[go: up one dir, main page]

CN1214041A - 磺化的氨基酸衍生物及含有它的金属蛋白酶抑制剂 - Google Patents

磺化的氨基酸衍生物及含有它的金属蛋白酶抑制剂 Download PDF

Info

Publication number
CN1214041A
CN1214041A CN97193226A CN97193226A CN1214041A CN 1214041 A CN1214041 A CN 1214041A CN 97193226 A CN97193226 A CN 97193226A CN 97193226 A CN97193226 A CN 97193226A CN 1214041 A CN1214041 A CN 1214041A
Authority
CN
China
Prior art keywords
replaces arbitrarily
replaces
compound
formula
arbitrarily
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
Application number
CN97193226A
Other languages
English (en)
Other versions
CN100413859C (zh
Inventor
渡边文彦
续木博茂
大谷光昭
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shionogi and Co Ltd
Original Assignee
Shionogi and Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26368369&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1214041(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Shionogi and Co Ltd filed Critical Shionogi and Co Ltd
Publication of CN1214041A publication Critical patent/CN1214041A/zh
Application granted granted Critical
Publication of CN100413859C publication Critical patent/CN100413859C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • 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
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C07C311/32—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/42—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
    • C07C311/49—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/67—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pyrrole Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Furan Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

有金属蛋白酶抑制活性的化合物,含有用式Ⅰ表示的化合物,其光学活性体,或它们制药上可容许的盐、或它们的水合物。

Description

磺化的氨基酸衍生物及含有它的金属蛋白酶抑制剂
技术领域
本发明涉及磺化的氨基酸衍生物及含有它的金属蛋白酶抑制剂。
背景技术
细胞外基质是由胶原、蛋白多糖等构成的，它具有支持组织功能同时有保持细胞的增生、分化、粘着等细胞功能的作用。对于细胞外基质分解，作为基质金属蛋白酶(MMP)的明胶酶、基质溶素(stromelysin)及胶原酶等起着重要的作用，这些酶在生理学的状况下，在成长及组织改良等上起着作用。因此，可认为这些酶，与伴随着组织破坏及纤维化的各种病症，即变形性关节病、风湿性关节炎、角膜溃疡、牙周病、肿瘤的转移或浸润或病毒感染症(例如HIV感染症)的发生有关。目前，其中任何一种酶是否都与上述病症有较大关系还不太清楚，但这些酶，与组织破坏相关联这一点上是一致的。作为氨基酸衍生物的金属蛋白酶抑制剂，例如有公开的氨基酸的羟肟酸衍生物(特开平6-256293)、氨基酸的羧酸衍生物或其羟肟酸衍生物(WO 95/35276)等。
发明的公开
只要可抑制上述MMP的活性，就可极大地改善或防止由其活性引起或有关的上述病症，因此希望能开发出MMP抑制剂。
本发明者们鉴于上述情况，进行了潜心研究结果发现，某种新的磺胺类衍生物，显示了强的MMP抑制活性。即，本发明是涉及含有用式Ⅰ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物的金属蛋白酶抑制剂，式中，R1是任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或者任意取代的杂芳烷基；R2是氢、任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或者任意取代的杂芳烷基；R3是单键、任意取代的亚芳基或任意取代的杂亚芳基；R4是单键、-(CH2)m-、-CH=CH-、-C≡C-、-CO-、-CO-NH-、-N=N-、-N(RA)-、-NH-CO-NH-、-NH-CO-、-O-、-S-、-SO2NH-、-SO2-NH-N=CH-或四唑二基；R5是任意取代的低级烷基、任意取代的C3～C8环烷基、任意取代的芳基、任意取代的杂芳基、或者任意取代的非芳性杂环基；RA是氢或低级烷基；Y是NHOH或OH；m是1或2；但是Y是NHOH时R2是氢。更详细地说是涉及以下的发明a)～b)、1)～16)、及A)～C)。a)涉及含有用式Ⅰ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物的金属蛋白酶抑制剂，
Figure A9719322600111
式中，R1是任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或者任意取代的杂芳烷基；R2是氢、任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或者任意取代的杂芳烷基；R3是单键、任意取代的亚芳基或任意取代的杂亚芳基；R4是单键、-(CH2)m-、-CH=CH-、-C≡C-、-CO-、-CO-NH-、-N=N-、-N(RA)-、-NH-CO-NH-、-NH-CO-、-O-、-S-、-SO2NH-、-SO2-NH-N=CH-或四唑二基；R5是任意取代的低级烷基、任意取代的C3～C8环烷基、任意取代的芳基、任意取代的杂芳基、或者任意取代的非芳性杂环基；RA是氢或低级烷基；Y是NHOH或OH；m是1或2；但是Y是NHOH时R2是氢、R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是-CO-NH-或者-NH-CO-时，R5是任意取代的芳基或任意取代的杂芳基、R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是四唑二基时，R5是任意取代的芳基或任意取代的杂芳基、R3是任意取代的亚芳基、R4是单键时，R5是低级烷基、用低级烷基或任意取代的芳基取代的芳基、或者用低级烷基或任意取代的芳基取代的杂芳基、R3及R4不同时是单键、R3是任意取代的亚芳基或任意取代的杂亚芳基时，R4不是-O-。b)上述的金属蛋白酶抑制剂是Ⅳ型胶原酶抑制剂。
详细地说明本发明时，可以用下述通式表示。1)用式Ⅰ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600121
式中，R1是任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或者任意取代的杂芳烷基；R2是氢、任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或者任意取代的杂芳烷基；R3是单键、任意取代的亚芳基或任意取代的杂亚芳基；R4是单键、-(CH2)m-、-CH=CH-、-C≡C-、-CO-、-CO-NH-、-N=N-、-N(RA)-、-NH-CO-NH-、-NH-CO-、-O-、-S-、-SO2NH-、-SO2-NH-N=CH-或四唑二基；R5是任意取代的低级烷基、任意取代的C3～C8环烷基、任意取代的芳基、任意取代的杂芳基、或者任意取代的非芳性杂环基；RA是氢或低级烷基；Y是NHOH或OH；m是1或2；但是Y是NHOH时，R2是氢、R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是-CO-NH-或者-NH-CO-时，R5是任意取代的芳基或任意取代的杂芳基(R3是亚苯基、R4是-CO-NH-时，R1不是甲基或苯基、R5不是2-氯苯基、4-氯苯基及2,4-二氯苯基)、R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是四唑二基时，R5是低级烷基、任意取代的芳基、或者任意取代的杂芳基、R3是任意取代的亚芳基、R4是单键时，R5是低级烷基、用低级烷基或任意取代的芳基取代的芳基、或者用低级烷基或任意取代的芳基取代的杂芳基、R3及R4不同时是单键、R3是任意取代的亚芳基或任意取代的杂亚芳基时，R4不是-O-。2)用式Ⅱ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R6是-CH=CH-、-C≡C-、-N=N-、-NH-CO-NH-、-S-、-SO2NH-或-SO2-NH-N=CH-；R7是任意取代的芳基或任意取代的杂芳基、R8及R9分别独立地表示氢、低级烷氧基或硝基；R1、R2及Y与上述定义相同。3)用式Ⅲ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600131
式中，R10是-(CH2)m-、-CO-、-CO-NH-、-N(RA)-、-NH-CO-、或四唑二基；m是1或2；R1、R2、R7、R8、R9、RA及Y与上述定义相同。但是R10是-NH-CO-时，R1不是甲基或苯基、R7不是2-氯苯基、4-氯苯基及2,4-二氯苯基。4)用式Ⅳ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R11是单键、-CH=CH-、或-C≡C-；X是氧原子或硫原子；R1、R2、R7及Y与上述定义相同。5)用式Ⅰ′表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R1′是苄基、(吲哚-3-基)甲基、(1-甲基吲哚-3-基)甲基、(5-甲基吲哚-3-基)甲基、(5-氟吲哚-3-基)甲基、(1-乙酰基吲哚-3-基)甲基、(1-甲基磺酰基吲哚-3-基)甲基、(1-烷氧羰基-3-基)甲基(例如乙氧羰基甲基)、或异丙基；R2′是氢、甲基、4-氨基丁基、或苄基；R3′是1,4-亚苯基；R4′是-O-；R5′是苯基或4-羟基苯基；Y与上述定义相同。6)用式Ⅰ″表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R1″是4-噻唑基甲基、(吲哚-3-基)甲基、(5-甲氧基吲哚-3-基)甲基、1-萘基甲基、2-萘基甲基、4-联苯基甲基、2,2,2-三氟乙基、2-苯基乙基、苄基、异丙基、4-硝基苄基、4-氟苄基、环己基甲基、(1-甲基吲哚-3-基)甲基、(5-甲基吲哚-3-基)甲基、(5-氟吲哚-3-基)甲基、(吡啶-4-基)甲基、(苯并噻唑-2-基)甲基、(苯基)(羟基)甲基、苯基、羧基甲基、2-羧基乙基、羟基甲基、苯基甲氧基甲基、4-羧基苄基、(苯并咪唑-2-基)甲基、(1-甲基磺酰基吲哚-3-基)甲基、或(1-乙氧羰基吲哚-3-基)甲基；R2″是氢原子；R3是1,4-亚苯基；R4″是单键；R5″是苯基、3-甲氧基苯基、4-甲氧基苯基、4-甲基苯基、4-叔丁基苯基、4-三氟甲基苯基、4-氟苯基、4-甲硫基苯基、4-联苯基、2-噻吩基、苯并噁唑-2-基、苯并噻唑-2-基、或四唑-2-基；Y与上述定义相同。7)用式Ⅴ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R12是-CH=CH-、或-C≡C-；R1、R2、R7、R8及R9与上述定义相同。8)用式Ⅵ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600151
式中，R2、R8及R9与上述定义相同、R13表示任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或任意取代的杂芳烷基、R14是任意取代的芳基或任意取代的杂芳基。但是R13不是甲基或苯基、R14不是2-氯苯基、4-氯苯基、及2,4-二氯苯基。9)用式Ⅶ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R1、R2、R7、R8、及R9与上述定义相同。10)用式Ⅷ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600153
式中，R1、R2、R7、及R11与上述定义相同。11)用式Ⅸ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600161
式中，R1、R2、R7、R8、及R9与上述定义相同。12)用式Ⅹ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600162
式中，R12表示-CH=CH-、或-C≡C-；R1、R7、R8、及R9与上述定义相同。13)用式Ⅺ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600163
式中，R8、R9、R13及R14与上述定义相同，但是R13不是甲基或苯基、R14不是2-氯苯基、4-氯苯基、及2,4-二氯苯基。14)用式Ⅻ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600164
式中，R1、R7、R8、及R9与上述定义相同。15)用式ⅩⅢ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R1、R7及R11与上述定义相同。16)用式ⅪⅤ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600172
式中，R1、R7、R8、及R9与上述定义相同。
进而，特定表示本发明化合物时，A)上述1)～16)的任何一项中所述的化合物，其中的，R1、R1＇、R1″及R13是异丙基、苄基、或(吲哚-3-基)甲基。B)上述1)～4)及7)～16)的任何一项中所述的化合物，其中的，R5、R7、及R14是烷氧基、烷硫基、或用1或2以上烷基任意取代的苯基。C)上述1)～16)的任何一项中所述的化合物，其中的，R1、R1＇、R1″及R13结合的不对称碳构型是R。
进而，本发明涉及含有上述通式1)～16)及A)～C)所述的化合物的医药组合物、金属蛋白酶及Ⅳ型胶原酶。
上述通式1)～16)及A)～C)所述的化合物显示了强的金属蛋白酶抑制活性，但特别优选的是以下所示的化合物。
式Ⅰ：
1)R1为异丙基、苄基、或(吲哚-3-基)甲基、R2为氢原子、R3为1,4-亚苯基、R4为-C≡C-、R5为任意取代的苯基表示的化合物。
2)R1为异丙基、苄基或(吲哚-3-基)甲基、R2为氢原子、R3为任意取代的2,5-噻吩二基、R4为-C≡C-、R5为任意取代的苯基表示的化合物。
3)异丙基、苄基或(吲哚-3-基)甲基、R2为氢原子、R3为1,4～亚苯基、R4为四唑二基、R5为任意取代的苯基表示的化合物。
本说明书中，“烷基”是指直链或支链的C1～C10的烷基、例如可举出甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基等。
本说明书中，“低级烷基”是指直链或支链的C1～C6的烷基，例如可举出甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等。
本说明书中，“C3～C8环烷基”可举出例如环丙基、环丁基、环戊基、环己基、环庚基等。
本说明书中，“芳基”是指单环或稠环芳族烃，例如可举出苯基、萘基等。
本说明书中，“芳烷基”是指在上述芳基上的取代芳基，它们可在可取代的所有位置上结合。例如可举出苄基、苯乙基、苯丙基(例如，3-苯基丙基)、萘基甲基(例如α-萘基甲基)、蒽基甲基(例如9-蒽基甲基)等。其中，优选的是苄基。在这些芳基部分中，也可具有任意的取代基。
本说明书中，“杂芳基”是指在环内含有1个以上的任选的氧原子、硫原子或氮原子，且也可与碳环或其他杂环稠合的5～6元的芳环，它们可在可取代的所有位置上结合。例如可举出吡咯基(例如，1-吡咯基)、吲哚基(例如，2-吲哚基)、咔唑基(例如，3-咔唑基)、咪唑基(例如，4-咪唑基)、吡唑基(例如，1-吡唑基)、苯并咪唑基(例如，2-苯并咪唑基)、吲唑基(例如，3-吲唑基)、中氮茚(例如，6-中氮茚)、吡啶基(例如，4-吡啶基)、喹啉基(例如，5-喹啉基)、异喹啉基(例如，3-异喹啉基)、吖啶基(例如，1-吖啶基)、菲啶基(例如，2-菲啶基)、哒嗪基(例如，3-哒嗪基)、嘧啶基(例如，4-嘧啶基)、吡嗪基(例如，2-吡嗪基)、噌啉基(例如，3-噌啉基)、二氮杂萘基(例如，2-二氮杂萘基)、喹唑啉基(例如，2-喹唑啉基)、异噁唑基(例如，3-异噁唑基)、苯并异噁唑基(例如，3-苯并异噁唑基)、噁唑基(例如，2-噁唑基)、苯并噁唑基(例如，2-苯并噁唑基)、苯并噁二唑基(例如，4-苯并噁二唑基)、异噻唑基(例如，3-异噻唑基)、苯并异噻唑基(例如，2-苯并异噻唑基)、噻唑基(例如，2-噻唑基)、苯并噻唑基(例如，2-苯并噻唑基)、呋喃基(例如，3-呋喃基)、苯并呋喃基(例如，3-苯并呋喃基)、噻吩基(例如，2-噻吩基)、苯并噻吩基(例如，2-苯并噻吩基)、四唑基等。这些芳基部分上可以有任意的取代基。
本说明书中，“杂芳基烷基”是指在上述烷基的任意位置上取代有上述杂芳基，它们可以在可取代的所有位置上结合。例如噻唑基甲基(例如，4-噻唑基甲基)、噻唑基乙基(例如，5-噻唑基-2-乙基)、吲哚基甲基(例如，2-吲哚基甲基)、咪唑基甲基(例如，4-咪唑基甲基)、苯并噻唑基甲基(例如，2-苯并噻唑基甲基)、苯并吡唑基甲基(例如，1-苯并吡唑基甲基)、苯并三唑基甲基(例如，4-苯并三唑基甲基)、苯并喹啉基甲基(例如，2-苯并喹啉基甲基)、苯并咪唑基甲基(例如，2-苯并咪唑基甲基)、吡啶基甲基(例如，2-吡啶基甲基)等。在这些芳基部分上，也可具有任意的取代基。
本说明书中，“亚芳基”是指例如亚苯基、亚萘基等，进而详细地可举出1,2-亚苯基、1,3-亚苯基、1,4-亚苯基等。
本说明书中，“杂亚芳基”是指例如噻吩二基、呋喃二基、吡啶二基等，进而详细地可举出2,5-噻吩二基、2,5-呋喃二基等。
本说明书中，“非芳性杂环基”是指在环内含有1个以上任选的氧原子、硫原子或氮原子，非芳性的5～6元环，它们可在可取代的所有位置上结合。例如指吗啉代基、哌啶子基、吡咯烷基(pyrrolidino)等。
本说明书中，“烷氧基”是指烷基部分是上述烷基的烷氧基，例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基等。
本说明书中，“低级烷氧基”是指烷基部分是上述低级烷基的烷氧基，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等。
本说明书中，“卤素”是指氟、氯、溴及碘。
本说明书中，“烷硫基”是指烷基部分是上述低级烷基的烷硫基，例如甲硫基、乙硫基等。
本说明书中，“任意取代的烷基”、“任意取代的C3～C8环烷基”、或“任意取代的非芳性杂环基”的取代基，可举出羟基、烷氧基(例如甲氧基、乙氧基)、巯基、烷硫基(例如甲硫基)、环烷基(例如环丙基、环丁基、环戊基、环己基)、卤素(例如氟、氯、溴、碘)、羧基、烷氧羰基(例如甲氧羰基、乙氧羰基)、硝基、氰基、卤代烷基(例如三氟甲基)、取代或非取代氨基(例如甲基氨基、二甲基氨基、氨基甲酰氨基)、胍基、苯基、苄氧基等。它们可在所有可能的位置上取代1个以上。
本说明书中，“任意取代的芳基”、“任意取代的芳烷基”、“任意取代的杂芳基”、“任意取代的杂芳烷基”、“任意取代的亚芳基”及“任意取代的杂亚芳基”的芳环上的取代基，可举出例如羟基、烷氧基(例如甲氧基、乙氧基)、巯基、烷硫基(例如甲硫基)、环烷基(例如环丙基、环丁基、环戊基)、卤素(例如氟、氯、溴、碘)、羧基、烷氧羰基(例如甲氧羰基、乙氧羰基)、硝基、氰基、卤代烷基(例如三氟甲基)、芳氧基(例如苯氧基)、取代或非取代氨基(例如甲氨基、二甲基氨基、二乙基氨基、亚苄氨基)、胍基、烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基)、烯基(例如乙烯基、丙烯基)、炔基(例如乙炔基、苯基乙炔基)、烷酰基(例如甲酰基、乙酰基、丙酰基)、酰氧基(例如乙酰氧基)、酰氨基、烷基磺酰基(例如甲基磺酰基)、苯基、苄基、偶氮基(例如苯偶氮基)、任意取代的杂芳基(例如3-吡啶基)、任意取代的脲基(例如脲基、苯基脲基)等。它们可在所有可取代的位置上取代1个以上。
实施本发明的最佳方案
本发明化合物(Ⅰa)及(Ⅰb)可以用通式(ⅩⅤ)表示的对应的α-氨基酸作为初始原料，用以下所示的6种合成方法制得。一般，使用A法时，可合成本发明化合物，但也可按各个形式，使用B法～F法进行合成。但是，这只不过是化合物Ⅰ的制法中的1个例子，用其它方法制造的化合物Ⅰ，也包括在本发明范围内。
A法：是关于化合物Ⅰ通常的合成方法。
B法：是关于R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是-C≡C-、R5是任意取代的芳基或任意取代的杂芳基的化合物的合成方法。
C法：是关于R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是单键、R5是任意取代的芳基或任意取代的杂芳基的化合物的合成方法。
D法：是关于R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是-CO-NH-、R5是任意取代的芳基或任意取代的杂芳基的化合物的合成方法。
E法：是关于R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是四唑二基、R5是任意取代的芳基或任意取代的杂芳基的化合物的合成方法。
F法：是关于R3是任意取代的亚芳基，或任意取代的杂亚芳基、R4是-CH=CH-、R5是任意取代的芳基或任意取代的杂芳基的化合物的合成方法。
以下，对于这些方法，详细地说明。
(A法)(式中，R1、R2、R3、R4及R5与上述定义相同，R15表示氢或羧基保护基、R16表示羟基保护基、Hal表示卤素。)
从化合物(ⅩⅤ)到化合物(Ⅰa-1)的反应，是将化合物(ⅩⅤ)
从化合物(ⅩⅤ)到化合物(Ⅰa-1)的反应，是将化合物(ⅩⅤ)的氨基磺酰化的反应(工序1)、需要时，反应后，进行N-烷基化等和除去羧基保护基。从化合物(Ⅰa-1)到化合物(Ⅰb-1)的反应是将羧基进行羟肟酸化的反应(工序2)。另外，从化合物(Ⅰa-1)到化合物(Ⅰb-1)的反应，可将具有羟基保护基的羟胺或其酸加成盐，与化合物(Ⅰa-1)作用，得到化合物(ⅩⅥ)后(工序3)、也可进行脱保护反应(工序4)。磺酰化及羟肟酸化反应可按常法进行。例如在碱存在下，将用磺酰化试剂，例如R5-R4-R3-SO2Hal(R3、R4及R5与上述定义相同；Hal=卤素)表示的磺酰卤化物等，与用式(ⅩⅤ)表示的氨基酸反应，接着，与羟胺反应。以下，对于各工序详细叙述。
(工序1)
原料化合物的，用式(ⅩⅤ)表示的氨基酸或其酸加成盐(例如盐酸盐、对甲苯磺酸盐、三氟醋酸盐)的一部分，可作为市售品得到。其它的，可按照实验化学讲座22卷、第4版(日本化学会编)中所述的氨基酸合成法、J.Med.Chem.38,1689-1700(1995)Gary M.Ksander等，进行合成。另外，磺酰化试剂(例如磺酰卤化物)的一部分，作为市售品可得到，其他的，可按照新实验化学讲座14卷、1787页、(1978)、Synthesis 852-854(1986)Tatsuo Hamada等进行合成。作为保护了的羧基，例如可举出酯(例如甲酯、叔丁酯、苄基酯)化了的羧基。这些保护基的脱离，可根据保护基，在酸(例如盐酸、三氟醋酸)或碱(例如氢氧化钠等)存在下，进行水解或接触还原(例如10％钯碳催化剂存在下)进行，但为了得到化合物(Ⅰb-1)，也可直接进行酯的第2工序的羟肟酸化。作为磺酰化反应的溶剂，在化合物(ⅩⅤ)的R15是氢的氨基酸时，优选的是二甲基甲酰胺、四氢呋喃、二噁烷、二甲基亚砜、乙腈、水或它们的混合溶剂，但在R15是保护基酯体时，可举出此外的水不溶性溶剂(例如苯、二氯甲烷)和上述溶剂的混合溶剂。磺酰化反应所用的碱，是三乙胺、N-甲基吗啉等的有机碱、或氢氧化钠、氢氧化钾、碳酸钾等无机碱等。反应温度通常是冰冷～室温。另外，化合物(Ⅰa-1)的R1、R3、R4、R5或R15是具有对于磺酰化成为阻碍的取代基(例如羟基、巯基、氨基、胍基)的基时，可用Protective Groupsin Organic Synthesis,Theodora W Green(John Wiley&Sons)等所述的方法预先保护，在合适的阶段中，除去其保护基就可以。另外，R2不是氢时，进而，在二甲基甲酰胺、四氢呋喃、二噁烷等溶剂中，在冰冷～80℃下，优选的在冰冷下～室温下，加入卤化烷(例如甲基碘、乙基碘)和卤化芳烷(例如苄基氯、苄基溴)等、搅拌3～30小时，优选10～20小时，可得到目的的N-R2体。
(工序2)
通过将羟胺，与化合物(Ⅰa-1)或其反应性衍生物反应，可制得羟肟酸(Ⅰb-1)，但羟胺通常，将其酸加成盐(例如盐酸盐、磷酸盐、硫酸盐；作为市售品可得到的)，在碱存在下用于反应。作为碱，可举出三乙胺、N,N-二甲基苯胺、N-甲基吗啉等有机碱、或氢氧化钠、氢氧化钾、碳酸钾等无机碱。在将化合物(Ⅰa-1)，直接作为羟肟酸化原料使用时，在肽缩合试剂(例如二环己基碳化二亚胺、1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺、N,N＇-羰基二咪唑、或它们的任何一个和1-羟基苯并三唑、N-羟基琥珀酰亚胺等的混合物)等存在下，进行反应。作为溶剂，可使用二甲基甲酰胺、四氢呋喃、二噁烷、二甲基亚砜、乙腈、水或它们的混合溶剂，反应温度是-20℃～40℃、优选的是冰冷～室温，反应时间是1小时～16小时。
作为化合物(Ⅰa-1)的反应衍生物，使用酸酐(特别是混合酸酐)、酰卤化物、酰基叠氮或酯。这些反应性衍生物，可用通常的方法制造，酸酐例如可在碱(例如三乙胺)的存在下，将酰卤化物(例如氯碳酸乙酯)，与化合物(Ⅰa-1)作用，酰卤化物，例如可将卤化试剂(例如乙二酰氯、亚硫酰氯)，与化合物(Ⅰa-1)作用而制得。
另外，酯可从非活性酯或活性酯选择，但非活性酯，在工序1中的化合物(ⅩⅤ)中的R15是羧基保护基(例如甲基、叔丁基、苄基)时，不将磺酰化的生成物脱保护，而直接使用就可以，将(Ⅰa-1)与碳化二亚胺(例如二环己基碳化二亚胺、1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺)和1-羟基苯并三唑或N-羟基琥珀酰亚胺等活性酯残基对应的羟基体作用，可制得活性酯。化合物(Ⅰa-1)的反应性衍生物的羟肟酸化的反应条件，可与直接使用化合物(Ⅰa-1)时的羟肟酸化条件相同，另外，工序1及工序2的反应，可在单一反应槽(所谓单釜)中进行。
作为本工序使用的保护了的羟胺，例如可举出邻苄基羟胺、邻-(对甲氧基苄基)羟胺、邻-(叔丁基)羟胺等。反应条件也可与工序2的反应条件相同。
(工序4)
本工序中，通过在氢氛围下的接触还原、或与浓盐酸或三氟醋酸的处理除去保护基，得到用目的式(Ⅰb-1)表示的化合物。这样制得的本发明化合物(Ⅰa-1)和(Ⅰb-1)，可通过公知的分离、精制手段(例如色谱、结晶化法等)进行分离精制。
(B法)
Figure A9719322600241
式中，R1、R2、R7、R15及Hal，与上述定义相同，R17表示任意取代的芳基或任意取代的杂芳基。
从化合物(ⅩⅤ)到化合物(ⅩⅦ)的反应，是将化合物(ⅩⅤ)的氨基进行磺酰化的反应(工序1)、可与A法工序1相同地进行。从化合物(ⅩⅦ)到化合物(ⅩⅧ)的反应，是将R17的卤取代基作为基础，进行赫克(Heck)反应(在K.Sonogashira,Y.Tohda,and N.Hagihara,Tetrahedron Lett.,4467(1975)等叙述)，导入三键的反应(工序2)。从化合物(ⅩⅧ)到化合物(Ⅰa-2)的反应，是化合物(ⅩⅧ)的N-烷基化等和除去羧基保护基的反应(工序3)，可与A法工序1相同地进行。从化合物(Ⅰa-2)到化合物(Ⅰb-2)的反应，是将羧酸衍生物变成羟肟酸衍生物的反应(工序4)，可与A法工序2～4相同地进行。以下，进一步详述各工序。
(工序1)
可与A法工序1相同地进行。
(工序2)
在二甲基甲酰胺、甲苯、二甲苯、苯、四氢呋喃等溶剂中、钯催化剂(例如Pd(Ph3P)2Cl2等)、2价铜试剂(例如CuI等)、有机碱(例如三乙胺、二异丙基乙胺等)的存在下，使化合物(ⅩⅦ)与乙炔基苯等的具有乙炔基的，任意取代的芳基或任意取代的杂芳基衍生物反应(Heck反应)，可得到目的化合物(ⅩⅧ)。反应温度是室温～100℃、优选的是室温～80℃、反应时间是3～30小时、优选的是10～20小时。在任意取代的芳基或任意取代的杂芳基衍生物，具有成为阻碍本反应的取代基时，用Protective Groups in Organic Synthesis,Theodora WGreen(John Wiley&Sons)等所述的方法预先保护，在合适的阶段，除去其保护基就可以。
(工序3)
可与A法工序1相同地进行。
(工序4)
可与A法工序2～4相同地进行。
(C法)
Figure A9719322600251
式中，R1、R2、R7、R15、R17及Hal与上述定义相同。
从化合物(ⅩⅦ)到化合物(ⅪⅩ)的反应，是以R17的卤素取代基作为基础，用铃木反应(M.J.Sharp and V.Snieckus,Tetrahedron Lett.26,5997(1985)等所述)，导入芳基或杂芳基的反应(工序1)。从化合物(ⅪⅩ)到化合物(Ⅰa-3)的反应，是化合物(ⅪⅩ)的N-烷基化等和除去羧基保护基的反应(工序2)，可与A法工序1相同地进行。从化合物(Ⅰa-3)到化合物(Ⅰb-3)的反应，是将羧酸衍生物变成羟肟酸衍生物的反应(工序3)，可与A法工序2～4相同地进行。以下，进一步详细地说明各工序。
(工序1)
在二甲基甲酰胺、甲苯、二甲苯、苯、四氢呋喃等溶剂中，在钯催化剂(例如Pd(Ph3P)4等)、碱(例如碳酸钾、碳酸钙、三乙胺、甲醇钠等)的存在下，使化合物(ⅩⅧ)与苯基硼酸等的具有B(OH)2(其他是B(Et)2等)基的，任意取代的芳基或任意取代的杂芳基衍生物反应(铃木反应)，可得到目的化合物(ⅪⅩ)。反应温度是室温～100℃、优选的是室温～80℃、反应时间是5～50小时，优选的是15～30小时。在任意取代的芳基或任意取代的杂芳基衍生物具有阻碍本反应的取代基时，用Protective Groups in Organic Synthesis,Theodora W Green(JohnWiley&Sons)等所述的方法预先保护，在合适的阶段除去其保护就可以。
(工序2)
可与A法工序1相同地进行。
(工序3)
可与A法工序2～4相同地进行。
(D法)
Figure A9719322600271
式中，R1、R2、R7、R15、R17及Hal与上述定义相同。
从化合物(ⅩⅤ)到化合物(ⅩⅩ)的反应，是将化合物(ⅩⅤ)的氨基进行磺酰化反应(工序1)，可与A法工序1相同地进行。从化合物(ⅩⅩ)到化合物(ⅩⅪ)的反应，是将R17的硝基取代基还原成氨基的反应(工序2)。可在接触还原法或盐酸-铁、盐酸-锡的反应条件等下进行。从化合物(ⅩⅪ)到化合物(ⅩⅫ)的反应，是以R17的氨基为基础，形成酰胺键的反应(工序3)。可通过通常使用的，形成酰胺键反应进行。从化合物(ⅩⅫ)到化合物(Ⅰa-4)的反应，是化合物(ⅩⅫ)的N-烷基化等和除去羧基保护基的反应(工序4)、可与A法工序1相同地进行。从化合物(Ⅰa-4)到化合物(Ⅰb-4)的反应，是将羧酸衍生物变成羟肟酸衍生物的反应(工序5)、可与A法工序2～4相同地进行。以下，进一步详细地说明各工序。
(工序1)
可与A法工序1相同地进行。
(工序2)
在甲醇、乙醇、醋酸乙酯、醋酸等溶剂中，催化剂(Pd-C,PtO2,Raney Ni等)存在下，氢氛围下，常压或加压条件下，使化合物(ⅩⅩ)反应，可得到目的化合物(ⅩⅪ)。反应温度是冰冷下～80℃、优选的是室温～50℃、反应时间是1～10小时、优选的是2～5小时。
(工序3)
在二甲基甲酰胺、四氢呋喃、二噁烷、二甲基亚砜、乙腈、二甲苯、甲苯、苯、二氯甲烷等溶剂中，碱(例如三乙胺、N-甲基吗啉、碳酸钾等)的存在下，使化合物(ⅩⅪ)，与苯甲酰氯等的具有酰卤官能基(其他活性酯基等)的，任意取代的芳基或任意取代的杂芳基衍生物反应，可得到目的化合物(ⅩⅫ)。反应温度是冰冷下～100℃、优选的是室温～60℃、反应时间是3～30小时，优选的是10～25小时。
(工序4)
可与A法工序1相同地进行。
(工序5)
可与A法工序2～4相同地进行。
(E法)
Figure A9719322600281
式中，R1、R2、R7、R15、R17及Hal与上述定义相同。
从化合物(XV)到化合物(ⅩⅩⅢ)的反应，是将化合物(ⅩⅤ)的氨基磺酰化的反应(工序1)，可与A法工序1相同地进行。从化合物(ⅩⅩⅢ)到化合物(ⅩⅩⅣ)的反应，是将R17的乙烯取代基变成醛的反应(工序2)。从化合物(ⅩⅩⅣ)到化合物(ⅩⅩⅥ)的反应，是构建四唑环的反应(工序3、4)。从化合物(ⅩⅩⅥ)到化合物(Ⅰa-5)的反应，是化合物(ⅩⅩⅥ)的N-烷基化等和除去羧基保护基的反应(工序5)，可与A法工序1相同地进行。从化合物(Ⅰa-5)到化合物(Ⅰb-5)的反应是将羧酸衍生物变成羟肟酸衍生物的反应(工序6)、可与A法工序2～4相同地进行。以下，进一步详细地说明各工序。
(工序1)
可与A法工序1相同地进行。
(工序2)
将化合物(ⅩⅩⅢ)，在二氯甲烷、醋酸乙酯、甲醇等溶剂中，添加臭氧，形成臭氧化物，接着，在同一体系中，加入锌-醋酸、三乙基膦、或二甲基硫等，进行还原处理，可得到目的的醛衍生物(化合物(ⅩⅩⅣ))(还原处理也可添加接触氢)。反应温度是-100℃～室温、优选的是-78℃～冰冷下，反应时间是O.5～10小时，优选的是1～3小时。
(工序3)
将化合物(ⅩⅩⅣ)，在四氢呋喃、乙醚等溶剂和甲醇、乙醇等溶剂的混合溶剂中，与苯磺酰肼反应，得到目的化合物(ⅩⅩⅤ)。反应温度是冰冷下～80℃、优选的是室温～50℃、反应时间是3～30小时，优选的是10～20小时。
(工序4)
将苯胺等的具有氨基的，任意取代的芳基或任意取代的杂芳基衍生物，溶解在醇(例如乙醇等)-水的混合溶剂中，在系统的温度是-20℃～10℃、优选的是0℃～5℃下，加入浓盐酸及亚硝酸钠水溶液等的重氮化剂，变成重氮鎓盐。反应时间是5分钟～1小时，优选的是10～30分钟。将该反应溶液，加入到化合物(ⅩⅩⅤ)的吡啶溶液中，在-30℃～50℃、优选的是-15℃～室温下，反应1～10小时、优选的，反应2～5小时，可得到目的化合物(ⅩⅩⅥ)。任意取代的芳基或任意取代的杂芳基衍生物具有阻碍本反应的取代基时，用ProtectiveGroups in Organic Synthesis,Theodora W Green(John Wiley&Sons)等所述的方法预先保护，在合适阶段，除去其保护基就可以。
(工序5)
可与A法工序1相同地进行。
(工序6)
可与A法工序2～4相同地进行。
(F法)
Figure A9719322600301
式中，R1、R2、R7、R15、R17及Hal与上述定义相同。
从化合物(ⅩⅩⅣ)到化合物(ⅩⅩⅦ)的反应，是将R17的醛作为基础，使用一般使用的维悌锡(Wittig)反应(G Wittig et a1.,Chem.Berr.87,1318(1954))的条件，通过双键，导入芳基或杂芳基的反应(工序1)。从化合物(ⅩⅩⅦ)到化合物(Ⅰa-6)的反应是化合物(ⅩⅩⅦ)的N-烷基化等和除去羧基保护基的反应(工序2)，可与A法工序1相同地进行。从化合物(Ⅰa-6)到化合物(Ⅰb-6)的反应，是将羧酸衍生物变成羟肟酸衍生物的反应(工序3)，可与A法工序2～4相同地进行。以下，进一步详细地说明各工序。
(工序1)
在化合物(ⅩⅩⅣ)的甲苯、二甲苯、四氢呋喃、醚、二甲基甲酰胺等溶剂中，在-100℃～室温、优选的是-78℃～冰冷下，加入用其它通常的方法制备的Ph3P=CHPh等的任意取代的芳基或任意取代的杂芳基衍生物的内鎓体，搅拌1～20小时、优选的是1～5小时，可得到目的化合物(ⅩⅩⅦ)。任意取代的芳基或任意取代的杂芳基衍生物具有阻碍本反应的取代基时，用Protective Groups in Organic SynthesisTheodora W Green(John Wiley&Sons)等所述的方法预先保护，在合适的阶段，除去其保护就可以。
(工序2)
可与A法工序1相同地进行。
(工序3)
可与A法工序2～4相同地进行。
所说“本发明化合物”，也包括制药上容许的盐、或其水合物。例如可举出碱金属(锂、钠、钾等)、碱土类金属(镁、钙等)、铵、有机碱及氨基酸的盐、或无机酸(盐酸、氢溴酸、磷酸、硫酸等)、及有机酸(醋酸、柠檬酸、马来酸、富马酸、苯磺酸、对甲苯磺酸等)的盐。可通过通常的方法形成这些盐。
另外，本发明化合物不是限定于特定的异构体的，是包括所有可能的异构体和外消旋体的。
如以下实验例所述，本发明化合物显示了优良的金属蛋白酶抑制活性、特别是MMP抑制活性，抑制基质分解。因此，本发明化合物，对于MMP及其相关的酶的TNF-α转换酶等引起的疾病是有效的。
具体地，可举出对变形性关节病、风湿性关节炎、角膜溃疡、牙周炎、肿瘤的转移和浸润、病毒感染症(例如HIV感染症)的进行、闭塞性动脉硬化症、动脉硬化性动脉瘤、粥样动脉硬化症、再狭窄、败血症、败血症休克、冠状血栓症、异常血管新生、巩膜炎、多发性硬化症、开放角白内障、视网膜症、增殖性视网膜症、血管新生白内障、翼状皮肤、角膜炎、大疱性表皮松解、牛皮癣、糖尿病、肾炎、神经性疾病、龈炎、肿瘤增殖、肿瘤血管新生、眼肿瘤、血管纤维瘤、血管瘤、热病、出血、凝固、恶病质、食欲不振、急性感染症、休克、自身免疫症、疟疾、克罗恩氏病(Crohn′s disease)、脑髓膜炎及胃肠溃疡的预防或治疗剂使用。
将本发明化合物，以上述疾病的治疗或预防为目的，对人体给药时，可作为散剂、颗粒剂、片剂、胶囊剂、丸剂、溶液剂等经口，或作为注射剂、栓剂、经皮吸收剂、吸入剂等非经口给药。另外，对于本化合物的有效量，可根据需要，混合适合于其剂型的赋形剂、粘合剂、湿润剂、崩解剂、润滑剂等医药用添加剂，作成医药制剂。在注射剂时，可与适当的载体一起，进行灭菌处理，作成制剂。
给药量可根据疾病的状态、给药的途径、患者的年龄或体重而不同，最终要依靠医师的判断决定，但对于成人经口给药时，通常是O.1～100mg/kg/日、优选的是1～20mg/kg/日、非经口给药时，通常是0.01～10mg/kg/日，优选的是0.1～1mg/kg/日给药。可将其分成1次或数次给药。
以下，举出实施例及实验例，进一步详细地说明本发明，但本发明不限于这些例子。
实施例中，使用以下代号：
p-TsOH：对甲苯磺酸
DMSO  ：二甲基亚砜
Me    ：甲基
tBu   ：叔丁基
实施例1(A法)
Figure A9719322600321
在(R)-(+)苯基丙氨基(化合物ⅩⅤ-1)1.65g(10mmol)的二甲基甲酰胺50ml、水35ml悬浊液中，在冰冷、搅拌下，加入三乙胺2.78ml(20mmol)。接着，5分钟内加入4-联苯磺酰氯2.52g(10mmol)的二甲基甲酰胺10ml溶液。在相同温度下搅拌2小时后，加入1-羟基苯并三唑水合物1.35g(10mmol)、1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐2.1g(11mmol)、羟胺盐酸盐3.47g(50mmol)、三乙胺7ml(50mmol)。在室温下搅拌16小时后，将反应液注入到水中，用醋酸乙酯萃取。用2N-盐酸、5％碳酸氢钠水溶液、水依次洗涤。减压浓缩后，将残渣加在硅胶柱色谱上，收集用氯仿/甲醇=40/1～20/1洗脱部分，得到泡状残渣(化合物Ⅰb-1-1)1.70g。收率是43％、熔点是169-170℃。元素分析值(％)C21H20N2O4S计算值：C；63.62,H；5.08,N；7.07,S；8.09实测值：C；63.61.H；5.12,N；6.98,S；8.06IR ν max(cm-1)(Nujol):3365,3295,3266,1674,1320,1159NMR(δppm)d 6-DMS0:2.61(dd,J=8.6,13.4Hz,1H),2.80(dd,J=6.0,13.6Hz,1H),3.80(m,1H)[α]D:+18.5±1.2(c=0.503％, 25℃,DMSO)实施例1′化合物Ⅰb-1-1的另一个合成方法
Figure A9719322600341
工序1
在(R)-苯基丙氨酸苄基酯·对甲苯磺酸盐(化合物ⅩⅤ-1′)2.5g(5.85mmol)的二氯甲烷60ml溶液中，加入三乙胺1.8ml(12.87mmol)，接着在冰冷下，加入4-联苯磺酰氯1.63g(6.44mmol)。在室温下搅拌2小时后，用2N-盐酸、5％碳酸氢钠水溶液、水顺次洗涤。减压浓缩后，将残渣加在硅胶柱色谱上，收集用氯仿/甲醇=40/1～20/1洗脱部分，在二氯甲烷/己烷中重结晶，得到化合物Ⅰa-1-1′2.32g。收率是84.1％。熔点是130-131℃。
元素分析值(％)C28H25NO4S
计算值：C；71.32,H；5.34,N；2.97,S；6.80
实测值：C；71.05,H；5.41,N；3.00,S；6.81IR ν max(cm-1)(Nujol):3352,1732,1341,1190,1163NMR(δppm)(CDCl3):3.06(d,J=5.8Hz,2H),4.30(dt,J=6.0,9.0Hz,IH),4.89(s,2H),5.12(d,J=9.0Hz,1H),6.98-7.81(m,14H)[α]D:-16.4±1.1(c=0.506％,25℃,MeOH)
工序2
将工序1得到的化合物Ⅰa-1-1′2.28g，溶解在甲醇/醋酸乙酯=1/1的50ml混合液中，与10％钯-碳200mg一起，氢化25分钟。滤出催化剂后，减压浓缩，在二氯甲烷/己烷中，将残渣重结晶，得到化合物Ia-1-1″1.83g。收率是99.1％。熔点是146-147℃。
元素分析值(％)C21H19NO4S
计算值：C；66.12,H；5.02,N；3.67,S；8.41
实测值：C；65.97.H；5.06.N；3.61,S；8.48IRνmax(cm-1)(Nujol):3408,3305,1751,1325,1161,1134NMR(δppm)(CDCl3):2.97(dd,J=7.0,13.8Hz,1H),3.14(dd,J=5.2,14.0Hz,1H),4.13(m,1H),7.03-7.78(m,14H)[α]D: -4.0±0.4(c=1.000％,25℃,MeOH)
工序3
在工序2得到的化合物Ia-1-1″1.0g(2.62mmol)的二氯甲烷20ml溶液中，加入草酰氯0.33ml(3.93mmol)、二甲基甲酰胺1滴，在室温下搅拌1小时。减压浓缩后，溶解在四氢呋喃10ml中。另一方面，将羟胺盐酸盐911mg(13.1mmol)，在含有碳酸氢钠1.54g(18.34mmol)的四氢呋喃10ml、水10ml的混合液中，在冰冷下，搅拌5分钟。在其中，加入上述酰氯的四氢呋喃溶液，搅拌30分钟。将反应液加入水中，用醋酸乙酯萃取，用5％碳酸氢钠水溶液、水，依次洗涤，减压浓缩，得到残渣969mg(化合物Ia-1)。收率是93.3％。
工序4
在工序2得到的化合物Ia-1-1″2.0g(5.24mmol)的二甲基甲酰胺20ml溶液中，加入1-羟基苯基三唑水合物0.7g(5.24mmol)、N-甲基吗啉2.9ml(26.2mmol)、1-乙基-3-(3-二异丙基氨基)碳化二亚胺盐酸盐(8mmol)，接着，加入邻苄基羟胺盐酸盐1.67g(10.48mmol)，在室温下，搅拌6小时。将反应液加入到水中，用醋酸乙酯萃取，用2N-盐酸、5％碳酸氢钠水溶液、水，依次洗涤。减压浓缩后，将残渣加在硅胶柱色谱上，收集用醋酸乙酯/己烷=1/1洗脱部分，从二氯甲烷/己烷中重结晶，得到化合物ⅩⅥ-12.04g。收率是80％。熔点是171-173℃。
元素分析值(％)C28H26N2O4S
计算值：C；69.12,H；5.39,N；5.76,S；6.59
实验值：C；68.85,H；5.46,N；5.76,S；6.78IRνmax(cm-1)(Nujol):3248,1661,1594,1333,1163NMR(δppm)(CDCl3):2.85-3.60(m,2H),3.86(m,1H),4.77(ABq-Apart,J=11.4Hz,1H),4.82(ABq-Bpart,J=11.4Hz,1H),5.00(m,1H),6.95-7.70(m,19H)[α]D:-40.2±1.6(c=0.505％,25℃,DMSO)
工序5
将1.97g的工序4得到的化合物ⅩⅥ-1溶解在甲醇/醋酸乙酯=1/1的60ml混合液中，与10％钯-碳200mg一起，氢化3.5小时。滤去催化剂后，减压浓缩，将残渣在二氯甲烷/己烷中重结晶，得到化合物Ⅰb-1-1 1.35g。收率是84.4％。
实施例2-91
与实施例1′相同地，合成表1～22所示的化合物。
表1
Figure A9719322600371
Figure A9719322600372
表2
Figure A9719322600381
Figure A9719322600382
表3
Figure A9719322600391
Figure A9719322600392
表4
Figure A9719322600401
Figure A9719322600402
表5
Figure A9719322600411
Figure A9719322600412
表6
Figure A9719322600421
表7
Figure A9719322600431
Figure A9719322600432
表8
Figure A9719322600441
表9
Figure A9719322600452
表10
Figure A9719322600462
表11
Figure A9719322600471
Figure A9719322600472
表12
表13
Figure A9719322600491
Figure A9719322600492
表14
Figure A9719322600501
Figure A9719322600502
表15
Figure A9719322600511
表16
Figure A9719322600521
表17
Figure A9719322600531
Figure A9719322600532
表18
Figure A9719322600541
Figure A9719322600542
表19
Figure A9719322600551
Figure A9719322600552
表20
Figure A9719322600561
Figure A9719322600562
表21
Figure A9719322600571
表22
Figure A9719322600581
实施例92(B法)
Figure A9719322600591
工序1
在D-缬氨酸甲酯盐酸盐(ⅩⅤ-2)755mg(4.5mmol)的二氯甲烷12ml溶液中，加入N-甲基吗啉1.49ml(3×4.5mmol)，接着，在冰冷下，加入5-溴基噻吩-2-磺酰氯1.24g(1.05×4.5mmol)。在室温下，搅拌15小时后，用2N-盐酸、5％碳酸氢钠水、水，依次洗涤。用芒硝干燥后，减压浓缩，将得到的残渣，进行硅胶柱色谱分析。收集用醋酸乙酯/正己烷=1/3洗脱部分，用正己烷洗涤，得到熔点109-110℃的目的物(ⅩⅦ-1)1.32g(收率82％)。元素分析C10H14BrNO4S2
计算值：C；33.71 H；3.96 Br；22.43 N；3.93 S；18.00
实验值：C；33.75 H；3.89 Br；22.43 N；3.96 S；17.86[α]D-34.5±0.7(c=1.012 CHCl3 25℃)IR(CHCl3,νmax cm-1)1737,1356,1164,1138NMR(CDCl3,δppm):0.89(d,J=6.8Hz,3H),1.00(d,J=6.8Hz,3H),2.00(m,1H),3.60(s,3H),3.83(dd,J=5.2,10.0Hz,1H),5.20(d,J=10.0Hz,1H),7.04(d,J=4.1Hz,1H),7.32(d,J=4.1Hz,1H)
工序2
在化合物(ⅩⅦ-1)400mg(1.12mmol)的二甲基甲酰胺5ml溶液中，加入4-甲氧基苯乙炔222mg(1.5×1.12mmol)、碘化铜(Ⅰ)21mg(0.1×1.12mmol)，在氩气氛围下，良好地脱气，接着，加入氯化双(三苯膦)合钯(Ⅱ)39mg(0.05×1.12mmol)、三乙胺0.47ml(3×1.12mmol)，在氩气氛围下，进一步良好地脱气。将该混合物，在50℃下，在氩气氛围中加热、搅拌1夜。用醋酸乙酯稀释反应液，用1N-盐酸、5％碳酸氢钠水、水，依次洗涤。用芒硝干燥，减压浓缩，将得到的残渣，加在硅胶柱色谱上。收集用正己烷/醋酸乙酯= 2/1洗脱部分，在醋酸乙酯/正己烷中重结晶，得到熔点131-132℃的目的物(ⅩⅧ-1)392mg(收率86％)。分析值C19H21NO5S2·0.2H2O
计算值：C；55.51 H；5.25 N；3.41 S；15.60
实验值：C；55.80 H；5.19 N；3.38 S；15.36IR(KBr,νmax cm-1)3268,2203,1736,1604,1524,1348,1164NMR(CDCl3,δppm):0.90(d,J=6.6Hz,3H),1.00(d,J=7.0Hz,3H),2.00(m,1H),3.60(s,3H),3.84(s,3H),3.86(dd,J=5.0,10.2Hz,1H),5.21(d,J=10.2Hz,1H),6.90(d,J=9.0Hz,2H),7.44(d,J=9.0Hz,2H),7.12(d,J=4.0Hz,1H),7.44(d,J=4.0Hz,1H)
工序3
在化合物(ⅩⅦ-1)407mg(1mmol)的四氢呋喃8ml、甲醇8ml的混合溶液中，加入1N-氢氧化钠5.1ml，在60℃下，加热搅拌6小时。减压浓缩反应液除去有机溶剂，用醋酸乙酯稀释残渣。用柠檬酸水溶液配成酸性后，用醋酸乙酯、盐水洗涤。芒硝干燥、减压浓缩，得到化合物(Ⅰa-2-1)373mg(收率是100％)。熔点：147～148℃IR(KBr,νmax cm-1)：1710,1604,1351,1216元素分析C18H19NO5S2·0.2H2O
计算值：C；54.45 H；4.92 N；3.53 S；16.15
实验值：C；54.39 H；4.93 N；3.79 S；15.96实施例93～156与实施例92相同地，合成表23～30所示的化合物。
表23
Figure A9719322600621
Figure A9719322600622
表24
Figure A9719322600631
Figure A9719322600632
表25
Figure A9719322600641
Figure A9719322600642
表26
Figure A9719322600651
Figure A9719322600652
表27
Figure A9719322600662
表28
Figure A9719322600671
Figure A9719322600672
表29
Figure A9719322600681
Figure A9719322600682
表30
实施例157、158
Figure A9719322600701
工序1(R2=CH3)
在与实施例96相同地合成的化合物(ⅩⅧ-2)150mg(0.33mmol)的二甲基甲酰胺2ml溶液中，加入碳酸钾227mg(5×0.33mmol)、甲基碘0.1ml(5×0.33mmol)，在室温下，搅拌1夜。将反应液加入到水中，用醋酸乙酯萃取。水洗、芒硝干燥、减压浓缩后、得到油状的N-甲基体化合物373mg(收率91％)。
分析值C24H23NO5S2
计算值：C；61.39 H；4.94 N；2.98 S；13.66
实验值：C；61.22 H；5.18 N；2.93 S；13.27
进而，在上述得到的油状化合物140mg的甲醇2ml溶液中，加入1N-NaOH 0.6ml，在室温下搅拌1夜。用2N-HCl将反应液配成酸性后，用醋酸乙酯萃取。水洗、芒硝干燥、减压浓缩后，得到熔点185～186℃的化合物(Ⅰa-2- 66)(R=Me)105mg(收率77％)。
分析值C23H21NO5S
计算值：C；60.64 H；4.65 N；3.07 S；14.08
实验值：C；60.56 H；4.84 N；3.01 S；13.94IR(KBr,νmax cm-1)3600-2300br,3426,2203,1710,1604,1503,1344,1151NMR(d6-DMSO,δppm):2.88(s,3H),2.93(dd,J=12.0,10.2Hz,1H),3.19(dd,J=14.2,5.6Hz,1H),3.81(s,3H),4.74(dd,J=5.4,10.2Hz,1H),6.99-7.04(m,2H),7.20-7.35(m,7H),7.52-7.56(m,2H),6.90(d,J=9.0Hz,2H),7.44(d,J=9.0Hz,2H),7.12(d,J=4.0Hz,1H),7.44(d,J=4.0Hz,1H)同样，作为实施例157，合成R2=CH2Ph的化合物(Ⅰa-2-67)。IR(KBr,νmax cm-1):2200,1722,1340,1151NMR(d6-DMSO,δppm);2.94(dd,J=7.6,13.8Hz,1H),3.19(dd,J=7.2,14.4Hz,1H),3.83(s,3H),4.29(d.J=16.2Hz,1H),4.62(d,J=16.2Hz,1H)(只表示特征峰)实施例159(C法)
Figure A9719322600711
工序1
在实施例96得到的化合物(ⅩⅦ-2)500mg(1.4mmol)的干燥四氢呋喃12ml溶液中，加入粉末碳酸钾387mg(2×1.4mmol)、4-甲氧基苯基硼酸319mg(1.5×1.4mmol)、四·三苯基膦钯81mg(0.05×1.4mmol)，在氩气氛围下，在75℃下，搅拌48小时。用醋酸乙酯，稀释反应液，用1N-盐酸、5％碳酸氢钠水、水，依次洗涤。芒硝干燥、减压浓缩后，将残渣加在硅胶柱色谱上。收集用正己烷/醋酸乙酯=3/1洗脱的部分，用正己烷结晶，得到熔点是122-123℃的目的物(ⅪⅩ-1)447mg(收率是83％)。元素分析C17H21NO5S2
计算值C；53.25 H；5.52 N；3.65 S；16.72
实验值C；53.26 H；5.50 N；3.69 S；16.63[α]D-21.7±0.6(c=1.000 DMSO 25℃)IR(KBr,νmax cm-1)1735,1605,1505,1350,1167,1136NMR(CDCl3,δppm):0.90(d,J=7.0Hz,3H),1.00(d,J=6.6Hz,3H), 2.10(m,1H),3.54(s,3H),3.85(s,3H),3.87(dd,J=5.0,10.2Hz,1H),5.20(d,J=10.2Hz,1H),6.94(d,J=9.0Hz,2H),7.52(d,J=9.0Hz,2H),7.11(d,J=4.0Hz,1H),7.49(d,J=4.0Hz,1H)
工序2
在化合物(ⅩⅪ-1)390mg(1.01mmol)的四氢呋喃8ml、甲醇8ml的混合溶液中，加入1N-氢氧化钠5.1ml，在60℃下，加热搅拌6小时。从反应液中，减压浓缩。除去有机溶剂，用醋酸乙酯稀释残渣。用柠檬酸水溶液配成酸性后，用醋酸乙酯萃取，用盐水洗涤。芒硝干燥、减压浓缩后，得到373mg(收率是100％)的化合物(Ⅰa-3-1)。
熔点：174～176℃
IR(KBr,νmax cm-1):1735,1503,1343,1163
实施例160～175
与实施例159相同地，合成表31～32所示的化合物。
表31
Figure A9719322600732
表32
Figure A9719322600741
Figure A9719322600742
实施例176(D法)
Figure A9719322600751
工序1
在D-缬氨酸叔丁酯盐酸盐(XV-3)10g(47.68mmol)的二氯甲烷100ml溶液中，加入N-甲基吗啉15.7ml(3×47.68mmol),接着，在冰冷下，加入4-硝基苯磺酰氯14.1g(1.2×47.68mmol)。在室温下，搅拌5小时后，用2N-盐酸、5％碳酸氢钠水、水，依次洗涤。芒硝干燥后，减压浓缩，将残渣，用二氯甲烷/正己烷重结晶，得到熔点89.90℃的目的物(ⅩⅩ-1)13.3g(收率是77.8％)。元素分析C15H22N2O6S
计算值C;50.27 H;6.19 N;7.82 S;8.95
实验值C;50.04 H;6.10 N;7.89 S;8.84[α]D-2.9±0.8(c=0.512 DMSO 23℃)IR(KBr,νmax cm-1)3430br,3301,1722,1698,1525,1362,1348,1181,1174,1159
工序2
在化合物(XX-1)13.29g(37.08mmol)的甲醇200ml溶液中，加入10％钯/碳1g，在室温下，与氢气一起进行接触还原。2小时后，滤去催化剂，减压浓缩。将残渣用丙酮/正己烷重结晶，得到熔点是164-166℃的胺体(ⅩⅪ-1)11.5g(收率是94.4％)。元素分析C15H24N2O4S
计算值C;54.86 H;7.37 N;8.53 S;9.76
实验值C;54.84 H;7.33 N;8.63 S;9.50[α]D+10.3±1.0(c=0.515 DMSO 23℃)IR(KBr,νmax cm-1)3461,3375,1716,1638,1598,1344,1313NMR(d-DMSO.δppm):0.80(d,J=6.8Hz,3H),0.82(d,J=6.6Hz,3H),1.23(s,9H),1.83(m,1H),3.30(m,1H),5.86(s,2H),6.56(d,J=8.8Hz,2H), 7.36(d,J=8.6Hz,2H),7.47(d,J=9.6Hz,1H)
工序3
在化合物(ⅩⅪ-1)328mg(1mmol)的二氯甲烷10ml溶液中，加入N-甲基吗啉0.33ml(3×1mmol)，接着，在冰冷下，依次加入4-甲硫基苯甲酰氯280mg(1.5×1mmol)。在室温下，搅拌1夜，加入乙醚。收集析出的结晶，用冰水、乙醚洗涤。用丙酮/乙醚重结晶，得到熔点是235-238℃的目的物(ⅩⅫ-1)433mg(收率90.5％)。元素分析C23H30N2O5S2
计算值C；57.72 H；6.32 N；5.85 S；13.40
实验值C；57.63 H；6.28 N；5.86 S；13.20[α]D+5.7±0.9(c=0.512 DMSO 25℃)IR(KBr,νmax cm-1)3366,3284,1713,1667,1592,1514,1498,1341,1317NMR(d6-DMSO,δppm):0.82(d,J=6.6Hz,3H),0.84(d,J=6.8Hz,3H),1.22(s,9H),1.91(m,1H),2.55(s,3H),3.32(s,3H),3.44(dd,J=6.2,8.6Hz,1H),7.40(d,J=8.6Hz,2H),7.73(d,J=8.6Hz,2H),7.90-8.01(m,5H),10.48(s,1H)
工序4
在化合物(ⅩⅫ-1)405mg(0.85mmol)的二氯甲烷3ml溶液中，加入三氟醋酸3.3ml(50×0.85mmol)，在室温下，搅拌2小时。减压浓缩后，用乙醚洗涤残渣，得到熔点是231-234℃的目的物(Ⅰa-4-1)340mg(收率是94.7％)。熔点：231～234℃IR(KBr,νmax cm-1):1748,1655,1592,1323,1161元素分析C19H22N2O5S2·0.1CF3COOH
计算值：C;53.14 H;5.13 N;6.46 S;14.78
实验值：C;53.48 H:5.31 N;6.57 S：15.06
实施例177～208
与实施例176相同地，合成表33～36所示的化合物。
表33
Figure A9719322600781
表34
Figure A9719322600792
表35
Figure A9719322600802
表36
Figure A9719322600811
Figure A9719322600812
实施例209(E法)
工序1
在D-缬氨酸叔丁酯盐酸盐(ⅩⅤ-3)20.94g(99.8mmol)的二氯甲烷200ml溶液中，加入N-甲基吗啉22ml(2×99.8mmol)，接着，在冰冷下加入对苯乙烯磺酰氯20.27g(99.8mmol)。在室温下搅拌15小时后，用2N-盐酸、5％碳酸氢钠水、水，依次洗涤。用芒硝干燥后，减压浓缩，将得到的残渣加在硅胶柱色谱上。收集用醋酸乙酯/正己烷/氯仿=1/3/1洗脱的部分，用正己烷洗涤，得到熔点是118-120℃的目的物(ⅩⅩⅢ-1)28.93g(收率是85％)。IR(KBr,νmax cm-1)3419,3283,1716,1348,1168NMR(CDCl3,δppm):0.85(d,J=6.9Hz,3H),1.00(d,J=6.6Hz,3H),1.21(s,9H),2.04(m,1H),3.62(dd,J=9.8,4.5Hz,1H),5.09(d,J=9.8Hz,1H),5.41(dd,J=0.5,10.9Hz,1H),5.84(dd,J=0.5,17.6Hz,1H),6.72(dd,J=10.9,17.6Hz,1H),7.49(d,J=8.4Hz,2H),7.79(d,J=8.4Hz,2H)
工序2
在化合物(ⅩⅩⅢ-1)5.09g(15mmol)的二氯甲烷300ml溶液中，在78℃下，通入臭氧15分钟。接着，加入甲基硫化物22ml(20×15mmol)，经过80分钟降至室温后，减压浓缩，得到6.03g的醛体(ⅩⅩⅣ-1)。IR(CHCl3,νmax cm-1)3322,1710,1351,1170NMR(CDCl3,δppm):0.85(d,J=6.9Hz.3H),1.00(d,J=6.9Hz,3H),1.22(s,9H),2.07(m,1H),3.69(dd,J=4.5,9.9Hz,1H),8.01(s,4H),10.08(s,1H)
工序3
在化合物(ⅩⅩⅣ-1)6.02g(15mmol)的乙醇60ml、四氢呋喃15ml的混合溶液中，加入苯磺酰肼2.72g(1.05×15mmol)，在室温下搅拌2小时。将减压浓缩后，得到的残渣加在硅胶柱色谱上，收集用氯仿/酯酸乙酯=1/4洗脱的部分。用醋酸乙酯重结晶，得到熔点是163-164℃的目的物(ⅩⅩⅤ-1)4.44g。从工序2的60％。元素分析C22H29N3O6S2
计算值C；53.32 H；5.90 N；8.48 S；12.94
实验值C；53.15 H；5.87 N；8.32 S；12.82[α]D-11.6±1.0(c=0.509 DMSO 23.5℃)IR(KBr,νmax cm-1)3430,3274,1711,1364,1343,1172NMR(CDCl3,δppm):0.84(d,J=6.9Hz,3H),0.99(d,J=6.6Hz,3H),1.19(s,9H),2.00(m,1H),3.63(dd,J=4.5,9.9Hz,1H),5.16(d,J=9.9Hz,1H),7.50-7.68(m,5H),7.73(s,1H),7.78-7.84(m,2H),7.96-8.02(m,2H),8.16(brs,1H)
工序4
在4-甲基巯基苯胺0.14ml(1.11×1mmol)的50％乙醇水溶液中，加入浓盐酸0.3ml，在内温0～5℃下搅拌。在其中，加入亚硝酸钠78.4mg(1.14×1mmol)的水1ml溶液，在该温度下搅拌15分钟。另一方面，在-25℃下，搅拌化合物(ⅩⅩⅤ-1)496mg(1mmol)的干燥吡啶5ml溶液，在其中，8分钟加入原先的反应液。进而，从-15℃到室温，搅拌4小时。将反应液注入水中，用醋酸乙酯萃取。用2N-盐酸、5％碳酸氢钠水、水，依次洗涤后，用芒硝干燥、减压浓缩。将残渣加在硅胶柱色谱上，收集用氯仿/醋酸乙酯=1/9洗脱的部分，得到374mg(收率是74％)的目的物(ⅩⅩⅥ-1)。元素分析C23H29N5O4S2·0.3H2O
计算值C；54.27 H；5.86 N；13.76 S；12.60
实验值C；54.25 H；5.77 N；13.87 S；12.52IR(KBr,νmax cm-1)3422,3310,1705,1345,1171NMR(d6-DMSO,δppm):0.83(d,J=6.9Hz,3H),0.86(d,J=7.2Hz,3H),1.19(s,9H),2.00(m,1H),2.59(s,3H),3.54(d d,J=6.3,9.6Hz,1H),7.56(d,J=8.7Hz,2H),8.00(d,J=8.6Hz,2H),8.10(d,J=8.7Hz,2H),8.33(d, J=9.6Hz,2H),8.34(d,J=8.7Hz,2H)
工序5
在室温下，搅拌化合物(ⅩⅩⅥ-1)353mg的二氯甲烷2.5ml、三氟醋酸2.5ml的混合液3小时。减压浓缩后，用乙醚洗涤残渣，得到化合物(Ⅰa-5-1)308mg(收率是98％)。熔点：194～195℃IR(KBr,νmax cm-1):1720,1343,1166元素分析C19H21N5O4S2·1.1H2O
计算值：C；48.83 H；5.00 N；14.99 S；13.72
实验值：C；49.13 H；5.25 N；14.55 S；13.34
实施例210～251
与实施例209相同地，合成表37～43所示的化合物。
表37
Figure A9719322600851
表38
Figure A9719322600861
表39
Figure A9719322600872
表40
Figure A9719322600881
表41
Figure A9719322600891
Figure A9719322600892
表42
表43
Figure A9719322600911
Figure A9719322600912
实施例252～266
与实施例157相同地，合成表44～45所示的化合物。
表44
Figure A9719322600931
Figure A9719322600932
表45
Figure A9719322600942
实施例267
与实施例92相同地，合成表46所示的化合物。
表46
Figure A9719322600951
Figure A9719322600952
以下，说明本发明化合物的实验例，被检化合物与实施例及表中所用的相对应。
实验例
(1)MMP-9(92kDa、明胶酶B)的分离、精制
参照以下文献，精制Ⅳ型胶原酶(MMP-9)。
Scott M.Wilhelm et al,J.Biol.Chem.,264,17213-17221,(1989)SV40-transformed Human Lung Fibroblasts Secrete a 92-kDa Type ⅣCollagenase Which Is Idemical to That Secreted by Normal HumanMacrophages(用SV40转形变异的人体肺纤维芽细胞，分泌与由正常人的巨噬细胞分泌的相同的92-kDa Ⅳ型胶原酶)；Yasunori Okada et al,J.Biol.Chem.,267,21712-21719,(1992)Matrix Metalloproteinase 9(92-kDa Gelatinase/TypeⅣ Collagenase)from HT 1080 HumanFibrosarcoma Cells(来自HT 1080株的人体纤维芽肉瘤细胞的基质金属蛋白酶9(92k-Da明胶酶/Ⅳ型胶原酶)；Robin V.Ward et al,Biochem.J.,(1991)278,179-187 The purification of tissue inhibitor ofmetalloproteinase-2 from its 72kDa progelatinase complex(来自72kDa前凝胶酶复合物的金属蛋白酶-2的组织抑制剂的精制)；
通过用12-四癸酰基佛波醇-13-醋酸酯(TPA)刺激人体纤维芽肉瘤ATCC HT 1080株，使MMP-9分泌在培养液中。确认用明胶-酶谱法(Hidekazu Tanaka et al,(1993)Biochem.Biophys.Res.Commun.,190,732-740,小鼠的105-kDa明胶酶cDNA的分子克隆及发现)在该培养液中，产生MMP-9。浓缩该HT 1080株的培养上清液，用明胶琼脂糖4B、刀豆球蛋白A琼脂糖和塞弗克耳S-200(Sephacryl S-200)进行精制。该精制pro-MMP-9(92kDa、明胶酶B)，用明胶-酶谱法，显示了单一的活性谱带。接着，用胰蛋白酶进行活化，得到了活性型MMP-9。
(2)Ⅳ型胶原酶抑制剂测定法
胶原酶是上述MMP-9、基质及测定工具盒，使用(株)YAGAI的Ⅳ型胶原酶活性测定工具盒，测定法按照(株)YAGAI的配方。抑制剂的测定是对于1个化合物(抑制剂)，进行以下4个测定。
(A)基质(Ⅳ型胶原)、酶(MMP-9)、抑制剂
(B)基质(Ⅳ型胶原)、抑制剂
(C)基质(Ⅳ型胶原)、酶(MMP-9)
(D)基质(Ⅳ型胶原)
对于它们，按照(株)YAGAI的测定方法，测定荧光强度，用下式，求出抑制率(％)。
抑制率(％)={1-(A-B)/(C-D)}×100
IC50表示抑制率(％)为50％的浓度。结果如表47～表54所示。
表47
实施例No. 化合物No. IC50(μM) 化合物No. IC50(μM)
    1     1a-1-1     0.24     1b-1-1     0.030
    2     1a-1-2     2.6     1b-1-2     0.04
    3     1a-1-3     0.18     1b-1-3     0.005
    4     1a-1-4     2.25
    5     1a-1-5     0.81     1b-1-5     0.041
    6     1a-1-6     0.68     1b-1-6     0.034
    7     1b-1-7     0.028
    8     1a-1-8     2.0     1b-1-8     2.0
    9     1b-1-9     0.41
    10     1b-1-10     2.1
    11     1b-1-11     1.7
    12     1b-1-12     0.085
    13     1b-1-13     0.38
    14     1a-1-14     3.7     1b-1-14     0.11
    15     1b-1-15     0.027
    16     1a-1-16     0.520     1b-1-16     0.0108
    17     1a-1-17     0.205     1b-1-17     0.0203
    18     1a-1-18     0.500     1b-1-18     0.0282
    20     1b-1-20     0.134
    21     1a-1-21     4.65     1b-1-21     0.0041
    23     1b-1-23     0.073
    24     1b-1-24     0.2
    26     1b-1-26     1.3
    27     1b-1-27     3.0
    30     1a-1-30     1.16     1b-1-30     0.213
    31     1b-1-31     0.0129
表48
实施例No. 化合物No. IC50(μM) 化合物No.   IC50(μM)
    33     1a-1-33     0.24     1b-1-33     0.005
    35     1a-1-35     2.6     1b-1-35     0.0216
    38     1a-1-38     0.018
    40     1a-1-40     0.076
    41     1a-1-41     0.312
    42     1a-1-42     0.0123
    43     1a-1-43     0.625
    44     1a-1-44     1.910
    45     1a-1-45     0.040
    46     1a-1-46     1.12
    47     1a-1-47     0.389
    48     1a-1-48     1.15
    49     1a-1-49     0.249
    50     1a-1-50     0.553
    51     1a-1-51     0.110
    52     1a-1-52     0.329
    53     1a-1-53     1.8
    54     1a-1-54     0.075
    55     1a-1-55     0.0398
    60     1a-1-60     1.31     1b-1-60     0.0012
    61     1a-1-61     0.247     1b-1-61     0.247
    62     1b-1-62     3.50
    63     1a-1-63     1.05     1b-1-63     0.00039
    64     1a-1-64     1.90     1b-1-64     0.0037
    65     1a-1-65     0.291     1b-1-65     0.0035
表49
实施例No. 化合物No. IC50(μM) 化合物No. IC50(μM)
    67     1a-1-67     1b-1-67     0.0061
    68     1a-1-68     0.231
    80     1a-1-80     1.91
    83     1a-1-83     1.77
    85     1a-1-85     1.2     1b-1-85     0.013
    86     1a-1-86     0.35     1b-1-86     0.0053
    87     1b-1-87     0.940
    93     1a-2-2     0.237
    94     1a-2-3     0.0109
    95     1a-2-4     0.0759
    96     1a-2-5     0.123
    97     1a-2-6     0.088
    98     1a-2-7     0.0699
    100     1a-2-9     0.0577
    101     1a-2-10     0.023
    102     1a-2-11     0.0475
    103     1a-2-12     0.0981
    104     1a-2-13     3.28
    105     1a-2-14     2.98
    106     1a-2-15     0.133
    107     1a-2-16     0.325
    109     1a-2-18     1.19
    110     1a-2-19     0.203
    111     1a-2-20     3.41
    112     1a-2-21     3.74
    114     1a-2-23     0.929
表50
实施例No. 化合物No.  IC50(μM)
    115     1a-2-24     0.161
    117     1a-2-26     1.19
    118     1a-2-27     0.088
    119     1a-2-28     1.11
    120     1a-2-29     1.53
    121     1a-2-30     0.0736
    122     1a-2-31     0.224
    123     1a-2-32     0.0234
    124     1a-2-33     0.0218
    125     1a-2-34     0.0144
    126     1a-2-35     0.156
    127     1a-2-36     0.0243
    128     1a-2-37     0.0922
    129     1a-2-38     0.222
    160     1a-3-2     0.040
    161     1a-3-3     0.0108
    162     1a-3-4     0.873
    163     1a-3-5     0.0126
    164     1a-3-6     0.0965
    165     1a-3-7     0.230
    166     1a-3-8     1.28
    167     1a-3-9     0.014
    168     1a-3-10     0.0083
    169     1a-3-11     0.244
    170     1a-3-12     2.03
    171     1a-3-13     0.0395
表51
实施例No. 化合物No.    IC50(μM)
    177     1a-4-2     0.684
    178     1a-4-3     0.0252
    179     1a-4-4     2.36
    180     1a-4-5     0.045
    181     1a-4-6     0.0539
    182     1a-4-7     0.0059
    183     1a-4-8     0.0027
    184     1a-4-9     0.00325
    185     1a-4-10     0.0422
    186     1a-4-11     0.0982
    187     1a-4-12     0.177
    188     1a-4-13     0.843
    189     1a-4-14     0.0375
    190     1a-4-15     0.0597
    191     1a-4-16     0.0095
    192     1a-4.17     0.324
    193     1a-4-18     0.722
    195     1a-4-20     1.1
    196     1a-4-21     0.0573
    197     1a-4-22     0.0161
    198     1a-4-23     0.493
    199     1a-4-24     2.06
    200     1a-4-25     0.173
    201     1a-4-26     0.252
    202     1a-4-27     0.0114
    203     1a-4-28     0.173
表52
实施例No. 化合物No.    IC50(μM) 化合物No. IC50(μM)
    204     1a-4-29     3.95
    207     1a-4-30     4.44
    210     1a-5-2     0.024
    211     1a-5-3     0.210  1b-211  0.00565
    212     1a-5-4     0.393
    213     1a-5-5     0.128
    214     1a-5-6     0.832
    215     1a-5-7     0.110
    216     1a-5-8     0.107
    218     1a-5-10     0.744
    219     1a-5-11     0.574
    220     1a-5-12     0.0167
    221     1a-5-13     0.316
    222     1a-5-14     0.078
    223     1a-5-15     0.349
    224     1a-1-16     0.0101
    225     1a-5-17     0.0122
    226     1a-5-18     0.166
    227     1a-5-19     0.0198
    228     1a-5-20     0.106
    229     1a-5-21     0.215
    230     1a-5-22     0.281
    231     1a-5-23     0.197
    232     1a-5-24     0.144
    233     1a-5-25     0.0864
    234     1a-5-26     0.153
表53
实施例No. 化合物No.   IC50(μM) 化合物No.  IC50(μM)
    235     1a-5-27     0.265
    236     1a-5-28     0.304
    237     1a-5-29     1.32
    238     1a-5-30     2.85
    239     1a-5-31     0.243
    240     1a-5-32     0.0041
    241     1a-5-33     0.0131
    242     1a-5-34     0.0239
    243     Ia-5-35     0.0529
    244     1a-5-36     0.0165
    245     1a-5-37     0.0059
    246     1a-5-38     0.0108
    247     1a-5-39     0.0035
    267     1a-2-66     1.5     1b-2-66     0.011
表54
实施例No. 化合物No.    IC50(μM)
    252     1-252     0.24
    253     1-253     0.000039
    254     1-254     0.00063
    255     1-255     0.529
    256     1-256     0.601
    257     1-257     0.776
    258     1-258     0.908
    259     1-259     0.130
    260     1-260     0.159
    261     1-260     0.182
本发明化合物显示了强的Ⅳ型胶原酶抑制活性。
产业上的可利用性
本发明化合物，由于具有强的金属蛋白酶抑制活性，特别是MMP抑制活性，所以可认为对于变形性关节病、风湿性关节炎、角膜溃疡、牙周炎、肿瘤转移或浸润、病毒感染症(例如HIV感染症)的进行、闭塞性动脉硬化症、动脉硬化性动脉瘤、粥样动脉硬化症、再狭窄、败血病、败血病休克、冠状血栓症、异常血管增生、巩膜炎、多发性硬化症、开放角白内障、视网膜症、增殖性视网膜症、血管增生白内障、翼状皮肤、角膜炎、大疱性表皮松解、牛皮癣、糖尿病、肾炎、神经性疾病、龈炎、肿瘤增生、肿瘤血管增生、眼肿瘤、血管纤维瘤、血管瘤、热病、出血、凝固、恶病质、食欲不振、急性感染性、休克、自身免疫症、疟疾、克罗恩氏病(Crohn′s disease)、脑髓膜炎及胃肠溃疡的预防或治疗是有用的。

Claims (25)

1．金属蛋白酶抑制剂，其中含有用式Ⅰ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600021
式中，R1是任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或者任意取代的杂芳烷基；R2是氢、任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基或者任意取代的杂芳烷基；R3是单键、任意取代的亚芳基、或任意取代的杂亚芳基；R4是单键、-(CH2)m-、-CH=CH-、-C≡C-、-CO-、-CO-NH-、-N=N-、-N(RA)-、-NH-CO-NH-、-NH-CO-、-O-、-S-、-SO2NH-、-SO2-NH-N=CH-或四唑二基；R5是任意取代的低级烷基、任意取代的C3～C8环烷基、任意取代的芳基、任意取代的杂芳基、或者任意取代的非芳性杂环基；RA是氢或低级烷基；Y是NHOH或OH；m是1或2；但是Y是NHOH时R2是氢。
2．金属蛋白酶抑制剂，其中含有用式Ⅰ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600022
式中，R1是任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或者任意取代的杂芳烷基；R2是氢、任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或者任意取代的杂芳烷基；R3是单键、任意取代的亚芳基或任意取代的杂亚芳基；R4是单键、-(CH2)m-、-CH=CH-、-C≡C-、-CO-、-CO-NH-、-N=N-、-N(RA)-、-NH-CO-NH-、-NH-CO-、-O-、-S-、-SO2NH-、-SO2-NH-N=CH-或四唑二基；R5是任意取代的低级烷基、任意取代的C3～C8环烷基、任意取代的芳基、任意取代的杂芳基、或者任意取代的非芳性杂环基；RA是氢或低级烷基；Y是NHOH或OH；m是1或2；但是Y是NHOH时R2是氢、R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是-CO-NH-或者-NH-CO-时，R5是任意取代的芳基或任意取代的杂芳基、R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是四唑二基时，R5是任意取代的芳基或任意取代的杂芳基、R3是任意取代的亚芳基、R4是单键时，R5是低级烷基、用低级烷基或任意取代的芳基取代的芳基、或者用低级烷基或任意取代的芳基取代的杂芳基、R3及R4不同时是单键、R3是任意取代的亚芳基或任意取代的杂亚芳基时，R4不是-O-。
3．权利要求1或2所述的金属蛋白酶抑制剂，其是Ⅳ型胶原酶抑制剂。
4．用式Ⅰ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R1是任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或者任意取代的杂芳烷基；R2是氢、任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或者任意取代的杂芳烷基；R3是单键、任意取代的亚芳基或任意取代的杂亚芳基；R4是单键、-(CH2)m-、-CH=CH-、-C≡C-、-CO-、-CO-NH-、-N=N-、-N(RA)-、-NH-CO-NH-、-NH-CO-、-O-、-S-、-SO2NH-、-SO2-NH-N=CH-或四唑二基；R5是任意取代的低级烷基、任意取代的C3～C8环烷基、任意取代的芳基、任意取代的杂芳基、或者任意取代的非芳性杂环基；RA是氢或低级烷基；Y是NHOH或OH；m是1或2；但是Y是NHOH时，R2是氢、R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是-CO-NH-或者-NH-CO-时，R5是任意取代的芳基或任意取代的杂芳基、但R3是亚苯基、R4是-CO-NH-时，R1不是甲基或苯基、R5不是2-氯苯基、4-氯苯基及2,4-二氯苯基、R3是任意取代的亚芳基或任意取代的杂亚芳基、R4是四唑二基时，R5是低级烷基、任意取代的芳基、或者任意取代的杂芳基、R3是任意取代的亚芳基、R4是单键时，R5是低级烷基、用低级烷基或任意取代的芳基取代的芳基、或者用低级烷基或任意取代的芳基取代的杂芳基、R3及R4不同时是单键、R3是任意取代的亚芳基或任意取代的杂亚芳基时，R4不是-O-。
5．用式Ⅱ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600041
式中，R6是-CH=CH-、-C≡C-、-N=N-、-NH-CO-NH-、-S-、-SO2NH-或-SO2-NH-N=CH-；R7是任意取代的芳基或任意取代的杂芳基；R8和R9分别独立地表示氢、低级烷氧基或硝基；R1、R2和Y与上述定义相同。
6．用式Ⅲ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R10是-(CH2)m-、-CO-、-CO-NH-、-N(RA)-、-NH-CO-、或四唑二基；m是1或2;R1、R2、R7、R8、R9、RA和Y与上述定义相同。但是R10是-NH-CO-时，R1不是甲基或苯基、R7不是2-氯苯基、4-氯苯基和2,4-二氯苯基。
7．用式Ⅳ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600043
式中，R11是单键、-CH=CH-、或-C≡C-；X是氧原子或硫原子；R1、R2、R7和Y与上述定义相同。
8．用式Ⅰ′表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600051
式中，R1＇是苄基、(吲哚-3-基)甲基、(1-甲基吲哚-3-基)甲基、(5-甲基吲哚-3-基)甲基、(5-氟吲哚-3-基)甲基、(1-乙酰基吲哚-3-基)甲基、(1-甲基磺酰基吲哚-3-基)甲基、(1-烷氧羰基-3-基)甲基(例如乙氧羰基甲基)、或异丙基；R2′是氢、甲基、4-氨基丁基、或苄基；R3′是1,4-亚苯基；R4′是-O-；R5′是苯基或4-羟基苯基；Y与上述定义相同。
9．用式Ⅰ″表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600052
式中，R1″是4-噻唑基甲基、(吲哚-3-基)甲基、(5-甲氧基吲哚-3-基)甲基、1-萘基甲基、2-萘基甲基、4-联苯基甲基、2,2,2-三氟乙基、2-苯基乙基、苄基、异丙基、4-硝基苄基、4-氟苄基、环己基甲基、(1-甲基吲哚-3-基)甲基、(5-甲基吲哚-3-基)甲基、(5-氟吲哚-3-基)甲基、(吡啶-4-基)甲基、(苯并噻唑-2-基)甲基、(苯基)(羟基)甲基、苯基、羧基甲基、2-羧基乙基、羟基甲基、苯基甲氧基甲基、4-羧基苄基、(苯并咪唑-2-基)甲基、(1-甲基磺酰基吲哚-3-基)甲基、或(1-乙氧羰基吲哚-3-基)甲基；R2″是氢原子；R3″是1,4-亚苯基；R4″是单键；R5″是苯基、3-甲氧基苯基、4-甲氧基苯基、4-甲基苯基、4-叔丁基苯基、4-三氟甲基苯基、4-氟苯基、4-甲硫基苯基、4-联苯基、2-噻吩基、苯并噁唑-2-基、苯并噻唑-2-基、或四唑-2-基；Y与上述定义相同。
10．用式Ⅴ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R12是-CH=CH-、或-C≡C-;R1、R2、R7、R8和R9与上述定义相同。
11．用式Ⅵ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600062
式中，R2、R8和R9与上述定义相同、R13表示任意取代的低级烷基、任意取代的芳基、任意取代的芳烷基、任意取代的杂芳基、或任意取代的杂芳烷基、R14是任意取代的芳基或任意取代的杂芳基，但是R13不是甲基或苯基、R14不是2-氯苯基、4-氯苯基、和2,4-二氯苯基。
12．用式Ⅶ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R1、R2、R7、R8、和R9与上述定义相同。
13．用式Ⅷ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600071
式中，R1、R2、R7、和R11与上述定义相同。
14．用式Ⅸ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600072
式中，R1、R2、R7、R8、和R9与上述定义相同。
15．用式Ⅹ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600073
式中，R12表示-CH=CH-、或-C≡C-；R1、R7、R8、和R9与上述定义相同。
16．用式Ⅺ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600074
式中，R1、R8、R9、R13、和R14与上述定义相同，但是R13不是甲基或苯基、R14不是2-氯苯基、4-氯苯基、和2,4-二氯苯基。
17．用式Ⅻ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600081
式中，R1、R7、R8、和R9与上述定义相同。
18．用式ⅩⅢ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，
Figure A9719322600082
式中，R1、R7和R11与上述定义相同。
19．用式ⅪⅤ表示的化合物、其光学活性体、或它们制药上可容许的盐、或它们的水合物，式中，R1、R7、R8、和R9与上述定义相同。
20．权利要求4～19的任何一项中所述的化合物，其中的，R1、R1＇、R1″和R13是异丙基、苄基、或(吲哚-3-基)甲基。
21．权利要求4～7和10～19的任何一项中所述的化合物，其中的，R5、R7和R14是烷氧基、烷硫基、或1个或2个以上烷基任意取代的苯基。
22．权利要求4～19的任何一项中所述的化合物，其中的，R1、R1＇、R1″和R13结合的不对称碳构型为R。
23．含有权利要求4～19任何一项中所述的化合物的医药组合物。
24．含有权利要求4～19任何一项中所述的化合物的金属蛋白酶抑制剂。
25．含有权利要求4～19任何一项中所述的化合物的Ⅳ型胶原酶抑制剂。
CNB971932263A 1996-01-23 1997-01-22 磺化的氨基酸衍生物及含有它的金属蛋白酶抑制剂 Expired - Fee Related CN100413859C (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP30082/96 1996-01-23
JP3008296 1996-01-23
JP213555/96 1996-08-13
JP21355596 1996-08-13

Publications (2)

Publication Number Publication Date
CN1214041A true CN1214041A (zh) 1999-04-14
CN100413859C CN100413859C (zh) 2008-08-27

Family

ID=26368369

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB971932263A Expired - Fee Related CN100413859C (zh) 1996-01-23 1997-01-22 磺化的氨基酸衍生物及含有它的金属蛋白酶抑制剂

Country Status (21)

Country Link
US (4) US6207698B1 (zh)
EP (2) EP0950656B1 (zh)
JP (1) JP3628335B2 (zh)
KR (2) KR100338861B1 (zh)
CN (1) CN100413859C (zh)
AT (1) ATE359264T1 (zh)
AU (1) AU715764B2 (zh)
BR (1) BR9707010B1 (zh)
CZ (1) CZ298814B6 (zh)
DE (1) DE69737605T2 (zh)
ES (1) ES2284180T3 (zh)
HU (1) HU226006B1 (zh)
IL (1) IL125378A0 (zh)
NO (1) NO312665B1 (zh)
NZ (1) NZ325939A (zh)
PL (2) PL205341B1 (zh)
RU (1) RU2198656C2 (zh)
SK (1) SK282995B6 (zh)
TR (1) TR199801419T2 (zh)
TW (3) TWI244475B (zh)
WO (1) WO1997027174A1 (zh)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100381424C (zh) * 2003-12-04 2008-04-16 惠氏公司 联芳基磺酰胺及其使用方法
CN102993052A (zh) * 2012-12-29 2013-03-27 吉首大学 芳基丙酰氧肟酸类尿素酶抑制剂及其合成和用途
CN103012207A (zh) * 2012-12-29 2013-04-03 吉首大学 二芳基丙酰-n-甲基氧肟酸类尿素酶抑制剂及其合成和用途
CN102105174B (zh) * 2008-07-22 2014-07-02 伯拉考成像股份公司 对金属蛋白酶选择性的诊断剂
CN115141128A (zh) * 2022-06-24 2022-10-04 沈阳药科大学 3-芳基-3-(磺胺苯甲酰胺基)丙(烯)酸衍生物及其制备方法及应用
CN116283895A (zh) * 2023-01-09 2023-06-23 怀化宝华生物科技有限公司 一种2-[2-(噻吩基)乙基]苯甲酸的制备方法

Families Citing this family (97)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6500948B1 (en) 1995-12-08 2002-12-31 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof
IL134816A (en) * 1995-12-08 2003-02-12 Agouron Pharma Substituted diarylether sulfonic acids and their preparation
US6919375B1 (en) 1996-01-23 2005-07-19 Shionogi & Co., Ltd. Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same
KR100338861B1 (ko) 1996-01-23 2003-02-20 시오노기세이야쿠가부시키가이샤 술폰화아미노산유도체및이를함유한메탈로프로테이나제저해제
EP0915086A4 (en) * 1996-05-24 2001-01-17 Ono Pharmaceutical Co PHENYLSULFONAMIDE DERIVATIVES
KR20000068414A (ko) * 1996-09-04 2000-11-25 로즈 암스트롱, 크리스틴 에이. 트러트웨인 매트릭스 메탈로프로테이나제 억제제 및 그의 치료적 용도
NZ333064A (en) * 1996-09-04 2000-11-24 Warner Lambert Co Subsituted dibenzofurans as inhibitors of matrix metalloproteinases
US6624177B1 (en) 1996-09-04 2003-09-23 Warner-Lambert Company Matrix metalloproteinase inhibitors and their therapeutic uses
US5929097A (en) * 1996-10-16 1999-07-27 American Cyanamid Company Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
US6548524B2 (en) 1996-10-16 2003-04-15 American Cyanamid Company Preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors
US6228869B1 (en) 1996-10-16 2001-05-08 American Cyanamid Company Ortho-sulfonamido bicyclic hydroxamic acids as matrix metalloproteinase and TACE inhibitors
US5962481A (en) * 1996-10-16 1999-10-05 American Cyanamid Company Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
US5977408A (en) * 1996-10-16 1999-11-02 American Cyanamid Company Preparation and use of β-sulfonamido hydroxamic acids as matrix metalloproteinase and TACE inhibitors
US5804593A (en) * 1996-10-22 1998-09-08 Pharmacia & Upjohn Company α-Amino sulfonyl hydroxamic acids as matrix metalloproteinase inhibitors
US6174915B1 (en) 1997-03-25 2001-01-16 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses
US6008243A (en) * 1996-10-24 1999-12-28 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use
BR9714385A (pt) * 1996-12-09 2000-05-16 Warner Lambert Co Método para tratamento e prevenção de deficiência cardìaca e dilatação ventricular
UA59384C2 (uk) 1996-12-20 2003-09-15 Пфайзер, Інк. Похідні сульфонамідів та амідів як агоністи простагландину, фармацевтична композиція та способи лікування на їх основі
ES2234103T3 (es) 1997-03-04 2005-06-16 Pharmacia Corporation Compuestos de acido tioarilsulfonamidohidroxamico.
WO1998043963A1 (en) * 1997-04-01 1998-10-08 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses
US5985900A (en) * 1997-04-01 1999-11-16 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses
US5756545A (en) * 1997-04-21 1998-05-26 Warner-Lambert Company Biphenysulfonamide matrix metal alloproteinase inhibitors
AU7294098A (en) * 1997-05-09 1998-11-27 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses
DE19719621A1 (de) * 1997-05-09 1998-11-12 Hoechst Ag Sulfonylaminocarbonsäuren
WO1999004780A1 (fr) * 1997-07-22 1999-02-04 Shionogi & Co., Ltd. Agent therapeutique ou prophylactique de traitement de la glomerulopathie
IL134273A0 (en) 1997-07-31 2001-04-30 Procter & Gamble Acyclic metalloprotease inhibitors
EP1053226A1 (en) * 1998-02-04 2000-11-22 Novartis AG Sulfonylamino derivatives which inhibit matrix-degrading metalloproteinases
US6410580B1 (en) 1998-02-04 2002-06-25 Novartis Ag Sulfonylamino derivatives which inhibit matrix-degrading metalloproteinases
DE19814546A1 (de) * 1998-04-01 1999-10-07 Hoechst Marion Roussel De Gmbh (S)-2-(Biphenyl-4-sulfonylamino)-3-(1H-indol-3-yl)-propionsäurederivate
AU756248B2 (en) 1998-04-03 2003-01-09 Sankyo Company Limited Sulfonamide derivatives
AU5647099A (en) * 1998-09-11 2000-04-03 Shionogi & Co., Ltd. Remedal or preventive agent for congestive heart failure
US6753337B2 (en) 1999-01-27 2004-06-22 Wyeth Holdings Corporation Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors
US6200996B1 (en) 1999-01-27 2001-03-13 American Cyanamid Company Heteroaryl acetylenic sulfonamide and phosphinic acid amide hydroxamic acid tace inhibitors
US6326516B1 (en) 1999-01-27 2001-12-04 American Cyanamid Company Acetylenic β-sulfonamido and phosphinic acid amide hydroxamic acid TACE inhibitors
US6277885B1 (en) 1999-01-27 2001-08-21 American Cyanamid Company Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors
US6313123B1 (en) 1999-01-27 2001-11-06 American Cyanamid Company Acetylenic sulfonamide thiol tace inhibitors
US6225311B1 (en) 1999-01-27 2001-05-01 American Cyanamid Company Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors
US6340691B1 (en) 1999-01-27 2002-01-22 American Cyanamid Company Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and tace inhibitors
US6762178B2 (en) 1999-01-27 2004-07-13 Wyeth Holdings Corporation Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors
EP1147085B1 (en) 1999-01-27 2005-11-16 Wyeth Holdings Corporation Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase (mmp) inhibitors / tnf-alpha converting enzyme (tace) inhibitors
US6946473B2 (en) 1999-01-27 2005-09-20 Wyeth Holdings Corporation Preparation and use of acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as TACE inhibitors
MXPA01008855A (es) 1999-03-03 2002-07-02 Procter & Gamble Inhibidores de metaloproteasa que contienen alquenilo y alquinilo.
HUP0201714A3 (en) 1999-03-03 2003-05-28 Procter & Gamble Substituted heterocyclic compounds and pharmaceutical compositions containing them
PL351374A1 (en) 1999-04-19 2003-04-07 Shionogi & Co Sulfonamide derivatives having oxadiazole rings
GB9911071D0 (en) * 1999-05-12 1999-07-14 Darwin Discovery Ltd Hydroxamic and carboxylic acid derivatives
US6541521B1 (en) 1999-07-12 2003-04-01 Warner-Lambert Company Benzene butyric acids and their derivatives as inhibitors of matrix metalloproteinases
WO2001005389A2 (en) * 1999-07-16 2001-01-25 G.D. Searle & Co. N-sulfonylaminiacid derivatives as inhibitors of metalloprteinase
US6869951B1 (en) 1999-07-16 2005-03-22 Pharmacia Corporation Method of changing conformation of a matrix metalloproteinase
GB9918684D0 (en) 1999-08-09 1999-10-13 Novartis Ag Organic compounds
WO2001023363A1 (fr) * 1999-09-29 2001-04-05 Sankyo Company, Limited Derives de sulfonamide
CA2389681C (en) 1999-11-26 2010-11-02 Shionogi & Co., Ltd. Npy y5 antagonist
AU2709001A (en) * 2000-01-26 2001-08-07 Shionogi & Co., Ltd. Substituted tryptophan derivatives
US20030134880A1 (en) * 2000-02-24 2003-07-17 Gordon Bruton Novel cd23 inhibitors
US6465508B1 (en) 2000-02-25 2002-10-15 Wyeth Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase inhibitors
EP1265865A2 (en) 2000-03-21 2002-12-18 The Procter & Gamble Company Difluorobutyric acid derivatives and their use as metalloprotease inhibitors
SK13362002A3 (sk) * 2000-03-21 2003-04-01 The Procter & Gamble Company Metalloproteázové inhibítory zahŕňajúce vedľajší karbocyklický reťazec
HUP0300235A2 (hu) 2000-03-21 2003-08-28 The Procter & Gamble Co. Heterociklikus oldalláncot tartalmazó, N-szubsztituált metalloproteáz inhibitorok, ezeket tartalmazó gyógyszerkészítmények és alkalmazásuk
MXPA02009839A (es) * 2000-04-06 2003-09-22 Ono Pharmaceutical Co Remedios para enfermedades debidas a lesiones estenoticas de vasos sanguineos.
CN1198821C (zh) 2000-04-19 2005-04-27 盐野义制药株式会社 磺酰胺衍生物的制备方法及其晶体
AU4882101A (en) 2000-04-28 2001-11-12 Shionogi & Co., Ltd. Mmp-12 inhibitors
AU2000265100A1 (en) * 2000-07-12 2002-01-21 G.D. Searle And Co. N sulfonyl aminoacid derivatives as inhibitors of metalloproteinase
CN1273456C (zh) 2000-09-29 2006-09-06 盐野义制药株式会社 噻唑和噁唑衍生物
FR2819253B1 (fr) * 2001-01-11 2004-12-03 Servier Lab Nouveaux derives d'acide hydroxamique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
GB0103303D0 (en) 2001-02-09 2001-03-28 Novartis Ag Organic compounds
JP4294321B2 (ja) * 2001-03-14 2009-07-08 ノバルティス アクチエンゲゼルシャフト Ｍｍｐ阻害剤としての使用のためのアザシクロアルキル置換酢酸誘導体
FR2822827B1 (fr) * 2001-03-28 2003-05-16 Sanofi Synthelabo Nouveaux derives de n-(arylsulfonyl) beta-aminoacides comportant un groupe aminomethyle substitue, leur procede de preparation et les compositions pharmaceutiques en contenant
US20030105144A1 (en) 2001-04-17 2003-06-05 Ping Gao Stabilized oral pharmaceutical composition
JP4448902B2 (ja) 2001-06-08 2010-04-14 株式会社医薬分子設計研究所 スルホンアミド誘導体
US20030082618A1 (en) * 2001-10-15 2003-05-01 Guangshan Li Methods for detecting genetic aberrations
BR0213736A (pt) 2001-11-01 2004-10-19 Wyeth Corp ácidos hidroxâmicos de sulfonamida de arila alênica como metaloproteinase matriz e inibidores de tace
WO2003072085A1 (fr) * 2002-02-27 2003-09-04 Shionogi & Co., Ltd. Preparations solides contenant un medicament a peine soluble dans l'eau d'une meilleure absorbabilite
TW200406197A (en) * 2002-04-25 2004-05-01 Ono Pharmaceutical Co Therapelitic agent for inflammatory bowel disease containing hydroxamic acid as effective component
MXPA04011767A (es) 2002-05-29 2005-03-31 Merck & Co Inc COMPUESTOS UTILES EN EL TRATAMIENTO DE áNTRAX E INHIBIDORES DEL FACTOR LETAL.
WO2005021489A2 (en) 2002-12-23 2005-03-10 Wyeth Holdings Corporation Acetylenic aryl sulfonate hydroxamic acid tace and matrix metalloproteinase inhibitors
WO2004080452A1 (ja) * 2003-03-10 2004-09-23 Shionogi & Co., Ltd. 網膜疾患治療薬
US20040248937A1 (en) * 2003-04-14 2004-12-09 The Institute For Pharmaceutical Discovery Llc Substituted phenylalkanoic acids for the treatment of diabetes
MXPA05011524A (es) 2003-04-30 2006-03-21 Inst For Pharm Discovery Inc Acidos carboxilicos sustituidos.
US7365223B2 (en) * 2003-06-18 2008-04-29 Nst Neurosurvival Technologies Ltd Method for selective targeting of apoptotic cells and small molecule ligands used thereof
WO2004113258A1 (ja) * 2003-06-20 2004-12-29 Shionogi & Co., Ltd. 炭素−炭素結合生成反応
EP1650199A4 (en) 2003-07-30 2008-11-19 Shionogi & Co SULPHONAMIDE DERIVATIVE WITH ISOXAZOL RING
RU2006123559A (ru) 2003-12-04 2008-01-10 Уайт (Us) Биарилсульфонамиды в качестве ммр-ингибиторов
CN1901971A (zh) 2003-12-15 2007-01-24 日本烟草产业株式会社 环丙烷化合物及其药物应用
WO2005058808A1 (en) * 2003-12-15 2005-06-30 Japan Tobacco Inc. N-substituted-n-sulfonylaminocyclopropane compounds and pharmaceutical use thereof
CN1660811A (zh) * 2004-02-27 2005-08-31 中国科学院上海药物研究所 1，4－二取代苯类化合物及其制备方法和用途
US7579487B2 (en) 2004-05-11 2009-08-25 Merck & Co., Inc. Process for making N-sulfonated-amino acid derivatives
JP2006036691A (ja) * 2004-07-27 2006-02-09 Shionogi & Co Ltd 腎炎の治療または予防剤
ITFI20040174A1 (it) * 2004-08-03 2004-11-03 Protera S R L Derivati arilsolfonammidici dell'acido idrossammico ad azione inibitoria di metalloproteinasi
EP1805136A1 (en) * 2004-10-28 2007-07-11 The Institutes for Pharmaceutical Discovery, LLC Substituted phenylalkanoic acids
US20060112494A1 (en) * 2004-12-01 2006-06-01 David Oppong Method of protecting an animal skin product from metalloproteinase activity
US7576222B2 (en) 2004-12-28 2009-08-18 Wyeth Alkynyl-containing tryptophan derivative inhibitors of TACE/matrix metalloproteinase
EP1997804A1 (en) 2006-03-03 2008-12-03 Shionogi & Co., Ltd. Mmp-13-selective inhibitor
US8153166B2 (en) * 2006-06-08 2012-04-10 Chih-Hsiung Lin Composition for prophylaxis or treatment of urinary system infection and method thereof
WO2008053913A1 (fr) 2006-11-02 2008-05-08 Shionogi & Co., Ltd. Dérivé de sulfonylurée capable d'inhiber sélectivement mmp-13
WO2008106167A1 (en) * 2007-02-28 2008-09-04 Conatus Pharmaceuticals, Inc. Combination therapy comprising matrix metalloproteinase inhibitors and caspase inhibitors for the treatment of liver diseases
ATE525068T1 (de) 2007-02-28 2011-10-15 Conatus Pharmaceuticals Inc Verfahren zur behandlung von chronischer viraler hepatitis c mithilfe von ro 113-0830
RU2646752C2 (ru) * 2016-02-25 2018-03-07 Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" Ингибиторы цинк-зависимых металлопротеиназ (ММП-2 и ММП-9) в ряду бензоиламино(фенилсульфонил)-замещенных циклических аминокислот как потенциальные лекарственные средства, препятствующие постинфарктному ремоделированию левого желудочка сердца
TW202227394A (zh) * 2020-09-11 2022-07-16 美商工匠生物科技股份有限公司 細菌毒素之小分子抑制劑

Family Cites Families (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA113A (en) * 1869-10-28 J. Munson Improvements in beehives
US3784701A (en) 1970-09-21 1974-01-08 American Cyanamid Co Compositions containing substituted benzoylpropionic acids and method of use to treat inflammation and pain
US4347372A (en) 1978-09-01 1982-08-31 Ciba-Geigy Corporation Benzoxazolyl-glyoxylonitrile-2-oxime ether derivatives
US4269775A (en) 1978-09-01 1981-05-26 Ciba-Geigy Corporation Oxime derivatives for protecting plant crops
JPS5759969A (en) * 1980-09-29 1982-04-10 Pentel Kk Water-based ink
FR2508444A1 (fr) * 1981-06-29 1982-12-31 Irceba Nouveaux derives sulfonyle du tryptophane utiles en tant que medicaments et leur procede de preparation
FI80022C (fi) * 1982-07-05 1990-04-10 Otsuka Pharma Co Ltd Foerfarande foer framstaellning av ett nytt, terapeutiskt anvaendbart karbostyrilderivat.
ES8705871A1 (es) * 1984-12-29 1987-05-16 Kaken Pharma Co Ltd Un procedimiento para preparar un derivado de benzofurano
US4599361A (en) 1985-09-10 1986-07-08 G. D. Searle & Co. Hydroxamic acid based collagenase inhibitors
US4632931A (en) 1985-09-25 1986-12-30 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted amide-sulfonamide prostaglandin analogs useful in the treatment of thrombotic disease
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
US5270326A (en) 1990-11-21 1993-12-14 University Of Florida Treatment for tissue ulceration
JPH05255089A (ja) 1991-12-18 1993-10-05 Sanwa Kagaku Kenkyusho Co Ltd 抗ウイルス剤
GB9200209D0 (en) * 1992-01-07 1992-02-26 British Bio Technology Compounds
AU675689B2 (en) 1992-12-01 1997-02-13 Merck & Co., Inc. Fibrinogen receptor antagonists
US5455258A (en) * 1993-01-06 1995-10-03 Ciba-Geigy Corporation Arylsulfonamido-substituted hydroxamic acids
US5506242A (en) * 1993-01-06 1996-04-09 Ciba-Geigy Corporation Arylsufonamido-substituted hydroxamic acids
WO1995001332A1 (fr) 1993-07-01 1995-01-12 Nkk Corporation Derive d'arylsulfonamide et composition pharmaceutique le contenant
GB9323162D0 (en) * 1993-11-10 1994-01-05 British Bio Technology 4-(1h-2-methylimidazo(4,5-c)pyridinylmethyl)phenylsulphonamid e derivatives as antagonists of paf
GB9323165D0 (en) 1993-11-10 1994-01-05 Chiros Ltd Compounds
US5445258A (en) 1994-02-22 1995-08-29 Warn Industries, Inc. Pulse actuated hub locks and control arrangement
EP0766664B1 (en) * 1994-06-22 2000-04-05 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
AU695796B2 (en) 1994-10-05 1998-08-20 Darwin Discovery Limited Peptidyl compounds and their therapeutic use as inhibitors of metalloproteases
US5789434A (en) 1994-11-15 1998-08-04 Bayer Corporation Derivatives of substituted 4-biarylbutyric acid as matrix metalloprotease inhibitors
KR980009238A (ko) * 1995-07-28 1998-04-30 우에노 도시오 설포닐아미노산 유도체
PT757984E (pt) * 1995-08-08 2003-02-28 Ono Pharmaceutical Co Derivados de acido hidroxamico uteis para inibir a gelatinase
CA2242416C (en) * 1996-01-23 2006-03-21 Shionogi & Co., Ltd. Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same
KR100338861B1 (ko) 1996-01-23 2003-02-20 시오노기세이야쿠가부시키가이샤 술폰화아미노산유도체및이를함유한메탈로프로테이나제저해제
US5900427A (en) 1996-05-03 1999-05-04 Wisconsin Alumni Research Foundation N-heteroarenesulfonyl-protected amino acid reagents for peptide synthesis
EP0915086A4 (en) 1996-05-24 2001-01-17 Ono Pharmaceutical Co PHENYLSULFONAMIDE DERIVATIVES
NZ333064A (en) * 1996-09-04 2000-11-24 Warner Lambert Co Subsituted dibenzofurans as inhibitors of matrix metalloproteinases
BR9714385A (pt) * 1996-12-09 2000-05-16 Warner Lambert Co Método para tratamento e prevenção de deficiência cardìaca e dilatação ventricular
US5985900A (en) * 1997-04-01 1999-11-16 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses
US5756545A (en) 1997-04-21 1998-05-26 Warner-Lambert Company Biphenysulfonamide matrix metal alloproteinase inhibitors

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100381424C (zh) * 2003-12-04 2008-04-16 惠氏公司 联芳基磺酰胺及其使用方法
CN102105174B (zh) * 2008-07-22 2014-07-02 伯拉考成像股份公司 对金属蛋白酶选择性的诊断剂
CN102993052A (zh) * 2012-12-29 2013-03-27 吉首大学 芳基丙酰氧肟酸类尿素酶抑制剂及其合成和用途
CN103012207A (zh) * 2012-12-29 2013-04-03 吉首大学 二芳基丙酰-n-甲基氧肟酸类尿素酶抑制剂及其合成和用途
CN102993052B (zh) * 2012-12-29 2014-07-09 吉首大学 芳基丙酰氧肟酸类尿素酶抑制剂及其合成和用途
CN103012207B (zh) * 2012-12-29 2015-05-27 吉首大学 二芳基丙酰-n-甲基氧肟酸类尿素酶抑制剂及其合成和用途
CN115141128A (zh) * 2022-06-24 2022-10-04 沈阳药科大学 3-芳基-3-(磺胺苯甲酰胺基)丙(烯)酸衍生物及其制备方法及应用
CN116283895A (zh) * 2023-01-09 2023-06-23 怀化宝华生物科技有限公司 一种2-[2-(噻吩基)乙基]苯甲酸的制备方法

Also Published As

Publication number Publication date
EP1486207A2 (en) 2004-12-15
EP1486207A3 (en) 2011-01-05
US6207698B1 (en) 2001-03-27
JP3628335B2 (ja) 2005-03-09
IL125378A0 (en) 1999-03-12
BR9707010B1 (pt) 2009-05-05
HU226006B1 (en) 2008-02-28
CZ298814B6 (cs) 2008-02-13
KR100338861B1 (ko) 2003-02-20
WO1997027174A1 (fr) 1997-07-31
HUP9903687A3 (en) 2001-12-28
NO312665B1 (no) 2002-06-17
AU715764B2 (en) 2000-02-10
TW200407287A (en) 2004-05-16
TW200403216A (en) 2004-03-01
PL198905B1 (pl) 2008-07-31
EP0950656B1 (en) 2007-04-11
CZ225298A3 (cs) 1998-12-16
KR19990081866A (ko) 1999-11-15
EP0950656A1 (en) 1999-10-20
KR100338857B1 (ko) 2002-05-30
US6881727B2 (en) 2005-04-19
TWI244474B (en) 2005-12-01
CN100413859C (zh) 2008-08-27
US6235768B1 (en) 2001-05-22
US20030139379A1 (en) 2003-07-24
DE69737605D1 (de) 2007-05-24
SK282995B6 (sk) 2003-01-09
ES2284180T3 (es) 2007-11-01
DE69737605T2 (de) 2008-04-03
BR9707010A (pt) 1999-07-20
EP0950656A4 (en) 2003-04-16
NO983376D0 (no) 1998-07-22
SK98498A3 (en) 1999-04-13
AU1319597A (en) 1997-08-20
ATE359264T1 (de) 2007-05-15
PL328270A1 (en) 1999-01-18
NZ325939A (en) 2000-06-23
TWI244475B (en) 2005-12-01
RU2198656C2 (ru) 2003-02-20
TW575547B (en) 2004-02-11
US6441021B1 (en) 2002-08-27
HUP9903687A2 (hu) 2000-03-28
PL205341B1 (pl) 2010-04-30
NO983376L (no) 1998-09-14
TR199801419T2 (xx) 1998-10-21

Similar Documents

Publication Publication Date Title
CN1214041A (zh) 磺化的氨基酸衍生物及含有它的金属蛋白酶抑制剂
CN1167680C (zh) 稠环化合物及其药物用途
CN1203066C (zh) 作为环加氧酶－2抑制剂的(甲磺酰基)苯基－2－(5h)－呋喃酮
CN1188401C (zh) 杂环类酰胺化合物及其医药用途
CN1138546C (zh) 用作细胞因子的某些1,4,5-三取代咪唑化合物
CN1298709C (zh) 用作抗肿瘤剂的噻吩和噻唑磺酰胺化合物
CN1293042C (zh) 芳香族氨基酸衍生物及其药物组合物
CN1158254C (zh) 作为基质金属蛋白酶抑制剂的β-磺酰基异羟肟酸
CN1193276A (zh) 氧化－角鲨烯环化酶抑制剂的降低血中胆甾醇的应用
CN1040986A (zh) 环烷基取代的戊二酰胺衍生物的制备
CN1329596A (zh) 吡啶甲酰胺衍生物、含有其作为有效成分的有害生物防除剂
CN1168709C (zh) 作为基质金属蛋白酶抑制剂的β-磺酰基异羟肟酸的α-羟基、-氨基和卤代衍生物
CN1350452A (zh) 糖尿病的预防或治疗药
CN1354742A (zh) 人过氧化物酶体增殖剂活化受体(PPAR)a激动剂——取代苯基丙酸衍生物
CN1071930A (zh) 用作治疗艾滋病的人免疫缺陷病毒蛋白酶的抑制剂
CN1658855A (zh) O－取代羟基芳基衍生物
CN1503774A (zh) 羧酸衍生物及其盐
CN1767823A (zh) 哮喘和过敏性炎症调节剂
CN1812978A (zh) 作为蛋白酪氨酸磷酸酶－1b抑制剂的苯基取代羧酸
CN1364155A (zh) 用作蛋白酶抑制剂的n－氰基甲基酰胺
CN1330637A (zh) 用于治疗炎性疾病的化合物
CN1254337A (zh) N－羟基4－磺酰基丁酰胺化合物
CN1215055C (zh) 芳基磺酰氨基取代的异羟肟酸衍生物
CN1253555A (zh) 新的2－(亚氨基甲基)氨基－苯基衍生物,其制备方法、作为药物的应用及其药物组合物
CN1048030A (zh) 促进人神经生长因子的苯酚衍生物

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
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20080827

Termination date: 20120122