JPH03294252A - Amide compound or salt thereof - Google Patents
Amide compound or salt thereofInfo
- Publication number
- JPH03294252A JPH03294252A JP2098456A JP9845690A JPH03294252A JP H03294252 A JPH03294252 A JP H03294252A JP 2098456 A JP2098456 A JP 2098456A JP 9845690 A JP9845690 A JP 9845690A JP H03294252 A JPH03294252 A JP H03294252A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- methoxyphenyl
- compound
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 Amide compound Chemical class 0.000 title claims abstract description 24
- 150000003839 salts Chemical class 0.000 title claims abstract description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- JLXVXRXZFUBLPZ-UHFFFAOYSA-N n-hydroxy-2-methylhexanamide Chemical compound CCCCC(C)C(=O)NO JLXVXRXZFUBLPZ-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 33
- 102000029816 Collagenase Human genes 0.000 abstract description 12
- 108060005980 Collagenase Proteins 0.000 abstract description 12
- 229960002424 collagenase Drugs 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 102000008186 Collagen Human genes 0.000 abstract description 5
- 108010035532 Collagen Proteins 0.000 abstract description 5
- 229920001436 collagen Polymers 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 206010014989 Epidermolysis bullosa Diseases 0.000 abstract description 3
- 230000008595 infiltration Effects 0.000 abstract description 3
- 238000001764 infiltration Methods 0.000 abstract description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 abstract description 2
- 201000007717 corneal ulcer Diseases 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 2
- 206010064996 Ulcerative keratitis Diseases 0.000 abstract 1
- 238000010521 absorption reaction Methods 0.000 abstract 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 abstract 1
- 210000000988 bone and bone Anatomy 0.000 abstract 1
- 238000000354 decomposition reaction Methods 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 150000003573 thiols Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 238000004949 mass spectrometry Methods 0.000 description 13
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 239000002442 collagenase inhibitor Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000004036 acetal group Chemical group 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- JQASYHORSFXWGI-UHFFFAOYSA-N 5-methylhexanamide Chemical compound CC(C)CCCC(N)=O JQASYHORSFXWGI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 208000019664 bone resorption disease Diseases 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer 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
- 239000003921 oil Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- AXEOMQHKTSGLGS-VIFPVBQESA-N (2s)-2-amino-3-(4-hydroxy-2-methylphenyl)propanoic acid Chemical compound CC1=CC(O)=CC=C1C[C@H](N)C(O)=O AXEOMQHKTSGLGS-VIFPVBQESA-N 0.000 description 1
- ZSDQQJHSRVEGTJ-UHFFFAOYSA-N 2-(6-amino-1h-indol-3-yl)acetonitrile Chemical compound NC1=CC=C2C(CC#N)=CNC2=C1 ZSDQQJHSRVEGTJ-UHFFFAOYSA-N 0.000 description 1
- UBHABFFRHSJBSJ-UHFFFAOYSA-N 2-acetylsulfanyl-5-methylhexanoic acid Chemical compound CC(C)CCC(C(O)=O)SC(C)=O UBHABFFRHSJBSJ-UHFFFAOYSA-N 0.000 description 1
- ZRLFRWNYFMYZEG-UHFFFAOYSA-N 2-methylhexanamide Chemical compound CCCCC(C)C(N)=O ZRLFRWNYFMYZEG-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 101000645291 Bos taurus Metalloproteinase inhibitor 2 Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102100032860 Cell division cycle 5-like protein Human genes 0.000 description 1
- 229940122097 Collagenase inhibitor Drugs 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 101000868318 Homo sapiens Cell division cycle 5-like protein Proteins 0.000 description 1
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004407 Lactalbumin Human genes 0.000 description 1
- 108090000942 Lactalbumin Proteins 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 102000018721 Macroglobulins Human genes 0.000 description 1
- 108010091934 Macroglobulins Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GEYBMYRBIABFTA-VIFPVBQESA-N O-methyl-L-tyrosine Chemical compound COC1=CC=C(C[C@H](N)C(O)=O)C=C1 GEYBMYRBIABFTA-VIFPVBQESA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000011382 collagen catabolic process Effects 0.000 description 1
- 230000007691 collagen metabolic process Effects 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- HNBDRPTVWVGKBR-UHFFFAOYSA-N n-pentanoic acid methyl ester Natural products CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 210000004417 patella Anatomy 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、医薬として有用な、特にコラゲナーゼの作用
を特異的に阻害する新規なアミド化合物に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel amide compound that is useful as a medicine, and in particular, specifically inhibits the action of collagenase.
（従来の技術）
補乳動物の結合組織の主要な構成成分であるコラーゲン
はコラゲナーゼ（Ｅ Ｃ３，４，２３，７）によって特
異的に分解され他の蛋白分解酵素によっては分解されな
い。正常状態でのコラーゲンの代謝調節にはコラゲナー
ゼとメタロプロテアーゼの天然阻害剤である組織阻害剤
（Ｔｆｓｓｕｅ Ｉｎｈｉｂｉｔｏｒｏｆ Ｍｅｔａｌ
ｌｏｐｒｏｔｅａｓｅ ： Ｔ Ｉ ＭＰ ）及びα２
−マクログロブリンによって行なわれていると考えられ
ている。結合組織破壊が先進しているような疾患では蛋
白分解酵素と天然阻害剤のレベルのアンバランスによる
と考えられる。コラゲナーゼ阻害剤はコラゲナーゼによ
る分解を抑制することによシ組織破壊を抑えることが出
来ると考えられる。したがって、コラゲナーゼ阻害剤は
、コラ−ゲン分解活性が主な原因と考えられる慢性関節
リウマチ、変形性関節炎などの関節炎、歯周疾患、角膜
潰瘍２表皮水包症、腫瘍性浸潤および骨吸収疾患に対し
て有用である。(Prior Art) Collagen, which is a major component of the connective tissue of mammalian mammals, is specifically degraded by collagenase (EC3,4,23,7) and not by other proteolytic enzymes. Tissue Inhibitor of Metal, a natural inhibitor of collagenase and metalloprotease, is used to regulate collagen metabolism under normal conditions.
loprotease: T I MP ) and α2
- believed to be carried out by macroglobulins. Diseases in which connective tissue destruction is advanced are thought to be due to an imbalance in the levels of proteolytic enzymes and natural inhibitors. Collagenase inhibitors are thought to be able to suppress tissue destruction by inhibiting collagenase-induced degradation. Therefore, collagenase inhibitors are effective against chronic rheumatoid arthritis, osteoarthritis and other arthritis, periodontal disease, corneal ulcers, epidermolysis bullosa, tumorous infiltration, and bone resorption diseases, which are thought to be caused mainly by collagenase inhibitors. It is useful for
従来、このコラゲナーゼ阻害作用を有する化合物として
２例えば特開平１−１６０９９２号公報には、ある種の
リン酸誘導体が、また特開平１−１６０９９７号公報に
は、ペプチジルヒドロキサム酸誘導体が記載されている
。Conventionally, as compounds having this collagenase inhibitory effect, for example, JP-A-1-160992 describes certain phosphoric acid derivatives, and JP-A-1-160997 describes peptidylhydroxamic acid derivatives. .
（解決手段）
本発明者等は、コラゲナーゼ阻害作用を有する化合物に
ついて鋭意研究した結果２本発明を完成した。(Solution Means) The present inventors have completed two inventions as a result of intensive research on compounds having collagenase inhibitory action.
即ち２本発明は下記一般式（Ｉ）で示されるアミド化合
物、又はその塩である。That is, the second invention is an amide compound represented by the following general formula (I) or a salt thereof.
（式中、Ｒｔｉ水素原子又は水酸基を、Ｘは硫黄原子、
スルフィニル（−８ｏ−） 基、スルホニル（−８ｏ、
−）基、又はイミノ（−ＮＨ−）基を、 ｎｌ′ｉ１
乃至６の整数を２ｍ及びｎは、一方がＯであり、他方は
１を意味する。以下同様）本明細書において、「低級」
とは特に断らない限シ炭素数１乃至５個を有する直鎖又
は分岐状の炭素鎖を意味する。(In the formula, Rti is a hydrogen atom or a hydroxyl group, X is a sulfur atom,
Sulfinyl (-8o-) group, sulfonyl (-8o,
-) group or imino (-NH-) group, nl'i1
When 2m and n are integers from 6 to 6, one means O and the other means 1. (The same applies hereinafter) In this specification, "lower"
means a straight or branched carbon chain having 1 to 5 carbon atoms unless otherwise specified.
従って、低級アルキル基とは、メチル基、エチル基、プ
ロピル基、インプロピル基、ブチル基、イソブチル基、
１ｅｅ−ブチル基、 ｔａｒｔ−ブチル基、ペンチル
基、インペンチル基等である。Therefore, lower alkyl groups include methyl group, ethyl group, propyl group, inpropyl group, butyl group, isobutyl group,
Examples include 1ee-butyl group, tart-butyl group, pentyl group, and impentyl group.
また「ハロゲン原子」としてはフッ素原子。Also, a fluorine atom is a ``halogen atom.''
臭素原子、ヨウ素原子である。They are bromine and iodine atoms.
一般式ｆりに含まれる化合物として、特に好ましい化合
物としては。Particularly preferable compounds included in the general formula f are as follows.
３−［［３−（ｐ−メトキシフェニル）−２−（Ｎ−メ
チルカルバモイル）プロビルコスルホニルコー５−メチ
ル ヘキサノヒドロキサム酸
３− ［３−（ｐ−メトキシフェニル）−２−（Ｎ−メ
チルカルバモイル）プロピルチオコー５−メチル ヘキ
サンアミド
３−［３−（ｐ−メトキシフェニル）−２−Ｎ”−［３
−（Ｎ−ヒドロキシカルバモイル）−２−イソブチルプ
ロビルコー０−メチルチロシン Ｎ−メチルアミド
等が挙げられる。3-[[3-(p-methoxyphenyl)-2-(N-methylcarbamoyl)probylcosulfonyl-5-methyl hexanohydroxamic acid 3-[3-(p-methoxyphenyl)-2-(N-methyl carbamoyl)propylthioco5-methyl hexanamide 3-[3-(p-methoxyphenyl)-2-N”-[3
-(N-hydroxycarbamoyl)-2-isobutylprobil-co-0-methyltyrosine N-methylamide and the like.
一般式（Ｉ）で示される化合物は９分子中に不斉炭素原
子を有しており７本発明には化合物ＣＩ）のラセミ体２
光学異性体、ジアステレオマーなどの異性体の全てが包
含される。The compound represented by the general formula (I) has nine asymmetric carbon atoms in the molecule, and the present invention includes the racemic form 2 of compound CI).
All isomers such as optical isomers and diastereomers are included.
また、一般式ｆｌ）で示される化合物の塩としては、塩
酸、臭化水素酸、硫酸、リン酸、ギ酸。Further, examples of the salt of the compound represented by the general formula fl) include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and formic acid.
酢酸、プロピオン酸、マロン酸、コノ・り酸、乳酸、シ
ュウ酸等の鉱酸又は有機酸との塩が挙げられる。更に２
式（Ｉ）で示される化合物又はその塩は、溶媒和物又は
水和物の形態も取ることができ、これらも本発明の一部
を形成する。Examples include salts with mineral acids or organic acids such as acetic acid, propionic acid, malonic acid, cono-phosphoric acid, lactic acid, and oxalic acid. 2 more
The compounds of formula (I) or salts thereof can also take the form of solvates or hydrates, which also form part of the invention.
（製造法） 以下に本発明化合物ＣＩ）の製造法について説明する。(Manufacturing method) The method for producing the compound CI) of the present invention will be explained below.
（第１製法）
（Ｉｒｂ）
（第２製法）
σい
（式中、Ｒ７は、水酸基の保護基を、Ｘｌは、硫黄原子
又はイミノ基をｌ ｘｔは、硫黄原子又はスルフィニル
基ヲ、 Ｘｌはフルフィニル基又は゛スルホニル＆ヲ、
ｙ、、 ’Ｌ Ｉｄ 一方カ、−ロゲン原子であり、
他方がチオール基であるか、又は一方がアセタール基で
あり、他方がアミノ基であるか原料化合物が（Ｉ［ｂ）
の場合、 ｙ２Ｆｉアミ７基をｙ ｌ、はＯ又Ｆｉｌを
ｔ ｎ＋は１乃至５の整数を意味する。以下同様）
ここで、Ｒ１の水酸基の保護基としては、ベンジル基、
ｔ−ブチル基等が挙げられる。(First production method) (Irb) (Second production method) σ (In the formula, R7 is a hydroxyl protecting group, Xl is a sulfur atom or an imino group, xt is a sulfur atom or a sulfinyl group, and Xl is a sulfur atom or an imino group. Flufinyl group or ゛sulfonyl&wo,
y,, 'L Id is a ,-logen atom,
The other is a thiol group, or one is an acetal group and the other is an amino group, or the starting compound is (I[b)
In the case of y2Fi, y l is O or Fil, t n+ means an integer from 1 to 5. The same applies hereinafter) Here, as the protecting group for the hydroxyl group of R1, benzyl group,
Examples include t-butyl group.
（第１製法）
本発明の目的化合物のうち、一般式（Ｉａ）でで示され
る化合物は、一般式（ｎａ）で示される化合物又は一般
式（ＩＩｂ）で示される化合物と化合物（ｍ）を反応さ
せることＫよシ得ることができる。(First production method) Among the target compounds of the present invention, the compound represented by the general formula (Ia) is a compound represented by the general formula (na) or the compound represented by the general formula (IIb) and the compound (m). By reacting, K can be obtained.
■ 原料化合物（ＩＩａ）においてＹ、、Ｙ、の一方が
ハロゲン原子であり、他方がチオール基である場合は、
テトラヒドロフラン、クロロホルム、ジクロロメタン、
ベンゼン、トルエン。■ When one of Y, Y, in the starting compound (IIa) is a halogen atom and the other is a thiol group,
Tetrahydrofuran, chloroform, dichloromethane,
benzene, toluene.
ジメチルホルムアミド、メタノール、エタノール等の溶
媒中、室温下乃至加温下に実施することができる。This can be carried out in a solvent such as dimethylformamide, methanol, or ethanol at room temperature or with heating.
また２反応に際しては、トリメチルアミン。Also, for 2 reactions, trimethylamine.
トリエチルアミン、ジメチルアニリン、１，８−ジアザ
ビシクロ［５，４，０］−７−ウンデセン等の有機アミ
ン、ナトリウムメトキシド。Organic amines such as triethylamine, dimethylaniline, 1,8-diazabicyclo[5,4,0]-7-undecene, and sodium methoxide.
ナトリウムエトキシド、カリウムメトキシド等のアルカ
リ金属アルコキシド、ｎ−ブチルリチウム等のアルキル
リチウム等を添加するのが好ましい。反応溶媒２反応温
度は原料化合物の量２反応試薬により適宜調節すること
ができる。It is preferable to add alkali metal alkoxides such as sodium ethoxide and potassium methoxide, alkyl lithiums such as n-butyllithium, and the like. The reaction temperature of the reaction solvent 2 can be adjusted as appropriate by adjusting the amount of starting compounds and the reaction reagent.
■ 更に、原料化合物（Ｕｓ）においてｙ、、ｙ、の一
方がアセタール基であり、他方がアミノ基の場合 また
は、原料化合物（ＩＩｂ）を採用すル場合は、メタノー
ル、エタノール等のアルコール類やベンゼン等の反応に
不活性な有機溶媒中、室温下乃至加熱還流下に実施する
ことができる。ここで、Ｙ、、Ｙ、の意味する「アセタ
ール基」としては、低級アルキルへミアセタール、ジ低
級アルキルアセタール等が挙けられる。また１反応に際
し生成する水を除去しながら行うこともできる。その後
、得られた化合物を水素化ホウ素ナトリウム、水素化ホ
ウ素リチウムや水素化シアノホウ素ナトリウムなどのホ
ウ素化合物により還元する。■ Furthermore, if one of y, y, in the raw material compound (Us) is an acetal group and the other is an amino group, or if the raw material compound (IIb) is used, alcohols such as methanol, ethanol, etc. The reaction can be carried out in an organic solvent inert to the reaction, such as benzene, at room temperature or under heating under reflux. Here, the "acetal group" meant by Y, , Y includes lower alkyl hemiacetal, di-lower alkyl acetal, and the like. It is also possible to carry out one reaction while removing water generated during the reaction. Thereafter, the obtained compound is reduced with a boron compound such as sodium borohydride, lithium borohydride, or sodium cyanoborohydride.
還元反応はメタノール、エタノールなどのアルコール、
酢酸等の有機溶媒や水あるいはこれらの混合溶媒中２通
常、冷却下乃至室温下に行われる。Reduction reactions involve alcohols such as methanol and ethanol,
The reaction is usually carried out in an organic solvent such as acetic acid, water, or a mixed solvent thereof under cooling or at room temperature.
このようにして得られた化合物は２例えば。The compounds thus obtained are 2 examples.
接触還元による方法、トリフルオロ酢酸、フン化水素、
臭化水素、塩化水素、水酸化ナトリウム、水酸化カリウ
ム等によシ保護基を除去することができる。Method by catalytic reduction, trifluoroacetic acid, hydrogen fluoride,
The protecting group can be removed using hydrogen bromide, hydrogen chloride, sodium hydroxide, potassium hydroxide, and the like.
（第２製法）
一般式（Ｉｂ）で示される化合物は、一般式（ＩＶ）で
示される化合物を酸化したのち、保護基な除去すること
によシ製造することができる。酸化は、過酢酸２過安息
香酸１ｍ−クロロ過安息香醗等によりジクロロメタン、
クロロホルム、四塩化炭素等の反応に不活性な溶媒中２
行うことができる。反応温度は、冷却下乃至室温下であ
る。なお、保護基の除去は、第１製法で述べた方法が適
宜採用される。(Second Production Method) The compound represented by the general formula (Ib) can be produced by oxidizing the compound represented by the general formula (IV) and then removing the protective group. Oxidation is carried out by dichloromethane, peracetic acid, perbenzoic acid, 1m-chloroperbenzoic acid, etc.
2 in a reaction-inert solvent such as chloroform or carbon tetrachloride.
It can be carried out. The reaction temperature is between cooling and room temperature. In addition, the method described in the first production method is appropriately employed for removing the protecting group.
こうして製造された本発明化合物は、遊離のまま、塩と
して製造されるときは塩のまま、あるいは遊離化合物を
通常用いられる造塩反応に付してその塩となし、単離さ
れ、精製される。The compound of the present invention thus produced can be isolated as it is, or as a salt when produced as a salt, or subjected to a commonly used salt-forming reaction to form its salt, isolated, and purified. .
単離・精製は、濾過、抽出、再結晶、再沈殿。Isolation and purification include filtration, extraction, recrystallization, and reprecipitation.
各種クロマトグラフィー等通常の化学操作を適用して行
なうことができる。This can be carried out by applying ordinary chemical operations such as various types of chromatography.
（発明の効果）
本発明の化合物（１）又はその塩、溶媒和物又は水和物
は、コラ−ゲナーゼ阻害作用を有し。(Effects of the Invention) The compound (1) of the present invention or a salt, solvate or hydrate thereof has a collagenase inhibitory effect.
コラーゲン分解活性が主な原因と考えられる角膜Ｉｔ瘍
１表皮水包症、腫瘍性浸潤あるいは、骨吸収疾患等に対
して有効である。It is effective against corneal It ulcers 1, epidermolysis bullosa, tumor infiltration, bone resorption diseases, etc., which are thought to be mainly caused by collagen degrading activity.
以下にコラゲナーゼに対する阻害活性の測定法及びその
結果を掲記する。The method for measuring the inhibitory activity against collagenase and its results are described below.
コラゲナーゼに対する阻害活性の測定法Ｍ、ｂｕｔｙｒ
ｉｃｕｍ １０１１１１ｇ／ｍ７ （流動パラフィン）
をＬｅｗｉｓラットの尾根部に０．１ ｍｌ投与し、３
〜４週間後のＡｄｊｕｖａｎｔ関節灸発症ラットの膝関
節より膝蓋骨を含む骨膜組織を採取する。これを０．２
％ラクトアルブミンＭＥＭ培地で２日間培養する。この
培養上清中コラナーゼに対する阻害を水弁らの方法［炎
症４（２）、 １２３ （１９８４）参照コに基づき
螢光ＷＲコラーゲンを用いて測定した。Method for measuring inhibitory activity against collagenase M, butyr
icum 101111g/m7 (liquid paraffin)
Administer 0.1 ml to the ridge of Lewis rats,
~4 weeks later, periosteal tissues including the patella are collected from the knee joints of rats that have developed adjuvant arthropoxidation. This is 0.2
% lactalbumin MEM medium for 2 days. The inhibition of colanase in the culture supernatant was measured using fluorescent WR collagen based on the method of Mizuben et al. [Inflammation 4(2), 123 (1984)].
培養上溝中コラゲナーゼをトリプシンで活性化し、一方
２次にトリプシンは過剰の大豆トリプシン抑制剤で不活
性化する。次に阻害剤を加えてから基質コラーゲンを加
え ３６℃で反応させる。２〜数時間後ＥＤＴＡで反応
を停止し。Collagenase in the culture groove is activated with trypsin, while trypsin is then inactivated with excess soybean trypsin inhibitor. Next, an inhibitor is added and then a matrix collagen is added and reacted at 36°C. After 2 to several hours, the reaction was stopped with EDTA.
コラーゲン分解産物のみを７０％エタノールで抽出する
。これを遠心処理し、抽出された分解物の螢光強度を５
２０ｎｍ （Ｅｍ）／４９５ｎｍ （ＥＸ）で測定する
。Only collagen degradation products are extracted with 70% ethanol. This was centrifuged, and the fluorescence intensity of the extracted decomposed product was reduced to 5
Measure at 20nm (Em)/495nm (EX).
コラゲナーゼ阻害剤の活性は既知量の酵素を５０％まで
阻害する化合物の量（ｒｃｓｏ）として表わした。Collagenase inhibitor activity was expressed as the amount of compound that inhibits a known amount of enzyme by 50% (rcso).
結果 本測定法において２本発明化合物（１）のうち。result Among the two compounds of the present invention (1) in this assay method.
例えば実施例１の化合物は、 ＩＣ，値が０．９μＭ
と高いコラゲナーゼ阻害活性を示した。For example, the compound of Example 1 has an IC value of 0.9 μM
and showed high collagenase inhibitory activity.
一般式（Ｉ）で示される化合物、又はその塩。A compound represented by general formula (I) or a salt thereof.
溶媒和物又は水和物の１糧または２種以上を有効成分と
して含有する製剤は２通常用いられている製剤用の担体
や賦形剤、その他の添加剤を用いて２錠剤、散剤、細粒
剤、顆粒剤、カプセル剤、丸剤、液剤、注射剤、坐剤、
軟貴、財布剤等に調製され、経口的（舌下投与を含む）
本発明化合物の臨床投与量は適用される患者（実施例）
以下に実施例を掲記し本発明を更に詳細に説明する。Preparations containing one or more solvates or hydrates as active ingredients can be prepared into tablets, powders, or thin powders using commonly used pharmaceutical carriers, excipients, and other additives. Granules, granules, capsules, pills, liquids, injections, suppositories,
Orally (including sublingual administration), prepared as soft tablets, purse tablets, etc.
The clinical dosage of the compound of the present invention is applicable to patients (Example) The present invention will be explained in further detail with reference to Examples below.
尚、実施例で使用する原料化合物の製造例を参考例とし
て示した。Incidentally, production examples of raw material compounds used in Examples are shown as reference examples.
参考例 １゜
２−アセチルチオ−Ｎ−ベンジルオキシ−５−メチルヘ
キサンアミド 。Ｈ（ＣＨｓ）！２−アセチルチ
オー５−メチルヘキサン酸３．０６ｇを乾燥塩化メチレ
ン溶液４０ｍ７に溶解する。この溶液を０℃に冷却し、
トリエチルアミン１．６７ ｇを加えた後、クロル炭酸
イノブチル２ｇを塩化メチレン５ｍｌに溶解した溶液を
０℃で加える。３０分間０℃で攪拌した後、０−ベンジ
ルヒドロキシアミ７１．９ｇ、塩化メチレン１０ｔｎｌ
の混液を０℃で加える。Reference example 1゜2-acetylthio-N-benzyloxy-5-methylhexanamide. H(CHs)! 3.06 g of 2-acetylthio-5-methylhexanoic acid are dissolved in 40 m7 of dry methylene chloride solution. The solution was cooled to 0°C,
After adding 1.67 g of triethylamine, a solution of 2 g of inbutyl chlorocarbonate dissolved in 5 ml of methylene chloride is added at 0°C. After stirring for 30 minutes at 0°C, 71.9 g of 0-benzylhydroxyamide, 10 tnl of methylene chloride
Add the mixture at 0°C.
室温までゆっくり反応温度を上げ、さらに２時間攪拌し
た。反応液を飽和炭酸水素ナトリウム水溶液、希塩酸、
飽和食塩水で洗い、硫酸マグネシウムで乾燥後、減圧濃
縮した。残渣をシリカゲルクロマトに付し、クロロホル
ムで溶出し、２−アセチルチオ−Ｎ−ベンジルオキシ−
５−メチルヘキサンアミド２，７ｇを得た。The reaction temperature was slowly raised to room temperature, and the mixture was further stirred for 2 hours. The reaction solution was mixed with saturated aqueous sodium hydrogen carbonate solution, dilute hydrochloric acid,
The mixture was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with chloroform to give 2-acetylthio-N-benzyloxy-
2.7 g of 5-methylhexanamide was obtained.
理化学的性状
質量分析値（ｍ／ｚ） ： （ＦＡＢ Ｍａｓ３）３１
０ （Ｍ”＋１）
核磁気共鳴スペクトル（ＣＤＣＩ、、 ＴＭＳ内部標準
）δ： ８．２０ （ＩＨ，ｂｒ、 −ＣＯＮＨ−）
７．３６ （５Ｈ，ｓ、芳香環−Ｈ）４．９０ （
２Ｈ，ｓ、ベンジル−Ｈ−）３．７〜３．８（ＩＩ、ｂ
ｒ）
２．３０ （３Ｈ，ｓ、 ５ＣＯＣＨ，）０．８〜１
．０ （６Ｈ，ＣＨ（”３）ＣＨ。Physical and chemical properties Mass spectrometry value (m/z): (FAB Mas3) 31
0 (M”+1) Nuclear magnetic resonance spectrum (CDCI, TMS internal standard) δ: 8.20 (IH, br, -CONH-)
7.36 (5H,s, aromatic ring-H)4.90 (
2H,s, benzyl-H-)3.7-3.8(II,b
r) 2.30 (3H,s, 5COCH,)0.8~1
．． 0 (6H,CH(”3)CH.
参考例 ２゜
２−ナセチルチオーＮ−ベンジルオキシ−５＝メチルヘ
キサンアミド０．７ｇをエタノール１０ ｍｌに溶解す
る。アルゴン気流中で１規定エタノール性水酸化カリウ
ム溶液を室温で加える。室温で２時間攪拌し、規定塩酸
４ｍｌを加える。減圧濃縮後、酢酸４０ｍ１で残渣を溶
解し、飽和食塩水で洗う。硫酸マグネシウムで乾燥、濃
縮し、残渣をシリカゲルクロマトにて精製し、Ｎ−ベン
ジルオキシ−５−メチル−２−メルカプトヘキサンアミ
ド０．５３ｇを得た。Reference Example 2. Dissolve 0.7 g of 2-nacetylthio N-benzyloxy-5=methylhexanamide in 10 ml of ethanol. A 1N ethanolic potassium hydroxide solution is added at room temperature under a stream of argon. Stir at room temperature for 2 hours and add 4 ml of normal hydrochloric acid. After concentration under reduced pressure, the residue was dissolved in 40 ml of acetic acid and washed with saturated brine. The mixture was dried over magnesium sulfate and concentrated, and the residue was purified using silica gel chromatography to obtain 0.53 g of N-benzyloxy-5-methyl-2-mercaptohexanamide.
理化学的性状
質量分析値（ｍ／ｚ ） ： （ＦＡＢ Ｍａｓｓ）２
６８ （Ｍ”＋１）
核磁気共鳴スペクト＃ （ＣＤＣＩ、、 ＴＭＳ内部標
準）δ： ８．１〜８．２（ＩＨ，ｂｒ、 −ＣＯＮＨ
−）７．３６ （５Ｈ，ｓ、芳香環のＨ）４．９０
（２Ｈ，ｓ、ベンジルのＨ）
３．１〜３．３ （Ｉ Ｈ，ｍ、）
０・８〜１・０（６Ｈ・ＣＨ（♂顛）
実施例 １
（１，） Ｎ−ベンジルオキシ−３−口３−（ｐ−メ
トキシフェニル）−２−（Ｎ−メチルカルバモイル）プ
ロピルチオ］−５−メチルヘキサンアミド２−ブロモメ
チル−３−（ｐ−メトキシフェニル）−Ｎ−メチルプロ
ピオン酸アミド０．５７ｇ。Physical and chemical properties Mass spectrometry value (m/z): (FAB Mass)2
68 (M”+1) Nuclear magnetic resonance spectrum # (CDCI, TMS internal standard) δ: 8.1-8.2 (IH, br, -CONH
-) 7.36 (5H,s, H in aromatic ring) 4.90
(2H,s, H of benzyl) 3.1-3.3 (I H,m,) 0.8-1.0 (6H.CH(♂顛) Example 1 (1,) N-benzyloxy- 3-mouth 3-(p-methoxyphenyl)-2-(N-methylcarbamoyl)propylthio]-5-methylhexanamide 2-bromomethyl-3-(p-methoxyphenyl)-N-methylpropionic acid amide 0.57 g .
Ｎ−ベンジルオキシ−５−メチル−２−メルカプトヘキ
サンアミド０．５３ｇをテトラヒドロフラン１０ ｍｌ
に溶解する。アルゴン気流下で、１，８ジアザビシクロ
［５，４，Ｏ］ −７−ウンデセン（ＤＢＵ ） Ｏ，
ｔ９ｇを含むテトラヒドロフラン溶液を室温で滴下する
。室温にて終夜撹拌後、酢酸エチル４０ｍ１を加え、希
塩酸、飽和食塩水で洗う。乾燥、濃縮し、残渣をシリカ
ゲルクロマトに付し、クロロホルム−メタノールで溶出
し。0.53 g of N-benzyloxy-5-methyl-2-mercaptohexanamide was added to 10 ml of tetrahydrofuran.
dissolve in Under an argon stream, 1,8 diazabicyclo[5,4,O]-7-undecene (DBU)O,
A tetrahydrofuran solution containing 9 g of t is added dropwise at room temperature. After stirring overnight at room temperature, 40 ml of ethyl acetate was added, and the mixture was washed with dilute hydrochloric acid and saturated brine. It was dried and concentrated, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol.
Ｎ−ベンジルオキシ−３−［３−（ｐ−メトキシフェニ
ル）−２−（Ｎ−メチルカルバモイル）ブロビルチオコ
ー５−メチルヘキサノアミド０，２５ｇを得た。（４−
ジアステレオミックスチャ−）理化学的性状
質量分析値（ｍ／ｚ）
： （ＦＡＢ Ｍａｓｓ）
４７３（Ｍ”＋１）
核磁気共鳴スペクトル（ＣＤＣｌ、 、 ＴＭＳ内部標
準）δ：８．９〜９．１ （Ｉ Ｉ（、−ＣＯＮＨ−）
７．３５〜７．５（５Ｈ，芳香環のＨ）７．０６（２Ｈ
，ｄ、 Ｊ＝８．４Ｈｚ、芳香環のＨ）６．８０（２Ｈ
，ｄ、 Ｊ＝８．４Ｈｚ、芳香環のＨ）４．９２ （２
Ｈ９ＳｒベンジルのＨ）３．７７（３Ｉ（、ｓ、 ０Ｃ
Ｈ３）
（２） ３− ［３−（ｐ−メトキシフェニル）−２
−（Ｎ−メチルカルバモイル）プロピルチオ］−５−メ
チルヘキサンアミド
Ｈ，ＮＣ０ＣＲ，ＣＩ（Ｓ−にＭｔＵ１−ＩＬ’０Ｎ）
ｉに）ｉ。0.25 g of N-benzyloxy-3-[3-(p-methoxyphenyl)-2-(N-methylcarbamoyl)brobylthioko 5-methylhexanoamide was obtained. (4-
Diastereomixture) Physical and chemical properties Mass spectrometry value (m/z): (FAB Mass) 473 (M”+1) Nuclear magnetic resonance spectrum (CDCl, TMS internal standard) δ: 8.9-9.1 ( I I(,-CONH-)
7.35-7.5 (5H, aromatic ring H) 7.06 (2H
, d, J = 8.4 Hz, H of aromatic ring) 6.80 (2H
, d, J=8.4Hz, H of aromatic ring) 4.92 (2
H9Sr benzyl H)3.77(3I(,s, 0C
H3) (2) 3-[3-(p-methoxyphenyl)-2
-(N-methylcarbamoyl)propylthio]-5-methylhexanamide H,NC0CR,CI (MtU1-IL'ON in S-)
to i) i.
上記（１）で得られた化合物０．２ｇ、メタノール７ａ
Ｉｌ、 １０％パラジウム炭素０．１２ｇの混液を接
触還元に付す。ＴＬＣ（薄層クロマト）で原料の消失を
確認した後、触媒をｒ取し、Ｆ液を濃縮するる。残渣を
シリカゲルクロマトに付し、クロロホルム−メタノール
で溶出し、３−［３−（Ｐ−メトキシフェニル）−２−
（Ｎ−メチルカルバモイル）プロビルチオコー５−メチ
ルヘキサンアミド０．１ｇを得た。（４−ジアステレオ
ミックスチャ−）
理化学的性状
質量分析値Ｃｍ／ｚ’） ： （ＦＡＢ Ｍａｓｓ）３
６７（Ｍ”＋１）
核磁気共鳴スペクトル（ＣＤＣＩ、、 ＴＭＳ内部標準
）δ： ７．１４（２Ｈ，ｄ、 Ｊ＝８．８Ｈｚ、芳香
環のＨ）６．８８（２Ｈ，ｄ、 Ｊ＝８．８Ｈｚ、芳香
環のＨ）５．６７（２Ｈ，ｂｒ、 Ｃ０ＮＨ２）３．８
４（３Ｈ，ｓ、 Ｏ（’馬）
２．７５（３Ｈ，ｄ、 Ｊ＝４．９Ｈｚ、 ＮＨＣ馬）
０．８８〜０．９７ （６Ｈ，ｍ、 ＣＨ＜５）暢
実施例 ２
（１） Ｎ−ベンジルオキシ−３−［［３−（ｐ−メ
トキシフェニル）−２−（Ｎ−メチルカルバモイル）プ
ロピル］スルホニル］−５−メチルヘキサンアミド
Ｎ−ベンジルオキシ−３−［３−（ｐ−メトキシフェニ
ル）−２−（Ｎ−メチルカルバモイル）プロピルチオツ
ー５−メチルヘキサンアミド０．１５ｇを塩化メチレン
１０ｍ２に溶解し、氷冷する。ｍ−クロロ過安息香酸０
．１３ｇを含む塩化メチレン溶液３ｍｌを滴下する。滴
下終了後３時間、水冷下で撹拌する。反応液を飽和炭酸
水素ナトリウム水、飽和食塩水で洗い、乾燥、濃縮する
。残渣をシリカゲルクロマトに付し、クロロホルム−メ
タノールで溶出し、Ｎ−ベンジルオキシ−３−［［３−
（ｐ−メトキシフェニル）−２−（Ｎ−メチルカルバモ
イル）グロビルコスルホニル］−５−メチルヘキサンア
ミド０．１２ｇを得た。（４−ジアステレオミックスチ
ャ−）理化学的性状
質量分析値（ｍ／ ｚ ）
： （ＦＡＢ Ｍａｓｓ）
ｓｏｓ （Ｍ”＋１ ）
核磁気共鳴スペクトル（ＣＤＣ５，ＴＭＳ内部標準）δ
： ７．３〜７．９ （５Ｈ，ｂｒ、芳香環のＨ）７．
０６（２Ｈ，ａ、 Ｊ＝８．４１（Ｚ、芳香環のＨ）６
．８３（２Ｈ，ｄ、 Ｊ＝８．４Ｈｚ、芳香環のＨ）４
．９０（２Ｈ，ｓ、ベンジルのＨ）
３．７８（３）（、Ｓ、匹凸）
２．７０（３Ｈ，ｄ、 Ｊ−４，９Ｈｚ、 ＮＨＣＨ，
）（２） ３−［［３−（Ｐ−メトキシフェニル）−
２−（Ｎ−メチルカルバモイル）プロピル］スルホニル
コー５−メチルヘキサノヒドロキサム酸Ｎ−ベンジルオ
キシ−３−［［３−（Ｐ−メトキシフェニル）−２−（
Ｎ−メチルカルバモイル）グロビルコスルホニル］−５
−メチルヘキサンアミド０．１２ｇ、 メタノール５
ｔｎｌ、 １０％パラジウム炭素０．１ｇの混液な接触
還元する。触媒をｒ取し、Ｆ液を濃縮し、残渣にエーテ
ルを加え。0.2 g of the compound obtained in (1) above, methanol 7a
A mixture of Il and 0.12 g of 10% palladium on carbon is subjected to catalytic reduction. After confirming the disappearance of the raw materials by TLC (thin layer chromatography), the catalyst is taken out and the F solution is concentrated. The residue was subjected to silica gel chromatography and eluted with chloroform-methanol to give 3-[3-(P-methoxyphenyl)-2-
0.1 g of (N-methylcarbamoyl)probylthioko-5-methylhexanamide was obtained. (4-Diastereomixture) Physical and chemical properties Mass spectrometry value Cm/z'): (FAB Mass)3
67 (M”+1) Nuclear magnetic resonance spectrum (CDCI, TMS internal standard) δ: 7.14 (2H, d, J = 8.8 Hz, H in aromatic ring) 6.88 (2H, d, J = 8 .8Hz, aromatic ring H) 5.67 (2H, br, C0NH2) 3.8
4 (3H, s, O('horse) 2.75 (3H, d, J=4.9Hz, NHC horse)
0.88-0.97 (6H, m, CH<5) Example 2 (1) N-benzyloxy-3-[[3-(p-methoxyphenyl)-2-(N-methylcarbamoyl)propyl ]Sulfonyl]-5-methylhexanamide N-benzyloxy-3-[3-(p-methoxyphenyl)-2-(N-methylcarbamoyl)propylthio2-5-methylhexanamide 0.15 g was added to 10 m2 of methylene chloride. Dissolve and chill on ice. m-chloroperbenzoic acid 0
．． 3 ml of a methylene chloride solution containing 13 g is added dropwise. After the completion of the dropwise addition, the mixture was stirred under water cooling for 3 hours. The reaction solution was washed with saturated aqueous sodium bicarbonate and saturated brine, dried, and concentrated. The residue was subjected to silica gel chromatography and eluted with chloroform-methanol to give N-benzyloxy-3-[[3-
0.12 g of (p-methoxyphenyl)-2-(N-methylcarbamoyl)globilcosulfonyl]-5-methylhexanamide was obtained. (4-Diastereomixture) Physical and chemical properties Mass spectrometry value (m/z): (FAB Mass) sos (M”+1) Nuclear magnetic resonance spectrum (CDC5, TMS internal standard) δ
: 7.3-7.9 (5H, br, H in aromatic ring)7.
06 (2H, a, J = 8.41 (Z, H of aromatic ring) 6
．． 83 (2H, d, J = 8.4Hz, H in aromatic ring) 4
．． 90 (2H, s, H of benzyl) 3.78 (3) (, S, convex) 2.70 (3H, d, J-4,9Hz, NHCH,
)(2) 3-[[3-(P-methoxyphenyl)-
2-(N-Methylcarbamoyl)propyl]sulfonyl-5-methylhexanohydroxamate N-benzyloxy-3-[[3-(P-methoxyphenyl)-2-(
N-methylcarbamoyl)glovircosulfonyl]-5
-Methylhexanamide 0.12g, methanol 5
Catalytic reduction is carried out using a mixture of 0.1 g of 10% palladium on carbon. The catalyst was removed, the F solution was concentrated, and ether was added to the residue.
生じた沈殿をｒ取し、３−［［３−（ｐ−メトキシフェ
ニル）−２−（Ｎ−メチルカルバモイル）グロビル］ス
ルホニル］−５−メチルヘキサノヒドロキサムｉ１２０
．０４８ ｇを得た。（４−ジアステレオミックスチャ
−〕
理化学的性状
質量分析値（ｍ／ｚ） ： （ＦＡＢ Ｍａｓｓ）４１
５（Ｍ”＋１）
核磁気共鳴スペクトル（ｐｇｓｏ−ｄ、、ＴＭＳ内部標
準）δ： ７．１０（２Ｈ，ｄ、 Ｊ−８，３Ｈｚ、芳
香環のＨ）６．８５（２Ｈ，ｄ、 Ｊ＝８．３Ｈｚ、芳
香環のＨ）３．７２（３Ｈ，Ｉ、 ＱＣ！！、）
２．０８〜２．１４ （Ｉ Ｈ，ｍ ）１．５０−１．
７０ （２Ｈ，ｍ ）
１．２０〜１．４０ （Ｉ Ｈ。The resulting precipitate was collected and 3-[[3-(p-methoxyphenyl)-2-(N-methylcarbamoyl)globyl]sulfonyl]-5-methylhexanohydroxam i120
．． 048 g was obtained. (4-Diastereomixture) Physical and chemical properties Mass spectrometry value (m/z): (FAB Mass) 41
5 (M"+1) Nuclear magnetic resonance spectrum (pgso-d, TMS internal standard) δ: 7.10 (2H, d, J - 8,3 Hz, H in aromatic ring) 6.85 (2H, d, J = 8.3 Hz, H of the aromatic ring) 3.72 (3H, I, QC!!,) 2.08-2.14 (I H, m) 1.50-1.
70 (2H, m) 1.20-1.40 (IH.
ｍ）
参考例 ３
３−アミノ−Ｎ−ベンジルオキシ−５−メチルヘキサン
アミド
Ｎ−ベンジルオキシ−３−［（ｔ−ブトキシカルボニル
）アミン］−５−メチルヘキサンアミド１．８４ｇの塩
化メチレン１５ｍ７溶液に、水冷下でトリフルオロ酢酸
４ｍｌを滴下し、同条件にて３０分間撹拌、さらに室温
にて１時間３０分撹拌した。反応液を濃縮後、塩化メチ
レンに溶解した。これを５％炭酸水素ナトリウム水溶液
で洗浄後、洗液を塩化メチレンで２回抽出した。有機層
を合わせ。m) Reference Example 3 3-Amino-N-benzyloxy-5-methylhexanamide In a solution of 1.84 g of N-benzyloxy-3-[(t-butoxycarbonyl)amine]-5-methylhexanamide in 15 m7 of methylene chloride 4 ml of trifluoroacetic acid was added dropwise under water cooling, and the mixture was stirred for 30 minutes under the same conditions, and further stirred for 1 hour and 30 minutes at room temperature. The reaction solution was concentrated and then dissolved in methylene chloride. After washing this with a 5% aqueous sodium hydrogen carbonate solution, the washings were extracted twice with methylene chloride. Combine the organic layers.
硫酸マグネシウムで乾燥後、溶媒を減圧留去した。After drying over magnesium sulfate, the solvent was distilled off under reduced pressure.
残渣をシリカゲルカラムクロマトグラフィー（クロロホ
ルム：メタノール＝１０：１）にて精製し。The residue was purified by silica gel column chromatography (chloroform:methanol=10:1).
３−アミノ−Ｎ−ベンジルオキシ−５−メチルヘキサン
アミド１．２５ｇを淡黄色油状物として得た。1.25 g of 3-amino-N-benzyloxy-5-methylhexanamide was obtained as a pale yellow oil.
理化学的性状
質量分析値（ｍ／ｚ）
： （ＦＡＢ Ｍａｓｓ）
２５１ （Ｍ”＋ １ ）
核磁気共鳴スペクトル（ＣＤＣｌ、、 ＴＭＳ内部標準
）δ： ７．３３（５Ｈ，ｓ）
４．８８（２Ｈ，ｓ）
３．８７（３Ｈ，ｂｓ）
２．８８〜３．２４ （Ｉ Ｈ，ｍ ）１．１８（２Ｈ
，ｔ、 Ｊ＝７１（ｚ）０．８６（６Ｈ，ｄｄ、 Ｊ＝
７．２Ｈｚ）参考例４
３−とドロキシ−３−メトキシ−２−（ｐ−メトキシベ
ンジル）−Ｎ−メチルプロピオンアミドエチル
３−（ｐ−メトキシフェニル）−２−（Ｎ−メチルカル
バモイル）グロビオネート３．８２ｇのトルエン２０ｍ
１溶液に、アルゴン雰囲気下−７８℃でジインブチルア
ルミニウムヒドリドのＩＭヘキサン゛溶液１７．３ｎ＋
ｌを滴下し、同条件にて３時間撹拌した。同温にてメタ
ノール５ｍｌを加えた後、室温まで昇温させ、酢酸エチ
ル及びＩＮ塩酸を加え。Physical and chemical properties Mass spectrometry value (m/z): (FAB Mass) 251 (M"+ 1) Nuclear magnetic resonance spectrum (CDCl, TMS internal standard) δ: 7.33 (5H, s) 4.88 (2H , s) 3.87 (3H, bs) 2.88-3.24 (I H, m) 1.18 (2H
,t, J=71(z)0.86(6H,dd, J=
7.2Hz) Reference Example 4 3- and droxy-3-methoxy-2-(p-methoxybenzyl)-N-methylpropionamidoethyl 3-(p-methoxyphenyl)-2-(N-methylcarbamoyl)globionate 3 .82g toluene 20m
1 solution of diimbutylaluminum hydride in IM hexane at -78°C under an argon atmosphere.
1 was added dropwise, and the mixture was stirred for 3 hours under the same conditions. After adding 5 ml of methanol at the same temperature, the temperature was raised to room temperature, and ethyl acetate and IN hydrochloric acid were added.
３０分間激しく撹拌した。有機層を分取後、水層な酢酸
エチルで２回抽出した。有機層を合わせ、５％炭酸水素
ナトリウム水溶液で１回、飽和食塩水で１回洗浄し、硫
酸マグネシウムで乾燥後、溶媒を減圧留去した。残渣を
シリカゲルカラムクＯ？トゲラフイー（クロロホルム：
メタノール＝１００：１）にて精製し、３−ヒドロキシ
−３−メトキシ−２−（ｐ−メトキシベンジル）−Ｎ−
メチルプロピオンアミド１．８９ｇを白色結晶として得
た。Stir vigorously for 30 minutes. After separating the organic layer, the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed once with a 5% aqueous sodium bicarbonate solution and once with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. Coat the residue with silica gel column O? Thorntail (Chloroform:
3-hydroxy-3-methoxy-2-(p-methoxybenzyl)-N-
1.89 g of methylpropionamide was obtained as white crystals.
理化学的性状
質量分析値（ｍ／ｚ） ： （ＦＡＢ Ｍａｓｓ）２５
４ （Ｍ”＋ １ ）
核磁気共鳴スペクトル（ＣＤＣＩ、、ＴＭＳ内部標準）
δ： ７．１０（２Ｉ（、ｄ、 Ｊ＝９Ｈｚ）６．８１
（２Ｈ，ｄ、 Ｊ＝９Ｈｚ ）４．４５〜４．７５
（Ｉ Ｈ，ｍ ）３．７８ （３Ｈ，ｓ ）
３．３０〜３．４５（３Ｈ，ｍ）
２．６０〜２．８０ （３Ｈ，ｍ ）
実施例 ３
（］） ］Ｎ−ベンジルオキシー３−３−（ｐ−メトキ
シフェニル）−２−（Ｎ−メチルカルバモイル）プロピ
ルアミノコ−５−メチルヘキサンアミ ド
３−ヒドロキシ−３−メトキシ−２−（ｐ−メトキシベ
ンジル）−Ｎ−メチルヘキサンアミド０．２０ｇ、
３−アミノ−Ｎ−ベルジルオキシ−５−メチルヘキサン
アミド０．２０ｇのメタノール２ ｒｎｌ溶液を２時間
加熱還流した。 −氷冷下で、水素
化ホウ素ナトリウム３ｓ、ｉを加え同温で３０分間攪拌
した後、室温で２時間攪拌した。水素化ホウ素ナトリウ
ムをさらに３５．８ｍｇ加え、同温にてさらに１４時間
攪拌した。反応液を濃縮後。Physical and chemical properties Mass spectrometry value (m/z): (FAB Mass) 25
4 (M”+1) Nuclear magnetic resonance spectrum (CDCI, TMS internal standard)
δ: 7.10 (2I(, d, J=9Hz) 6.81
(2H, d, J=9Hz) 4.45-4.75
(I H, m) 3.78 (3H, s) 3.30-3.45 (3H, m) 2.60-2.80 (3H, m) Example 3 (]) ]N-benzyloxy-3 -3-(p-methoxyphenyl)-2-(N-methylcarbamoyl)propylaminoco-5-methylhexanamide 3-hydroxy-3-methoxy-2-(p-methoxybenzyl)-N-methylhexanamide 0.20g,
A solution of 0.20 g of 3-amino-N-berzyloxy-5-methylhexanamide in 2 rnl of methanol was heated under reflux for 2 hours. - Under ice cooling, 3s, i of sodium borohydride was added and stirred at the same temperature for 30 minutes, and then stirred at room temperature for 2 hours. An additional 35.8 mg of sodium borohydride was added, and the mixture was further stirred at the same temperature for 14 hours. After concentrating the reaction solution.
クロロホルムに溶解した。これを５％炭酸水素す） Ｉ
Ｊウム水溶液で洗浄後、洗液をクロロホルムで２回抽出
した。有機層を合わせ、硫酸マグネシウムで乾燥後、溶
媒を減圧留去した。残渣をシリカゲルカラムクロマトグ
ラフィー（クロロホルム：メタノール＝１００：１〜３
０：１）にて精製し、Ｎ−ベンジルオキシ−３−［３−
（ｐ−メトキシフェニル）−２−（Ｎ−メチルカルバモ
イル）プロピルアミノコ−５−メチルヘキサンアミド０
．２１ｇを淡黄色油状物として得た。Dissolved in chloroform. Add this to 5% hydrogen carbonate) I
After washing with an aqueous Jumium solution, the washings were extracted twice with chloroform. The organic layers were combined, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:methanol=100:1-3
0:1) to produce N-benzyloxy-3-[3-
(p-methoxyphenyl)-2-(N-methylcarbamoyl)propylaminoco-5-methylhexanamide 0
．． 21 g were obtained as a pale yellow oil.
理化学的性状
質量分析値（ｍ／ ｚ ） ： （ＦＡＢ Ｍａｓｓ）
４５６（Ｍ＋±１）
核磁気共鳴スペクトル（ＣＤＣＩ、、ＴＭＳ内部標準）
δ： ７．２４〜７．４４（５Ｈ，ｍ）７．００（２Ｈ
，ｄ、Ｊ＝１０Ｈｚ）
６．８０（２Ｈ，ｄ、Ｊ＝１０Ｈｚ）
４．８０〜５．ＯＯ（２Ｈ，ｍ ）
３．７８（３Ｈ，ｔｉ）
０．８０〜１．ＯＯ（６Ｈ，ｍ ）
＋２１ ３− ［３−（ｐ−メトキシフェニル）−２−
−（Ｎ−メチルカルバモイル）プロピルアミノコ５−メ
チルヘキサノヒドロキサム酸
Ｎ−ペンジルオキン−３−［３−（ｐ−メトキシフェニ
ル）−２−（Ｎ−メチルカルバモイル）プロピルアミン
］−５−メチルヘキサンアミド０．１７ｇのエタノール
５ ｒｎｌ溶液に１０％パラジウム炭素０．０９ｇ、シ
クロヘキセン０．２ｍＺを加え、１時間加熱還流した。Physical and chemical properties Mass spectrometry value (m/z): (FAB Mass)
456 (M+±1) Nuclear magnetic resonance spectrum (CDCI, TMS internal standard)
δ: 7.24-7.44 (5H, m) 7.00 (2H
, d, J=10Hz) 6.80 (2H, d, J=10Hz) 4.80-5. OO (2H, m) 3.78 (3H, ti) 0.80-1. OO(6H,m) +21 3- [3-(p-methoxyphenyl)-2-
-(N-Methylcarbamoyl)propylaminoco5-methylhexanohydroxamate N-pendyluoquine-3-[3-(p-methoxyphenyl)-2-(N-methylcarbamoyl)propylamine]-5-methylhexanamide 0.09 g of 10% palladium on carbon and 0.2 mZ of cyclohexene were added to a 0.17 g solution of 5 rnl of ethanol, and the mixture was heated under reflux for 1 hour.
今後、不溶物を戸数し、Ｐ液を濃縮した。これをシリカ
ゲルカラムクロマトグラフィー（クロロホルム：メタノ
ール２０：１）にて精製し、３−［３−（ｐ−メトキシ
フェニル）−２−（Ｎ−メチルカルバモイル）プロピル
アミン）−５−メチルヘキサノヒドロキサム酸０．０９
ｇを白色結晶として得た。From now on, insoluble matter was counted and the P solution was concentrated. This was purified by silica gel column chromatography (chloroform:methanol 20:1) and 3-[3-(p-methoxyphenyl)-2-(N-methylcarbamoyl)propylamine)-5-methylhexanohydroxamic acid 0.09
g was obtained as white crystals.
理化学的性状
質量分析値（ｍ／ｚ ） ： （ＦＡＢ Ｍａｓｓ）３
６６ （Ｍ”＋ １ ）
核磁気共鳴スペクトル（ＤＭＳＯ−ｄ、、 ＴＭＳ内部
標準）δ： ７．０８（２Ｈ，ｄ、 Ｊ＝８Ｈｚ）６．
８２（２Ｈ，ｄ、 Ｊ＝８Ｆ（ｚ）３．７０（３Ｈ，Ｓ
）
０．７６〜０．９６ （６Ｆ［、ｍ ）参考例 ５
１−ベンジルオキシ−５−ヒドロキシ−４−イソブチル
−２−ピロリドン
二チル２−［（Ｎ−ベンジルオキシカルバモイル）メチ
ル］−４−メチルバレレート１．５４ｇの塩化メチレン
１０ ｔｎｌ溶液に、アルゴン雰囲気下−７８００ジイ
ソブチルアルミニウムヒドリドの１Ｍヘキサン溶液６．
０ｍｌを滴下し、同条件にて４時間攪拌した。同温にて
メタノールアｍｌを加えた後、室温まで昇温させ、塩化
メチレン及びＩＮ塩酸？加え。Physical and chemical properties Mass spectrometry value (m/z): (FAB Mass)3
66 (M”+1) Nuclear magnetic resonance spectrum (DMSO-d, TMS internal standard) δ: 7.08 (2H, d, J=8Hz)6.
82 (2H, d, J = 8F (z) 3.70 (3H, S
) 0.76 to 0.96 (6F[,m) Reference Example 5 1-Benzyloxy-5-hydroxy-4-isobutyl-2-pyrrolidonedityl 2-[(N-benzyloxycarbamoyl)methyl]-4- A 1M hexane solution of -7800 diisobutylaluminum hydride was added to a solution of 1.54 g of methyl valerate in 10 tnl of methylene chloride under an argon atmosphere.6.
0 ml was added dropwise and stirred under the same conditions for 4 hours. After adding ml of methanol at the same temperature, the temperature was raised to room temperature, and methylene chloride and IN hydrochloric acid were added. Addition.
３０分間激しく攪拌した。有機層を分取後、水層な塩・
化メチレンで１回抽出した。有機層を合わせ。Stir vigorously for 30 minutes. After separating the organic layer, remove the salt from the aqueous layer.
Extracted once with methylene chloride. Combine the organic layers.
５％炭酸水素ナトリウム水溶液で１回、飽和食塩水で１
回洗浄し、硫酸マグネシウムで乾燥後、溶媒を減圧留去
した。残漬をシリカゲルカラムクロマトグラフィー（ク
ロロホルム：メタノール＝ ｌ０Ｃ＝１）にて精製し、
１−ベンジルオキシ−５−ヒドロキシ−４−イソブチル
−２−ピロリドンｏ、４８ｇを白色結晶として得た。Once with 5% sodium bicarbonate aqueous solution, once with saturated saline
After washing twice and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 10C = 1),
48 g of 1-benzyloxy-5-hydroxy-4-isobutyl-2-pyrrolidone was obtained as white crystals.
理化学的性状
質量分析値（ｍ／ｚ） ： （ＦＡＢ Ｍａｓｓ）２６
４（Ｍ”＋１）
核磁気共鳴スペクトル（ＣＤＣｌ、、 ＴＭＳ内部標準
）δ： ７．３２〜７．５０ （５Ｈ，ｍ）４．９２〜
５．１０ （２Ｈ，ｍ ）
０．８０〜０−９６ （６Ｈ，ｍ）
実施例４
（１） Ｎ”−［３−（Ｎ−ベンジルオキシカル／く
モイル）−２−インプチルプロビルコー０−メチルチロ
シンＮ−メチルアミド
１−ベンジルオキシ−５−ヒドロキシ−４−イソブチル
−２−ピロリドン０．２０ｇ、Ｏ−メチルチロシン Ｎ
−メチルアミド０．１６ｇのエタノール４Ｉ！ｌｌ溶液
を４０時間加熱還流した。水冷下で。Physical and chemical properties Mass spectrometry value (m/z): (FAB Mass) 26
4 (M”+1) Nuclear magnetic resonance spectrum (CDCl, TMS internal standard) δ: 7.32-7.50 (5H, m) 4.92-
5.10 (2H,m) 0.80-0-96 (6H,m) Example 4 (1) N''-[3-(N-benzyloxycar/cumoyl)-2-inptylprobilco 0-Methyltyrosine N-methylamide 1-benzyloxy-5-hydroxy-4-isobutyl-2-pyrrolidone 0.20g, O-methyltyrosine N
- Ethanol 4I with 0.16 g of methylamide! The ll solution was heated to reflux for 40 hours. Under water cooling.
水素化ホウ素ナトリウム３４．５ ｍｇを加え、室温に
て２時間攪拌後、水素化ホウ素す） ＩＪウムをさらに
３４．５１ｒ＠加え、同温にてさらに５時間攪拌した。34.5 mg of sodium borohydride was added, and after stirring at room temperature for 2 hours, an additional 34.51 r@ of sodium borohydride was added, and the mixture was further stirred at the same temperature for 5 hours.
反応液を濃縮後、クロロホルムに溶解した。The reaction solution was concentrated and then dissolved in chloroform.
これを、５％炭酸水素ナトリウム水溶液で洗浄後、洗液
をクロロホルムで２回抽出した。有機層を合わせ、硫酸
マグネシウムで乾燥後、溶媒を減圧留去した。残渣をシ
リカゲルカラムクロマトグラフィー（クロロホルム：メ
タノール＝５０＝１さらにヘキサン：酢酸エチル＝１＝
２〜１：３）にて精製し、Ｎ’−［３−（Ｎ〜ベンジル
オキシカルバモイル）−２−インブチルプロピル］−〇
−メチルチロシンＮ−メチルアアミド０２１ｇを無色油
状物として得た。After washing this with a 5% aqueous sodium hydrogen carbonate solution, the washings were extracted twice with chloroform. The organic layers were combined, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 50 = 1, and hexane: ethyl acetate = 1 =
2-1:3) to obtain 021 g of N'-[3-(N-benzyloxycarbamoyl)-2-inbutylpropyl]-0-methyltyrosine N-methylamide as a colorless oil.
理化学的性状
質量分析値（ｍ／′ｚ ） ： （ＦＡＢ Ｍａｓｓ）
４５６（Ｍ”＋１）
核磁気共鳴スペクトル（ＣＤＣｌ３． ＴＭＳ内部標準
）δ： ７．３５（５Ｈ，ｓ）
７．１０ （２Ｈ，ｄ、 Ｊ＝１０Ｈｚ）６．８０ （
２Ｈ，ｄ、 Ｊ＝１０Ｈｚ）４．６８（２Ｈ，ｓ）
３．７７ （３鴇Ｓ）
２．７４ （３Ｈ，ｄ、 Ｊ ＝５Ｈｚ）２．７８〜０
．９２ （６Ｈ，ｍ）
＋２） Ｎ’ −［３−（Ｎ−ヒドロキシカルバモイ
ル）−２−インブチルプロピル］−０−メチルチロシン
Ｎ−メチルアミド
Ｎ”−［３−（Ｎ−ベンジルオキシカルバモイル）＝２
−イソブチルグロビル］−０−メチルチロシン Ｎ−メ
チルアミドＯ，Ｉ４ｇのエタノール５ｒｎｌ溶液に１０
％パラジウム炭素０．０７ｇ、ンクロヘキセン０．２１
！ｌｌを加え、１時間加熱還流した。今後。Physical and chemical properties Mass spectrometry value (m/'z): (FAB Mass)
456 (M”+1) Nuclear magnetic resonance spectrum (CDCl3. TMS internal standard) δ: 7.35 (5H, s) 7.10 (2H, d, J=10Hz) 6.80 (
2H, d, J = 10Hz) 4.68 (2H, s) 3.77 (3S) 2.74 (3H, d, J = 5Hz) 2.78~0
．． 92 (6H, m) +2) N' -[3-(N-hydroxycarbamoyl)-2-inbutylpropyl]-0-methyltyrosine N-methylamide N"-[3-(N-benzyloxycarbamoyl) = 2
-isobutylglobil]-0-methyltyrosine 10 in a solution of 4 g of N-methylamide O,I in 5 rnl of ethanol
% palladium carbon 0.07g, nclohexene 0.21
! 1 liter was added and the mixture was heated under reflux for 1 hour. from now on.
不溶物を戸数し、Ｆ液を濃縮した。これをシリカゲルカ
ラムクロマトグラフィー（クロロホルム：メタノール＝
ＳＯ：ｔ）にて精製し、Ｎ“［３−（Ｎ−ヒドロキシカ
ルバモイル）−２−イソブチルプロビルコー０−メチル
チロシンＮ−メチルアミド０．０４ｇを無色油状物とし
て得た。Insoluble matter was removed and Solution F was concentrated. This was subjected to silica gel column chromatography (chloroform:methanol =
SO:t) to obtain 0.04 g of N"[3-(N-hydroxycarbamoyl)-2-isobutylprobilco-0-methyltyrosine N-methylamide as a colorless oil.
理化学的性状
質量分析値（ｍ／ ｚ ） ： （ＦＡＢ Ｍａｓｓ）
３６６ （Ｍ”＋１ ）
核磁気共鳴スペクトル（ＤＭＳＯ−ｄ、、 ＴＭＳ内部
標単）δ： ７．０８ （２Ｈ，ｄ、 Ｊ＝８Ｈｚ ）
６．７４〜６．８６ （２Ｈ，ｍ ）
３．７３（３Ｈ，ｓ）
０．７０〜０−９０ （６Ｈ，ｍ）Physical and chemical properties Mass spectrometry value (m/z): (FAB Mass)
366 (M”+1) Nuclear magnetic resonance spectrum (DMSO-d, TMS internal standard) δ: 7.08 (2H, d, J=8Hz)
6.74-6.86 (2H, m) 3.73 (3H, s) 0.70-0-90 (6H, m)
Claims (2)
ルフィニル（−ＳＯ−）基、スルホニル（−ＳＯ＿２−
）基、又はイミノ（−ＮＨ−）基を、ｎは１乃至６の整
数を、ｍ及びｌは、一方 は０であり、他方は１を意味する。） で示されるアミド化合物又はその塩。(1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is a hydrogen atom or a hydroxyl group,
) group or imino (-NH-) group, n is an integer of 1 to 6, m and l are one of 0 and the other of 1. ) An amide compound or a salt thereof.
Ｎ−メチルカルバモイル）プロピル］スルホニル］−５
−メチルヘキサノヒドロキサム酸である請求項（１）記
載のアミド化合物又はその塩。(2) 3-[[3-(p-methoxyphenyl)-2-(
N-methylcarbamoyl)propyl]sulfonyl]-5
- The amide compound or salt thereof according to claim (1), which is methylhexanohydroxamic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2098456A JPH03294252A (en) | 1990-04-13 | 1990-04-13 | Amide compound or salt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2098456A JPH03294252A (en) | 1990-04-13 | 1990-04-13 | Amide compound or salt thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03294252A true JPH03294252A (en) | 1991-12-25 |
Family
ID=14220209
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2098456A Pending JPH03294252A (en) | 1990-04-13 | 1990-04-13 | Amide compound or salt thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03294252A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998034915A1 (en) * | 1997-02-07 | 1998-08-13 | Pfizer Inc. | N-hydroxy-beta-sulfonyl-propionamide derivatives and their use as inhibitors of matrix metalloproteinases |
-
1990
- 1990-04-13 JP JP2098456A patent/JPH03294252A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998034915A1 (en) * | 1997-02-07 | 1998-08-13 | Pfizer Inc. | N-hydroxy-beta-sulfonyl-propionamide derivatives and their use as inhibitors of matrix metalloproteinases |
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