和脓毒性休克。
10．制备药物的方法，该方法包括用药用的和生理上可接受的赋形剂，如果需要，还有其它合适的活性化合物，添加剂或辅助剂使至少一种如权利要求1至5的一项或多项的式Ⅰ化合物成为适合于给药的形式。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19831980.0 | 1998-07-16 | ||
| DE19831980A DE19831980A1 (de) | 1998-07-16 | 1998-07-16 | Sulfonylaminophosphin- und phosphonsäurederivate |
| DE19921680.0 | 1999-05-12 | ||
| DE19921680A DE19921680A1 (de) | 1999-05-12 | 1999-05-12 | Sulfonylaminophosphin- und phosphonsäurederivate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1309660A true CN1309660A (zh) | 2001-08-22 |
| CN1194978C CN1194978C (zh) | 2005-03-30 |
Family
ID=26047473
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998086681A Expired - Fee Related CN1194978C (zh) | 1998-07-16 | 1999-07-07 | 用作药物的次膦酸和膦酸衍生物 |
Country Status (22)
| Country | Link |
|---|---|
| US (2) | US6235727B1 (zh) |
| EP (1) | EP1097159B1 (zh) |
| JP (1) | JP4567886B2 (zh) |
| KR (1) | KR100615345B1 (zh) |
| CN (1) | CN1194978C (zh) |
| AR (1) | AR019390A1 (zh) |
| AT (1) | ATE227295T1 (zh) |
| AU (1) | AU754050B2 (zh) |
| BR (1) | BR9912085A (zh) |
| CA (1) | CA2337828C (zh) |
| CZ (1) | CZ300780B6 (zh) |
| DE (1) | DE59903329D1 (zh) |
| DK (1) | DK1097159T3 (zh) |
| ES (1) | ES2187171T3 (zh) |
| HK (1) | HK1038363A1 (zh) |
| HU (1) | HUP0102837A3 (zh) |
| ID (1) | ID27133A (zh) |
| PL (1) | PL199234B1 (zh) |
| PT (1) | PT1097159E (zh) |
| RU (1) | RU2224762C2 (zh) |
| TR (1) | TR200100084T2 (zh) |
| WO (1) | WO2000004030A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108676031A (zh) * | 2018-05-29 | 2018-10-19 | 重庆威鹏药业有限公司 | 水溶性三唑类抗真菌膦酸化合物及其制备方法和应用 |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100686988B1 (ko) * | 1999-07-06 | 2007-02-27 | 메틸진, 인크. | β-락타마제의 술폰아미도메틸 포스포네이트 저해제 |
| EP1546137A1 (en) * | 2002-08-08 | 2005-06-29 | SmithKline Beecham Corporation | Benzimidazol-1-yl-thiophene compounds for the treatment of cancer |
| JP4450192B2 (ja) | 2004-07-01 | 2010-04-14 | 信越化学工業株式会社 | 珪素複合体及びその製造方法並びに非水電解質二次電池用負極材 |
| ES2543842T3 (es) * | 2006-05-22 | 2015-08-24 | Methylgene Inc. | Nuevos inhibidores de la beta-lactamasa |
| AU2007268081A1 (en) * | 2006-05-22 | 2007-12-06 | Methylgene Inc. | Novel sulfonamidomethylphosphonate inhibitors of beta-lactamase |
| JP5399219B2 (ja) * | 2009-11-24 | 2014-01-29 | 株式会社ケイティーバイオ | 関節リウマチに対するヒト型抗ＴＮＦα抗体薬の薬効予測方法、及び薬効予測装置 |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3996040A (en) * | 1974-06-28 | 1976-12-07 | Monsanto Company | Increasing sucrose content of sugar cane employing N-phenylsulfonamido-N-phosphonomethyl glycine and certain derivatives thereof |
| JPS6137800A (ja) * | 1984-07-31 | 1986-02-22 | Kyowa Hakko Kogyo Co Ltd | 含リンペプチド |
| DE3435156A1 (de) * | 1984-09-25 | 1986-04-03 | Boehringer Mannheim Gmbh, 6800 Mannheim | Verfahren zur herstellung der stereoisomeren von 1-amino-alkylphosphonsaeuren oder 1-aminoalkylphosphinsaeuren |
| JPS62148493A (ja) * | 1985-12-24 | 1987-07-02 | Teijin Ltd | 新規ホスホン酸誘導体および除草剤 |
| DE3770982D1 (de) * | 1986-04-24 | 1991-08-01 | Fujisawa Pharmaceutical Co | Diphosphonsaeure-verbindungen, verfahren zu deren herstellung und sie enthaltende arzneimittel. |
| JP2764262B2 (ja) | 1987-08-28 | 1998-06-11 | 持田製薬株式会社 | ヒダントイン誘導体及びそれを有効成分とする医薬組成物 |
| TW201303B (zh) | 1990-07-05 | 1993-03-01 | Hoffmann La Roche | |
| JP2525977B2 (ja) * | 1991-10-17 | 1996-08-21 | 昭和電工株式会社 | Ｎ−アシルアミノメチルホスホン酸の製造法 |
| US5455258A (en) | 1993-01-06 | 1995-10-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
| ATE182581T1 (de) | 1994-06-22 | 1999-08-15 | British Biotech Pharm | Metalloproteinase-inhibitoren |
| US5863949A (en) | 1995-03-08 | 1999-01-26 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
| KR980009238A (ko) * | 1995-07-28 | 1998-04-30 | 우에노 도시오 | 설포닐아미노산 유도체 |
| SK282863B6 (sk) * | 1996-05-17 | 2002-12-03 | Warner-Lambert Company | Bifenylsulfonamidy, ich použitie a farmaceutické prostriedky na ich báze |
| JP2001509795A (ja) * | 1997-01-27 | 2001-07-24 | ニィコメド・オーストリア・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 血液調節作用を有する新規化合物 |
| DE19719621A1 (de) * | 1997-05-09 | 1998-11-12 | Hoechst Ag | Sulfonylaminocarbonsäuren |
| PT877019E (pt) | 1997-05-09 | 2002-05-31 | Hoechst Ag | Acidos diaminocarboxilicos substituidos |
| AU7294098A (en) * | 1997-05-09 | 1998-11-27 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
-
1999
- 1999-07-07 ES ES99932841T patent/ES2187171T3/es not_active Expired - Lifetime
- 1999-07-07 AT AT99932841T patent/ATE227295T1/de not_active IP Right Cessation
- 1999-07-07 CZ CZ20010144A patent/CZ300780B6/cs not_active IP Right Cessation
- 1999-07-07 KR KR1020017000698A patent/KR100615345B1/ko not_active IP Right Cessation
- 1999-07-07 PT PT99932841T patent/PT1097159E/pt unknown
- 1999-07-07 WO PCT/EP1999/004740 patent/WO2000004030A1/de active IP Right Grant
- 1999-07-07 DE DE59903329T patent/DE59903329D1/de not_active Expired - Lifetime
- 1999-07-07 EP EP99932841A patent/EP1097159B1/de not_active Expired - Lifetime
- 1999-07-07 AU AU49082/99A patent/AU754050B2/en not_active Ceased
- 1999-07-07 ID IDW20010108A patent/ID27133A/id unknown
- 1999-07-07 CA CA2337828A patent/CA2337828C/en not_active Expired - Fee Related
- 1999-07-07 CN CNB998086681A patent/CN1194978C/zh not_active Expired - Fee Related
- 1999-07-07 PL PL345653A patent/PL199234B1/pl not_active IP Right Cessation
- 1999-07-07 HU HU0102837A patent/HUP0102837A3/hu unknown
- 1999-07-07 TR TR2001/00084T patent/TR200100084T2/xx unknown
- 1999-07-07 RU RU2001104433/04A patent/RU2224762C2/ru not_active IP Right Cessation
- 1999-07-07 JP JP2000560136A patent/JP4567886B2/ja not_active Expired - Fee Related
- 1999-07-07 DK DK99932841T patent/DK1097159T3/da active
- 1999-07-07 BR BR9912085-2A patent/BR9912085A/pt not_active Application Discontinuation
- 1999-07-14 AR ARP990103449A patent/AR019390A1/es active IP Right Grant
- 1999-07-15 US US09/353,086 patent/US6235727B1/en not_active Expired - Lifetime
-
2001
- 2001-03-20 US US09/811,698 patent/US6500811B2/en not_active Expired - Lifetime
- 2001-12-27 HK HK01109113A patent/HK1038363A1/xx not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108676031A (zh) * | 2018-05-29 | 2018-10-19 | 重庆威鹏药业有限公司 | 水溶性三唑类抗真菌膦酸化合物及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| PL199234B1 (pl) | 2008-08-29 |
| CA2337828C (en) | 2010-08-17 |
| US6235727B1 (en) | 2001-05-22 |
| AU4908299A (en) | 2000-02-07 |
| ATE227295T1 (de) | 2002-11-15 |
| CA2337828A1 (en) | 2000-01-27 |
| US20020082246A1 (en) | 2002-06-27 |
| BR9912085A (pt) | 2001-04-10 |
| HUP0102837A2 (hu) | 2001-12-28 |
| TR200100084T2 (tr) | 2001-07-23 |
| CZ2001144A3 (en) | 2001-05-16 |
| KR20010071940A (ko) | 2001-07-31 |
| US6500811B2 (en) | 2002-12-31 |
| EP1097159B1 (de) | 2002-11-06 |
| AU754050B2 (en) | 2002-10-31 |
| PL345653A1 (en) | 2002-01-02 |
| JP2002520418A (ja) | 2002-07-09 |
| RU2224762C2 (ru) | 2004-02-27 |
| AR019390A1 (es) | 2002-02-20 |
| CZ300780B6 (cs) | 2009-08-12 |
| JP4567886B2 (ja) | 2010-10-20 |
| DE59903329D1 (en) | 2002-12-12 |
| EP1097159A1 (de) | 2001-05-09 |
| ES2187171T3 (es) | 2003-05-16 |
| PT1097159E (pt) | 2003-03-31 |
| KR100615345B1 (ko) | 2006-08-25 |
| HUP0102837A3 (en) | 2002-04-29 |
| ID27133A (id) | 2001-03-01 |
| DK1097159T3 (da) | 2003-03-10 |
| CN1194978C (zh) | 2005-03-30 |
| HK1038363A1 (en) | 2002-03-15 |
| WO2000004030A1 (de) | 2000-01-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1280267C (zh) | 磺酰氨基羧酸 | |
| CN1123566C (zh) | 芳基磺酰基异羟肟酸衍生物 | |
| JPS63253061A (ja) | チオールプロテアーゼ阻害剤としてのアリールオキシおよびアリールアシルオキシメチルケトン | |
| JP2007500734A (ja) | Ｎ−スルホニル化アミノ酸誘導体およびマトリプターゼ阻害剤としてのそれらの使用 | |
| CN1309660A (zh) | 用作药物的次膦酸和膦酸衍生物 | |
| CN1332724A (zh) | N－芳基磺酰氨基酸ω－酰胺 | |
| CN1159295C (zh) | 金属蛋白酶抑制剂 | |
| CN1555372A (zh) | 作为ace和nep抑制剂的吡喃衍生物 | |
| US7538085B2 (en) | Peptide deformylase inhibitors as novel antibiotics | |
| CN100406449C (zh) | Cdc25磷酸酶抑制剂 | |
| JP4587955B2 (ja) | 骨粗鬆症の治療薬を開発するための新規分子 | |
| EP0796257B1 (en) | Malonic acid based matrix metalloproteinase inhibitors | |
| CN1206001A (zh) | 取代的二氨基羧酸 | |
| KR100883963B1 (ko) | 신규한 카보니트릴 화합물, 이의 제조방법 및 이를포함하는 류마티스성 관절염, 골관절염, 파제트병,악성고칼슘혈증, 대사성골질환 및 각종 암의 치료 및예방을 위한 약제학적 조성물 | |
| EP0716086A1 (en) | Malonic acid based matrix metalloproteinase inhibitors | |
| Vandevelde et al. | Synthesis and bioactivity of psilocybin analogues containing a stable carbon-phosphorus bond | |
| Comeau | Design, synthesis and testing of biologically active small molecules | |
| KR100877394B1 (ko) | 카보니트릴 화합물을 포함하는 골다공증 및 치은 질환의치료 및 예방을 위한 약제학적 조성물 | |
| JPS6059232B2 (ja) | エポキシサクシニルアミノ酸誘導体 | |
| FR2654430A1 (fr) | Nouveaux derives de peptides, utilisables comme inhibiteurs des collagenases bacteriennes. | |
| DE19921680A1 (de) | Sulfonylaminophosphin- und phosphonsäurederivate | |
| MXPA01000400A (en) | Phosphinous and phosphonic acid derivatives used as medicaments | |
| MXPA98003661A (en) | Acids sulfonilaminocarboxili |
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: SANOFI- AVENTIS GERMAN CO., LTD. Free format text: FORMER NAME OR ADDRESS: AVENTIS PHARMACY (GERMANY)INTERNATIONAL CO., LTD. |
|
| CP03 | Change of name, title or address |
Address after: Frankfurt, Germany Patentee after: Hoechst Marion Roussel de GmbH Address before: Frankfurt, Germany Patentee before: Awentis Medicines Deutschland GmbH |
|
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050330 Termination date: 20110707 |